[The epithelial junctional zones of the anal canal and cervix uterus: the ultrastructure of tumors of these zones].

PubMed

Chernyĭ, A P; Iakovleva, N I

1990-01-01

Relationships between squamous and columnar epithelia in the anal canal and cervix uteri of postnatal period and fetus were studied. The transitional stratified epithelial lining, which is called junctional epithelium, is interposed between the mentioned epithelia. The junctional epithelium has variable numbers of layers of epidermoid cells, which differ from cells of atypical squamous epithelium by some ultrastructural features of the cytoskeleton and cell surface and by a low content of glycogen. The hypothesis on the physiological significance of this epithelium is proposed. Ultrastructural features of the cytoskeleton and cell surface suggest that anal basaloid carcinomas and some cervical squamous carcinomas may develop from so-called junctional epithelium.

Mechanisms of asbestos-induced squamous metaplasia in tracheobronchial epithelial cells.

PubMed Central

Cameron, G; Woodworth, C D; Edmondson, S; Mossman, B T

1989-01-01

Within 1 to 4 weeks after exposure to asbestos, differentiated rodent and human tracheobronchial epithelial cells in organ culture undergo squamous metaplasia, a putative preneoplastic lesion characterized by conversion of mucociliary cell types to keratinizing cells. The exogenous addition of retinal acetate (RA) to culture medium of hamster tracheal organ cultures reverses preestablished, asbestos-induced squamous metaplasia, although data suggest that the effectiveness of RA decreases as the length of time between exposure to asbestos and initial application of RA increases. alpha-Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), inhibits squamous metaplasia caused by asbestos or vitamin A deficiency, whereas addition of methylglyoxal bis(guanylhydrazone) (MGBG), a structural analog of spermidine and inhibitor of S-adenosylmethionine decarboxylase, causes an enhancement of metaplasia under both circumstances. Basal cell hyperplasia and increased incorporation of 3H-thymidine by tracheal epithelial cells also are seen after addition of the polyamines, putrescine or spermidine, to tracheal organ cultures, an observation supporting the importance of polyamines in the development of this lesion. The use of retinoids and inhibitors of ODC could be promising as preventive and/or therapeutic approaches for individuals at high risk for development of asbestos-associated diseases. PMID:2924752

Alvespimycin Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors

ClinicalTrials.gov

2013-04-09

Male Breast Cancer; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Breast Cancer; Recurrent Colon Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Gastric Cancer; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Melanoma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Ovarian Epithelial Cancer; Recurrent Prostate Cancer; Recurrent Renal Cell Cancer; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Basal Cell Carcinoma of the Lip; Stage III Colon Cancer; Stage III Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage III Gastric Cancer; Stage III Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage III Lymphoepithelioma of the Nasopharynx; Stage III Lymphoepithelioma of the Oropharynx; Stage III Melanoma; Stage III Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Ovarian Epithelial Cancer; Stage III Renal Cell Cancer; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Gastric Cancer; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Melanoma; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Ovarian Epithelial Cancer; Stage IV Prostate Cancer; Stage IV Renal Cell Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Unspecified Adult Solid Tumor, Protocol Specific; Untreated Metastatic Squamous Neck Cancer With Occult Primary

Adherence of non-O157 Shiga-toxin Escherichia coli to bovine recto-anal junction squamous epithelial cells appears to be mediated by mechanisms distinct from those used by O157

USDA-ARS?s Scientific Manuscript database

This study presents evidence that the pattern of adherence of clinically relevant non-O157 Shiga-toxin producing Escherichia coli (STEC) to bovine recto-anal junction squamous epithelial cells (RSE) is similar to that of O157, although the mechanisms of adherence appear to be distinct. Our results f...

Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina.

PubMed

Miyagawa, Shinichi; Iguchi, Taisen

2015-10-20

Estrogen-mediated actions in female reproductive organs are tightly regulated, mainly through estrogen receptor 1 (ESR1). The mouse vaginal epithelium cyclically exhibits cell proliferation and differentiation in response to estrogen and provides a unique model for analyzing the homeostasis of stratified squamous epithelia. To address the role of ESR1-mediated tissue events during homeostasis, we analyzed mice with a vaginal epithelium-specific knockout of Esr1 driven by keratin 5-Cre (K5-Esr1KO). We show here that loss of epithelial ESR1 in the vagina resulted in aberrant epithelial cell proliferation in the suprabasal cell layers and led to failure of keratinized differentiation. Gene expression analysis showed that several known estrogen target genes, including erbB growth factor ligands, were not induced by estrogen in the K5-Esr1KO mouse vagina. Organ culture experiments revealed that the addition of erbB growth factor ligands, such as amphiregulin, could activate keratinized differentiation in the absence of epithelial ESR1. Thus, epithelial ESR1 integrates estrogen and growth factor signaling to mediate regulation of cell proliferation in squamous differentiation, and our results provide new insights into estrogen-mediated homeostasis in female reproductive organs.

Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina

PubMed Central

Miyagawa, Shinichi; Iguchi, Taisen

2015-01-01

Estrogen-mediated actions in female reproductive organs are tightly regulated, mainly through estrogen receptor 1 (ESR1). The mouse vaginal epithelium cyclically exhibits cell proliferation and differentiation in response to estrogen and provides a unique model for analyzing the homeostasis of stratified squamous epithelia. To address the role of ESR1-mediated tissue events during homeostasis, we analyzed mice with a vaginal epithelium-specific knockout of Esr1 driven by keratin 5-Cre (K5-Esr1KO). We show here that loss of epithelial ESR1 in the vagina resulted in aberrant epithelial cell proliferation in the suprabasal cell layers and led to failure of keratinized differentiation. Gene expression analysis showed that several known estrogen target genes, including erbB growth factor ligands, were not induced by estrogen in the K5-Esr1KO mouse vagina. Organ culture experiments revealed that the addition of erbB growth factor ligands, such as amphiregulin, could activate keratinized differentiation in the absence of epithelial ESR1. Thus, epithelial ESR1 integrates estrogen and growth factor signaling to mediate regulation of cell proliferation in squamous differentiation, and our results provide new insights into estrogen-mediated homeostasis in female reproductive organs. PMID:26438838

Claudins 1, 2, 3, 4, 5 and 7 in solar keratosis and squamocellular carcinoma of the skin

PubMed Central

Hintsala, Hanna-Riikka; Siponen, Maria; Haapasaari, Kirsi-Maria; Karihtala, Peeter; Soini, Ylermi

2013-01-01

Claudins are tight junction proteins regulating the paracellular permeability of cell layers. We investigated the expression of claudins 1, 2, 3, 4, 5 and 7 in a sample set consisting of a total of 93 cases representing normal skin, actinic keratoses and squamous cell carcinomas of the skin. There were several changes found in claudin expression. Claudin 1 appeared to be progressively decreased in solar keratosis and skin squamous cell carcinomas compared to normal skin while expression of claudin 2 was increased. With claudins 3 and 5 occasional immunoreactivity was found in squamous cell carcinomas. Claudins 4 and 7 were variably expressed in skin neoplasia compared to normal skin. According to the results expression of claudins 1 and 2 change in parallel with the severity of the epidermal preneoplastic and neoplastic lesions thus probably influencing the disturbed epithelial polarity characteristic of these lesions. Claudin 1 under- and claudin 2 overexpression also lead to a leakier epithelial barrier function of the skin with a resulting damage to skin epithelial resistance. Other claudins investigated in this study did not show progressive changes even though occasional overexpression of them was found in skin squamous cell carcinoma. PMID:24294371

7-Hydroxystaurosporine and Irinotecan Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Triple Negative Breast Cancer (Currently Accruing Only Triple-negative Breast Cancer Patients Since 6/8/2007)

ClinicalTrials.gov

2013-09-27

Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Estrogen Receptor-negative Breast Cancer; Extensive Stage Small Cell Lung Cancer; Gastrointestinal Stromal Tumor; HER2-negative Breast Cancer; Metastatic Gastrointestinal Carcinoid Tumor; Ovarian Sarcoma; Ovarian Stromal Cancer; Progesterone Receptor-negative Breast Cancer; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Primary Liver Cancer; Recurrent Anal Cancer; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Borderline Ovarian Surface Epithelial-stromal Tumor; Recurrent Breast Cancer; Recurrent Cervical Cancer; Recurrent Colon Cancer; Recurrent Endometrial Carcinoma; Recurrent Esophageal Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Cell Lung Cancer; Recurrent Small Intestine Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Anal Cancer; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Borderline Ovarian Surface Epithelial-stromal Tumor; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Endometrial Carcinoma; Stage IV Esophageal Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Gastric Cancer; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Pancreatic Cancer; Stage IV Prostate Cancer; Stage IV Rectal Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Stage IVA Cervical Cancer; Stage IVB Cervical Cancer; Triple-negative Breast Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer; Unspecified Adult Solid Tumor, Protocol Specific; Untreated Metastatic Squamous Neck Cancer With Occult Primary

TGFβ loss activates ADAMTS-1-mediated EGF-dependent invasion in a model of esophageal cell invasion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Le Bras, Grégoire F.; Taylor, Chase; Koumangoye, Rainelli B.

2015-01-01

The TGFβ signaling pathway is essential to epithelial homeostasis and is often inhibited during progression of esophageal squamous cell carcinoma. Recently, an important role for TGFβ signaling has been described in the crosstalk between epithelial and stromal cells regulating squamous tumor cell invasion in mouse models of head-and-neck squamous cell carcinoma (HNSCC). Loss of TGFβ signaling, in either compartment, leads to HNSCC however, the mechanisms involved are not well understood. Using organotypic reconstruct cultures (OTC) to model the interaction between epithelial and stromal cells that occur in dysplastic lesions, we show that loss of TGFβ signaling promotes an invasive phenotypemore » in both fibroblast and epithelial compartments. Employing immortalized esophageal keratinocytes established to reproduce common mutations of esophageal squamous cell carcinoma, we show that treatment of OTC with inhibitors of TGFβ signaling (A83-01 or SB431542) enhances invasion of epithelial cells into a fibroblast-embedded Matrigel/collagen I matrix. Invasion induced by A83-01 is independent of proliferation but relies on protease activity and expression of ADAMTS-1 and can be altered by matrix density. This invasion was associated with increased expression of pro-inflammatory cytokines, IL1 and EGFR ligands HB-EGF and TGFα. Altering EGF signaling prevented or induced epithelial cell invasion in this model. Loss of expression of the TGFβ target gene ROBO1 suggested that chemorepulsion may regulate keratinocyte invasion. Taken together, our data show increased invasion through inhibition of TGFβ signaling altered epithelial-fibroblasts interactions, repressing markers of activated fibroblasts, and altering integrin-fibronectin interactions. These results suggest that inhibition of TGFβ signaling modulates an array of pathways that combined promote multiple aspects of tumor invasion. - Highlights: • Chemical inhibition of TGFβ signaling advances collective invasion of esophageal keratinocytes. • Collective cell invasion is protease dependent and ADAMTS-1 is upregulated. • Inhibition of TGFβ signaling promotes EGF-mediated invasion. • Loss of TGFβ signaling promotes collagen binding and induces alterations in integrin expression. • The TGFβ target ROBO1 is downregulated in cell invasion implying mechanisms of chemorepulsion.« less

Neuropilin 1 Receptor Is Up-Regulated in Dysplastic Epithelium and Oral Squamous Cell Carcinoma.

PubMed

Shahrabi-Farahani, Shokoufeh; Gallottini, Marina; Martins, Fabiana; Li, Erik; Mudge, Dayna R; Nakayama, Hironao; Hida, Kyoko; Panigrahy, Dipak; D'Amore, Patricia A; Bielenberg, Diane R

2016-04-01

Neuropilins are receptors for disparate ligands, including proangiogenic factors such as vascular endothelial growth factor and inhibitory class 3 semaphorin (SEMA3) family members. Differentiated cells in skin epithelium and cutaneous squamous cell carcinoma highly express the neuropilin-1 (NRP1) receptor. We examined the expression of NRP1 in human and mouse oral mucosa. NRP1 was significantly up-regulated in oral epithelial dysplasia and oral squamous cell carcinoma (OSCC). NRP1 receptor localized to the outer suprabasal epithelial layers in normal tongue, an expression pattern similar to the normal skin epidermis. However, dysplastic tongue epithelium and OSCC up-regulated NRP1 in basal and proliferating epithelial layers, a profile unseen in cutaneous squamous cell carcinoma. NRP1 up-regulation is observed in a mouse carcinogen-induced OSCC model and in human tongue OSCC biopsies. Human OSCC cell lines express NRP1 protein in vitro and in mouse tongue xenografts. Sites of capillary infiltration into orthotopic OSCC tumors correlate with high NRP1 expression. HSC3 xenografts, which express the highest NRP1 levels of the cell lines examined, showed massive intratumoral lymphangiogenesis. SEMA3A inhibited OSCC cell migration, suggesting that the NRP1 receptor was bioactive in OSCC. In conclusion, NRP1 is regulated in the oral epithelium and is selectively up-regulated during epithelial dysplasia. NRP1 may function as a reservoir to sequester proangiogenic ligands within the neoplastic compartment, thereby recruiting neovessels toward tumor cells. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia

PubMed Central

Foster, K. Wade; Liu, Zhaoli; Nail, Clinton D.; Li, Xingnan; Fitzgerald, Thomas J.; Bailey, Sarah K.; Frost, Andra R.; Louro, Iuri D.; Townes, Tim M.; Paterson, Andrew J.; Kudlow, Jeffrey E.; Lobo-Ruppert, Susan M.; Ruppert, J. Michael

2006-01-01

KLF4/GKLF normally functions in differentiating epithelial cells, but also acts as a transforming oncogene in vitro. To examine the role of this zinc finger protein in skin, we expressed the wild-type human allele from inducible and constitutive promoters. When induced in basal keratinocytes KLF4 rapidly abolished the distinctive properties of basal and parabasal epithelial cells. KLF4 caused a transitory apoptotic response and the skin progressed through phases of hyperplasia and dysplasia. By 6 weeks, lesions exhibited nuclear KLF4 and other morphologic and molecular similarities to squamous cell carcinoma in situ. p53 determined the patch size sufficient to establish lesions, as induction in a mosaic pattern produced skin lesions only when p53 was deficient. Compared with p53 wild-type animals, p53 hemizygous animals had early onset of lesions and a pronounced fibrovascular response that included outgrowth of subcutaneous sarcoma. A KLF4-estrogen receptor fusion protein showed tamoxifen-dependent nuclear localization and conditional transformation in vitro. The results suggest that KLF4 can function in the nucleus to induce squamous epithelial dysplasia, and indicate roles for p53 and epithelial-mesenchymal signaling in these early neoplastic lesions. PMID:15674344

Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia.

PubMed

Foster, K Wade; Liu, Zhaoli; Nail, Clinton D; Li, Xingnan; Fitzgerald, Thomas J; Bailey, Sarah K; Frost, Andra R; Louro, Iuri D; Townes, Tim M; Paterson, Andrew J; Kudlow, Jeffrey E; Lobo-Ruppert, Susan M; Ruppert, J Michael

2005-02-24

KLF4/GKLF normally functions in differentiating epithelial cells, but also acts as a transforming oncogene in vitro. To examine the role of this zinc finger protein in skin, we expressed the wild-type human allele from inducible and constitutive promoters. When induced in basal keratinocytes, KLF4 rapidly abolished the distinctive properties of basal and parabasal epithelial cells. KLF4 caused a transitory apoptotic response and the skin progressed through phases of hyperplasia and dysplasia. By 6 weeks, lesions exhibited nuclear KLF4 and other morphologic and molecular similarities to squamous cell carcinoma in situ. p53 determined the patch size sufficient to establish lesions, as induction in a mosaic pattern produced skin lesions only when p53 was deficient. Compared with p53 wild-type animals, p53 hemizygous animals had early onset of lesions and a pronounced fibrovascular response that included outgrowth of subcutaneous sarcoma. A KLF4-estrogen receptor fusion protein showed tamoxifen-dependent nuclear localization and conditional transformation in vitro. The results suggest that KLF4 can function in the nucleus to induce squamous epithelial dysplasia, and indicate roles for p53 and epithelial-mesenchymal signaling in these early neoplastic lesions.

Immunohistochemical Expression of MCM-2 in Oral Epithelial Dysplasias.

PubMed

Zakaria, Samar H; Farag, Heba A; Khater, Dina S

2016-03-17

Oral cancer is one of the most frequent cancers in the world. It arises from epithelial dysplasia. Hence, identifying these lesions in an early stage could prevent their malignant transformation. The aim of the present work was to assess the cell proliferative activity of minichromosome maintenance protein (MCM-2) in oral epithelial dysplastic lesions and to correlate the results with different grades of epithelial dysplasia in an attempt to use MCM-2 in the early detection of malignancy. MCM-2 expression was determined by the nuclear count in a total of 30 oral epithelial dysplastic specimens roughly classified into 10 cases of mild, moderate, and severe dysplasia. Five cases of early invasive squamous-cell carcinomas and 5 cases of epithelial hyperplasia were also included. The MCM-2 immunostaining was found to increase gradually from mild to moderate to severe dysplasia and reached its maximum value in early invasive squamous cell carcinoma. MCM-2 is of prognostic value in cases of oral dysplasia that have a tendency to undergo malignant transformation.

Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma.

PubMed

Biddle, Adrian; Gammon, Luke; Liang, Xiao; Costea, Daniela Elena; Mackenzie, Ian C

2016-02-01

Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44(high)EpCAM(low/-) CD24(+) cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.

Prognostic Potential of N-Cadherin in Oral Squamous Cell Carcinoma via Immunohistochemical Methods.

PubMed

Chandolia, Betina; Rajliwal, Jai Parkash; Bajpai, Manas; Arora, Manika

2017-08-01

To assess the prognostic potential for N-cadherin in oral squamous cell carcinoma and oral epithelial dysplasia. Across-sectional study, analytical study. Maharishi Markandeshwar College of Dental Science Research (MMCDSR), Ambala, India, from 2011 to 2014. Immunohistochemistry was used to observe the N-cadherin expression in 100 cases having epithelium with normal oral mucosa, oral epithelial dysplastic lesions and oral squamous cell carcinoma (OSCC). For statistical significance, SPSS 13.0 was used to calculate the data by Mann-Whitney and Kruskal-Wallis tests. In OSCC, N-cadherin expression was more evident than in oral epithelial dysplasia followed by the normal oral epithelium that did not show any dysplastic changes (p=0.001). Conversely, N-cadherin expression was not significant among the histological grade of OSCC. N-cadherin can be used as a potential biomarker for early diagnosis of OSCC. However, the N-cadherin expression did not show any correlation with the histological grade of OSCC.

Cervical cytology of atypical squamous cells, cannot exclude high-grade squamous intra-epithelial lesion: significance of age, human papillomavirus DNA detection and previous abnormal cytology on follow-up outcomes.

PubMed

Sung, Chang Ohk; Oh, Young Lyun; Song, Sang Yong

2011-11-01

Despite the usefulness of Pap tests for cancer screening, outcomes can be difficult to predict when atypical squamous cells (ASCs) are identified. According to the 2001 Bethesda system, ASCs can be subdivided into two groups: ASCs of undetermined significance (ASC-US); and ASCs, cannot exclude high-grade squamous intra-epithelial lesion (ASC-H). ASC-H interpretations are uncommon, and studies involving this type of lesion are based on small numbers of cases. Cross-sectional, retrospective study of 392 ASC-H cases. The follow-up outcomes of ASC-H cases that were diagnosed during routine primary screening between 2002 and 2008 were investigated, and relationships between clinicopathological parameters were assessed, particularly positive test for high-risk HPV (HPV) DNA, patient age at diagnosis and previous abnormal cytology. Of the 392 cases, high-grade squamous intra-epithelial lesion (HSIL) was detected in 111 (28.3%) cases, squamous cell carcinoma was detected in 15 (3.8%) cases, low-grade squamous intra-epithelial lesion was detected in 37 (9.4%) cases, reactive change was detected in 178 (45.4%) cases, atrophy was detected in 47 (12.0%) cases, and adenocarcinoma was detected in four (1.0%) cases. The prevalence of HSIL or greater was 27.8% for women aged ≥ 40 years, and 52.3% for women aged <40 years (p<0.001). HPV positivity in ASC-H smears was significantly associated with HSIL or greater, irrespective of age (<40 years, p=0.003; ≥ 40 years, p<0.001). ASC-H with previous abnormal cytology greater than ASC-US showed a significantly higher detection rate for HSIL or greater at follow-up (p<0.001). Patient age, positive HPV DNA test and previous abnormal cytology are useful predictors of underlying HSIL or greater in women with ASC-H. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Continual exposure to cigarette smoke extracts induces tumor-like transformation of human nontumor bronchial epithelial cells in a microfluidic chip.

PubMed

Li, Encheng; Xu, Zhiyun; Liu, Fen; Wang, Huiling; Wen, Jiabin; Shao, Shujuan; Zhang, Lichuan; Wang, Lei; Liu, Chong; Lu, Jianxin; Wang, Wenxin; Gao, Zhancheng; Wang, Qi

2014-08-01

Heavy cigarette smoking-related chronic obstructive pulmonary disease is an independent risk factor for lung squamous carcinoma. However, the mechanisms underlying the malignant transformation of bronchial epithelial cells are unclear. In our study, human tumor-adjacent bronchial epithelial cells were obtained from 10 cases with smoking-related chronic obstructive pulmonary disease and lung squamous carcinoma and cultured in an established microfluidic chip for continual exposure to cigarette smoke extracts (CSE) to investigate the potential tumor-like transformation and mechanisms. The integrated microfluidic chip included upstream concentration gradient generator and downstream cell culture chambers supplied by flowing medium containing different concentrations of CSE. Our results showed that continual exposure to low doses of CSE promoted cell proliferation whereas to high doses of CSE triggered cell apoptosis. Continual exposure to CSE promoted reactive oxygen species production in human epithelial cells in a dose-dependent manner. More importantly, continual exposure to low dose of CSE promoted the epithelial-to-mesenchymal transition process and anchorage-independent growth, and increased chromosome instability in bronchial epithelial cells, accompanied by activating the GRP78, NF-κB, and PI3K pathways. The established microfluidic chip is suitable for primary culture of human tumor-adjacent bronchial epithelial cells to investigate the malignant transformation. Continual exposure to low doses of CSE promoted tumor-like transformation of human nontumor bronchial epithelial cells by inducing reactive oxygen species production and activating the relevant signaling.

Ultrastructural characteristics of carcinogen-induced nondysplastic changes in tracheal epithelium.

PubMed Central

Klein-Szanto, A. J.; Topping, D. C.; Heckman, C. A.; Nettesheim, P.

1980-01-01

Nondysplastic hypotrophic and metaplastic epithelial alterations induced by dimethylbenz(a)anthracene in isogenic tracheal transplants were studied by light and electron microscopy 3--24 months after cessation of a 4-week carcinogen exposure. Hypotrophic epithelium observed at all time points was characterized by the presence of nonciliated cells that adopted either cuboidal or squamous shapes, forming simple or bistratified epithelia. Most of these cells, as well as some metaplastic cells, exhibited features of mucin-secreting cells. The metaplastic epithelia showed nonkeratinizing squamous metaplasia, closely related to transitional metaplasia, and keratinizing squamous metaplasia, which presented either an atrophic or an acanthotic epithelium. Although many of these epithelia showed morphologic features of normal stratified epithelia, several nonkeratinizing squamous metaplasias and acanthotic keratinizing squamous metaplasias exhibited some irregularities, probably representing very early atypical ultrastructural features (ie, perinuclear concentration of tonofilament bundles, the presence of dark and clear basal epithelial cells, interruptions and alterations of the basal lamina). These features were not observed in a group of early squamous metaplasias studied for comparative purposes 2 weeks after cessation of dimethylbenz(a)anthracene exposure, which were characterized by a combination of degenerative phenomena and increased cell proliferation. Images Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 14 Figure 15 Figure 6 Figure 7 PMID:6766047

Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett’s metaplasia

PubMed Central

Wang, David H.; Tiwari, Anjana; Kim, Monica E.; Clemons, Nicholas J.; Regmi, Nanda L.; Hodges, William A.; Berman, David M.; Montgomery, Elizabeth A.; Watkins, D. Neil; Zhang, Xi; Zhang, Qiuyang; Jie, Chunfa; Spechler, Stuart J.; Souza, Rhonda F.

2014-01-01

Metaplasia can result when injury reactivates latent developmental signaling pathways that determine cell phenotype. Barrett’s esophagus is a squamous-to-columnar epithelial metaplasia caused by reflux esophagitis. Hedgehog (Hh) signaling is active in columnar-lined, embryonic esophagus and inactive in squamous-lined, adult esophagus. We showed previously that Hh signaling is reactivated in Barrett’s metaplasia and overexpression of Sonic hedgehog (SHH) in mouse esophageal squamous epithelium leads to a columnar phenotype. Here, our objective was to identify Hh target genes involved in Barrett’s pathogenesis. By microarray analysis, we found that the transcription factor Foxa2 is more highly expressed in murine embryonic esophagus compared with postnatal esophagus. Conditional activation of Shh in mouse esophageal epithelium induced FOXA2, while FOXA2 expression was reduced in Shh knockout embryos, establishing Foxa2 as an esophageal Hh target gene. Evaluation of patient samples revealed FOXA2 expression in Barrett’s metaplasia, dysplasia, and adenocarcinoma but not in esophageal squamous epithelium or squamous cell carcinoma. In esophageal squamous cell lines, Hh signaling upregulated FOXA2, which induced expression of MUC2, an intestinal mucin found in Barrett’s esophagus, and the MUC2-processing protein AGR2. Together, these data indicate that Hh signaling induces expression of genes that determine an intestinal phenotype in esophageal squamous epithelial cells and may contribute to the development of Barrett’s metaplasia. PMID:25083987

Rate of Opportunistic Pap Smear Screening and Patterns of Epithelial Cell Abnormalities in Pap Smears in Ajman, United Arab Emirates

PubMed Central

Al Eyd, Ghaith J.; Shaik, Rizwana B.

2012-01-01

Objectives: The aim of this study was to estimate the proportion of women undergoing Papanicolaou (Pap) smear examinations, and the frequency of epithelial cell abnormalities in a teaching hospital in one emirate of the United Arab Emirates (UAE) during a three-year period. Methods: A retrospective study of 602 patient records from July 2007 to July 2010 was done in a teaching hospital in Ajman, UAE. The variables studied were age, ethnicity, menopausal status, and abnormalities in the Pap smear. Data were analysed using the Statistical Package for the Social Sciences and presented mainly as percentages; to assess associations, the chi-square test was used. Results: The total number of outpatients who attended the Obstetrics & Gynaecology Department from July 2007 to July 2010 was 150,111 patients, of which 602 (0.4% of the total) had a Pap smear test. The sample was 50.1% Arabs and 49.9% other nationalities. While 73% of the outpatients had specific complaints, 27% came for a routine screening. Epithelial cell abnormalities were seen in 3.3% of the sample, with atypical squamous cells of undetermined significance (ASCUS) found in 1.8%, low-grade squamous intraepithelial lesions (LSILs) found in 1.2%, and high-grade squamous intraepithelial lesions (HSILs) found in 0.3%. There were no cases of squamous cell carcinoma. Conclusion: Voluntary routine Pap smear screening was remarkably low in the study group. ASCUS was the most common epithelial cell abnormality. Community health education and opportunistic screening for cervical cancer are recommended for both national and expatriate women in the region. PMID:23275844

Mandibular pseudocarcinomatous hyperplasia.

PubMed

Warter, A; Walter, P; Meyer, C; Barrière, P; Galatir, L; Wilk, A

2000-08-01

Three unusual cases of pseudocarcinomatous (pseudoepitheliomatous) hyperplasia (PH) affecting chronic osteomyelitic mandibular sequestra are reported to highlight the differences with the various squamous neoplasms which occur in that site. In two patients carrying a mandibular graft following the excision of an ameloblastoma, mucosal ulcers resulted in chronic osteomyelitis. In a third patient, an apical dental infection was associated with fistulated osteomyelitis. Histology of the three sequestra showed an intraosseous squamous proliferation. It was characterized by a peripheral involvement of medullary spaces, the more mature epithelial layer covering the bone trabeculae without intervening stroma, and the basal type epithelial layer surrounding a central fibrovascular core. There were no histological or cytological signs of malignancy. PH shows an inverted pattern when compared with the centro-medullary tumoural islands seen in the various oral or odontogenic squamous neoplasms which occur in the jaws. The lack of signs of malignancy distinguish PH from common squamous cell carcinomas. A short clinical course is an important feature in the distinction of PH from the well differentiated squamous cell carcinomas which may develop in fistulated chronic osteomyelitis.

Nasal Colonisation by Staphylococcus aureus Depends upon Clumping Factor B Binding to the Squamous Epithelial Cell Envelope Protein Loricrin

PubMed Central

Mulcahy, Michelle E.; Geoghegan, Joan A.; Monk, Ian R.; O'Keeffe, Kate M.; Walsh, Evelyn J.

2012-01-01

Staphylococcus aureus asymptomatically colonises the anterior nares, but the host and bacterial factors that facilitate colonisation remain incompletely understood. The S. aureus surface protein ClfB has been shown to mediate adherence to squamous epithelial cells in vitro and to promote nasal colonisation in both mice and humans. Here, we demonstrate that the squamous epithelial cell envelope protein loricrin represents the major target ligand for ClfB during S. aureus nasal colonisation. In vitro adherence assays indicated that bacteria expressing ClfB bound loricrin most likely by the “dock, lock and latch” mechanism. Using surface plasmon resonance we showed that ClfB bound cytokeratin 10 (K10), a structural protein of squamous epithelial cells, and loricrin with similar affinities that were in the low µM range. Loricrin is composed of three separate regions comprising GS-rich omega loops. Each loop was expressed separately and found to bind ClfB, However region 2 bound with highest affinity. To investigate if the specific interaction between ClfB and loricrin was sufficient to facilitate S. aureus nasal colonisation, we compared the ability of ClfB+ S. aureus to colonise the nares of wild-type and loricrin-deficient (Lor−/−) mice. In the absence of loricrin, S. aureus nasal colonisation was significantly impaired. Furthermore a ClfB− mutant colonised wild-type mice less efficiently than the parental ClfB+ strain whereas a similar lower level of colonisation was observed with both the parental strain and the ClfB− mutant in the Lor−/− mice. The ability of ClfB to support nasal colonisation by binding loricrin in vivo was confirmed by the ability of Lactococcus lactis expressing ClfB to be retained in the nares of WT mice but not in the Lor−/− mice. By combining in vitro biochemical analysis with animal model studies we have identified the squamous epithelial cell envelope protein loricrin as the target ligand for ClfB during nasal colonisation by S. aureus. PMID:23300445

Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma

PubMed Central

Biddle, Adrian; Gammon, Luke; Liang, Xiao; Costea, Daniela Elena; Mackenzie, Ian C.

2016-01-01

Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44highEpCAMlow/− CD24+ cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs. PMID:26981578

Treatment of oral squamous cell carcinoma using anti-HER2 immunonanoshells.

PubMed

Fekrazad, Reza; Hakimiha, Neda; Farokhi, Enice; Rasaee, Mohammad Javad; Ardestani, Mehdi Shafiee; Kalhori, Katayoun A M; Sheikholeslami, Farzaneh

2011-01-01

Worldwide, oral squamous cell carcinoma (potentially mediated by HER2) is recognized as the most commonly occurring malignant neoplasm of the oral cavity. Anti-HER2 nanobodies conjugated to gold-silica nanoshells and used as photothermal treatment for oral squamous cell carcinoma may provide a novel therapeutic alternative to current treatment for this disease. KB epithelial or HeLaS3 cell cultures (controls) were exposed to these immunonanoshells, and plasmon resonance electron initiation specific to gold was employed to burn the tumor cells. Following this treatment, significant cell death occurred in the KB tumor cell cultures while there was no evidence of cellular damage or death in the HeLaS3 cell cultures. These findings suggest that photothermal treatment of oral squamous cell carcinoma has considerable advantages.

Phase I/II Study of IMMU-132 in Patients With Epithelial Cancers

ClinicalTrials.gov

2018-04-23

Colorectal Cancer; Gastric Adenocarcinoma; Esophageal Cancer; Hepatocellular Carcinoma; Non-small Cell Lung Cancer; Small Cell Lung Cancer; Ovarian Epithelial Cancer; Carcinoma Breast Stage IV; Hormone-refractory Prostate Cancer; Pancreatic Ductal Adenocarcinoma; Head and Neck Cancers- Squamous Cell; Renal Cell Cancer; Urinary Bladder Neoplasms; Cervical Cancer; Endometrial Cancer; Follicular Thyroid Cancer; Glioblastoma Multiforme; Triple Negative Breast Cancer

Airway Basal Cell Heterogeneity and Lung Squamous Cell Carcinoma.

PubMed

Hynds, Robert E; Janes, Sam M

2017-09-01

Basal cells are stem/progenitor cells that maintain airway homeostasis, enact repair following epithelial injury, and are a candidate cell-of-origin for lung squamous cell carcinoma. Heterogeneity of basal cells is recognized in terms of gene expression and differentiation capacity. In this Issue, Pagano and colleagues isolate a subset of immortalized basal cells that are characterized by high motility, suggesting that they might also be heterogeneous in their biophysical properties. Motility-selected cells displayed an increased ability to colonize the lung in vivo The possible implications of these findings are discussed in terms of basal cell heterogeneity, epithelial cell migration, and modeling of metastasis that occurs early in cancer evolution. Cancer Prev Res; 10(9); 491-3. ©2017 AACR See related article by Pagano et al., p. 514 . ©2017 American Association for Cancer Research.

In vivo microscopic imaging of the bronchial mucosa using an endo-cytoscopy system.

PubMed

Shibuya, Kiyoshi; Fujiwara, Taiki; Yasufuku, Kazuhiro; Alaa, Mohamed; Chiyo, Masako; Nakajima, Takahiro; Hoshino, Hidehisa; Hiroshima, Kenzo; Nakatani, Yukio; Yoshino, Ichiro

2011-05-01

We investigated the capabilities of an endo-cytoscopy system (ECS) that enables microscopic imaging of the tracheobronchial tree during bronchoscopy, including normal bronchial epithelium, dysplastic mucosa and squamous cell carcinoma. The newly developed ECS has a 3.2 mm diameter that can be passed through the 4.2 mm working channel of a mother endoscope for insertion of the ECS. It has a high magnification of 570× on a 17 in. video monitor. Twenty-two patients (7 squamous cell carcinoma, 11 squamous dysplasia and 4 after PDT therapies) were underwent white light, NBI light and AFI bronchoscopy. Both abnormal areas of interest and normal bronchial mucosa were stained with 0.5% methylene blue and examined with ECS at high magnification (570×). Histological examinations using haematoxylin and eosin staining were made of biopsied specimens. Analyzed ECS images were compared with the corresponding histological examinations. In normal bronchial mucosa, ciliated columnar epithelial cells were visible. In bronchial squamous dysplasia, superficial cells with abundant cytoplasm were arranged regularly. In squamous cell carcinoma, large, polymorphic tumor cells showed increased cellular densities with irregular stratified patterns. These ECS images corresponded well with the light-microscopic examination of conventional histology. ECS was useful for the discrimination between normal bronchial epithelial cells and dysplastic cells or malignant cells during bronchoscopy in real time. This novel technology has an excellent potential to provide in vivo diagnosis during bronchoscopic examinations. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Ectopic Cdx2 Expression in Murine Esophagus Models an Intermediate Stage in the Emergence of Barrett's Esophagus

PubMed Central

Kong, Jianping; Crissey, Mary Ann; Funakoshi, Shinsuke; Kreindler, James L.; Lynch, John P.

2011-01-01

Barrett's esophagus (BE) is an intestinal metaplasia that occurs in the setting of chronic acid and bile reflux and is associated with a risk for adenocarcinoma. Expression of intestine-specific transcription factors in the esophagus likely contributes to metaplasia development. Our objective was to explore the effects of an intestine-specific transcription factor when expressed in the mouse esophageal epithelium. Transgenic mice were derived in which the transcription factor Cdx2 is expressed in squamous epithelium using the murine Keratin-14 gene promoter. Effects of the transgene upon cell proliferation and differentiation, gene expression, and barrier integrity were explored. K14-Cdx2 mice express the Cdx2 transgene in esophageal squamous tissues. Cdx2 expression was associated with reduced basal epithelial cell proliferation and altered cell morphology. Ultrastructurally two changes were noted. Cdx2 expression was associated with dilated space between the basal cells and diminished cell-cell adhesion caused by reduced Desmocollin-3 mRNA and protein expression. This compromised epithelial barrier function, as the measured trans-epithelial electrical resistance (TEER) of the K14-Cdx2 epithelium was significantly reduced compared to controls (1189 Ohm*cm2 ±343.5 to 508 Ohm*cm2±92.48, p = 0.0532). Secondly, basal cells with features of a transitional cell type, intermediate between keratinocytes and columnar Barrett's epithelial cells, were observed. These cells had reduced keratin bundles and increased endoplasmic reticulum levels, suggesting the adoption of secretory-cell features. Moreover, at the ultrastructural level they resembled “Distinctive” cells associated with multilayered epithelium. Treatment of the K14-Cdx2 mice with 5′-Azacytidine elicited expression of BE-associated genes including Cdx1, Krt18, and Slc26a3/Dra, suggesting the phenotype could be advanced under certain conditions. We conclude that ectopic Cdx2 expression in keratinocytes alters cell proliferation, barrier function, and differentiation. These altered cells represent a transitional cell type between normal squamous and columnar BE cells. The K14-Cdx2 mice represent a useful model to study progression from squamous epithelium to BE. PMID:21494671

Ectopic Cdx2 expression in murine esophagus models an intermediate stage in the emergence of Barrett's esophagus.

PubMed

Kong, Jianping; Crissey, Mary Ann; Funakoshi, Shinsuke; Kreindler, James L; Lynch, John P

2011-04-06

Barrett's esophagus (BE) is an intestinal metaplasia that occurs in the setting of chronic acid and bile reflux and is associated with a risk for adenocarcinoma. Expression of intestine-specific transcription factors in the esophagus likely contributes to metaplasia development. Our objective was to explore the effects of an intestine-specific transcription factor when expressed in the mouse esophageal epithelium. Transgenic mice were derived in which the transcription factor Cdx2 is expressed in squamous epithelium using the murine Keratin-14 gene promoter. Effects of the transgene upon cell proliferation and differentiation, gene expression, and barrier integrity were explored. K14-Cdx2 mice express the Cdx2 transgene in esophageal squamous tissues. Cdx2 expression was associated with reduced basal epithelial cell proliferation and altered cell morphology. Ultrastructurally two changes were noted. Cdx2 expression was associated with dilated space between the basal cells and diminished cell-cell adhesion caused by reduced Desmocollin-3 mRNA and protein expression. This compromised epithelial barrier function, as the measured trans-epithelial electrical resistance (TEER) of the K14-Cdx2 epithelium was significantly reduced compared to controls (1189 Ohm*cm(2) ±343.5 to 508 Ohm*cm(2)±92.48, p = 0.0532). Secondly, basal cells with features of a transitional cell type, intermediate between keratinocytes and columnar Barrett's epithelial cells, were observed. These cells had reduced keratin bundles and increased endoplasmic reticulum levels, suggesting the adoption of secretory-cell features. Moreover, at the ultrastructural level they resembled "Distinctive" cells associated with multilayered epithelium. Treatment of the K14-Cdx2 mice with 5'-Azacytidine elicited expression of BE-associated genes including Cdx1, Krt18, and Slc26a3/Dra, suggesting the phenotype could be advanced under certain conditions. We conclude that ectopic Cdx2 expression in keratinocytes alters cell proliferation, barrier function, and differentiation. These altered cells represent a transitional cell type between normal squamous and columnar BE cells. The K14-Cdx2 mice represent a useful model to study progression from squamous epithelium to BE.

The human squamous oesophagus has widespread capacity for clonal expansion from cells at diverse stages of differentiation.

PubMed

Barbera, Mariagnese; di Pietro, Massimiliano; Walker, Elaine; Brierley, Charlotte; MacRae, Shona; Simons, Benjamin D; Jones, Phil H; Stingl, John; Fitzgerald, Rebecca C

2015-01-01

Knowledge of the cellular mechanisms involved in homeostasis of human squamous oesophagus in the steady state and following chronic injury is limited. We aimed to better understand these mechanisms by using a functional 3D approach. Proliferation, mitosis and the expression of progenitor lineage markers were assessed in normal squamous oesophagus from 10 patients by immunofluorescence on 3D epithelial whole mounts. Cells expressing differential levels of epithelial and progenitor markers were isolated using flow cytometry sorting and characterised by qPCR and IF. Their self-renewing potential was investigated by colony forming cells assays and in vitro organotypic culture models. Proliferation and mitotic activity was highest in the interpapillary basal layer and decreased linearly towards the tip of the papilla (p<0.0001). The orientation of mitosis was random throughout the basal layer, and asymmetric divisions were not restricted to specific cell compartments. Cells sorted into distinct populations based on the expression of epithelial and progenitor cell markers (CD34 and EpCAM) showed no difference in self-renewal in 2D culture, either as whole populations or as single cells. In 3D organotypic cultures, all cell subtypes were able to recapitulate the architecture of the tissue of origin and the main factor determining the success of the 3D culture was the number of cells plated, rather than the cell type. Oesophageal epithelial cells demonstrate remarkable plasticity for self-renewal. This situation could be viewed as an ex vivo wounding response and is compatible with recent findings in murine models. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Phenotypic plasticity and epithelial-to-mesenchymal transition in the behaviour and therapeutic response of oral squamous cell carcinoma.

PubMed

Vig, Navin; Mackenzie, Ian C; Biddle, Adrian

2015-10-01

It is increasingly recognised that phenotypic plasticity, apparently driven by epigenetic mechanisms, plays a key role in tumour behaviour and markedly influences the important processes of therapeutic survival and metastasis. An important source of plasticity in malignancy is epithelial-to-mesenchymal transition (EMT), a common epigenetically controlled event that results in transition of malignant cells between different phenotypic states that confer motility and enhance survival. In this review, we discuss the importance of phenotypic plasticity and its contribution to cellular heterogeneity in oral squamous cell carcinoma with emphasis on aspects of drug resistance and EMT. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Treatment of oral squamous cell carcinoma using anti-HER2 immunonanoshells

PubMed Central

Fekrazad, Reza; Hakimiha, Neda; Farokhi, Enice; Rasaee, Mohammad Javad; Ardestani, Mehdi Shafiee; Kalhori, Katayoun AM; Sheikholeslami, Farzaneh

2011-01-01

Background Worldwide, oral squamous cell carcinoma (potentially mediated by HER2) is recognized as the most commonly occurring malignant neoplasm of the oral cavity. Anti-HER2 nanobodies conjugated to gold-silica nanoshells and used as photothermal treatment for oral squamous cell carcinoma may provide a novel therapeutic alternative to current treatment for this disease. Methods KB epithelial or HeLaS3 cell cultures (controls) were exposed to these immunonanoshells, and plasmon resonance electron initiation specific to gold was employed to burn the tumor cells. Results Following this treatment, significant cell death occurred in the KB tumor cell cultures while there was no evidence of cellular damage or death in the HeLaS3 cell cultures. Conclusion These findings suggest that photothermal treatment of oral squamous cell carcinoma has considerable advantages. PMID:22131825

Ultramicroscopic examination of the ovine tonsillar epithelia.

PubMed

Casteleyn, Christophe; Cornelissen, Maria; Simoens, Paul; Van den Broeck, Wim

2010-05-01

As solid morphological knowledge of ovine tonsillar epithelia might contribute to a better understanding of the pathogenesis of several diseases including prion diseases, the epithelia of all tonsils of 7 one-year-old Texel sheep were examined using scanning and transmission electron microscopy. Major parts of the pharyngeal and tubal tonsils were covered by pseudostratified columnar ciliated epithelia that were interrupted by patches of epithelium containing cells with densely packed microfolds or microvilli, and cells with both microvilli and cilia. Smaller parts were covered by either flattened polygonal cells with densely packed microvilli or microfolds, squamous epithelial cells, or patches of reticular epithelium. The palatine and paraepiglottic tonsils were mainly lined by squamous epithelial cells with apical microplicae or short knobs. Additionally, regions of reticular epithelium containing epithelial cells with apical microvilli were seen. The lingual tonsil was uniformly covered by a keratinized squamous epithelium and devoid of microvillous cells and patches of reticular epithelium. The rostral half of the tonsil of the soft palate was lined by a pseudostratified columnar ciliated epithelium with characteristics of the pharyngeal and tubal tonsils. The epithelium of the caudal part resembled the epithelia of the palatine and paraepiglottic tonsils. Putative M cells, mainly characterized by apical microvilli or microfolds and a close association with lymphoid cells, seem manifestly present on the nasopharyngeal tonsils. The reticular epithelium of the palatine and paraepiglottic tonsils also harbor cells with small apical microvilli. The exact nature of these presumptive M cells should, however, be elucidated in functional studies.

Influence of Ionizing Radiation on Stromal-Epithelial Intercellular Communication in Esophageal Carcinogenesis

NASA Technical Reports Server (NTRS)

Patel, Zarana S.; Kalabis, Jiri; Rustgi, Anil K.; Cucinotta, Francis A.; Huff, Janice L.

2010-01-01

Esophageal cancer is the 6th leading cause of cancer death worldwide. Its development is associated with a variety of risk factors including tobacco use, heavy alcohol consumption, human papilloma virus infection, and certain dietary factors such as trace mineral and vitamin deficiencies. An association with ionizing radiation exposure is revealed by the high excess relative risk for squamous cell carcinoma of the esophagus observed in the survivors of the atomic bomb detonations in Japan. It is also seen as a secondary malignancy in patients who received radiotherapy for breast and thoracic cancers; additionally, patients with head/neck and oral squamous cell cancers are at increased risk for metachronous esophageal squamous cell cancers. This malignancy is rapidly fatal, mainly because it remains asymptomatic until late, advanced stages when the disease is rarely curable. The stromal microenvironment plays an essential role in the maintenance and modulation of normal epithelial cell growth and differentiation and cross talk between the epithelial and stromal compartments can influence many aspects of malignant progression, including tumor cell proliferation, migration, invasion and recruitment of new blood vessels. To test the hypothesis that radiation exposure plays a role in esophageal carcinogenesis via non-targeted mechanisms involving stromal-epithelial cell communication, we are studying radiation effects on hTERT-immortalized human esophageal epithelial cells and genetic variants grown in co-culture with human esophageal stromal fibroblasts (Okawa et al., Genes & Dev. 2007. 21: 2788-2803). We examined how radiation treatment of stromal fibroblasts affected epithelial migration and invasion, behaviors associated with cancer promotion and progression. Chemotactic and haptotactic migration of epithelial cells stimulated by conditioned media from irradiated fibroblasts was measured using assays conducted in Transwell cell culture chambers. Our results using low LET radiation showed a dose-dependent increase in migration of epithelial cells when exposed to conditioned media from irradiated vs. non-irradiated fibroblasts. We also observed enhanced invasion through a basement membrane simulant. To identify chemotactic proteins secreted by irradiated stromal fibroblasts, we used antibody capture cytokine arrays and have identified several proteins as candidates. Increased secretion of these factors by irradiated fibroblasts was confirmed using ELISA. We are currently analyzing the contribution of these individual factors on epithelial migration and invasion, as well as their influence on cell survival and DNA repair. Studies using high-LET radiation will help determine radiation quality effects on these processes. These results should further our understanding of the mechanisms by which radiation impacts the tissue microenvironment and how it influences cancer development processes.

Immunocytochemistry of cell surface heparan sulfate proteoglycan in mouse tissues. A light and electron microscopic study.

PubMed

Hayashi, K; Hayashi, M; Jalkanen, M; Firestone, J H; Trelstad, R L; Bernfield, M

1987-10-01

The core protein of the proteoglycan at the cell surface of NMuMG mouse mammary epithelial cells bears both heparan and chondroitin sulfate chains and is recognized by the monoclonal antibody 281-2. Using this antibody and the peroxidase-antiperoxidase staining technique in adult mouse tissues, we found that the antibody recognizes the antigen in a highly restricted distribution, staining a variety of epithelial cells but no cells derived from embryonic mesoderm or neural crest. The antibody fails to stain any stromal (mesenchymal) or neuronal cells, with the exception of plasma cells and Leydig cells. Squamous and transitional epithelia stain intensely over their entire surfaces, whereas cuboidal and columnar epithelia stain moderately and only at the lateral surface of the basal cells. Within squamous and transitional epithelial tissues that undergo physiological regeneration (e.g., epidermis), the most superficial and differentiated cell types fail to stain. Within glandular and branched epithelia (e.g., pancreas), the secretory alveolar cells fail to stain. When evaluated by electron microscopy, granular deposits of stain are seen on the plasma membrane, especially on lateral surfaces, but none are noted within the cells or the basement membrane. These results indicate that in adult tissues the core protein of this heparan sulfate-rich proteoglycan is expressed almost exclusively at epithelial cell surfaces. Expression appears to be lost as the cells become either mature or highly differentiated.

Comparison of staining of mitotic figures by haematoxylin and eosin-and crystal violet stains, in oral epithelial dysplasia and squamous cell carcinoma.

PubMed

Ankle, Madhuri R; Kale, Alka D; Charantimath, Seema

2007-01-01

Mitosis of cells gives rise to tissue integrity. Defects during mitosis bring about abnormalities. Excessive proliferation of cells due to increased mitosis is one such outcome, which is the hallmark in precancer and cancer. The localization of proliferating cells or their precursors may not be obvious and easy. Establishing an easy way to distinguish these mitotic cells will help in grading and understanding their biological potential. Although immunohistochemistry is an advanced method in use, the cost and time factor makes it less feasible for many laboratories. Selective histochemical stains like toluidine blue, giemsa and crystal violet have been used in tissues including the developing brain, neural tissue and skin. 1) To compare the staining of mitotic cells in haematoxylin and eosin with that in crystal violet. 2) To compare the number of mitotic figures present in normal oral mucosa, epithelial dysplasia and oral squamous cell carcinoma in crystal violet-stained sections with that in H and E-stained sections. Ten tissues of normal oral mucosa and 15 tissues each of oral epithelial dysplasia seen in tobacco-associated leukoplakia and squamous cell carcinoma were studied to evaluate the selectivity of 1% crystal violet for mitotic figures. The staining was compared with standard H and E staining. Statistical analysis was done using Mann-Whitney U test. A statistically significant increase in the mean mitotic count was observed in crystal violet-stained sections of epithelial dysplasia as compared to the H and E-stained sections (p=0.0327). A similar increase in the mitotic counts was noted in crystal violet-stained sections of oral squamous cell carcinoma as compared to the H and E-stained sections.(p=0.0443). No significant difference was found in the mitotic counts determined in dysplasia or carcinoma by either the crystal violet (p=0.4429) or the H and E-staining techniques (p=0.2717). One per cent crystal violet provides a definite advantage over the H and E-stained sections in selectively staining the mitotic figures.

Detection of Epstein-Barr virus genome and latent infection gene expression in normal epithelia, epithelial dysplasia, and squamous cell carcinoma of the oral cavity.

PubMed

Kikuchi, Kentaro; Noguchi, Yoshihiro; de Rivera, Michelle Wendoline Garcia-Niño; Hoshino, Miyako; Sakashita, Hideaki; Yamada, Tsutomu; Inoue, Harumi; Miyazaki, Yuji; Nozaki, Tadashige; González-López, Blanca Silvia; Ide, Fumio; Kusama, Kaoru

2016-03-01

A relationship between Epstein-Barr virus (EBV) infection and cancer of lymphoid and epithelial tissues such as Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma (NPC), gastric carcinoma, and oral cancer has been reported. EBV is transmitted orally and infects B cells and epithelial cells. However, it has remained uncertain whether EBV plays a role in carcinogenesis of oral mucosal tissue. In the present study, we detected the EBV genome and latent EBV gene expression in normal mucosal epithelia, epithelial dysplasia, and oral squamous cell carcinoma (OSCC) to clarify whether EBV is involved in carcinogenesis of the oral cavity. We examined 333 formalin-fixed, paraffin-embedded tissue samples (morphologically normal oral mucosa 30 samples, gingivitis 32, tonsillitis 17, oral epithelial dysplasia 83, OSCC 150, and NPC 21). EBV latent infection genes (EBNA-2, LMP-1) were detected not only in OSCC (50.2 %, 10.7 %) but also in severe epithelial dysplasia (66.7 %, 44.4 %), mild to moderate epithelial dysplasia (43.1 %, 18.5 %), gingivitis (78.1 %, 21.9 %), and normal mucosa (83.3 %, 23.3 %). Furthermore, the intensity of EBV latent infection gene expression (EBER, LMP-1) was significantly higher in severe epithelial dysplasia (94.4 %, 72.2 %) than in OSCC (34.7 %, 38.7 %). These results suggest that EBV latent infection genes and their increased expression in severe epithelial dysplasia might play an important role in the dysplasia-carcinoma sequence in the oral cavity.

Erlotinib in Treating Patients With Solid Tumors and Liver or Kidney Dysfunction

ClinicalTrials.gov

2013-01-15

Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Pilocytic Astrocytoma; Adult Primary Hepatocellular Carcinoma; Adult Subependymoma; Advanced Adult Primary Liver Cancer; Advanced Malignant Mesothelioma; Male Breast Cancer; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Brain Tumor; Recurrent Adult Primary Liver Cancer; Recurrent Anal Cancer; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Bladder Cancer; Recurrent Breast Cancer; Recurrent Cervical Cancer; Recurrent Colon Cancer; Recurrent Esophageal Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Malignant Mesothelioma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Pancreatic Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage II Esophageal Cancer; Stage II Pancreatic Cancer; Stage III Esophageal Cancer; Stage III Pancreatic Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Anal Cancer; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Bladder Cancer; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Esophageal Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Pancreatic Cancer; Stage IV Prostate Cancer; Stage IV Rectal Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Stage IVA Cervical Cancer; Stage IVB Cervical Cancer; Unspecified Adult Solid Tumor, Protocol Specific; Untreated Metastatic Squamous Neck Cancer With Occult Primary

Distribution and ultrastructural characteristics of dark cells in squamous metaplasias of the respiratory tract epithelium.

PubMed Central

Klein-Szanto, A. J.; Nettesheim, P.; Pine, A.; Martin, D.

1981-01-01

Dark epithelial basal cells were found in both carcinogen-induced and non-carcinogen-induced squamous metaplasias of the tracheal epithelium. Formaldehyde-induced squamous metaplasias exhibited 4% dark cells in the basal layer. Metaplasias induced by vitamin A deficiency and those induced by dimethylbenz(alpha)anthracene (DMBA) without atypia showed 18--20% basal dark cells. DMBA-induced metaplasias with moderate to severe atypia exhibited 50% basal dark cells. The labeling index of basal cells in metaplastic epithelia, regardless of the inducing agent, was 16--18%, ie, the same as that of the normal esophageal stratified squamous epithelium. The percentage of labeled dark basal cells per total dark cell population was approximately 19% in the non-carcinogen-induced metaplasias and in the DMBA-induced metaplasias without atypia. In the atypical metaplasias induced by DMA this percentage increased to 26. On the basis of ultrastructural observations, five types of dark epithelial cells could be distinguished in the metaplastic epithelia: Type I (ovoid or fusiform dark cell with abundant cytoplasmic filaments, desmosomes, and free ribosomes--dark keratinocyte type); Type II (ovoid or spherical small cell with scant cytoplasm with few organelles--basal respiratory type); Type III (irregular or ovoid, few cytoplasmic filaments and organelles and desmosomes, extremely abundant free ribosomes--dedifferentiated type); Type IV (fusiform or ovoid, large mitochondria, prominent ergastoplasm, secretion droplets--mucous cell type); and type V (irregular shape, organelle remnants, vacuoles, pyknotic nuclei--involutional-cell type). Type I was the predominant cell type in formaldehyde-induced metaplasias and was also commonly seen in DMBA-induced metaplasias without atypia. Type II predominated in metaplasias induced by vitamin A deficiency. Type III was seen in DMBA-induced metaplasias and was the predominant cell type in the atypical epithelial alterations. Type IV cells occurred only in the latter, and Type V cells were occasionally seen in formaldehyde- as well as in DMBA-induced atypical metaplasias. Each type of squamous metaplasia could thus be recognized by a determined numerical distribution of dark cells in the basal layer and a specific pattern of distribution of the ultrastructurally defined dark cell categories. Images Figure 3 Figure 4 Figure 5 Figure 1 Figure 2 Figure 6 Figure 7 PMID:6786102

Molecular Characterization of Squamous Cell Carcinomas From Recessive Dystrophic Epidermolysis Bullosa

DTIC Science & Technology

2006-09-01

junctions found primarily in epithelial tissues but also in certain non-epithelial tissues including the meninges, dendritic reticular cells of lymph node...epidermal thickening, a phenotype becoming more prominent in adult animals. To further examine the transition between the stratum granulosum and stratum...granular cell layers of wild-type and transgenic skin. In control epidermis, an abrupt transition was observed from the granular layer to the stratum

Nintedanib in Treating Patients With Recurrent or Persistent Endometrial Cancer

ClinicalTrials.gov

2017-09-08

Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mucinous Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Squamous Cell Carcinoma; Endometrial Transitional Cell Carcinoma; Endometrial Undifferentiated Carcinoma; Malignant Uterine Corpus Mixed Epithelial and Mesenchymal Neoplasm; Recurrent Uterine Corpus Carcinoma

Interleukin-12 and Trastuzumab in Treating Patients With Cancer That Has High Levels of HER2/Neu

ClinicalTrials.gov

2013-02-27

Advanced Adult Primary Liver Cancer; Anaplastic Thyroid Cancer; Bone Metastases; Carcinoma of the Appendix; Distal Urethral Cancer; Fallopian Tube Cancer; Gastrinoma; Glucagonoma; Inflammatory Breast Cancer; Insulinoma; Liver Metastases; Localized Unresectable Adult Primary Liver Cancer; Lung Metastases; Male Breast Cancer; Malignant Pericardial Effusion; Malignant Pleural Effusion; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Parathyroid Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Newly Diagnosed Carcinoma of Unknown Primary; Occult Non-small Cell Lung Cancer; Pancreatic Polypeptide Tumor; Primary Peritoneal Cavity Cancer; Proximal Urethral Cancer; Pulmonary Carcinoid Tumor; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adrenocortical Carcinoma; Recurrent Adult Primary Liver Cancer; Recurrent Anal Cancer; Recurrent Bladder Cancer; Recurrent Breast Cancer; Recurrent Carcinoma of Unknown Primary; Recurrent Cervical Cancer; Recurrent Colon Cancer; Recurrent Endometrial Carcinoma; Recurrent Esophageal Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Pancreatic Cancer; Recurrent Parathyroid Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Renal Cell Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Intestine Cancer; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Thyroid Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Recurrent Vaginal Cancer; Recurrent Vulvar Cancer; Skin Metastases; Small Intestine Adenocarcinoma; Somatostatinoma; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Adrenocortical Carcinoma; Stage III Bladder Cancer; Stage III Cervical Cancer; Stage III Colon Cancer; Stage III Endometrial Carcinoma; Stage III Esophageal Cancer; Stage III Follicular Thyroid Cancer; Stage III Gastric Cancer; Stage III Malignant Testicular Germ Cell Tumor; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Ovarian Epithelial Cancer; Stage III Pancreatic Cancer; Stage III Papillary Thyroid Cancer; Stage III Prostate Cancer; Stage III Rectal Cancer; Stage III Renal Cell Cancer; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Vaginal Cancer; Stage III Vulvar Cancer; Stage IIIA Anal Cancer; Stage IIIA Breast Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Anal Cancer; Stage IIIB Breast Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Adrenocortical Carcinoma; Stage IV Anal Cancer; Stage IV Bladder Cancer; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Endometrial Carcinoma; Stage IV Esophageal Cancer; Stage IV Follicular Thyroid Cancer; Stage IV Gastric Cancer; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Pancreatic Cancer; Stage IV Papillary Thyroid Cancer; Stage IV Prostate Cancer; Stage IV Rectal Cancer; Stage IV Renal Cell Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IVA Cervical Cancer; Stage IVA Vaginal Cancer; Stage IVB Cervical Cancer; Stage IVB Vaginal Cancer; Stage IVB Vulvar Cancer; Thyroid Gland Medullary Carcinoma; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer; Urethral Cancer Associated With Invasive Bladder Cancer; WDHA Syndrome

Ectopic decidua and metastatic squamous carcinoma: presentation in a single pelvic lymph node.

PubMed

Cobb, C J

1988-06-01

The presence of ectopic decidua in pelvic lymph nodes from patients with squamous carcinoma of the cervix makes evaluation for metastatic disease difficult due to the light microscopic similarity between decidua and sheets of squamous epithelial cells. A patient is present in whom decidualized endometriosis was intimately associated with metastatic moderately differentiate squamous carcinoma in a single pelvic lymph node. This phenomenon afforded an excellent opportunity to study the unique morphologic features that distinguish these two entities. A prior report of this kind was not found. In the absence of obvious squamous differentiation (i.e., intercellular bridges, dyskeratosis, and keratin "pearl" formation), as is frequently the case with squamous carcinoma of the cervix, the light microscopic features that are most useful in distinguishing squamous carcinoma from decidua include the presence of well-defined nests of cohesive cells, nuclear hyperchromasia, and cellular pleomorphism.

APR-246/PRIMA-1Met Inhibits and Reverses Squamous Metaplasia in Human Conjunctival Epithelium.

PubMed

Li, Jing; Li, Cheng; Wang, Guoliang; Liu, Zhen; Chen, Pei; Yang, Qichen; Dong, Nuo; Wu, Huping; Liu, Zuguo; Li, Wei

2016-02-01

Squamous metaplasia is a common pathologic condition in ocular surface diseases for which there is no therapeutic medication in clinic. In this study, we investigated the effect of a small molecule, APR-246/PRIMA-1(Met), on squamous metaplasia in human conjunctival epithelium. Human conjunctival explants were cultured for up to 12 days under airlifting conditions. Epithelial cell differentiation and proliferation were assessed by Cytokeratin 10 (K10), K14, K19, Pax6, MUC5AC, and p63 immunostaining patterns. β-catenin and TCF-4 immunofluorescent staining and real-time PCR characterized Wnt signaling pathway involvement. Pterygium clinical samples were cultured under airlifting conditions with or without APR-246 for 4 days. p63, K10, β-catenin, and TCF-4 expression in pterygial epithelium was determined by immunofluorescent staining and real-time PCR. Airlift conjunctival explants resulted in increased stratification and intrastromal epithelial invagination. Such pathology was accompanied by increases in K10, K14, and p63 expression, whereas K19 and Pax6 levels declined when compared to those in freshly isolated tissue. On the other hand, APR-246 reversed all of these declines in K10, K14, and p63 expression. Furthermore, K19 and Pax6 increased along with rises in goblet cell density. These effects of APR-246 were accompanied by near restoration of normal conjunctival epithelial histology. APR-246 also reversed squamous metaplasia in pterygial epithelium that had developed after 4 days in ex vivo culture. Reductions in squamous metaplasia induced by APR-246 suggest it may provide a novel therapeutic approach in different squamous metaplasia-associated ocular surface diseases.

[Electron microscopic study on the petechial hemorrhagic spots in patients with epidemic hemorrhage fever (EHF)].

PubMed

Wang, S Q; Feng, M; Yang, L

1994-12-01

EHF viral particles were found in the squamous epithelial cells and capillary endothelial cells of the petechial spots located at the mucous membrane of the soft palate in cases of early stage of severe type EHF by transmission electron microscopy. The viral particles are round or oval in shape, about 100 nm in diameter with a lipid bilayer envelope from which spikes are protruding. The virions matured by budding through the intracytoplasmic membranes into the smooth surfaced vesicles. The morphological characteristics of the virion coincided with the viral particles of Family Bunyaviridae. It was the first time to demonstrate that the squamous epithelial cells of the soft palate is one of the target cells in EHF virus infection and to describe the subcellular morphological evidence of the petechial spots at the soft palate by EM.

Rapid onset of squamous cell carcinoma in a thin skin graft donor site.

PubMed

Herard, C; Arnaud, D; Goga, D; Rousseau, P; Potier, B

2016-01-01

Squamous cell carcinomas are malignant tumours of epithelial origin that can appear on sites subjected to chronic inflammation after a period of several years. The rapid development of squamous cell carcinoma at the donor site for a thin skin graft is a rare and poorly understood situation. We report the case of a patient undergoing thin skin grafting to cover the area of removal of a vertex squamous cell carcinoma and in whom squamous cell carcinoma appeared at the donor site within 9 weeks. In our case, we ruled out intraoperative contamination because two sets of surgical instruments were used. Given the number of cases reported in the literature, a chance event seems unlikely. The hypothesis of an acute inflammatory process caused by scarring of the thin skin graft site appears to us the most convincing. Development of cancer at the graft donor site may thus be added to the list of complications of thin skin grafting. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

High-grade squamous intraepithelial lesion (HSIL) of the cervix with bizarre cytological appearances ('pleomorphic HSIL'): a review of 19 cases.

PubMed

Stewart, Colin J R

2017-08-01

Cervical high-grade squamous intraepithelial lesions (HSILs) are typically characterised by a proliferation of immature basaloid cells with relatively uniform hyperchromatic nuclei. In this report we describe 19 cases of HSIL exhibiting focal but very marked nuclear atypia often associated with multinucleation ('pleomorphic HSIL'). The bizarre cytological changes mainly involved the basal epithelium particularly in endocervical crypts where the neoplastic cells undermined the native glandular epithelial cells. Superficially invasive squamous cell carcinoma (SISCCA) was present in three cases (16%) and while this was more common than in a comparative series of 40 'conventional' HSIL excision specimens (5%), the difference was not statistically significant. All three invasive cases demonstrated additional histological features that have been associated with increased risk of SISCAA (expansile crypt involvement by HSIL, luminal necrosis, and/or intraepithelial squamous maturation), and the invasive foci were associated microanatomically with conventional-type rather than pleomorphic HSIL. The bizarre cells expressed p16 and p63 proteins but usually lacked mitotic activity and showed less Ki-67 labelling than adjacent conventional HSIL. These findings suggest that pleomorphic epithelial changes in HSIL do not necessarily indicate more aggressive biological behaviour and may, in some cases, represent a degenerative phenomenon. Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

Primary intraosseous squamous cell carcinoma: a devil in disguise

PubMed Central

Pardhe, Nilesh; Bhagalia, Sanjay; Nayak, Prathibha Anand; Sireesha, Sundaragiri Krishna

2013-01-01

Primary intraosseous squamous cell carcinoma (PIOSCC) is a rare central jaw carcinoma derived from odontogenic epithelial remnants. When the tumour arises in an existing cyst, it may be difficult to recognise early PIOSCC and carry out necessary treatment. We report a case diagnosed in a 50-year-old man where timely intervention was delayed and prognosis was affected and the case diagnosed eventually by comprehensive clinical, radiological and histopathological examination. PMID:23749827

ZEB1 promotes the progression and metastasis of cervical squamous cell carcinoma via the promotion of epithelial-mesenchymal transition

PubMed Central

Ma, Yihui; Zheng, Xiangyu; Zhou, Jun; Zhang, Ying; Chen, Kuisheng

2015-01-01

Objective: The process of epithelial-mesenchymal transition (EMT) clearly contributes to cancer metastasis. The aim of this study was to investigate the expression of the EMT-related transcription repressor ZEB1 and the expression of EMT-associated markers (E-cadherin, β-catenin and N-cadherin) in cervical squamous cell carcinoma. In addition, the role of ZEB1 and these EMT-associated markers in the progression and metastasis of cervical squamous cell carcinoma was explored. Methods: The expression of ZEB1, E-cadherin, β-catenin and N-cadherin was evaluated in 81 specimens of cervical squamous cell carcinoma by immunohistochemistry; the clinicopathological significance of these markers was then analyzed. Results: 1) Of the 81 samples, 37 cases (45.7%) were positive for ZEB1, and nuclear expression of ZEB1 in tumor cells was positively associated with the differentiation status of the tumor tissue (P < 0.05), vascular invasion (P < 0.05) and lymph node metastasis (P < 0.05). 2) The loss of E-cadherin and β-catenin expression in tumor cells and the acquisition of N-cadherin expression were positively associated with the differentiation status of the tumor tissue (P < 0.05) and with the occurrence of vascular invasion (P < 0.05). 3) A significant negative correlation was observed between ZEB1 and E-cadherin expression (Spearman = -0.636, P < 0.05) and between ZEB1 and β-catenin expression (Spearman = -0.417, P < 0.05). Moreover, a significant positive correlation was observed between ZEB1 and N-cadherin expression (Spearman = 0.557, P < 0.05). Conclusions: These results emphasize the role of EMT in cervical squamous cell carcinoma. The upregulation of ZEB1 is associated with the abnormal expression of E-cadherin, β-catenin and N-cadherin, which might promote the progression and metastasis of cervical squamous cell carcinoma. PMID:26617850

Influence of Ionizing Radiation on Stromal-Epithelial Communication in Esophageal Carcinogenesis

NASA Astrophysics Data System (ADS)

Huff, Janice; Patel, Zarana; Grugan, Katharine; Rustgi, Anil; Cucinotta, Francis A.

Esophageal cancer is the 6th leading cause of cancer death worldwide and is associated with a variety of risk factors including tobacco use, heavy alcohol consumption, human papilloma virus infection, and certain dietary factors such as trace mineral and vitamin deficiencies. A connection with ionizing radiation exposure is revealed by the high excess relative risk for esophageal squamous cell carcinoma observed in the survivors of the atomic bomb detonations in Japan. Esophageal carcinomas are also seen as secondary malignancies in patients who received radiotherapy for breast and thoracic cancers; additionally, patients with head/neck and oral squamous cell cancers are at increased risk for metachronous esophageal squamous cell cancers. This malignancy is rapidly fatal, mainly because it remains asymptomatic until late, advanced stages when the disease is rarely responsive to treatment. In normal epithelium, the stromal microenvironment is essential for the maintenance and modulation of cell growth and differentiation. Cross talk between the epithelial and stromal compartments can influence many aspects of malignant progression, including tumor cell proliferation, migration, invasion and recruitment of new blood vessels. To test the hypothesis that radiation exposure plays a role in esophageal carcinogenesis via non-targeted mechanisms involving stromal-epithelial cell communication, we are studying radiation effects on hTERT-immortalized human esophageal epithelial cells and genetic variants grown in co-culture with human esophageal stromal fibrob-lasts (Okawa et al., Genes Dev. 2007. 21: 2788-2803). We examined how irradiation of stromal fibroblasts affected epithelial migration and invasion, behaviors associated with cancer promotion and progression. These assays were conducted in modified Boyden chambers using conditioned media from irradiated fibroblasts. Our results using low LET gamma radiation showed a dose-dependent increase in migration of epithelial cells when exposed to conditioned media from irradiated vs. non-irradiated fibroblasts. We also observed enhanced invasion through a basement membrane matrix in similarly treated cells. Candidate factors that me-diate these effects were identified using antibody capture arrays, and their increased secretion in irradiated fibroblasts was confirmed using ELISAs. We are currently analyzing the effect of these individual factors on epithelial migration and invasion, as well as their influence on cell survival and DNA repair. Our current studies using high-LET radiation will elucidate radiation quality effects on these processes. These results should further our understanding of the mechanisms by which radiation impacts the tissue microenvironment and how it influences cancer development processes.

Analysis of metaplastic breast carcinoma: FNAC; histopathology and immunohistochemistry are complementary for diagnosis.

PubMed

Abd El Hafez, Amal; Shawky, Abd El-Aty

2013-01-01

Metaplastic breast carcinoma (MBC) is a rare malignancy comprised of ductal, squamous and/or mesenchymal elements with problematic diagnosis. This study analyses MBC identifying its cytologic and histologic features and emphasizing the combined role of FNAC, histopathology and immunohistochemistry (IHC) in its diagnosis. Cytology and histopathology files search yielded 21 cases identified as MBC from January 2005 to December 2010. FNAC and the histopathology slides were re-examined for the presence and frequency of various elements. Cytological and histopathological diagnoses were made and the cases subtyped according to WHO classification. Cytokeratin and vimenten IHC were used to confirm diagnosis when required. On FNAC, 52.4% were diagnosed as malignant, 9.5% as suspicious for malignancy and 38.1% as benign lesions. Most frequent cytologic findings were squamous and spindle cell elements (52.4% each). Histopathology revealed 76.2% pure epithelial tumors and 23.8% mixed epithelial-mesenchymal tumors. Squamous cell carcinoma was the most frequent histological subtype (33.3%). Carcinosarcomas were dimorphic on IHC& spindle cell carcinomas were positive for both cytokeratin and vimentin. Presence of dual components, squamous, spindle elements, mesenchymal fragments and necrosis in moderate to high cellularity breast FNAC provides clues for the diagnosis of MBC. FNAC; histopathology and IHC complement for diagnosis.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vilches, J.; Lopez, A.; Martinez, M.C.

This paper discusses the value of scanning electron microscopy (SEM) and x-ray microanalysis in the classification of craniopharyngiomas. This neoplasm shows epithelial nest, cords of cuboid cells, foci of squamous metaplasia, and microcystic degeneration. SEM reveals that the epithelial cysts are lined with elongated cells that possess numerous microvilli and blebs and that some cysts are lined with polyhedral cells. The microvilli are interpreted as characteristic of the fast growing craniopharyngiomas. A microanalytical study of the calcified areas reveals the presence of magnesium, phosphorus, and calcium.

Comparison of myofibroblasts expression in oral squamous cell carcinoma, verrucous carcinoma, high risk epithelial dysplasia, low risk epithelial dysplasia and normal oral mucosa.

PubMed

Chaudhary, Minal; Gadbail, Amol Ramchandra; Vidhale, Gaurav; Mankar Gadbail, Mugdha P; Gondivkar, Shailesh M; Gawande, Madhuri; Patil, Swati

2012-09-01

The aim was to evaluate and compare the presence of myofibroblasts in oral squamous cell carcinoma (OSCC), verrucous carcinoma (VC), high-risk epithelial dysplasia (HRED), low-risk epithelial dysplasia (LRED), and normal oral mucosa (NOM). The study consisted of 37 OSCC, 15 VC, 15 HRED, 15 LRED and 15 NOM. α-smooth muscle actin (α-SMA) antibody was used to identify myofibroblasts. The α-SMA expression was not observed in NOM and LRED. The α-SMA was expressed in 97.29% of OSCC, 86.66% of VC, 46.66 % of HRED. The α-SMA expression was significantly higher in OSCC than VC (p = 0.023) and HRED (p < 0.000). The α-SMA expression was significantly higher in VC than HRED (p = 0.043). Myofibroblastic expression, as highlighted by α-SMA, is undetectable in NOM and LRED but increases as the disease progresses from potentially malignant disorders, as HRED to VC to invasive OSCC. Thus, proliferation of myofibroblasts may be used as a stromal marker of oral premalignancy and malignancy.

Separation of cell survival, growth, migration, and mesenchymal transdifferentiation effects of fibroblast secretome on tumor cells of head and neck squamous cell carcinoma.

PubMed

Metzler, Veronika Maria; Pritz, Christian; Riml, Anna; Romani, Angela; Tuertscher, Raphaela; Steinbichler, Teresa; Dejaco, Daniel; Riechelmann, Herbert; Dudás, József

2017-11-01

Fibroblasts play a central role in tumor invasion, recurrence, and metastasis in head and neck squamous cell carcinoma. The aim of this study was to investigate the influence of tumor cell self-produced factors and paracrine fibroblast-secreted factors in comparison to indirect co-culture on cancer cell survival, growth, migration, and epithelial-mesenchymal transition using the cell lines SCC-25 and human gingival fibroblasts. Thereby, we particularly focused on the participation of the fibroblast-secreted transforming growth factor beta-1.Tumor cell self-produced factors were sufficient to ensure tumor cell survival and basic cell growth, but fibroblast-secreted paracrine factors significantly increased cell proliferation, migration, and epithelial-mesenchymal transition-related phenotype changes in tumor cells. Transforming growth factor beta-1 generated individually migrating disseminating tumor cell groups or single cells separated from the tumor cell nest, which were characterized by reduced E-cadherin expression. At the same time, transforming growth factor beta-1 inhibited tumor cell proliferation under serum-starved conditions. Neutralizing transforming growth factor beta antibody reduced the cell migration support of fibroblast-conditioned medium. Transforming growth factor beta-1 as a single factor was sufficient for generation of disseminating tumor cells from epithelial tumor cell nests, while other fibroblast paracrine factors supported tumor nest outgrowth. Different fibroblast-released factors might support tumor cell proliferation and invasion, as two separate effects.

Expression of SRSF3 is Correlated with Carcinogenesis and Progression of Oral Squamous Cell Carcinoma.

PubMed

Peiqi, Liu; Zhaozhong, Guo; Yaotian, Yin; Jun, Jia; Jihua, Guo; Rong, Jia

2016-01-01

Oral squamous cell carcinoma (OSCC) is the most common malignancy of head and neck with high mortality rates. The mechanisms of initiation and development of OSCC remain largely unknown. Dysregulated alternative splicing of pre-mRNA has been associated with OSCC. Splicing factor SRSF3 is a proto-oncogene and overexpressed in multiple cancers. The aim of this study was to uncover the relationship between SRSF3 and carcinogenesis and progression of oral squamous cell carcinoma. The expression of SRSF3 in oral normal, dysplasia, or carcinoma tissues was analyzed by immunohistochemistry. The expression levels of EMT-related genes were quantified by real-time quantitative RT-PCR. The expression of SRSF3 in DMBA treated primary cultured oral epithelial cells were analyzed by western blot. SRSF3 is overexpressed in oral cancer and moderate or severe dysplasia tissues. Patients with high grade cancer or lymphatic metastasis showed up-regulated expression of SRSF3. Knockdown of SRSF3 repressed the expression of Snail and N-cadherin in vitro. Carcinogen DMBA treated primary cultured oral epithelial cells showed significantly increased SRSF3 level than in control cells. Our results suggested that SRSF3 is associated with the initiation and development of OSCC and may be a biomarker and therapeutic target of OSCC.

The role of apical contractility in determining cell morphology in multilayered epithelial sheets and tubes

NASA Astrophysics Data System (ADS)

Zhen Tan, Rui; Lai, Tanny; Chiam, K.-H.

2017-08-01

A multilayered epithelium is made up of individual cells that are stratified in an orderly fashion, layer by layer. In such tissues, individual cells can adopt a wide range of shapes ranging from columnar to squamous. From histological images, we observe that, in flat epithelia such as the skin, the cells in the top layer are squamous while those in the middle and bottom layers are columnar, whereas in tubular epithelia, the cells in all layers are columnar. We develop a computational model to understand how individual cell shape is governed by the mechanical forces within multilayered flat and curved epithelia. We derive the energy function for an epithelial sheet of cells considering intercellular adhesive and intracellular contractile forces. We determine computationally the cell morphologies that minimize the energy function for a wide range of cellular parameters. Depending on the dominant adhesive and contractile forces, we find four dominant cell morphologies for the multilayered-layered flat sheet and three dominant cell morphologies for the two-layered curved sheet. We study the transitions between the dominant cell morphologies for the two-layered flat sheet and find both continuous and discontinuous transitions and also the presence of multistable states. Matching our computational results with histological images, we conclude that apical contractile forces from the actomyosin belt in the epithelial cells is the dominant force determining cell shape in multilayered epithelia. Our computational model can guide tissue engineers in designing artificial multilayered epithelia, in terms of figuring out the cellular parameters needed to achieve realistic epithelial morphologies.

The under-reporting of skin disease in association with squamous cell carcinoma of the vulva.

PubMed

Zaki, I; Dalziel, K L; Solomonsz, F A; Stevens, A

1996-09-01

Histology sections from 61 cases of squamous cell carcinoma (SCC) of the vulva presenting after 1988 were reviewed for evidence of associated epithelial abnormality. Of the 50 patients with epithelium adjacent to the tumour, 24 had histological evidence of lichen sclerosus (LS), 20 of severe vulvar intraepithelial neoplasia (VIN 3), 22 of human papilloma virus (HPV) infection and three of lichen planus (LP). The clinical records and the original histology report were also subsequently reviewed and with the exception of VIN 3, these disorders were poorly reported by both clinicians and pathologists. Lichen sclerosus was diagnosed clinically in only two of the 36 hospital records available for inspection. Old terminology was used to describe some patients with epithelial disease (erythroleucoplakia in one patient with LS, leucoplakia in two patients with LS and one with LP). This study demonstrates the need to adopt standard nomenclature and increase the awareness of epithelial disease associated with SCC of the vulva among clinicians and pathologists.

Risk factors and etiopathogenesis of potentially premalignant oral epithelial lesions.

PubMed

Porter, Stephen; Gueiros, Luiz Alcino; Leão, Jair Carneiro; Fedele, Stefano

2018-06-01

Potentially malignant oral mucosal disease has some ability to give rise to malignancy of the oral epithelium, that is, oral squamous cell carcinoma (OSCC). The present article provides a succinct review of the possible or probable causes of potentially premalignant oral epithelial lesions. There is a focus upon studies that examined the causes or etiologic associations with clinically likely or histopathologically detectable oral epithelial dysplasia. Copyright © 2018 Elsevier Inc. All rights reserved.

Differential immunohistochemical expression profiles of perlecan-binding growth factors in epithelial dysplasia, carcinoma in situ, and squamous cell carcinoma of the oral mucosa.

PubMed

Hasegawa, Mayumi; Cheng, Jun; Maruyama, Satoshi; Yamazaki, Manabu; Abé, Tatsuya; Babkair, Hamzah; Saito, Chikara; Saku, Takashi

2016-05-01

The intercellular deposit of perlecan, a basement-membrane type heparan sulfate proteoglycan, is considered to function as a growth factor reservoir and is enhanced in oral epithelial dysplasia and carcinoma in situ (CIS). However, it remains unknown which types of growth factors function in these perlecan-enriched epithelial conditions. The aim of this study was to determine immunohistochemically which growth factors were associated with perlecan in normal oral epithelia and in different epithelial lesions from dysplasia and CIS to squamous cell carcinoma (SCC). Eighty-one surgical tissue specimens of oral SCC containing different precancerous stages, along with ten of normal mucosa, were examined by immunohistochemistry for growth factors. In normal epithelia, perlecan and growth factors were not definitely expressed. In epithelial dysplasia, VEGF, SHH, KGF, Flt-1, and Flk-1were localized in the lower half of rete ridges (in concordance with perlecan, 33-100%), in which Ki-67 positive cells were densely packed. In CIS, perlecan and those growth factors/receptors were more strongly expressed in the cell proliferating zone (63-100%). In SCC, perlecan and KGF disappeared from carcinoma cells but emerged in the stromal space (65-100%), while VEGF, SHH, and VEGF receptors remained positive in SCC cells (0%). Immunofluorescence showed that the four growth factors were shown to be produced by three oral SCC cell lines and that their signals were partially overlapped with perlecan signals. The results indicate that perlecan and its binding growth factors are differentially expressed and function in specific manners before (dysplasia/CIS) and after (SCC) invasion of dysplasia/carcinoma cells. Copyright © 2016 Elsevier GmbH. All rights reserved.

Cancer stem cell markers in patterning differentiation and in prognosis of oral squamous cell carcinoma.

PubMed

Mohanta, Simple; Siddappa, Gangotri; Valiyaveedan, Sindhu Govindan; Dodda Thimmasandra Ramanjanappa, Ravindra; Das, Debashish; Pandian, Ramanan; Khora, Samanta Sekhar; Kuriakose, Moni Abraham; Suresh, Amritha

2017-06-01

Differentiation is a major histological parameter determining tumor aggressiveness and prognosis of the patient; cancer stem cells with their slow dividing and undifferentiated nature might be one of the factors determining the same. This study aims to correlate cancer stem cell markers (CD44 and CD147) with tumor differentiation and evaluate their subsequent effect on prognosis. Immunohistochemical analysis in treatment naïve oral cancer patients (n = 53) indicated that the expression of CD147 was associated with poorly differentiated squamous cell carcinoma and moderately differentiated squamous cell carcinoma (p < 0.01). Furthermore, co-expression analysis showed that 45% each of moderately differentiated squamous cell carcinoma and poorly differentiated squamous cell carcinoma patients were CD44 high /CD147 high as compared to only 10% of patients with well-differentiated squamous cell carcinoma. A three-way analysis indicated that differentiation correlated with recurrence and survival (p < 0.05) in only the patients with CD44 high /CD147 high cohort. Subsequently, relevance of these cancer stem cell markers in patterning the differentiation characteristics was evaluated in oral squamous cell carcinoma cell lines originating from different grades of oral cancer. Flowcytometry-based analysis indicated an increase in CD44 + /CD147 + cells in cell lines of poorly differentiated squamous cell carcinoma (94.35 ± 1.14%, p < 0.001) and moderately differentiated squamous cell carcinoma origin (93.49 ± 0.47%, p < 0.001) as compared to cell line of well-differentiated squamous cell carcinoma origin (23.12% ± 0.49%). Expression profiling indicated higher expression of cancer stem cell and epithelial-mesenchymal transition markers in SCC029B (poorly differentiated squamous cell carcinoma originated; p ≤ 0.001), which was further translated into increased spheroid formation, migration, and invasion (p < 0.001) as compared to cell line of well-differentiated squamous cell carcinoma origin. This study suggests that CD44 and CD147 together improve the prognostic efficacy of tumor differentiation; in vitro results further point out that these markers might be determinant of differentiation characteristics, imparting properties of increased self-renewal, migration, and invasion.

De-repression of the RAC activator ELMO1 in cancer stem cells drives progression of TGFβ-deficient squamous cell carcinoma from transition zones

PubMed Central

McCauley, Heather A; Chevrier, Véronique; Birnbaum, Daniel; Guasch, Géraldine

2017-01-01

Squamous cell carcinomas occurring at transition zones are highly malignant tumors with poor prognosis. The identity of the cell population and the signaling pathways involved in the progression of transition zone squamous cell carcinoma are poorly understood, hence representing limited options for targeted therapies. Here, we identify a highly tumorigenic cancer stem cell population in a mouse model of transitional epithelial carcinoma and uncover a novel mechanism by which loss of TGFβ receptor II (Tgfbr2) mediates invasion and metastasis through de-repression of ELMO1, a RAC-activating guanine exchange factor, specifically in cancer stem cells of transition zone tumors. We identify ELMO1 as a novel target of TGFβ signaling and show that restoration of Tgfbr2 results in a complete block of ELMO1 in vivo. Knocking down Elmo1 impairs metastasis of carcinoma cells to the lung, thereby providing insights into the mechanisms of progression of Tgfbr2-deficient invasive transition zone squamous cell carcinoma. DOI: http://dx.doi.org/10.7554/eLife.22914.001 PMID:28219480

Penile Analogue of Stratified Mucin-Producing Intraepithelial Lesion of the Cervix: The First Described Case. A Diagnostic Pitfall.

PubMed

Michal, Michael; Michal, Michal; Miesbauerova, Marketa; Hercogova, Jana; Skopalikova, Barbora; Kazakov, Dmitry V

2016-05-01

The authors report a case where undifferentiated (classic) penile intraepithelial neoplasia was associated with the presence of goblet cells throughout the full epithelial thickness and which later progressed into an invasive carcinoma. The lesion evolved in three consecutive biopsies from only surface epithelium occupying numerous goblet cells in the first to variably sized solid nodules in the dermis composed of atypical squamous and/or basaloid cells intermixed with numerous goblet cells in the third biopsy. Both cellular components expressed CK7 and p16 protein. Human Papillomavirus (HPV) genotyping revealed high risk HPV type 16. To the best of our knowledge, this is the first description of such a lesion occurring on the penis, which can be considered the penile analogue of cervical stratified mucin-producing intraepithelial lesion (SMILE). The correct diagnosis was rendered retrospectively, after recognition of the existence of a vulvar lesion resembling cervical SMILE. The initial biopsy was misinterpreted as extramammary Paget disease, which also constitutes the main pitfall in the differential diagnosis. Another important differential diagnosis is penile/vulvar mucinous metaplasia. The finding of atypical squamous epithelial cells positive for p16 associated with mucinous cells present throughout the full epithelial thickness is a clue to the diagnosis of penile SMILE.

Y Box-Binding Protein 1 Promotes Epithelial-Mesenchymal Transition, Invasion, and Metastasis of Cervical Cancer via Enhancing the Expressions of Snail.

PubMed

Pang, Tianyun; Li, Min; Zhang, Ye; Yong, Weiwei; Kang, Haixian; Yao, Yunhong; Hu, Xinrong

2017-10-01

Y box-binding protein 1 (YB-1) is a potent oncogenic protein. How it regulates Snail in most tumors including cervical cancer is unknown. This article is to study if YB-1 plays a role in cervical cancer via regulating the expression of Snail. Immunohistochemical staining of YB-1, Snail, and E-cadherin (E-cad) was performed on tissue specimens including 35 cases of chronic cervicitis (as a control), 35 cases of cervical intraepithelial neoplasm (CIN) I, 35 cases of CIN II/III, 28 cases of unmetastatic cervical squamous cell carcinoma, and 19 cases of metastatic cervical squamous cell carcinoma. RNA interference technique was used to knock down YB-1, E6, and Snail genes. Quantitative polymerase chain reaction, western blot, and transwell experiment were used to detect RNA, protein, and cell invasion of cervical cancer cell lines Hela and C33A, respectively. First, YB-1 knockdown significantly reduced messenger RNA (mRNA) and protein levels of Snail, followed by the increased mRNA and protein levels of E-cad and the decreased invasive ability in both Hela (human papillomavirus [HPV] 18+) and C33A (HPV-) cell lines. Second, YB-1 and Snail protein were correlatively expressed in the group order of metastatic cervical squamous cell carcinoma > unmetastatic cervical squamous cell carcinoma > CINs > cervicitis, with the inverse expression mode of E-cad in the group order, P value less than 0.01, between any 2 groups. Finally, HPV18 E6 knockdown reduced the mRNA and protein levels of YB-1 and Snail in Hela cells. The results firstly reported that YB-1 whose mRNA expression is regulated by HPV18 E6 promotes epithelial-mesenchymal transition and progression of cervical cancer via enhancing the expressions of Snail, which indicated that YB-1/Snail/epithelial-mesenchymal transition axis could have a potential use in the diagnosis and therapy of cervical cancer metastasis as a cancer marker and molecular target.

Three-dimensional telomere architecture of esophageal squamous cell carcinoma: comparison of tumor and normal epithelial cells.

PubMed

Sunpaweravong, S; Sunpaweravong, P; Sathitruangsak, C; Mai, S

2016-05-01

Telomeres are repetitive nucleotide sequences (TTAGGG)n located at the ends of chromosomes that function to preserve chromosomal integrity and prevent terminal end-to-end fusions. Telomere loss or dysfunction results in breakage-bridge-fusion cycles, aneuploidy, gene amplification and chromosomal rearrangements, which can lead to genomic instability and promote carcinogenesis. Evaluating the hypothesis that changes in telomeres contribute to the development of esophageal squamous cell carcinoma (ESCC) and to determine whether there are differences between young and old patients, we compared the three-dimensional (3D) nuclear telomere architecture in ESCC tumor cells with that of normal epithelial cells obtained from the same patient. Patients were equally divided by age into two groups, one comprising those less than 45 years of age and the other consisting of those over 80 years of age. Tumor and normal epithelial cells located at least 10 cm from the border of the tumor were biopsied in ESCC patients. Hematoxylin and eosin staining was performed for each sample to confirm and identify the cancer and normal epithelial cells. This study was based on quantitative 3D fluorescence in situ hybridization (Q-FISH), 3D imaging and 3D analysis of paraffin-embedded slides. The 3D telomere architecture data were computer analyzed using 100 nuclei per slide. The following were the main parameters compared: the number of signals (number of telomeres), signal intensity (telomere length), number of telomere aggregates, and nuclear volume. Tumor and normal epithelial samples from 16 patients were compared. The normal epithelial cells had more telomere signals and higher intensities than the tumor cells, with P-values of P < 0.0001 and P = 0.0078, respectively. There were no statistically significant differences in the numbers of telomere aggregates or the nuclear volumes between the tumor and normal epithelial cells. Secondary analyses examined the effects of age on 3D telomere architecture and found no statistically significant differences in any parameter tested between the young and old patients in either the tumor or epithelial cells. The 3D nuclear telomeric signature was able to detect differences in telomere architecture between the ESCC and normal epithelial tissues. However, there were no differences observed between the young and old patients. © 2015 International Society for Diseases of the Esophagus.

Unique roles of estrogen-dependent Pten control in epithelial cell homeostasis of mouse vagina.

PubMed

Miyagawa, S; Sato, M; Sudo, T; Yamada, G; Iguchi, T

2015-02-19

Numerous studies support a role of phosphatase and tensin homolog deleted from chromosome 10 (Pten) as a tumor suppressor gene that controls epithelial cell homeostasis to prevent tumor formation. Mouse vaginal epithelium cyclically exhibits cell proliferation and differentiation in response to estrogen and provides a unique model for analyzing homeostasis of stratified squamous epithelia. We analyzed vaginal epithelium-specific Pten conditional knockout (CKO) mice to provide new insights into Pten/phosphoinositide-3-kinase (PI3K)/Akt function. The vaginal epithelium of ovariectomized (OVX) mice (control) was composed of 1-2 layers of cuboidal cells, whereas OVX CKO mice exhibited epithelial hyperplasia in the suprabasal cells with increased cell mass and mucin production. This is possibly due to misactivation of mammalian target of rapamycin and mitogen-activated protein kinase. Intriguingly, estrogen administration to OVX Pten CKO mice induced stratification and keratinized differentiation in the vaginal epithelium, as in estrogen-treated controls. We found that Pten is exclusively expressed in the suprabasal cells in the absence of estrogens, whereas estrogen administration induced Pten expression in the basal cells. This suggests that Pten acts to prevent excessive cell proliferation as in the case of other squamous tissues. Thus, Pten exhibits a dual role on the control of vaginal homeostasis, depending on whether estrogens are present or absent. Our results provide new insights into how Pten functions in tissue homeostasis.

Pathophysiology of ocular surface squamous neoplasia

PubMed Central

Gichuhi, Stephen; Ohnuma, Shin-ichi; Sagoo, Mandeep S.; Burton, Matthew J.

2014-01-01

The incidence of ocular surface squamous neoplasia (OSSN) is strongly associated with solar ultraviolet (UV) radiation, HIV and human papilloma virus (HPV). Africa has the highest incidence rates in the world. Most lesions occur at the limbus within the interpalpebral fissure particularly the nasal sector. The nasal limbus receives the highest intensity of sunlight. Limbal epithelial crypts are concentrated nasally and contain niches of limbal epithelial stem cells in the basal layer. It is possible that these are the progenitor cells in OSSN. OSSN arises in the basal epithelial cells spreading towards the surface which resembles the movement of corneo-limbal stem cell progeny before it later invades through the basement membrane below. UV radiation damages DNA producing pyrimidine dimers in the DNA chain. Specific CC → TT base pair dimer transformations of the p53 tumour-suppressor gene occur in OSSN allowing cells with damaged DNA past the G1-S cell cycle checkpoint. UV radiation also causes local and systemic photoimmunosuppression and reactivates latent viruses such as HPV. The E7 proteins of HPV promote proliferation of infected epithelial cells via the retinoblastoma gene while E6 proteins prevent the p53 tumour suppressor gene from effecting cell-cycle arrest of DNA-damaged and infected cells. Immunosuppression from UV radiation, HIV and vitamin A deficiency impairs tumour immune surveillance allowing survival of aberrant cells. Tumour growth and metastases are enhanced by; telomerase reactivation which increases the number of cell divisions a cell can undergo; vascular endothelial growth factor for angiogenesis and matrix metalloproteinases (MMPs) that destroy the intercellular matrix between cells. Despite these potential triggers, the disease is usually unilateral. It is unclear how HPV reaches the conjunctiva. PMID:25447808

Breast implant capsule-associated squamous cell carcinoma: a report of 2 cases.

PubMed

Olsen, Daniel L; Keeney, Gary L; Chen, Beiyun; Visscher, Daniel W; Carter, Jodi M

2017-09-01

The use of prosthetic implants for breast augmentation has become commonplace. Although implants do not increase the risk of conventional mammary carcinoma, they are rarely associated with anaplastic large cell lymphoma. We report 2 cases of breast implant capsule-associated squamous cell carcinoma with poor clinical outcomes. Both patients (56-year-old woman and 81-year-old woman) had long-standing implants (>25 years) and presented with acute unilateral breast enlargement. In both cases, squamous cell carcinoma arose in (focally dysplastic) squamous epithelium-lined breast implant capsules and widely invaded surrounding breast parenchyma or chest wall. Neither patient had evidence of a primary mammary carcinoma or squamous cell carcinoma at any other anatomic site. Within 1 year, one patient developed extensive, treatment-refractory, locoregional soft tissue metastasis, and the second patient developed hepatic and soft tissue metastases and died of disease. There are 2 prior reported cases of implant-associated squamous cell carcinoma in the plastic surgery literature; one provides no pathologic staging or outcome information, and the second case was a capsule-confined squamous cell carcinoma. Together, all 4 cases share notable commonalities: the patients had long-standing breast implants and presented with acute unilateral breast pain and enlargement secondary to tumors arising on the posterior aspect of squamous epithelialized implant capsules. Because of both its rarity and its unusual clinical presentation, implant capsule-associated squamous cell carcinoma may be underrecognized. The aggressive behavior of the tumors in this series underscores the importance of excluding malignancy in patients with long-standing breast implants who present with acute unilateral breast pain and enlargement. Copyright © 2017 Elsevier Inc. All rights reserved.

Stromal loss of TGFβ drives cancer growth in the epithelium via inflammation | Center for Cancer Research

Cancer.gov

Interactions between epithelial and stromal cells play an important role in cancer development and progression. Epithelial cancers develop when changes occur to tumor suppressor genes in stromal fibroblast cells. For example, loss of tumor suppressor, p53, in stromal fibroblasts leads to p53 inactivation in the epithelium in a prostate cancer model, and disruption of the transforming growth factor-b receptor II (TGF-βRII) in stromal fibroblasts results in intraepithelial dysplasia in prostate cancer and invasive squamous cell carcinoma (SCC) in mouse forestomach.

Aberrant expression of the tight junction molecules claudin-1 and zonula occludens-1 mediates cell growth and invasion in oral squamous cell carcinoma.

PubMed

Babkair, Hamzah; Yamazaki, Manabu; Uddin, Md Shihab; Maruyama, Satoshi; Abé, Tatsuya; Essa, Ahmed; Sumita, Yoshimasa; Ahsan, Md Shahidul; Swelam, Wael; Cheng, Jun; Saku, Takashi

2016-11-01

We reported that altered cell contact mediated by E-cadherin is an initial event in the pathogenesis of oral epithelial malignancies. To assess other effects of cell adhesion, we examined the expression levels of tight junction (TJ) molecules in oral carcinoma in situ (CIS) and squamous cell carcinoma (SCC). To identify changes in the expression of TJ molecules, we conducted an analysis of the immunohistochemical profiles of claudin-1 (CLDN-1) and zonula occludens-1 (ZO-1) in surgical specimens acquired from patients with oral SCC containing foci of epithelial dysplasia or from patients with CIS. We used immunofluorescence, Western blotting, reverse-transcription polymerase chain reaction, and RNA interference to evaluate the functions of CLDN-1 and ZO-1 in cultured oral SCC cells. TJ molecules were not detected in normal oral epithelial tissues but were expressed in SCC/CIS cells. ZO-1 was localized within the nucleus of proliferating cells. When CLDN-1 expression was inhibited by transfecting cells with specific small interference RNAs, SCC cells dissociated, and their ability to proliferate and invade Matrigel was inhibited. In contrast, although RNA interference-mediated inhibition of ZO-1 expression did not affect cell morphology, it inhibited cell proliferation and invasiveness. Our findings indicated that the detection of TJ molecules in the oral epithelia may serve as a marker for the malignant phenotype of cells in which CLDN-1 regulates proliferation and invasion. Copyright © 2016 Elsevier Inc. All rights reserved.

Nuclear factor κB and cyclooxygenase-2 immunoexpression in oral dysplasia and oral squamous cell carcinoma.

PubMed

Pontes, Hélder Antônio Rebelo; Pontes, Flávia Sirotheau Corrêa; Fonseca, Felipe Paiva; de Carvalho, Pedro Luiz; Pereira, Erika Martins; de Abreu, Michelle Carvalho; de Freitas Silva, Brunno Santos; dos Santos Pinto, Décio

2013-02-01

Oral leukoplakia is the main potentially malignant oral lesion, and oral squamous cell carcinoma accounts for more than 95% of all malignant neoplasms in the oral cavity. Therefore, the aim of this study was to verify the immunoexpression of nuclear factor κB (NF-κB) and cyclooxygenase-2 (COX-2) proteins in dysplastic oral lesions and oral squamous cell carcinoma. Immunohistochemical reactions were performed on 6 inflammatory fibrous hyperplasia, 28 oral leukoplakia, and 15 oral squamous cell carcinoma paraffin-embedded samples. Immunoperoxidase reaction for NF-κB and COX-2 was applied on the specimens, and the positivity of the reactions was calculated for 1000 epithelial cells. Using the analysis of variance and the Tukey post hoc statistical analyses, a significantly increased immunoexpression for NF-κB was observed when oral squamous cell carcinoma samples were compared with the other groups studied. However, using the Kruskal-Wallis and the Dunn post hoc tests, a statistically significant result for COX-2 expression was obtained only when the moderate dysplasia group was compared with the inflammatory fibrous hyperplasia group. Nuclear factor κB may participate in the malignant phenotype acquisition process of the oral squamous cell carcinoma in its late stages, whereas COX-2 may be involved in the early stages of oral carcinogenesis process. Copyright © 2013 Elsevier Inc. All rights reserved.

The expression and prognostic value of protein tyrosine kinase 6 in early-stage cervical squamous cell cancer.

PubMed

Wang, Xiao-Jing; Xiong, Ying; Ma, Ze-Biao; Xia, Jian-Chuan; Li, Yan-Fang

2016-06-16

Protein tyrosine kinase 6 (PTK6) is overexpressed in many epithelial tumors and predicts poor prognosis. However, PTK6 expression status and its role in cervical squamous cell cancer are unknown. This study aimed to investigate the expression level and clinical significance of PTK6 in early-stage cervical squamous cell cancer. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting analysis were performed to detect PTK6 mRNA and protein expression levels in 10 freshly frozen, early-stage cervical squamous cell cancer specimens and adjacent non-tumorous cervical tissues. The expression of PTK6 was detected using immunohistochemical staining in 150 formalin-fixed, paraffin-embedded, early-stage cervical squamous cell cancer sections and 10 normal cervical tissue sections. The mRNA and protein levels of PTK6 in cancer tissues were higher than those in adjacent non-tumorous cervical tissues. Immunohistochemical analysis showed that PTK6 was not expressed in normal cervical tissues but was overexpressed in the cytoplasm of cervical squamous cell cancer cells. The level of PTK6 expression was significantly associated with tumor grade (P = 0.020). The 5-year overall survival rate of patients with high PTK6 expression was lower than that of patients with low PTK6 expression (81.3% vs. 96.2%, P = 0.008). Multivariate Cox regression analysis showed that the expression level of PTK6 in cervical squamous cell cancer was an independent prognostic factor for patient survival (hazard ratio = 5.999, 95% confidence interval 1.622-22.191, P < 0.05). PTK6 is overexpressed in cervical squamous cell cancer. Increased PTK6 expression is associated with reduced 5-year overall survival. PTK6 expression is an independent prognostic predictor for cervical cancer.

Histomorphometric Analysis of Angiogenesis using CD31 Immunomarker and Mast Cell Density in Oral Premalignant and Malignant Lesions: A Pilot Study.

PubMed

Jyothsna, M; Rammanohar, M; Kumar, Kiran

2017-01-01

Mast cells have been implicated in promoting angiogenesis in malignant tumors of lung, oesophagus and breast, but there are few studies on Oral Squamous Cell Carcinomas (OSCC). Most oral squamous cell carcinomas arise from pre-existing precancerous lesions exhibiting epithelial dysplasia. The present pilot study attempts to compare Mast Cell Density (MCD), Microvessel Density (MVD), Microvessel Area (MVA) histomorphometrically between normal buccal mucosa, severe epithelial dysplasia and OSCC and to correlate the role of mast cells and angiogenesis in tumor progression. The retrospective study was conducted on eight cases of OSCC, eight cases of severe epithelial dysplasia and five cases of normal buccal mucosa. Immunohistochemical staining with anti CD-31, to demonstrate angiogenesis and toluidine blue staining for mast cells were employed. MVA, MVD and MCD were calculated using the measurement tools of the image analysis software and compared between the groups. One way ANOVA (Analysis of Variance) was used for comparing the parameter for multiple groups followed by Games Howell test. To assess the relationship between micro vessel density and mast cell density, Karl Pearson's correlation was used. MCD and MVD increased with disease progression and were statistically higher in OSCC than in severe epithelial dysplasia and normal buccal mucosa (p<0.001). MVA increased from normal to severe dysplasia and decreased from dysplasia to OSCC, may be due to revascularization of tumor tissue. A positive correlation was observed between MCD and MVD in OSCC and dysplasia, though were not statistically significant. These findings suggest that mast cells may up regulate angiogenesis in OSCC. MCD and MVD may be used as indicators for disease progression.

Identification of epithelial label-retaining cells at the transition between the anal canal and the rectum in mice

PubMed Central

Runck, Laura A; Kramer, Megan; Ciraolo, Georgianne; Lewis, Alfor G

2010-01-01

In certain regions of the body, transition zones exist where stratified squamous epithelia directly abut against other types of epithelia. Certain transition zones are especially prone to tumorigenesis an example being the anorectal junction, although the reason for this is not known. One possibility is that the abrupt transition of the simple columnar epithelium of the colon to the stratified squamous epithelium of the proximal portion of the anal canal may contain a unique stem cell niche. We investigated whether the anorectal region contained cells with stem cell properties relative to the adjacent epithelium. We utilized a tetracycline-regulatable histone H2B-GFP transgenic mice model, previously used to identify hair follicle stem cells, to fluorescently label slow-cycling anal epithelial cells (e.g., prospective stem cells) in combination with a panel of putative stem cell markers. We identified a population of long-term GFP label-retaining cells concentrated at the junction between the anal canal and the rectum. These cells are BrdU-retaining cells and expressed the stem cell marker CD34. Moreover, tracking the fate of the anal label-retaining cells in vivo revealed that the slow-cycling cells only gave rise to progeny of the anal epithelium. In conclusion, we identified a unique population of cells at the anorectal junction which can be separated from the other basal anal epithelial cells based upon the expression of the stem cell marker CD34 and integrin α6, and thus represent a putative anal stem cell population. PMID:20647777

GLUT-1 immunoexpression in oral epithelial dysplasia, oral squamous cell carcinoma, and verrucous carcinoma.

PubMed

Angadi, Vidya C; Angadi, Punnya V

2015-06-01

Glucose transporters, such as GLUT-1, mediate the important mechanisms involved in cellular glucose influx, allowing cells to proliferate and survive. The significance of GLUT-1 expression in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC) has been less explored, and no study has investigated it in relation to verrucous carcinoma (VC). We evaluated 30 cases each of OED, OSCC, and VC, graded further on the basis of their differentiation, immunohistochemically for GLUT-1 expression, along with 10 specimens of normal oral mucosa (NOM) as controls. In OSCC, GLUT-1 expression increased with the degree of dysplasia and increasing grade (P < 0.001). The expression in VC was predominantly membranous and intense, resembling well differentiated OSCC. This increase of GLUT-1 expression in OSCC along with the degree of dysplasia and the histologic grade reflects the expanding glycolytic response to hypoxia. This is the first study to have revealed prominent GLUT-1 expression in VC, highlighting its inherent metabolic capacity.

Keratin, luminal epithelial antigen and carcinoembryonic antigen in human urinary bladder carcinomas. An immunohistochemical study.

PubMed

Nathrath, W B; Arnholdt, H; Wilson, P D

1982-01-01

14 urinary bladder carcinomas of all main types were investigated with antisera to "broad spectrum keratin" (aK), "luminal epithelial antigen" (aLEA) and carcinoembryonic antigen (aCEA), using an indirect immunoperoxidase method on formalin fixed paraffin embedded sections. Keratin and LEA were both present in normal transitional epithelium, papilloma and carcinoma in situ whereas CEA was absent. Transitional cell carcinomas reacted with both aK and aLEA whereas CEA was seen only in a few foci. In squamous metaplasia and squamous carcinoma reaction with aK was particularly strong, while LEA was almost lacking and CEA was present in necrotic centres. In adenocarcinomas aK and aLEA reacted equally while aCEA reacted only on the surface.

Effects of vitamin D receptor knockout on cornea epithelium gap junctions.

PubMed

Lu, Xiaowen; Watsky, Mitchell A

2014-05-06

Gap junctions are present in all corneal cell types and have been shown to have a critical role in cell phenotype determination. Vitamin D has been shown to influence cell differentiation, and recent work demonstrates the presence of vitamin D in the ocular anterior segment. This study measured and compared gap junction diffusion coefficients among different cornea epithelium phenotypes and in keratocytes using a noninvasive technique, fluorescence recovery after photobleaching (FRAP), and examined the influence of vitamin D receptor (VDR) knockout on epithelial gap junction communication in intact corneas. Previous gap junction studies in cornea epithelium and keratocytes were performed using cultured cells or ex vivo invasive techniques. These invasive techniques were unable to measure diffusion coefficients and likely were disruptive to normal cell physiology. Corneas from VDR knockout and control mice were stained with 5(6)-carboxyfluorescein diacetate (CFDA). Gap junction diffusion coefficients of the corneal epithelium phenotypes and of keratocytes, residing in intact corneas, were detected using FRAP. Diffusion coefficients equaled 18.7, 9.8, 5.6, and 4.2 μm(2)/s for superficial squamous cells, middle wing cells, basal cells, and keratocytes, respectively. Corneal thickness, superficial cell size, and the superficial squamous cell diffusion coefficient of 10-week-old VDR knockout mice were significantly lower than those of control mice (P < 0.01). The superficial cell diffusion coefficient of heterozygous mice was significantly lower than control mice (P < 0.05). Our results demonstrate differences in gap junction dye spread among the epithelial cell phenotypes, mirroring the epithelial developmental axis. The VDR knockout influences previously unreported cell-to-cell communication in superficial epithelium.

Cells of Origin of Epithelial Ovarian Cancers

DTIC Science & Technology

2015-09-01

cells in oral squamous cell carcinomas by a novel pathway-based lineage tracing approach in a murine model. ! 13! Specific aims: 1. Determine...SUNDARESAN Lineage tracing and clonal analysis of oral cancer initiating cells The goal of this project is to study cancer stem cells /cancer initiating...whether oral cancer cells genetically marked based on their activities for stem cell -related pathways exhibit cancer stem cell properties in vivo by

Image analysis assisted study of mitotic figures in oral epithelial dysplasia and squamous cell carcinoma using differential stains.

PubMed

Tandon, Ankita; Singh, Narendra Nath; Brave, V R; Sreedhar, Gadiputi

2016-11-01

Mitosis is a process of cell division resulting in two genetically equivalent daughter cells. Excessive proliferation of cells due to mitosis is the hallmark in pre cancer and cancer. This study was conducted to count the number of mitotic figures in normal oral mucosa, oral epithelial dysplasia and squamous cell carcinoma in both Hematoxylin and Eosin (H&E) and Crystal Violet stained sections. Also the overall number of mitotic figures with both stains were compared along with the evaluation of staining efficacy of both the stains. The present study was conducted on 20 specimens each of the three categories. These were further divided into two groups for staining with H&E and with 1% Crystal Violet respectively. Images were captured and analyzed using image analysis software Dewinter Biowizard 4.1. Comparison of mitotic figure count in three categories in sections stained with both stains showed statistically significant difference ( p  < 0.001). The mean number of mitotic figures seen in Crystal Violet reagent were significantly higher as seen in H&E stain ( p  < 0.001). The overall diagnostic efficacy of Crystal Violet was 87.6%. Crystal Violet scored over H&E stain and also helped to better appreciate metaphases in Squamous cell carcinoma and telophases in dysplasia. Number of mitotic figures progressively increase with the advancement of the pathology. Use of 1% Crystal Violet provides better appreciation of mitotic figures and can be employed as a selective stain in routine histopathology.

Expression of laminin-5 and integrins in actinic cheilitis and superficially invasive squamous cell carcinomas of the lip.

PubMed

Peixoto da-Silva, Janaína; Lourenço, Silvia; Nico, Marcello; Silva, Filomena H; Martins, Marília Trierveiler; Costa-Neves, Adriana

2012-10-15

The progression of carcinogenesis entails the detachment of cells, invasion and migration of neoplastic cells. Alterations in epithelial adhesion and basement membrane proteins might mediate the early stages of carcinogenesis. This study investigated the expression of adhesion molecules and the basement membrane protein laminin-5 in actinic cheilitis (AC) and incipient squamous cell carcinoma of the lower lip to understand early photocarcinogenesis. Ln-5γ2 chain as well as α3, β1 subunits of α3β1 heterodimer and β4 subunit of integrin α6β4 were evaluated by immunohistochemistry in 16 cases of AC and 16 cases of superficially invasive squamous cell carcinoma (SISCC). Most AC cases showed reduced expression of β1, β4 and α3 integrins, and SISCCs lacked β1, β4 and α3 integrins in the invasive front. AC cases were negative for the Ln-5γ2 chain. Five cases of SISCC (31%) showed heterogeneous Ln-5γ2 chain expression in the invasive front of the tumor. Integrin β1, β4 and α3 expression is lost during the early stages of lip carcinogenesis. Expression of Ln-5γ2 in the invasive front in cases and its correlation with tumor progression suggest that it mediates the acquisition of the migrating and invading epithelial cell phenotype. Copyright © 2012 Elsevier GmbH. All rights reserved.

Curcumin targets fibroblast–tumor cell interactions in oral squamous cell carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dudás, József, E-mail: jozsef.dudas@i-med.ac.at; Fullár, Alexandra, E-mail: fullarsz@gmail.com; 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, 1085 Budapest

Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of OSCC tumor cells. We hypothesized that Curcumin targets this dynamic mutual interaction between CAFs and tumor cells. Normal and 2 μM Curcumin-treated co-culture were performed for 4 days, followed by analysis of tumor cell invasivity, mRNA/protein expression of EMT-markers and mediators, activity measure of matrix metalloproteinase 9 (MMP-9), and western blot analysis of signal transduction in tumor cells and fibroblasts. In Curcumin-treated co-culture, in tumor cells, the levels of nuclear factormore » κB (NFκBα) and early response kinase (ERK)—decreased, in fibroblasts, integrin αv protein synthesis decreased compared to corresponding cells in normal co-culture. The signal modulatory changes induced by Curcumin caused decreased release of EMT-mediators in CAFs and reversal of EMT in tumor cells, which was associated with decreased invasion. These data confirm the palliative potential of Curcumin in clinical application. - Graphical abstract: Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of tumor cells. Curcumin targets this dynamic mutual interaction between CAFs and tumor cells by inhibiting the production of EMT mediators in CAFs and by modification of intracellular signaling in tumor cells. This causes less invasivity and reversal of EMT in tumor cells. Highlights: ► Curcumin targets tumor–fibroblast interaction in head and neck cancer. ► Curcumin suppresses mediators of epithelial–mesenchymal transition. ► Curcumin decreases the invasivity of tumor cells.« less

Cytological analysis of atypical squamous epithelial cells of undetermined significance using the world wide web.

PubMed

Washiya, Kiyotada; Abe, Ichinosuke; Ambo, Junichi; Iwai, Muneo; Okusawa, Estuko; Asanuma, Kyousuke; Watanabe, Jun

2011-01-01

The low-level consistency of the cytodiagnosis of uterine cervical atypical squamous epithelial cells of undetermined significance (ASC-US) employing the Bethesda System has been reported, suggesting the necessity of a wide survey. We presented cases judged as ASC-US on the Web and analyzed the voting results to investigate ASC-US cytologically. Cytology samples from 129 patients diagnosed with ASC-US were used. Images of several atypical cells observed in these cases were presented on the Web. The study, based on the voting results, was presented and opinions were exchanged at the meeting of the Japanese Society of Clinical Cytology. The final diagnosis of ASC-US was benign lesions in 76 cases and low- and high-grade squamous intraepithelial lesions in 44, but no definite diagnosis could be made for the remaining 9. The total number of votes was 17,884 with a 36.5% consistency of cases judged as ASC-US. Benign cases were divided into 6 categories. Four categories not corresponding to the features of koilocytosis and small abnormal keratinized cells were judged as negative for an intraepithelial lesion or malignancy at a high rate. A Web-based survey would be useful which could be viewed at any time and thereby facilitate the sharing of cases to increase consistency. Copyright © 2011 S. Karger AG, Basel.

Bile Acids Down-Regulate Caveolin-1 in Esophageal Epithelial Cells through Sterol Responsive Element-Binding Protein

PubMed Central

Prade, Elke; Tobiasch, Moritz; Hitkova, Ivana; Schäffer, Isabell; Lian, Fan; Xing, Xiangbin; Tänzer, Marc; Rauser, Sandra; Walch, Axel; Feith, Marcus; Post, Stefan; Röcken, Christoph; Schmid, Roland M.; Ebert, Matthias P.A.

2012-01-01

Bile acids are synthesized from cholesterol and are major risk factors for Barrett adenocarcinoma (BAC) of the esophagus. Caveolin-1 (Cav1), a scaffold protein of membrane caveolae, is transcriptionally regulated by cholesterol via sterol-responsive element-binding protein-1 (SREBP1). Cav1 protects squamous epithelia by controlling cell growth and stabilizing cell junctions and matrix adhesion. Cav1 is frequently down-regulated in human cancers; however, the molecular mechanisms that lead to this event are unknown. We show that the basal layer of the nonneoplastic human esophageal squamous epithelium expressed Cav1 mainly at intercellular junctions. In contrast, Cav1 was lost in 95% of tissue specimens from BAC patients (n = 100). A strong cytoplasmic expression of Cav1 correlated with poor survival in a small subgroup (n = 5) of BAC patients, and stable expression of an oncogenic Cav1 variant (Cav1-P132L) in the human BAC cell line OE19 promoted proliferation. Cav1 was also detectable in immortalized human squamous epithelial, Barrett esophagus (CPC), and squamous cell carcinoma cells (OE21), but was low in BAC cell lines (OE19, OE33). Mechanistically, bile acids down-regulated Cav1 expression by inhibition of the proteolytic cleavage of 125-kDa pre-SREBP1 from the endoplasmic reticulum/Golgi apparatus and nuclear translocation of active 68-kDa SREBP1. This block in SREBP1's posttranslational processing impaired transcriptional activation of SREBP1 response elements in the proximal human Cav1 promoter. Cav1 was also down-regulated in esophagi from C57BL/6 mice on a diet enriched with 1% (wt/wt) chenodeoxycholic acid. Mice deficient for Cav1 or the nuclear bile acid receptor farnesoid X receptor showed hyperplasia and hyperkeratosis of the basal cell layer of esophageal epithelia, respectively. These data indicate that bile acid-mediated down-regulation of Cav1 marks early changes in the squamous epithelium, which may contribute to onset of Barrett esophagus metaplasia and progression to BAC. PMID:22474125

3-Deazaneplanocin A suppresses aggressive phenotype-related gene expression in an oral squamous cell carcinoma cell line

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hatta, Mitsutoki, E-mail: hatta@college.fdcnet.ac.jp; Naganuma, Kaori; Kato, Kenichi

In tumor tissues, alterations of gene expression caused by aberrant epigenetic modifications confer phenotypic diversity on malignant cells. Although 3-deazaneplanocin A (DZNep) has been shown to reactivate tumor suppressor genes in several cancer cells, it remains unclear whether DZNep attenuates the malignant phenotypes of oral squamous cell carcinoma (OSCC) cells. In this study, we investigated the effect of DZNep on the expression of genes related to aggressive phenotypes, such as epithelial–mesenchymal transition, in OSCC cells. We found that DZNep reduced the cellular levels of polycomb group proteins (EZH2, SUZ12, BMI1, and RING1A) and the associated trimethylation of Lys27 on histonemore » H3 and monoubiquitination of Lys119 on histone H2A in the poorly differentiated OSCC cell line SAS. Immunocytochemical staining demonstrated that DZNep induced the reorganization of filamentous actin and the membrane localization of E-cadherin associated with cell–cell adhesions. We also found an inhibitory effect of DZNep on cell proliferation using a WST assay. Finally, quantitative RT-PCR analysis demonstrated that genes involved in the aggressive phenotypes (TWIST2, EGFR, ACTA2, TGFB1, WNT5B, and APLIN) were down-regulated, whereas epithelial phenotype genes (CDH1, CLDN4, IVL, and TGM1) were up-regulated in SAS cells treated with DZNep. Collectively, our findings suggest that DZNep reverses the aggressive characteristics of OSCC cells through the dynamic regulation of epithelial plasticity via the reprogramming of gene expression patterns. - Highlights: • DZNep reduced PcG proteins and associated histone modifications in OSCC cells. • DZNep enhanced cell–cell adhesion indicative of epithelial phenotype in OSCC cells. • DZNep suppressed the aggressive phenotype-related gene expression in OSCC cells. • DZNep activated the gene expression of epithelial markers in OSCC cells.« less

Isolation and Characterization of Circulating Tumor Cells in Squamous Cell Carcinoma of the Lung Using a Non-EpCAM-Based Capture Method.

PubMed

Bozzetti, Cecilia; Quaini, Federico; Squadrilli, Anna; Tiseo, Marcello; Frati, Caterina; Lagrasta, Costanza; Azzoni, Cinzia; Bottarelli, Lorena; Galetti, Maricla; Alama, Angela; Belletti, Silvana; Gatti, Rita; Passaro, Antonio; Gradilone, Angela; Cavazzoni, Andrea; Alfieri, Roberta; Petronini, Pier Giorgio; Bonelli, Mara; Falco, Angela; Carubbi, Cecilia; Pedrazzi, Giuseppe; Nizzoli, Rita; Naldi, Nadia; Pinto, Carmine; Ardizzoni, Andrea

2015-01-01

The exclusion of circulating tumor cells (CTCs) that have lost epithelial antigens during the epithelial-to-mesenchymal transition (EMT) process by using Epithelial Cell Adhesion Molecule (EpCAM) based capture methods is still a matter of debate. In this study, cells obtained after depletion procedure from blood samples of squamous cell lung cancer (SQCLC) patients were identified based on morphology and characterized with the combination of FISH assessment and immunophenotypic profile. Five mL blood samples, collected from 55 advanced SQCLC patients, were analyzed by a non-EpCAM-based capture method. After depletion of leukocytes and erythroid cells, the negative fraction was characterized by both FISH using a fibroblast growth factor receptor 1 (FGFR1) probe and by immunocytochemistry. Thirty healthy donors were also tested. Based on morphology (nuclear dimension ≥10 μm, shape and hypercromatic aspect) suspicious circulating cells clearly distinguishable from contaminant leukocytes were observed in 49/55 (89%) SQCLC patients. Thirty-four of the 44 (77%) samples evaluable for FGFR1 FISH showed ≥ 6 FGFR1 gene copy number on average per cell. Vimentin expression involved 43% (18/42) of pooled circulating SQCLC cells, whereas only 29% (14/48) were EpCAM positive. Confocal microscopy confirmed the localization of FGFR1 probe in suspicious circulating cells. Suspicious circulating elements were also observed in healthy donors and did not show any epithelial associated antigens. A significantly lower number of suspicious circulating cells in healthy donors compared to SQCLC patients was found. Among the heterogeneous cell population isolated by depletion procedure, the coexistence of cells with epithelial and/or mesenchymal phenotype suggests that EMT may participate to transendothelial invasion and migration of tumor cells in advanced SQCLC. The finding of cells with neither EpCAM or EMT phenotype, retrieved after non-EpCAM-based systems, underlines the presence of suspicious elements in the blood of both SQCLC patients and healthy donors. Further phenotyping and molecular analyses are necessary to fully characterize these circulating elements.

Paclitaxel Albumin-Stabilized Nanoparticle Formulation and Bevacizumab in Treating Patients With Stage IV Melanoma That Cannot Be Removed by Surgery or Gynecological Cancers

ClinicalTrials.gov

2018-02-05

Cervical Adenosarcoma; Cervical Adenosquamous Carcinoma; Cervical Carcinosarcoma; Cervical Squamous Cell Carcinoma, Not Otherwise Specified; Endometrial Clear Cell Adenocarcinoma; Endometrial Endometrioid Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Mucinous Adenocarcinoma; Endometrial Squamous Cell Carcinoma; Endometrial Transitional Cell Carcinoma; Endometrial Undifferentiated Carcinoma; Fallopian Tube Adenocarcinoma; Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Epithelial Tumor; Malignant Peritoneal Neoplasm; Ovarian Carcinosarcoma; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Melanoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage IV Skin Melanoma; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma; Uterine Corpus Carcinosarcoma

Trefoil Factor 3 as a Novel Biomarker to Distinguish Between Adenocarcinoma and Squamous Cell Carcinoma

PubMed Central

Wang, Xiao-Nan; Wang, Shu-Jing; Pandey, Vijay; Chen, Ping; Li, Qing; Wu, Zheng-Sheng; Wu, Qiang; Lobie, Peter E.

2015-01-01

Abstract In carcinoma, such as of the lung, the histological subtype is important to select an appropriate therapeutic strategy for patients. However, carcinomas with poor differentiation cannot always be distinguished on the basis of morphology alone nor on clinical findings. Hence, delineation of poorly differentiated adenocarcinoma and squamous cell carcinoma, the 2 most common epithelial-origin carcinomas, is pivotal for selection of optimum therapy. Herein, we explored the potential utility of trefoil factor 3 (TFF3) as a biomarker for primary lung adenocarcinoma and extrapulmonary adenocarcinomas derived from different organs. We observed that 90.9% of lung adenocarcinomas were TFF3-positive, whereas no expression of TFF3 was observed in squamous cell carcinomas. The subtype of lung carcinoma was confirmed by four established biomarkers, cytokeratin 7 and thyroid transcription factor 1 for adenocarcinoma and P63 and cytokeratin 5/6 for squamous cell carcinoma. Furthermore, expression of TFF3 mRNA was observed by quantitative PCR in all of 11 human lung adenocarcinoma cell lines and highly correlated with markers of the adenocarcinomatous lineage. In contrast, little or no expression of TFF3 was observed in 4 lung squamous cell carcinoma cell lines. By use of forced expression, or siRNA-mediated depletion of TFF3, we determined that TFF3 appeared to maintain rather than promote glandular differentiation of lung carcinoma cells. In addition, TFF3 expression was also determined in adenocarcinomas from colorectum, stomach, cervix, esophagus, and larynx. Among all these extrapulmonary carcinomas, 93.7% of adenocarcinomas exhibited TFF3 positivity, whereas only 2.9% of squamous cell carcinomas were TFF3-positive. Totally, 92.9% of both pulmonary and extrapulmonary adenocarcinomas exhibited TFF3 positivity, whereas only 1.5% of squamous cell carcinomas were TFF3-positive. In conclusion, TFF3 is preferentially expressed in adenocarcinoma and may function as an additional biomarker for distinguishing adenocarcinoma from squamous cell carcinoma. PMID:25997063

Fractionated irradiation-induced EMT-like phenotype conferred radioresistance in esophageal squamous cell carcinoma

PubMed Central

Zhang, Hongfang; Luo, Honglei; Jiang, Zhenzhen; Yue, Jing; Hou, Qiang; Xie, Ruifei; Wu, Shixiu

2016-01-01

The efficacy of radiotherapy, one major treatment modality for esophageal squamous cell carcinoma (ESCC) is severely attenuated by radioresistance. Epithelial-to-mesenchymal transition (EMT) is a cellular process that determines therapy response and tumor progression. However, whether EMT is induced by ionizing radiation and involved in tumor radioresistance has been less studied in ESCC. Using multiple fractionated irradiation, the radioresistant esophageal squamous cancer cell line KYSE-150R had been established from its parental cell line KYSE-150. We found KYSE-150R displayed a significant EMT phenotype with an elongated spindle shape and down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker N-cadherin in comparison with KYSE-150. Furthermore, KYSE-150R also possessed some stemness-like properties characterized by density-dependent growth promotion and strong capability for sphere formation and tumorigenesis in NOD-SCID mice. Mechanical studies have revealed that WISP1, a secreted matricellular protein, is highly expressed in KYSE-150R and mediates EMT-associated radioresistance both in ESCC cells and in xenograft tumor models. Moreover, WISP1 has been demonstrated to be closely associated with the EMT phenotype observed in ESCC patients and to be an independent prognosis factor of ESCC patients treated with radiotherapy. Our study highlighted WISP1 as an attractive target to reverse EMT-associated radioresistance in ESCC and can be used as an independent prognostic factor of patients treated with radiotherapy. PMID:27125498

Two rare entities in the same palate lesion: hyalinizing-type clear cell carcinoma and necrotizing sialometaplasia.

PubMed

Arpaci, Rabia Bozdoğan; Kara, Tuba; Porgali, Canan; Serinsoz, Ebru; Polat, Ayse; Vayisoglu, Yusuf; Ozcan, Cengiz

2014-05-01

Hyalinizing clear cell carcinoma is a low-grade malignant epithelial neoplasm of the salivary glands. The tumor has epithelial cells and lacks myoepithelial cells. Necrotizing sialometaplasia is a benign, self-limiting lesion of the salivary glands. The clinical and histologic features mimic those of mucoepidermoid carcinoma or squamous cell carcinoma. The importance of these entities are the rarity of both of them and their potential to be misdiagnosed as other lesions. Pathologists and clinicians should be aware of these entities to prevent misdiagnosis. This is the first clinical report of 2 rare and consecutive different entities of the same location on the hard palate to our knowledge.

MDA-9/Syntenin regulates differentiation and angiogenesis programs in head and neck squamous cell carcinoma.

PubMed

Oyesanya, Regina A; Bhatia, Shilpa; Menezes, Mitchell E; Dumur, Catherine I; Singh, Karan P; Bae, Sejong; Troyer, Dean A; Wells, Robert B; Sauter, Edward R; Sidransky, David; Fisher, Paul B; Semmes, Oliver J; Dasgupta, Santanu

2014-01-01

Little is known about the molecular pathways regulating poor differentiation and invasion of head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to determine the role of MDA-9/Syntenin, a metastasis associated molecule in HNSCC tumorigenesis. Elevated MDA-9/Syntenin expression was evident in 67% (54/81) primary HNSCC tumors (p=0.001-0.002) and 69% (9/13) pre-neoplastic tissues (p=0.02-0.03). MDA-9/Syntenin overexpression was associated with the stage (p=0.001), grade (p=0.001) and lymph node metastasis (p=0.0001). Silencing of MDA-9/Syntenin in 3 poorly differentiated HNSCC cell lines induced squamous epithelial cell differentiation, disrupted angiogenesis and reduced tumor growth in vitro and in vivo. We confirmed SPRR1B and VEGFR1 as the key molecular targets of MDA-9/Syntenin on influencing HNSCC differentiation and angiogenesis respectively. MDA-9/Syntenin disrupted SPRR1B expression interacting through its PDZ1 domain and altered VEGFR1 expression in vitro and in vivo. VEGFR1 co-localized with MDA-9/Syntenin in HNSCC cell lines and primary tumor. Downregulation of growth regulatory molecules CyclinD1, CDK4, STAT3, PI3K and CTNNB1 was also evident in the MDA-9/Syntenin depleted cells, which was reversed following over-expression of MDA-9/Syntenin in immortalized oral epithelial cells. Our results suggest that early induction of MDA-9/Syntenin expression influences HNSCC progression and should be further evaluated for potential biomarker development.

MDA-9/Syntenin regulates differentiation and angiogenesis programs in head and neck squamous cell carcinoma

PubMed Central

Dumur, Catherine I.; Singh, Karan P; Bae, Sejong; Troyer, Dean A.; Wells, Robert B.; Sauter, Edward R.; Sidransky, David; Fisher, Paul B.; Semmes, Oliver J.; Dasgupta, Santanu

2014-01-01

Little is known about the molecular pathways regulating poor differentiation and invasion of head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to determine the role of MDA-9/Syntenin, a metastasis associated molecule in HNSCC tumorigenesis. Elevated MDA-9/Syntenin expression was evident in 67% (54/81) primary HNSCC tumors (p=0.001-0.002) and 69% (9/13) pre-neoplastic tissues (p=0.02-0.03). MDA-9/Syntenin overexpression was associated with the stage (p=0.001), grade (p=0.001) and lymph node metastasis (p=0.0001). Silencing of MDA-9/Syntenin in 3 poorly differentiated HNSCC cell lines induced squamous epithelial cell differentiation, disrupted angiogenesis and reduced tumor growth in vitro and in vivo. We confirmed SPRR1B and VEGFR1 as the key molecular targets of MDA-9/Syntenin on influencing HNSCC differentiation and angiogenesis respectively. MDA-9/Syntenin disrupted SPRR1B expression interacting through its PDZ1 domain and altered VEGFR1 expression in vitro and in vivo. VEGFR1 co-localized with MDA-9/Syntenin in HNSCC cell lines and primary tumor. Downregulation of growth regulatory molecules CyclinD1, CDK4, STAT3, PI3K and CTNNB1 was also evident in the MDA-9/Syntenin depleted cells, which was reversed following over-expression of MDA-9/Syntenin in immortalized oral epithelial cells. Our results suggest that early induction of MDA-9/Syntenin expression influences HNSCC progression and should be further evaluated for potential biomarker development. PMID:25593999

Atypical glandular cells in cervical smears: histological correlation and a suggested plan of management based on age of the patient in a low-resource setting.

PubMed

Adhya, A K; Mahesha, V; Srinivasan, R; Nijhawan, R; Rajwanshi, A; Suri, V; Dhaliwal, L K

2009-12-01

To perform an audit of all smears reported as atypical glandular cells (AGC) using the Bethesda system (TBS) 2001. A total of 18 376 cervical smears were screened from January 2005 to June 2007, of which 65 cases were reported as AGC. Follow-up histology was available in 31 cases (47.7%), in whom a detailed cytological/histological correlation was carried out. AGC constituted 0.35% of all Pap smears. Follow-up histology was normal or benign in 20 cases, whereas a squamous or glandular abnormality was seen in 11 cases. Squamous abnormalities included one case each of cervical intraepithelial neoplasia (CIN)1, CIN2 and CIN3 and five cases of squamous cell carcinoma. All glandular epithelial abnormalities were endometrial in origin and included two endometrial adenocarcinomas and one uterine serous carcinoma. Neither in situ nor invasive adenocarcinoma of the endocervix was observed. Review of smears and reclassification as AGC, not otherwise specified and favour neoplasia revealed a higher proportion of abnormality in the latter group, reaffirming the utility of subtyping. The median age of women with AGC was 41 years. The outcome was analysed with respect to the median age. In women aged equal or more than 40 years, AGC reflected a high-grade squamous or glandular epithelial abnormality in 50% of cases compared with none in those less than 40 years old (P = 0.010). The age of the woman as well as the subtype of atypical glandular cells influences outcome and hence must be taken into consideration while formulating an acceptable management strategy in these women in a low-resource setting.

The administration of multipotent stromal cells at precancerous stage precludes tumor growth and epithelial dedifferentiation of oral squamous cell carcinoma.

PubMed

Bruna, Flavia; Arango-Rodríguez, Martha; Plaza, Anita; Espinoza, Iris; Conget, Paulette

2017-01-01

Multipotent stromal cells (MSCs) are envisioned as a powerful therapeutic tool. As they home into tumors, secrete trophic and vasculogenic factors, and suppress immune response their role in carcinogenesis is a matter of controversy. Worldwide oral squamous cell carcinoma (OSCC) is the fifth most common epithelial cancer. Our aim was to determine whether MSC administration at precancerous stage modifies the natural progression of OSCC. OSCC was induced in Syrian hamsters by topical application of DMBA in the buccal pouch. At papilloma stage, the vehicle or 3×10 6 allogenic bone marrow-derived MSCs were locally administered. Four weeks later, the lesions were studied according to: volume, stratification (histology), proliferation (Ki-67), apoptosis (Caspase 3 cleaved), vasculature (ASMA), inflammation (Leukocyte infiltrate), differentiation (CK1 and CK4) and gene expression profile (mRNA). Tumors found in individuals that received MSCs were smaller than those presented in the vehicle group (87±80 versus 54±62mm 3 , p<0.05). The rate of proliferation was two times lower and the apoptosis was 2.5 times higher in lesions treated with MSCs than in untreated ones. While the laters presented dedifferentiated cells, the former maintained differentiated cells (cytokeratin and gene expression profile similar to normal tissue). Thus, MSC administration at papilloma stage precludes tumor growth and epithelial dedifferentiation of OSCC. Copyright © 2016. Published by Elsevier B.V.

Squamous epithelial proliferation induced by walleye dermal sarcoma retrovirus cyclin in transgenic mice

PubMed Central

Lairmore, Michael D.; Stanley, James R.; Weber, Stacy A.; Holzschu, Donald L.

2000-01-01

Walleye dermal sarcoma (WDS) is a common disease of walleye fish in the United States and Canada. These proliferative lesions are present autumn through winter and regress in the spring. Walleye dermal sarcoma virus (WDSV), a retrovirus distantly related to other members of the family Retroviridae, has been etiologically linked to the development of WDS. We have reported that the D-cyclin homologue [retroviral (rv) cyclin] encoded by WDSV rescues yeast conditionally deficient for cyclin synthesis from growth arrest and that WDSV-cyclin mRNA is present in developing tumors. These data strongly suggest that the rv-cyclin plays a central role in the development of WDS. To test the ability of the WDSV rv-cyclin to induce cell proliferation, we have generated transgenic mice expressing the rv-cyclin in squamous epithelia from the bovine keratin-5 promoter. The transgenic animals were smaller than littermates, had reduced numbers of hair follicles, and transgenic females did not lactate properly. Following injury the transgenic animals developed severe squamous epithelial hyperplasia and dysplasia with ultrastructural characteristics of neoplastic squamous epithelium. Immunocytochemistry studies demonstrated that the hyperplastic epithelium stained positive for cytokeratin and were abnormally differentiated. Furthermore, the rv-cyclin protein was detected in the thickened basal cell layers of the proliferating lesions. These data are the first to indicate that the highly divergent WDSV rv-cyclin is a very potent stimulator of eukaryotic cell proliferation and to demonstrate the potential of a cyclin homologue encoded by a retrovirus to induce hyperplastic skin lesions. PMID:10811912

A chemically defined culture medium containing Rho kinase inhibitor Y-27632 for the fabrication of stratified squamous epithelial cell grafts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aslanova, Afag; Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666; Takagi, Ryo

With the development of a culture method for stratified squamous epithelial cells, tissue-engineered epithelial cell sheets have been successfully applied as clinical cell grafts. However, the implementation of these cell sheets without the use of any animal-derived materials is highly desirable. In this study, Rho-associated protein kinase inhibitor Y-27632 was used to develop a chemically defined culture medium for the fabrication of stratified epithelial cell grafts consisting of human epidermal and oral keratinocytes, and the proliferation activity, cell morphology, and gene expressions of the keratinocytes were analyzed. The results of a colorimetric assay indicated that Y-27632 significantly promoted the proliferationmore » of the keratinocytes in culture media both with and without fetal bovine serum (FBS), although there were no indications of Y-27632 efficacy on cell morphology and stratification of the keratinocytes in culture medium without any animal-derived materials. The results of quantitative RT-PCR revealed that gene expressions correlated with cell adhesion, cell–cell junction, proliferation markers, and stem/progenitor markers in cultured keratinocytes were not strongly affected by the addition of Y-27632 to the culture medium. Moreover, gene expressions of differentiation markers in stratified keratinocytes cultured in medium without FBS were nearly identical to those of keratinocytes co-cultured with 3T3 feeder cells. Interestingly, the expressions of differentiation markers in cultured stratified keratinocytes were suppressed by FBS, whereas they were reconstructed by either co-culture of a 3T3 feeder layer or addition of Y-27632 into the culture medium containing FBS. These findings indicate that Y-27632 is a useful supplement for the development of a chemically defined culture medium for fabrication of stratified epithelial cell grafts for clinical applications for the purpose of developing the culture medium with a lower risk of pathogen transmission that might arise from animal-derived materials. - Highlights: • Y-27632 promotes the proliferation of human keratinocytes. • Human keratinocytes with Y-27632 can stratify similarly to traditional method. • Y-27632 is useful for culture medium of human keratinocyte in clinical setting.« less

Epithelial-type and neural-type cadherin expression in malignant noncarcinomatous neoplasms with epithelioid features that involve the soft tissues.

PubMed

Laskin, William B; Miettinen, Markku

2002-04-01

Transmembrane adhesion molecules, epithelial-type cadherin (ECAD) and neural-type cadherin (NCAD), help in regulating transformations between epithelial and mesenchymal cells in the developing embryo and in maintaining the epithelioid phenotype. Consequently, the presence of epithelioid cells in certain malignant noncarcinomatous neoplasms raises speculation that the expression of ECAD and NCAD in these neoplasms may have diagnostic significance. To investigate the utility of ECAD and NCAD immunoexpression in distinguishing malignant (noncarcinomatous) neoplasms with epithelioid features that involve the soft tissues. Membranous immunoreactivity of anti-ECAD and anti-NCAD was evaluated on archived cases selected from the files of the Armed Forces Institute of Pathology. Epithelial-type cadherin was found in biphasic synovial sarcoma (35 of 35 cases), malignant melanoma (13/21), monophasic fibrous synovial sarcoma (13/26), clear cell sarcoma (4/9), poorly differentiated synovial sarcoma (3/13), diffuse mesothelioma (4/20), malignant epithelioid peripheral nerve sheath tumor (1/6), and epithelioid sarcoma (5/62). Neural-type cadherin was observed in chordoma (11/11), biphasic synovial sarcoma (30/35), diffuse mesothelioma (14/20), malignant melanoma (14/25), epithelioid sarcoma (24/63), epithelioid angiosarcoma (1/4), poorly differentiated synovial sarcoma (2/13), clear cell sarcoma (1/10), and monophasic fibrous synovial sarcoma (1/26). Eighteen cases of primary cutaneous squamous cell carcinomas all tested positive for ECAD, whereas NCAD was focally observed in 5 cases. No expression of either molecule was observed in cases of epithelioid hemangioendothelioma (n = 9), alveolar soft part sarcoma (n = 8), and extraskeletal myxoid chondrosarcoma (n = 7). Epithelial-type and neural-type cadherins are found in a variety of noncarcinomatous neoplasms with epithelioid features that involve the soft tissues and can be utilized, in association with other immunomarkers, in distinguishing chordoma (100% NCAD) from extraskeletal myxoid chondrosarcoma and conventional chondrosarcoma of bone (0% NCAD), squamous cell carcinoma (100% ECAD) from epithelioid sarcoma (8% ECAD), and biphasic synovial sarcoma (100% ECAD) from diffuse mesothelioma (20% ECAD).

Nasal lavage cellularity, grain dust, and airflow obstruction.

PubMed

Blaski, C A; Watt, J L; Quinn, T J; Thorne, P S; Schwartz, D A

1996-04-01

To evaluate the clinical utility of nasal lavage (NL), we performed post-work shift NL on 172 grain workers and 78 postal worker control subjects. The grain worker group included a higher percentage of current smokers (25.7% vs 16.7%) and a lower percentage of former smokers (21.15% vs 35.9%) compared with the postal workers. The control subjects included more female workers and were slightly older than the grain workers. Compared with the postal workers, the grain workers were exposed to significantly greater concentrations of total dust (0.1 +/- 0.0 vs 6.8 +/- 1.4 mg/m3; mean +/- SEM) and total endotoxin (4.3 +/- 0.8 vs 2,372.4 +/- 653.8 endotoxin units/m3). NL from gain workers showed a higher concentration of total cells (55,000 +/- 14,000 vs 25,000 +/- 5,000 cells per milliliter; p=0.03), a higher concentration of squamous epithelial cells (17,029.0 +/- 4,177 .0 vs 7,103.7 +/- 1,479.8 cells per milliliter; p=0.03), and a higher concentration of neutrophils (40,058.0 +/- 12,803.2 vs 17,891.0 +/- 3,822.3 cells per milliliter; p=0.10) compared with postal workers. Importantly, these differences in NL cellularity between grain workers and postal workers were observed within the three strata of smokers. To further assess the importance of total cells, squamous epithelial cells, and neutrophils in the NL fluid of grain workers, we investigated the relationship between these cell concentrations and (1) measures of dust and endotoxin exposure during the work shift. (2) spirometric measures of airflow obtained immediately before the NL, and (3) work-related respiratory symptoms. The concentration of total cells, the concentration of squamous epithelial cells, or the concentration of neutrophils in the NL was not associated with ambient levels of dust or endotoxin, with baseline or cross-shift changes in lung function, or with work-related respiratory symptoms. These findings suggest that increased NL cellularity may be seen in workers exposed to high dust levels. However, the NL cellularity does not appear to be associated with ambient concentrations of dusts or endotoxins, with signs of airflow obstruction, or with work-related respiratory symptoms.

Infection of Hysterectomized Mice with Chlamydia muridarum and Chlamydia trachomatis

PubMed Central

Yang, Chunfu; Whitmire, William M.; Sturdevant, Gail L.; Bock, Kevin; Moore, Ian

2017-01-01

ABSTRACT We studied infection and immunity of hysterectomized mice infected with Chlamydia muridarum and Chlamydia trachomatis to determine if there were differences between these species in their ability to infect vaginal squamous epithelial cells in vivo independently of proximal upper genital tract tissues. We found that C. muridarum readily colonized and infected vaginal squamous epithelial cells, whereas C. trachomatis did not. Primary infection of the vaginal epithelium with C. muridarum produced infections of a duration longer than that reported for normal mice. Infection resulted in an inflammatory response in the vagina characterized by neutrophils and infiltrating submucosal plasma cells consisting primarily of T cells. Despite the delayed clearance, rechallenged C. muridarum-infected mice were highly immune. Mice vaginally infected with C. muridarum produced serum and vaginal wash antibodies and an antigen-specific gamma interferon-dominated Th1-biased T cell response. By comparison, mice vaginally infected with C. trachomatis exhibited transient low-burden infections, produced no detectable tissue inflammatory response, and failed to seroconvert. We discuss how these marked differences in the biology of vaginal infection between these otherwise genetically similar species are possibly linked to pathogen-specific virulence genes and how they may influence pathology and immunity in the upper genital tract. PMID:28461392

Analysis of the olfactory mucosa in chronic rhinosinusitis

PubMed Central

Yee, Karen K.; Pribitkin, Edmund A.; Cowart, Beverly J.; Rosen, David; Feng, Pu; Rawson, Nancy E

2009-01-01

The impact of chronic rhinosinusitis (CRS) on the olfactory mucosa (OM) is dramatic. Cellular profiles and epithelial integrity in OM biopsies were evaluated using histological and immunohistochemical methods to define a strategy for future histological studies of CRS. We have examined nasal biopsies of 54 CRS patients (18 - 63 years old) and have defined specific histopathological patterns of the OM: normal pseudostratified, goblet cell hyperplasia, squamous metaplasia and erosion. Goblet cell hyperplasia was most similar to a normal pseudostratified OM pattern but with goblet cells intermixed in the apical layers. Squamous metaplasia exhibited an absence of olfactory supporting cells and had olfactory sensory neurons that were morphologically abnormal. It is unknown if these neurons would be functional in this type of tissue transformation. The pattern of erosion exhibited a severe loss of epithelial layers and a higher prevalence of infiltrating inflammatory cells within the olfactory epithelium when compared to the other OM patterns. Although it is not known if the OM remodeling patterns we have noted correspond to specific stages or distinct pathways of the disease, the template proposed here can be used in further studies to understand how the histopathological progression of CRS relates to olfactory loss and the response to treatment. PMID:19686198

The leaves of Diospyros kaki exert beneficial effects on a benzalkonium chloride-induced murine dry eye model.

PubMed

Kim, Kyung-A; Hyun, Lee Chung; Jung, Sang Hoon; Yang, Sung Jae

2016-01-01

In this study, the beneficial effects of the oral administration of ethanol extract of Diospyros kaki (EEDK) were tested on a mouse dry eye model induced by benzalkonium chloride (BAC). A solution of 0.2% BAC was administered topically to mouse eyes for 14 days, twice daily, to induce dry eye. Various concentrations of EEDK were administrated daily by oral gavage for 14 days after BAC treatment. Preservative-free eye drops were instilled in the positive-control group. The tear secretion volume (Schirmer's test), tear break-up time (BUT), and fluorescein score were measured on the ocular surface. BAC-induced corneal damage was tested with hematoxylin-eosin staining. Moreover, apoptotic cell death in the corneal epithelial layer was investigated with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. The protein expression level of interleukin-1alpha (IL-1α), IL-1β, IL-6, tumor necrosis factor- alpha (TNF-α), and monocyte chemotactic protein-1 (MCP-1) was determined with western blot analysis. Furthermore, squamous metaplasia in the corneal epithelial layer was detected with immunofluorescent staining for cytokeratine-10. The cellular proliferation in the cornea was examined with immunohistochemical staining for Ki-67. EEDK treatment resulted in prolonged BUT, decreased fluorescein score, increased tear volume, and smoother epithelial cells compared with BAC treatment alone in the cornea. Moreover, EEDK treatment inhibited the inflammatory response and corneal epithelial cell death in a BAC-induced murine dry eye model, and changes in squamous cells were inhibited. Proliferative activity in the corneal epithelium cells was improved with EEDK. EEDK could be a potential therapeutic agent in the clinical treatment of dry eye.

Mucoepidermoid carcinoma in a salivary duct cyst of the parotid gland. Contribution to the development of tumours in salivary gland cysts.

PubMed

Seifert, G

1996-12-01

Concerning the hypothesis that distinct types of salivary gland cysts may be the starting point of a salivary gland tumour, a histological examination of 1,661 salivary gland cysts was performed in order to analyse the cell types and their proliferative activity. Epithelial alterations were found especially in salivary duct cysts of parotid gland and in mucous retention cysts of minor salivary glands. Characteristic cellular changes were epithelial metaplasias (goblet cells, clear cells, squamous cells) and focal epithelial proliferations with plump or papillary plaques projecting into the cyst lumen. Only in one case had a mucoepidermoid carcinoma developed in the wall of a parotid duct cyst. The epithelial metaplasia and focal proliferative activity in salivary duct cysts is comparable to similar alterations in odontogenic cysts as possible early manifestation of a tumour, especially of an ameloblastoma or mucoepidermoid carcinoma. The differential diagnosis of salivary duct cysts must take primarily cystadenomas and cystic mucoepidermoid carcinomas of well-differentiated type into account.

Immunohistochemical Evaluation of Glucose Transporter Type 1 in Epithelial Dysplasia and Oral Squamous Cell Carcinoma.

PubMed

Pereira, Karuza Maria Alves; Feitosa, Sthefane Gomes; Lima, Ana Thayssa Tomaz; Luna, Ealber Carvalho Macedo; Cavalcante, Roberta Barroso; de Lima, Kenio Costa; Chaves, Filipe Nobre; Costa, Fábio Wildson Gurgel

2016-01-01

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity and some of these have been documented in association or preceded by oral epithelial dysplasia (OED). Aggressive cancers with fast growth have demonstrated overexpression of some glucose transporters (GLUTs). Thus, the aim of this study was to analyze the immunohistochemical expression of the glucose transporter, GLUT-1, in OEDs and OSCCs, seeking to better elucidate the biological behavior of neoplasias. Fifteen cases were selected this research of both lesions. Five areas were analyzed from each case by counting the percentage of positive cells at 400x magnification. Immunoreactivity of GLUT-1 was observed in 100% of the samples ranging from 54.2% to 86.2% for the OSCC and 73.9% to 97.4% for the OED. Statistical test revealed that there was greater overexpression of GLUT-1 in OED than the OSCC (p=0.01). It is believed the high expression of GLUT-1 may reflect the involvement of GLUT-1 in early stages of oral carcinogenesis.

Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma.

PubMed

Natsuizaka, Mitsuteru; Whelan, Kelly A; Kagawa, Shingo; Tanaka, Koji; Giroux, Veronique; Chandramouleeswaran, Prasanna M; Long, Apple; Sahu, Varun; Darling, Douglas S; Que, Jianwen; Yang, Yizeng; Katz, Jonathan P; Wileyto, E Paul; Basu, Devraj; Kita, Yoshiaki; Natsugoe, Shoji; Naganuma, Seiji; Klein-Szanto, Andres J; Diehl, J Alan; Bass, Adam J; Wong, Kwok-Kin; Rustgi, Anil K; Nakagawa, Hiroshi

2017-11-24

Notch1 transactivates Notch3 to drive terminal differentiation in stratified squamous epithelia. Notch1 and other Notch receptor paralogs cooperate to act as a tumor suppressor in squamous cell carcinomas (SCCs). However, Notch1 can be stochastically activated to promote carcinogenesis in murine models of SCC. Activated form of Notch1 promotes xenograft tumor growth when expressed ectopically. Here, we demonstrate that Notch1 activation and epithelial-mesenchymal transition (EMT) are coupled to promote SCC tumor initiation in concert with transforming growth factor (TGF)-β present in the tumor microenvironment. We find that TGFβ activates the transcription factor ZEB1 to repress Notch3, thereby limiting terminal differentiation. Concurrently, TGFβ drives Notch1-mediated EMT to generate tumor initiating cells characterized by high CD44 expression. Moreover, Notch1 is activated in a small subset of SCC cells at the invasive tumor front and predicts for poor prognosis of esophageal SCC, shedding light upon the tumor promoting oncogenic aspect of Notch1 in SCC.

The impact of aging on epithelial barriers.

PubMed

Parrish, Alan R

2017-10-02

The epithelium has many critical roles in homeostasis, including an essential responsibility in establishing tissue barriers. In addition to the fundamental role in separating internal from external environment, epithelial barriers maintain nutrient, fluid, electrolyte and metabolic waste balance in multiple organs. While, by definition, barrier function is conserved, the structure of the epithelium varies across organs. For example, the skin barrier is a squamous layer of cells with distinct structural features, while the lung barrier is composed of a very thin single cell to minimize diffusion space. With the increased focus on age-dependent alterations in organ structure and function, there is an emerging interest in the impact of age on epithelial barriers. This review will focus on the impact of aging on the epithelial barrier of several organs, including the skin, lung, gastrointestinal tract and the kidney, at a structural and functional level.

[Clinicopathologic study of sinonasal teratocarcinosarcoma and its contrast with olfactory neuroblastoma].

PubMed

Li, Xue; Liu, Hong-Gang; Xie, Xin-Ji; Han, Yi-Ding; Li, Ming

2008-07-01

To study the clinicopathologic features, diagnosis and differential diagnosis of sinonasal teratocarcinosarcoma (SNTCS) and olfactory neuroblastoma (ONB), and to discuss the histogenesis and possible relationship between SNTCS and ONB. Seven cases of SNTCS and 34 cases of ONB were retrieved from the pathological archives together with one case each of malignant teratoma and immature embryonic tissue at 8 weeks were collected from Beijing Tongren Hospital. The clinicopathologic features were analyzed and immunohistochemical staining was performed on paraffin sections. Six of the SNTCS patients were male and one was female. The patients age range was 25 to 69 years (mean age 46). Four cases were initial presentation and three were recurrences. Histologically, the tumor shows multiple tissue components derived from three germ layers. There were mixture of teratoma-like tissue and carcinosarcoma. The components include fetal clear cell squamous epithelium derived from ectoderm. Glandular and tubular structures and ciliated columnar epithelium derived from endoderm. Fibroblasts, striated muscle, smooth muscle, cartilage and osteoid matrix derived from mesoderm. The carcinoma component exhibited mostly adenocarcinoma and squamous cell carcinoma, whereas the sarcoma component mostly exhibited rhabdomyosarcoma, leiomyosarcoma, and fibrosarcoma. In addition, carcinoid, and primitive mesenchymal tissue and the ONB component were also seen. The morphological characteristics of SNTCS comprised fetal clear cell squamous epithelium, carcinosarcoma and the ONB component. By immunohistochemistry, the epithelial component and cells with epithelium differentiation were positive for cytokeratin (pan) and EMA. The ONB component was positive for Syn, NSE, CD99, NF and CgA to different degrees. Neurofibril bundles were positive for S-100, and Flexner-Wintersteiner rosettes expressed cytokeratin (pan) and EMA. The spindle cells expressed vimentin, SMA, desmin, myosin and myoglobin. The primitive mesenchymal tissue expressed vimentin, and the mucoid materials and glycogen were positive for PAS. GFAP was negative in all cases. The 34 cases of ONB, included 18 men and 16 women, the age ranged from 12 to 72 years (mean 42.8 years). Microscopically, the tumor shows epithelial nests, net of angioma-like fibrous connective tissues, small round and spindle cells, glandular, squamous-like cells, and cells of rhabdomyoblastic differentiation, Homer-Wright and Flexner rosette, bundles of neurofibrils, etc. NSE and CgA were expressed in small cells. S-100 protein was positive in the areas of bunches of neurofibril. Cytokeratin (pan) was positive in epithelial cells. Myoglobin was positive in the cells of rhabdomyoblastic differentiation. The single case of immature malignant teratoma exhibited primitive nerve tissue, but fetal clear cell squamous epithelium was not found. In the immature embryonic tissue, rudimentary organs were formed, with fetal clear cell squamous epithelium lining present on the nasal and oral cavities surface. SNTCS is a rare and aggressive malignant neoplasm. Most of ONB are low-grade malignant tumors. Morphological differences are the most important basis to make differentiate SNTCS from ONB. As SNTCS may demonstrate a multiplicity of structures and pleomorphism, inadequate sampling at biopsy, therefore, may lead to errors in diagnosis. No evidence show that SNTCS are derived from germ cells and sinonasal teratoid carcinosarcoma may be a more proper name. SNTCS probably arises from primitive totipotential cells of olfactory/sinonasal membrane, and the relationship between SNTCS and ONB needs further study.

YAP and TAZ in epithelial stem cells: A sensor for cell polarity, mechanical forces and tissue damage.

PubMed

Elbediwy, Ahmed; Vincent-Mistiaen, Zoé I; Thompson, Barry J

2016-07-01

The YAP/TAZ family of transcriptional co-activators drives cell proliferation in epithelial tissues and cancers. Yet, how YAP and TAZ are physiologically regulated remains unclear. Here we review recent reports that YAP and TAZ act primarily as sensors of epithelial cell polarity, being inhibited when cells differentiate an apical membrane domain, and being activated when cells contact the extracellular matrix via their basal membrane domain. Apical signalling occurs via the canonical Crumbs/CRB-Hippo/MST-Warts/LATS kinase cascade to phosphorylate and inhibit YAP/TAZ. Basal signalling occurs via Integrins and Src family kinases to phosphorylate and activate YAP/TAZ. Thus, YAP/TAZ is localised to the nucleus in basal stem/progenitor cells and cytoplasm in differentiated squamous cells or columnar cells. In addition, other signals such as mechanical forces, tissue damage and possibly receptor tyrosine kinases (RTKs) can influence MST-LATS or Src family kinase activity to modulate YAP/TAZ activity. © 2016 The Authors BioEssays Published by WILEY Periodicals, Inc.

Oral epithelial stem cells – implications in normal development and cancer metastasis

PubMed Central

Papagerakis, Silvana; Pannone, Giuseppe; Zheng, Li; About, Imad; Taqi, Nawar; Nguyen, Nghia P.T.; Matossian, Margarite; McAlpin, Blake; Santoro, Angela; McHugh, Jonathan; Prince, Mark E.; Papagerakis, Petros

2014-01-01

Oral mucosa is continuously exposed to environmental forces and has to be constantly renewed. Accordingly, the oral mucosa epithelium contains a large reservoir of epithelial stem cells necessary for tissue homeostasis. Despite considerable scientific advances in stem cell behavior in a number of tissues, fewer studies have been devoted to the stem cells in the oral epithelium. Most of oral mucosa stem cells studies are focused on identifying cancer stem cells (CSC) in oral squamous cell carcinomas (OSCCs) among other head and neck cancers. OSCCs are the most prevalent epithelial tumors of the head and neck region, marked by their aggressiveness and invasiveness. Due to their highly tumorigenic properties, it has been suggested that CSC may be the critical population of cancer cells in the development of OSCC metastasis. This review presents a brief overview of epithelium stem cells with implications in oral health, and the clinical implications of the CSC concept in OSCC metastatic dissemination. PMID:24803391

Immunohistochemical expression of matrix metalloproteinase-1, matrix metalloproteinase-2 and matrix metalloproteinase-9, myofibroblasts and Ki-67 in actinic cheilitis and lip squamous cell carcinoma.

PubMed

Bianco, Bianca C; Scotti, Fernanda M; Vieira, Daniella S C; Biz, Michelle T; Castro, Renata G; Modolo, Filipe

2015-10-01

Matrix metalloproteinases (MMPs), myofibroblasts (MFs) and epithelial proliferation have key roles in neoplastic progression. In this study immunoexpression of MMP-1, MMP-2 and MMP-9, presence of MFs and the epithelial proliferation index were investigated in actinic cheilitis (AC), lip squamous cell carcinoma (LSCC) and mucocele (MUC). Thirty cases of AC, thirty cases of LSCC and twenty cases of MUC were selected for immunohistochemical investigation of the proteins MMP-1, MMP-2, MMP-9, α-smooth muscle actin (α-SMA) and Ki-67. The MMP-1 expression in the epithelial component was higher in the AC than the MUC and LSCC. In the connective tissue, the expression was higher in the LSCC. MMP-2 showed lower epithelial and stromal immunostaining in the LSCC when compared to the AC and MUC. The epithelial staining for MMP-9 was higher in the AC when compared to the LSCC. However, in the connective tissue, the expression was lower in the AC compared to other lesions. The cell proliferation rate was increased in proportion to the severity of dysplasia in the AC, while in the LSCC it was higher in well-differentiated lesions compared to moderately differentiated. There were no statistically significant differences in number of MFs present in the lesions studied. The results suggest that MMPs could affect the biological behaviour of ACs and LSCCs inasmuch as they could participate in the development and progression from premalignant lesions to malignant lesions. © 2015 The Authors. International Journal of Experimental Pathology © 2015 International Journal of Experimental Pathology.

Deoxycholic acid promotes development of gastroesophageal reflux disease and Barrett's oesophagus by modulating integrin-αv trafficking.

PubMed

Prichard, David O; Byrne, Anne Marie; Murphy, James O; Reynolds, John V; O'Sullivan, Jacintha; Feighery, Ronan; Doyle, Brendan; Eldin, Osama Sharaf; Finn, Stephen P; Maguire, Aoife; Duff, Deirdre; Kelleher, Dermot P; Long, Aideen

2017-12-01

The fundamental mechanisms underlying erosive oesophagitis and subsequent development of Barrett's oesophagus (BO) are poorly understood. Here, we investigated the contribution of specific components of the gastric refluxate on adhesion molecules involved in epithelial barrier maintenance. Cell line models of squamous epithelium (HET-1A) and BO (QH) were used to examine the effects of bile acids on cell adhesion to extracellular matrix proteins (Collagen, laminin, vitronectin, fibronectin) and expression of integrin ligands (α 3 , α 4, α 5 , α 6 and α ν ). Experimental findings were validated in human explant oesophageal biopsies, a rat model of gastroesophageal reflux disease (GORD) and in patient tissue microarrays. The bile acid deoxycholic acid (DCA) specifically reduced adhesion of HET-1A cells to vitronectin and reduced cell-surface expression of integrin-α ν via effects on endocytic recycling processes. Increased expression of integrin-α v was observed in ulcerated tissue in a rat model of GORD and in oesophagitis and Barrett's intestinal metaplasia patient tissue compared to normal squamous epithelium. Increased expression of integrin-α ν was observed in QH BO cells compared to HET-1A cells. QH cells were resistant to DCA-mediated loss of adhesion and reduction in cell-surface expression of integrin-α ν . We demonstrated that a specific component of the gastric refluxate, DCA, affects the epithelial barrier through modulation of integrin α ν expression, providing a novel mechanism for bile acid-mediated erosion of oesophageal squamous epithelium and promotion of BO. Strategies aimed at preventing bile acid-mediated erosion should be considered in the clinical management of patients with GORD. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Expression of E-cadherin and vimentin in oral squamous cell carcinoma

PubMed Central

Zhou, Jingping; Tao, Detao; Xu, Qing; Gao, Zhenlin; Tang, Daofang

2015-01-01

The aim of the study is to determine the levels of E-cadherin, vimentin expression in tumor tissues from patients with oral squamous cell carcinoma (OSCC), and the relationship between the expression of E-cadherin, vimentin and epithelial-mesenchymal transition, in order to explore its values for predicting the invasion and metastasis of oral squamous cell carcinoma, short survival of patients in many types of cancer. E-cadherin and vimentin expression of 10 benign and 42 OSCC tumor tissues was examined by immunohistochemical staining. E-cadherin is positively expressed in normal oral mucosa epithelium, but vimentin expression is not found in normal oral mucosa epithelia; the E-cadherin and vimentin were expressed in 26 of 42 (61.9%) and 16 of 42 (38.1%), respectively. No statistically difference was found for E-cadherin and vimentin expression in patients with different age, gender and tumor location, E-cadherin and vimentin expression was significantly associated with lymph node metastasis and tissue location (P < 0.05); E-cadherin expression was also significantly associated with tumor stage (P < 0.05); there are significantly difference between infiltrative margin and central area in patients with oral squamous cell carcinoma for E-cadherin and vimentin positive expression (P < 0.05). E-cadherin and vimentin positive expression was associated with tumor metastasis of oral squamous cell carcinoma. Our study preliminarily confirmed that EMT phenomenon is existed during the development of oral squamous cell carcinoma. Co-evaluation of E-cadherin and vimentin might be a valuable tool for predicting OSCC patient outcome. PMID:26045832

TRANSITIONAL CELL CANCER OF THE ANUS AND RECTUM

PubMed Central

Grodsky, Lewis

1961-01-01

A study was made of all cases of transitional cell cancer of the anus or rectum in the records of the University of California Medical Center, San Francisco. None was listed until 1945, then an additional seven between 1954 and 1960. During the latter period there were 192 cases of adenocarcinoma of the rectum, six cases of squamous cell or epidermoid rectal cancer and 12 cases of squamous cell cancer of the anus. Distinctive and highly malignant anal and rectal epithelial tumors will occasionally arise at or near the anorectal junction from inconstant embryologic entodermal cloacal vestiges. These atypical nonkeratinizing lesions are very similar microscopically to transitional cell tumors found in the cloacogenic portions of the lower genitourinary tract. Review of the literature indicates that the prognosis of cloacogenic anal and rectal lesions appears to be relatively graver than that for the more common adenocarcinomas and keratinizing squamous cell epitheliomas. Early diagnosis and prompt, radical excision seem to offer the only hope for survival. ImagesFigure 1.Figure 2Figure 3Figure 4Figure 5Figure 6Figure 7 PMID:13902070

Evaluation of the Role of Vibrational Spectroscopy in the Assessment of Vulval Disease

ClinicalTrials.gov

2017-08-03

Normal Vulval Skin; Lichen Sclerosus; High Grade Dysplasia - Usual Type ('VIN 2-3'); High Grade Dysplasia - Differentiated Type ('VIN 2-3'); Squamous Cell Carcinoma; Epithelial Hyperplasia Without Atypia; Atypia Not Otherwise Specified/ Low Grade Dysplasia ('VIN 1'); Pagets Disease of the Vulva

[Bladder carcinosarcoma. A clinical case].

PubMed

Pena Outeiriño, J M; León Dueñas, E; Romero Gil, J R; Leal López, A

1995-03-01

Presentation of a new case of vesical carcinosarcoma in a 49 year-old male patient. The tumour's pathoanatomical study showed an epithelial pattern of transitional and squamous cells and a sarcomatous pattern composed of rabdomiosarcoma, osteochondrosarcoma and pleomorphous indifferentiated sarcoma with giant multinuclear cells. Histogenesis, signs and symptoms, and treatment, as well as the need of performing an immunohistochemical study for its diagnosis are discussed.

Decreased SMAD4 expression is associated with induction of epithelial-to-mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma

PubMed Central

Cheng, Haixia; Fertig, Elana J; Ozawa, Hiroyuki; Hatakeyama, Hiromitsu; Howard, Jason D; Perez, Jimena; Considine, Michael; Thakar, Manjusha; Ranaweera, Ruchira; Krigsfeld, Gabriel; Chung, Christine H

2015-01-01

Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and cetuximab, a monoclonal antibody targeting this receptor, is widely used to treat these patients. In the following investigation, we examined the role of SMAD4 down-regulation in mediating epithelial-to-mesenchymal transition (EMT) and cetuximab resistance in HNSCC. We determined that SMAD4 downregulation was significantly associated with increased cell motility, increased expression of vimentin, and cetuximab resistance in HNSCC cell lines. In the HNSCC genomic dataset obtained from The Cancer Genome Atlas, SMAD4 was altered in 20/279 (7%) of HNSCC via homozygous deletion, and nonsense, missense, and silent mutations. When SMAD4 expression was compared with respect to human papillomavirus (HPV) status, HPV-positive tumors had higher expression compared to HPV-negative tumors. Furthermore, higher SMAD4 expression also correlated with higher CDKN2A (p16) expression. Our data suggest that SMAD4 down-regulation plays an important role in the induction of EMT and cetuximab resistance. Patients with higher SMAD4 expression may benefit from cetuximab use in the clinic. PMID:26046389

The Fanconi Anemia Pathway: Repairing the Link Between DNA Damage and Squamous Cell Carcinoma

PubMed Central

Romick-Rosendale, Lindsey E.; Lui, Vivian W. Y.; Grandis, Jennifer R.; Wells, Susanne I.

2013-01-01

Fanconi anemia (FA) is a rare inherited recessive disease caused by mutations in one of fifteen genes known to encode FA pathway components. In response to DNA damage, nuclear FA proteins associate into high molecular weight complexes through a cascade of post-translational modifications and physical interactions, followed by the repair of damaged DNA. Hematopoietic cells are particularly sensitive to the loss of these interactions, and bone marrow failure occurs almost universally in FA patients. FA as a disease is further characterized by cancer susceptibility, which highlights the importance of the FA pathway in tumor suppression, and will be the focus of this review. Acute myeloid leukemia is the most common cancer type, often subsequent to bone marrow failure. However, FA patients are also at an extreme risk of squamous cell carcinoma (SCC) of the head and neck and gynecological tract, with an even greater incidence in those individuals who have received a bone marrow transplant and recovered from hematopoietic disease. FA tumor suppression in hematopoietic versus epithelial compartments could be mechanistically similar or distinct. Definition of compartment specific FA activities is now critical to assess the effects of today’s bone marrow failure treatments on tomorrow’s solid tumor development. It is our hope that current therapies can then be optimized to decrease the risk of malignant transformation in both hematopoietic and epithelial cells. Here we review our current understanding of the mechanisms of action of the Fanconi anemia pathway as it contributes to stress responses, DNA repair and squamous cell carcinoma susceptibility. PMID:23333482

Humanization of the mouse mammary gland by replacement of the luminal layer with genetically engineered preneoplastic human cells.

PubMed

Verbeke, Stephanie; Richard, Elodie; Monceau, Elodie; Schmidt, Xenia; Rousseau, Benoit; Velasco, Valerie; Bernard, David; Bonnefoi, Herve; MacGrogan, Gaetan; Iggo, Richard D

2014-12-20

The cell of origin for estrogen receptor α-positive (ERα+) breast cancer is probably a luminal stem cell in the terminal duct lobular units. To model these cells, we have used the murine myoepithelial layer in the mouse mammary ducts as a scaffold upon which to build a human luminal layer. To prevent squamous metaplasia, a common artifact in genetically-engineered breast cancer models, we sought to limit activation of the epidermal growth factor receptor (EGFR) during in vitro cell culture before grafting the cells. Human reduction mammoplasty cells were grown in vitro in WIT medium. Epidermal growth factor in the medium was replaced with amphiregulin and neuregulin to decrease activation of EGFR and increase activation of EGFR homologs 3 and 4 (ERBB3 and ERBB4). Lentiviral vectors were used to express oncogenic transgenes and fluorescent proteins. Human mammary epithelial cells were mixed with irradiated mouse fibroblasts and Matrigel, then injected through the nipple into the mammary ducts of immunodeficient mice. Engrafted cells were visualized by stereomicroscopy for fluorescent proteins and characterized by histology and immunohistochemistry. Growth of normal mammary epithelial cells in conditions favoring ERBB3/4 signaling prevented squamous metaplasia in vitro. Normal human cells were quickly lost after intraductal injection, but cells infected with lentiviruses expressing CCND1, MYC, TERT, BMI1 and a short-hairpin RNA targeting TP53 were able to engraft and progressively replace the luminal layer in the mouse mammary ducts, resulting in the formation of an extensive network of humanized ducts. Despite expressing multiple oncogenes, the human cells formed a morphologically normal luminal layer. Expression of a single additional oncogene, PIK3CA-H1047R, converted the cells into invasive cancer cells. The resulting tumors were ERα+, Ki67+ luminal B adenocarcinomas that were resistant to treatment with fulvestrant. Injection of preneoplastic human mammary epithelial cells into the mammary ducts of immunodeficient mice leads to replacement of the murine luminal layer with morphologically normal human cells. Genetic manipulation of the injected cells makes it possible to study defined steps in the transformation of human mammary epithelial cells in a more physiological environment than has hitherto been possible.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frost, J.K.; Ball, W.C. Jr.; Levin, M.L.

Sputum cytopathologic monitoring detects squamous cell lung cancers at an extremely early stage (x-ray negative). It holds further potential for preventing disease by detecting epithelial alterations which reflect environmental hazards. The addition of sputum cytology screening to screening by chest x-ray film does not significantly reduce mortality from all types of lung cancer, but preliminary analysis of Johns Hopkins Lung Project data suggests that mortality from squamous cell carcinoma is reduced. Quantitative automated cytopathology systems and biochemical/immunological cell markers enhance understanding of these precursors and offer great promise for increasing capacity, accuracy, and usefulness in cytopathology screening of workers. Cytologicalmore » specimens collected over years of screening workers considered at risk may be important to eventually understanding development and prevention of major occupational diseases.« less

Phenotypical changes in a differentiating immortalized bronchial epithelial cell line after exposure to mainstream cigarette smoke and e-cigarette vapor.

PubMed

Aufderheide, Michaela; Emura, Makito

2017-07-05

3D constructs composed of differentiated immortalized primary normal human bronchial epithelial (NHBE) cells (CL-1548) were repeatedly exposed at the air-liquid interface to non-lethal concentrations of mainstream cigarette smoke (4 cigarettes a day, 5days/week, 8 repetitions in total) and e-cigarette vapor (50 puffs a day, 5 days/week, 8 repetitions in total) to build up a permanent burden on the cells. Samples were taken after 4, 6 and 8 times of repeated smoke exposure and the cultures were investigated using histopathological methods Compared to the clean air-exposed cultures (process control) and incubator control, the aerosol-exposed cultures showed a reduction of ciliated, mucus-producing and club cells. At the end of the exposure phase, we even found metaplastic areas positive for CK13 antibody in the cultures exposed to mainstream cigarette smoke and e-liquid vapor, commonly seen in squamous cells as a marker for non-cornified squamous epithelium. The control cultures (incubator cells) showed no comparable phenotypical changes. In conclusion, our in vitro model presents a valuable tool to study the induction of phenotypical changes after exposure to hazardous airborne material. Copyright © 2017. Published by Elsevier GmbH.

Anterior gradient protein 2 expression in high grade head and neck squamous cell carcinoma correlated with cancer stem cell and epithelial mesenchymal transition

PubMed Central

Ma, Si-Rui; Wang, Wei-Ming; Huang, Cong-Fa; Zhang, Wen-Feng; Sun, Zhi-Jun

2015-01-01

Anterior gradient protein 2 (AGR2) is a novel biomarker with potential oncogenic role. We sought to investigate the diagnostic and prognostic role of AGR2 on head and neck squamous cell carcinoma (HNSCC) with an emphasis on its correlation of cancer stemloid cells (CSC) and epithelial mesenchymal transition (EMT). We found that AGR2 protein levels were higher in HNSCC than in normal oral mucosa. High levels of AGR2 were associated with the T category, pathological grade and lymph node metastasis of HNSCC. Expression of AGR2 increased in recurring HNSCC after radiotherapy and in post cisplatin-based chemotherapeutic tissues. In HNSCC cell lines, knock-down of AGR2 induced apoptosis, reduced sphere formation, and down-regulated Survivin, Cyclin D1, Bcl2, Bcl2l1, Slug, Snail, Nanog and Oct4. In addition, over-expressed AGR2 in transgenic mice with spontaneous HNSCC was associated with lost function of Tgfbr1 and/or lost function of Pten. In vitro knockdown TGFBR1 in HNSCC cell lines increased AGR2 expression. These results suggest that AGR2 is involved in EMT and self-renewal of CSC and may present a potential therapeutic target (oncotarget) for HNSCC. PMID:25871396

Nonlinear spectral imaging of human normal skin, basal cell carcinoma and squamous cell carcinoma based on two-photon excited fluorescence and second-harmonic generation

NASA Astrophysics Data System (ADS)

Xiong, S. Y.; Yang, J. G.; Zhuang, J.

2011-10-01

In this work, we use nonlinear spectral imaging based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) for analyzing the morphology of collagen and elastin and their biochemical variations in basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and normal skin tissue. It was found in this work that there existed apparent differences among BCC, SCC and normal skin in terms of their thickness of the keratin and epithelial layers, their size of elastic fibers, as well as their distribution and spectral characteristics of collagen. These differences can potentially be used to distinguish BCC and SCC from normal skin, and to discriminate between BCC and SCC, as well as to evaluate treatment responses.

The role of epithelial-mesenchymal transition in squamous cell carcinoma of the oral cavity.

PubMed

Zidar, Nina; Boštjančič, Emanuela; Malgaj, Marija; Gale, Nina; Dovšak, Tadej; Didanovič, Vojko

2018-02-01

Epithelial-mesenchymal transition (EMT) has emerged as a possible mechanism of cancer metastasizing, but strong evidence for EMT involvement in human cancer is lacking. Our aim was to compare oral spindle cell carcinoma (SpCC) as an example of EMT with oral conventional squamous cell carcinoma (SCC) with and without nodal metastases to test the hypothesis that EMT contributes to metastasizing in oral SCC. Thirty cases of oral SCC with and without nodal metastasis and 15 cases of SpCC were included. Epithelial (cytokeratin, E-cadherin), mesenchymal (vimentin, N-cadherin), and stem cell markers (ALDH-1, CD44, Nanog, Sox-2) and transcription repressors (Snail, Slug, Twist) were analyzed immunohistochemically. We also analyzed the expression of microRNAs miR-141, miR-200 family, miR-205, and miR-429. SpCC exhibited loss of epithelial markers and expression of mesenchymal markers or coexpression of both up-regulation of transcription repressors and down-regulation of the investigated microRNAs. SCC showed only occasional focal expression of mesenchymal markers at the invasive front. No other differences were observed between SCC with and without nodal metastases except for a higher expression of ALDH-1 in SCC with metastases. Our results suggest that SpCC is an example of true EMT but do not support the hypothesis that EMT is involved in metastasizing of conventional SCC. Regarding oral SCC progression and metastasizing, we have been facing a shift from the initial enthusiasm for the EMT concept towards a more critical approach with "EMT-like" and "partial EMT" concepts. The real question, though, is, is there no EMT at all?

The Escherichia coli O157:H7 cattle immuno-proteome includes outer membrane protein A (OmpA), a modulator of adherence to bovine recto-anal junction squamous epithelial (RSE) cells

PubMed Central

Kudva, Indira T.; Krastins, Bryan; Torres, Alfredo G.; Griffin, Robert W.; Sheng, Haiqing; Sarracino, David A.; Hovde, Carolyn J.; Calderwood, Stephen B.; John, Manohar

2015-01-01

SUMMARY Building on previous studies, we defined the repertoire of proteins comprising the immuno-proteome of E. coli O157:H7 (O157) cultured in DMEM supplemented with norepinephrine (NE; O157 immuno-proteome), a β-adrenergic hormone that regulates E. coli O157 gene expression in the gastrointestinal tract, using a variation of a novel proteomics-based platform proteome mining tool for antigen discovery, called Proteomics-based Expression Library Screening (PELS; Kudva et al., 2006). The E. coli O157 immuno-proteome (O157-IP) comprised 91 proteins, and included those identified previously using PELS, and also proteins comprising DMEM- and bovine rumen fluid- proteomes. Outer membrane protein A (OmpA), a common component of the above proteomes, and reportedly a contributor to E. coli O157 adherence to cultured Hep-2 epithelial cells, was interestingly found to be a modulator rather than a contributor to E. coli O157 adherence to bovine recto-anal junction squamous epithelial (RSE) cells. Our results point to a role for yet to be identified members of the O157-IP in E. coli O157 adherence to RSE-cells, and additionally implicate a possible role for the OmpA regulator, TdcA, in the expression of such adhesins. Our observations have implications for development of efficacious vaccines for preventing E. coli O157 colonization of the bovine gastrointestinal tract. PMID:25643951

BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis

PubMed Central

Jiang, Ming; Ku, Wei-Yao; Zhou, Zhongren; Dellon, Evan S.; Falk, Gary W.; Nakagawa, Hiroshi; Wang, Mei-Lun; Liu, Kuancan; Wang, Jun; Katzka, David A.; Peters, Jeffrey H.; Lan, Xiaopeng; Que, Jianwen

2015-01-01

Tissue homeostasis requires balanced self-renewal and differentiation of stem/progenitor cells, especially in tissues that are constantly replenished like the esophagus. Disruption of this balance is associated with pathological conditions, including eosinophilic esophagitis (EoE), in which basal progenitor cells become hyperplastic upon proinflammatory stimulation. However, how basal cells respond to the inflammatory environment at the molecular level remains undetermined. We previously reported that the bone morphogenetic protein (BMP) signaling pathway is critical for epithelial morphogenesis in the embryonic esophagus. Here, we address how this pathway regulates tissue homeostasis and EoE development in the adult esophagus. BMP signaling was specifically activated in differentiated squamous epithelium, but not in basal progenitor cells, which express the BMP antagonist follistatin. Previous reports indicate that increased BMP activity promotes Barrett’s intestinal differentiation; however, in mice, basal progenitor cell–specific expression of constitutively active BMP promoted squamous differentiation. Moreover, BMP activation increased intracellular ROS levels, initiating an NRF2-mediated oxidative response during basal progenitor cell differentiation. In both a mouse EoE model and human biopsies, reduced squamous differentiation was associated with high levels of follistatin and disrupted BMP/NRF2 pathways. We therefore propose a model in which normal squamous differentiation of basal progenitor cells is mediated by BMP-driven NRF2 activation and basal cell hyperplasia is promoted by disruption of BMP signaling in EoE. PMID:25774506

SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas

PubMed Central

Watanabe, Hideo; Ma, Qiuping; Peng, Shouyong; Adelmant, Guillaume; Swain, Danielle; Song, Wenyu; Fox, Cameron; Francis, Joshua M.; Pedamallu, Chandra Sekhar; DeLuca, David S.; Brooks, Angela N.; Wang, Su; Que, Jianwen; Rustgi, Anil K.; Wong, Kwok-kin; Ligon, Keith L.; Liu, X. Shirley; Marto, Jarrod A.; Meyerson, Matthew; Bass, Adam J.

2014-01-01

The transcription factor SOX2 is an essential regulator of pluripotent stem cells and promotes development and maintenance of squamous epithelia. We previously reported that SOX2 is an oncogene and subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we have further characterized the function of SOX2 in SCC. Using ChIP-seq analysis, we compared SOX2-regulated gene profiles in multiple SCC cell lines to ES cell profiles and determined that SOX2 binds to distinct genomic loci in SCCs. In SCCs, SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4, which is the preferred SOX2 binding partner in ES cells. SOX2 and p63 exhibited overlapping genomic occupancy at a large number of loci in SCCs; however, coordinate binding of SOX2 and p63 was absent in ES cells. We further demonstrated that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which was essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that the action of SOX2 in SCC differs substantially from its role in pluripotency. The identification of the SCC-associated interaction between SOX2 and p63 will enable deeper characterization the downstream targets of this interaction in SCC and normal squamous epithelial physiology. PMID:24590290

SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas.

PubMed

Watanabe, Hideo; Ma, Qiuping; Peng, Shouyong; Adelmant, Guillaume; Swain, Danielle; Song, Wenyu; Fox, Cameron; Francis, Joshua M; Pedamallu, Chandra Sekhar; DeLuca, David S; Brooks, Angela N; Wang, Su; Que, Jianwen; Rustgi, Anil K; Wong, Kwok-kin; Ligon, Keith L; Liu, X Shirley; Marto, Jarrod A; Meyerson, Matthew; Bass, Adam J

2014-04-01

The transcription factor SOX2 is an essential regulator of pluripotent stem cells and promotes development and maintenance of squamous epithelia. We previously reported that SOX2 is an oncogene and subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we have further characterized the function of SOX2 in SCC. Using ChIP-seq analysis, we compared SOX2-regulated gene profiles in multiple SCC cell lines to ES cell profiles and determined that SOX2 binds to distinct genomic loci in SCCs. In SCCs, SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4, which is the preferred SOX2 binding partner in ES cells. SOX2 and p63 exhibited overlapping genomic occupancy at a large number of loci in SCCs; however, coordinate binding of SOX2 and p63 was absent in ES cells. We further demonstrated that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which was essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that the action of SOX2 in SCC differs substantially from its role in pluripotency. The identification of the SCC-associated interaction between SOX2 and p63 will enable deeper characterization the downstream targets of this interaction in SCC and normal squamous epithelial physiology.

SOX2 and PI3K Cooperate to Induce and Stabilize a Squamous-Committed Stem Cell Injury State during Lung Squamous Cell Carcinoma Pathogenesis

PubMed Central

Kim, Bo Ram; Van de Laar, Emily; Tarumi, Shintaro; Hasenoeder, Stefan; Wang, Dennis; Virtanen, Carl; Bandarchi, Bizhan; Pham, Nhu An; Lee, Sharon; Keshavjee, Shaf; Tsao, Ming-Sound; Moghal, Nadeem

2016-01-01

Although cancers are considered stem cell diseases, mechanisms involving stem cell alterations are poorly understood. Squamous cell carcinoma (SQCC) is the second most common lung cancer, and its pathogenesis appears to hinge on changes in the stem cell behavior of basal cells in the bronchial airways. Basal cells are normally quiescent and differentiate into mucociliary epithelia. Smoking triggers a hyperproliferative response resulting in progressive premalignant epithelial changes ranging from squamous metaplasia to dysplasia. These changes can regress naturally, even with chronic smoking. However, for unknown reasons, dysplasias have higher progression rates than earlier stages. We used primary human tracheobronchial basal cells to investigate how copy number gains in SOX2 and PIK3CA at 3q26-28, which co-occur in dysplasia and are observed in 94% of SQCCs, may promote progression. We find that SOX2 cooperates with PI3K signaling, which is activated by smoking, to initiate the squamous injury response in basal cells. This response involves SOX9 repression, and, accordingly, SOX2 and PI3K signaling levels are high during dysplasia, while SOX9 is not expressed. By contrast, during regeneration of mucociliary epithelia, PI3K signaling is low and basal cells transiently enter a SOX2LoSOX9Hi state, with SOX9 promoting proliferation and preventing squamous differentiation. Transient reduction in SOX2 is necessary for ciliogenesis, although SOX2 expression later rises and drives mucinous differentiation, as SOX9 levels decline. Frequent coamplification of SOX2 and PIK3CA in dysplasia may, thus, promote progression by locking basal cells in a SOX2HiSOX9Lo state with active PI3K signaling, which sustains the squamous injury response while precluding normal mucociliary differentiation. Surprisingly, we find that, although later in invasive carcinoma SOX9 is generally expressed at low levels, its expression is higher in a subset of SQCCs with less squamous identity and worse clinical outcome. We propose that early pathogenesis of most SQCCs involves stabilization of the squamous injury state in stem cells through copy number gains at 3q, with the pro-proliferative activity of SOX9 possibly being exploited in a subset of SQCCs in later stages. PMID:27880766

Reference spectra from squamous epithelium and connective tissue allow whole section proteomics analysis.

PubMed

Roesch-Ely, Mariana; Schnölzer, Martina; Nees, Matthias; Plinkert, Peter K; Bosch, Franz X

2010-01-01

We reasoned that micro-dissection of tumour cells for protein expression studies should be omitted since tumour-stroma interactions are an important part of the biology of solid tumours. To study such interactions in head and neck squamous cell carcinoma (HNSCC) development, we generated reference protein spectra for normal squamous epithelium and connective tissue by SELDI-TOF-MS. Calgranulins A and B, Annexin1 and Histone H4 were found to be strongly enriched in the epithelium. The alpha-defensins 1-3 and the haemoglobin subunits were identified in the connective tissue. Tumour-distant epithelia, representing early pre-malignant lesions, showed up-regulated expression of the stromal alpha-defensins, whereas the epithelial Annexin 1 was down-regulated. Thus, tumour microenvironment interactions occur very early in the carcinogenic process. These data demonstrate that omitting micro-dissection is actually beneficial for studying changes in protein expression during development and progression of solid tumours.

Sodium Phenylbutyrate Inhibits Tumor Growth and the Epithelial-Mesenchymal Transition of Oral Squamous Cell Carcinoma In Vitro and In Vivo.

PubMed

Qian, Kun; Sun, Laiyu; Zhou, Guoqing; Ge, Haixia; Meng, Yue; Li, Jingfen; Li, Xiao; Fang, Xinqiang

2018-05-01

Sodium phenylbutyrate (SPB) as a salt of 4-phenylbutyric acid (4-PBA) has been reported to be an ammonia scavenger, histone deacetylase inhibitor, and an endoplasmic reticulum stress inhibitor in various diseases, including neurological diseases, inflammatory disorders, and carcinogenesis. Although phenylbutyrate showed effective antitumor properties in many cancers, its role in oral squamous cell carcinoma (OSCC) remains further characterized. Thus, the OSCC cell lines CAL27, HSC3, and SCC4 were treated with a series of doses of SPB for different times. The IC 50 of three cell lines for SPB was determined to be 4.0, 3.7, and 3.0 mM. The CCK-8 assay indicated that the treatment of SPB induced continuous inhibition of cell vitality of three cell lines. Apoptosis was assessed by Hoechst assay that showed that SPB could significantly promote cell apoptosis. Moreover, the apoptosis-related pathway was analyzed, and the results showed that the expression of antiapoptosis factor BCL-2 was downregulated by SPB but the cleavage of caspase-3 was increased. Meanwhile, it was found that SPB also impaired the migration and invasion of OSCC cells in vitro. Mechanistically, the transforming growth factor-β (TGFB) related epithelial-mesenchymal transition (EMT) was inhibited by SPB with decreased mesenchymal marker N-cadherin and increased epithelial marker E-cadherin. Furthermore, the antitumor effect of SPB in vivo was also demonstrated. The administration of SPB induced remarkably tumor regression with decreased tumor volume, and the TGFB level and EMT phenotype in vivo were also inhibited. These data demonstrated that the treatment of SPB could function as antitumor therapeutics for OSCC.

Flow cytometry of sputum: assessing inflammation and immune response elements in the bronchial airways

PubMed Central

Lay, John C.; Peden, David B.; Alexis, Neil E.

2012-01-01

Background The evaluation of sputum leukocytes by flow cytometry is an opportunity to assess characteristics of cells residing in the central airways, yet it is hampered by certain inherent properties of sputum including mucus and large amounts of contaminating cells and debris. Objective To develop a gating strategy based on specific antibody panels in combination with light scatter properties for flow cytometric evaluation of sputum cells. Methods Healthy and mild asthmatic volunteers underwent sputum induction. Manually selected mucus “plug” material was treated with dithiothrietol, filtered and total leukocytes acquired. Multicolor flow cytometry was performed using specific gating strategies based on light scatter properties, differential expression of CD45 and cell lineage markers to discriminate leukocytes from squamous epithelial cells and debris. Results The combination of forward scatter and CD45 expression reliably segregated sputum leukocytes from contaminating squamous epithelial cells and debris. Overlap of major leukocyte populations (neutrophils, macrophages/monocytes) required the use of specific antibodies (e.g. CD16, CD64, CD14, HLA-DR) that differentiated granulocytes from monocytes and macrophages. These gating strategies allowed identification of small populations of eosinophils, CD11c+ myeloid dendritic cells, B cells and NK cells. Conclusions Multicolor flow cytometry can be successfully applied to sputum samples to identify and characterize leukocyte populations residing on the surfaces of the central airways. PMID:21639708

Development of Urinary Bladder Pre-Neoplasia by Schistosoma haematobium Eggs and Chemical Carcinogen in Mice

PubMed Central

Chala, Bayissa; Choi, Min-Ho; Moon, Kyung Chul; Kim, Hyung Suk; Kwak, Cheol; Hong, Sung-Tae

2017-01-01

Schistosoma haematobium is a biocarcinogen of human urinary bladder (UB). The present study investigated developing UB cancer mouse model by injecting S. haematobium eggs into the bladder wall and introduction of chemical carcinogens. Histopathological findings showed mild hyperplasia to epithelial vacuolar change, and high grade dysplasia. Squamous metaplasia was observed in the S. haematobium eggs+NDMA group at week 12 but not in other groups. Immunohistochemistry revealed significantly high expression of Ki-67 in urothelial epithelial cells of the S. haematobium eggs+BBN group at week 20. The qRT-PCR showed high expression of p53 gene in S. haematobium eggs group at week 4 and S. haematobium eggs+BBN group at week 20. E-cadherin and vimentin showed contrasting expression in S. haematobium eggs+BBN group. Such inverse expression of E-cadherin and vimentin may indicate epithelial mesenchymal transition in the UB tissue. In conclusion, S. haematobium eggs and nitrosamines may transform UB cells into squamous metaplasia and dysplasia in correlation with increased expression of Ki-67. Marked decrease in E-cadherin and increase in p53 and vimentin expressions may support the transformation. The present study introduces a promising modified animal model for UB cancer study using S. haematobium eggs. PMID:28285503

Compounds From Celastraceae Targeting Cancer Pathways and Their Potential Application in Head and Neck Squamous Cell Carcinoma: A Review

PubMed Central

Hernandes, Camila; Pereira, Ana Maria Soares; Severino, Patricia

2017-01-01

Squamous cell carcinoma of the head and neck is one of the most common cancer types worldwide. It initiates on the epithelial lining of the upper aerodigestive tract, at most instances as a consequence of tobacco and alcohol consumption. Treatment options based on conventional therapies or targeted therapies under development have limited efficacy due to multiple genetic alterations typically found in this cancer type. Natural products derived from plants often possess biological activities that may be valuable in the development of new therapeutic agents for cancer treatment. Several genera from the family Celastraceae have been studied in this context. This review reports studies on chemical constituents isolated from species from the Celastraceae family targeting cancer mechanisms studied to date. These results are then correlated with molecular characteristics of head and neck squamous cell carcinoma in an attempt to identify constituents with potential application in the treatment of this complex disease at the molecular level. PMID:28503090

Compounds From Celastraceae Targeting Cancer Pathways and Their Potential Application in Head and Neck Squamous Cell Carcinoma: A Review.

PubMed

Hernandes, Camila; Pereira, Ana Maria Soares; Severino, Patricia

2017-02-01

Squamous cell carcinoma of the head and neck is one of the most common cancer types worldwide. It initiates on the epithelial lining of the upper aerodigestive tract, at most instances as a consequence of tobacco and alcohol consumption. Treatment options based on conventional therapies or targeted therapies under development have limited efficacy due to multiple genetic alterations typically found in this cancer type. Natural products derived from plants often possess biological activities that may be valuable in the development of new therapeutic agents for cancer treatment. Several genera from the family Celastraceae have been studied in this context. This review reports studies on chemical constituents isolated from species from the Celastraceae family targeting cancer mechanisms studied to date. These results are then correlated with molecular characteristics of head and neck squamous cell carcinoma in an attempt to identify constituents with potential application in the treatment of this complex disease at the molecular level.

Human papilloma virus--role in precancerous and cancerous oral lesions of tobacco chewers.

PubMed

Zil-A-Rubab; Baig, Saeeda; Siddiqui, Ayesha; Nayeem, Amena; Salman, Mohammad; Qidwai, Moiz Ahmed; Mallick, Raiya; Qidwai, Samrah

2013-10-01

Human papilloma viruses (HPV), members of the papillomaviridae family, infects squamous epithelial cells of cevix, lower genitalia, and oral cavity. The association of HPV with oropharyngeal carcinogenesis is well documented.The incidence of oral cancer ranks second in Karachi South in both genders according to World Health Organization (WHO) statistics. This is attributed to the popularity of chewable tobacco products among the general population. Studies on Gutka-eaters in a set population of Karachi showed high frequency of HPV (17%) and high prevalence of HPV in squamous cell carcinoma in Pakistani patients (68%). The exposure of oral mucosa to chewable tobacco causes abrasions making it susceptible to HPV. This review strives to summarise the role of HPV in chewable tobacco-related precancerous and cancerous lesions. The literature of about a decade was retrieved from Google and pubMed with the under mentioned key words. It was found that the use of chewable tobacco products, especially Gutka, may increase the risk of oral squamous cell carcinoma (OSCC).

Study of P21 Expression in Oral Lichen Planus and Oral Squamous Cell Carcinoma by Immunohistochemical Technique.

PubMed

Baghaei, Fahimeh; Shojaei, Setareh; Afshar-Moghaddam, Noushin; Zargaran, Massoumeh; Rastin, Verisheh; Nasr, Mohsen; Moghimbeigi, Abbas

2015-09-01

Lichen planus is a mucocutaneous disease that is relatively common in middle aged individuals. Some studies have shown that oral lichen planus has a potential to progress to squamous cell carcinoma.p21 is a cyclin-dependent kinase inhibitor that regulates the cell cycle, thus it acts as an inhibitor in cell proliferation. This study was aimed to evaluate and compare the immunostaining of p21 (as a proliferation inhibitory factor) in oral lichen planus (OLP) and oral squamous cell carcinoma (OSCC). In this descriptive cross-sectional study, p21expression was investigated in 24 samples of oral lichen planus (OLP), 24 samples of oral squamous cell carcinoma (OSCC) and 24 samples of oral epithelial hyperplasia (OEH) by employing immunohistochemical staining. The mean percentage of p21-positive cells in OSCC (54.5±6.6) was significantly higher than that in OLP (32.8±6.08) and OEH (9.4±3.8). Moreover, OLP samples expressed p21 significantly higher than the OEH. Kruskal Wallis test revealed a statistically significant difference between the groups regarding the intensity of staining (p< 0.001). According to the findings of this study, the expression of p21 might be related to the potential carcinogenic transformation of lichen planus to SCC. Therefore, continuous follow-up periods for OLP are recommended for diagnosis of the malignant transformations in early stages.

Transformation of the genital epithelial tract occurs early in California sea lion development

PubMed Central

Barragán-Vargas, Cecilia; Montano-Frías, Jorge; Ávila Rosales, Germán; Godínez-Reyes, Carlos R.; Acevedo-Whitehouse, Karina

2016-01-01

An unusually high prevalence of metastatic urogenital carcinoma has been observed in free-ranging California sea lions stranded off the coast of California in the past two decades. No cases have been reported for sea lions in the relatively unpolluted Gulf of California. We investigated occurrence of genital epithelial transformation in 60 sea lions (n=57 pups and 3 adult females) from the Gulf of California and examined whether infection by a viral pathogen previously found to be associated with urogenital carcinoma accounted for such alterations. We also explored the contribution of MHC class II gene expression on transformation. Cellular alterations, such as squamous cell atypia (ASC), atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions were observed in 42% of the pups and in 67% of the adult females. Normal genital epithelium was more common in male than female pups. ASC was five times more likely to occur in older pups. Epithelial alterations were unrelated to infection by the potentially oncogenic otarine type I gammaherpesvirus (OtHV-1), but ASCUS was more common in pups with marked and severe inflammation. Expression of MHC class II DRB loci (Zaca DRB-D) by peripheral antigen-presenting leucocytes showed a slightly ‘protective’ effect for ASC. We propose that transformation of the California sea lion genital epithelium is relatively common in young animals, increases with age and is probably the result of infection by an unidentified pathogen. Expression of a specific MHC class II gene, suggestive of presentation of specific antigenic peptides to immune effectors, appears to lower the risk of transformation. Our study provides the first evidence that epithelial transformation of the California sea lion genital tract is relatively common, even from an early age, and raises questions regarding differences in sea lion cancer-detection and -repair success between geographical regions. PMID:27069641

A model of early human embryonic stem cell differentiation reveals inter- and intracellular changes on transition to squamous epithelium.

PubMed

Galat, Vasiliy; Malchenko, Sergey; Galat, Yekaterina; Ishkin, Alex; Nikolsky, Yuri; Kosak, Steven T; Soares, Bento Marcelo; Iannaccone, Philip; Crispino, John D; Hendrix, Mary J C

2012-05-20

The molecular events leading to human embryonic stem cell (hESC) differentiation are the subject of considerable scrutiny. Here, we characterize an in vitro model that permits analysis of the earliest steps in the transition of hESC colonies to squamous epithelium on basic fibroblast growth factor withdrawal. A set of markers (GSC, CK18, Gata4, Eomes, and Sox17) point to a mesendodermal nature of the epithelial cells with subsequent commitment to definitive endoderm (Sox17, Cdx2, nestin, and Islet1). We assayed alterations in the transcriptome in parallel with the distribution of immunohistochemical markers. Our results indicate that the alterations of tight junctions in pluripotent culture precede the beginning of differentiation. We defined this cell population as "specified," as it is committed toward differentiation. The transitional zone between "specified" pluripotent and differentiated cells displays significant up-regulation of keratin-18 (CK18) along with a decrease in the functional activity of gap junctions and the down-regulation of 2 gap junction proteins, connexin 43 (Cx43) and connexin 45 (Cx45), which is coincidental with substantial elevation of intracellular Ca2+ levels. These findings reveal a set of cellular changes that may represent the earliest markers of in vitro hESC transition to an epithelial phenotype, before the induction of gene expression networks that guide hESC differentiation. Moreover, we hypothesize that these events may be common during the primary steps of hESC commitment to functionally varied epithelial tissue derivatives of different embryological origins.

A Model of Early Human Embryonic Stem Cell Differentiation Reveals Inter- and Intracellular Changes on Transition to Squamous Epithelium

PubMed Central

Malchenko, Sergey; Galat, Yekaterina; Ishkin, Alex; Nikolsky, Yuri; Kosak, Steven T.; Soares, Bento Marcelo; Iannaccone, Philip; Crispino, John D.; Hendrix, Mary J.C.

2012-01-01

The molecular events leading to human embryonic stem cell (hESC) differentiation are the subject of considerable scrutiny. Here, we characterize an in vitro model that permits analysis of the earliest steps in the transition of hESC colonies to squamous epithelium on basic fibroblast growth factor withdrawal. A set of markers (GSC, CK18, Gata4, Eomes, and Sox17) point to a mesendodermal nature of the epithelial cells with subsequent commitment to definitive endoderm (Sox17, Cdx2, nestin, and Islet1). We assayed alterations in the transcriptome in parallel with the distribution of immunohistochemical markers. Our results indicate that the alterations of tight junctions in pluripotent culture precede the beginning of differentiation. We defined this cell population as “specified,” as it is committed toward differentiation. The transitional zone between “specified” pluripotent and differentiated cells displays significant up-regulation of keratin-18 (CK18) along with a decrease in the functional activity of gap junctions and the down-regulation of 2 gap junction proteins, connexin 43 (Cx43) and connexin 45 (Cx45), which is coincidental with substantial elevation of intracellular Ca2+ levels. These findings reveal a set of cellular changes that may represent the earliest markers of in vitro hESC transition to an epithelial phenotype, before the induction of gene expression networks that guide hESC differentiation. Moreover, we hypothesize that these events may be common during the primary steps of hESC commitment to functionally varied epithelial tissue derivatives of different embryological origins. PMID:21861759

Expression of human telomerase reverse transcriptase protein in oral epithelial dysplasia and oral squamous cell carcinoma: An immunohistochemical study

PubMed Central

Raghunandan, Bangalore Nagarajachar; Sanjai, Karpagaselvi; Kumaraswamy, Jayalakshmi; Papaiah, Lokesh; Pandey, Bhavna; Jyothi, Bellur MadhavaRao

2016-01-01

Background: Telomerase is an RNA-dependent DNA polymerase that synthesizes TTAGGG telomeric DNA sequences and almost universally provides the molecular basis for unlimited proliferative potential. The telomeres become shorter with each cycle of replication and reach a critical limit; most cells die or enter stage of replicative senescence. Telomere length maintenance by telomerase is required for all the cells that exhibit limitless replicative potential. It has been postulated that reactivation of telomerase expression is necessary for the continuous proliferation of neoplastic cells to attain immortality. Use of immunohistochemistry (IHC) is a useful, reliable method of localizing the human telomerase reverse transcriptase (hTERT) protein in tissue sections which permits cellular localization. Although there exists a lot of information on telomerase in oral cancer, little is known about their expression in oral epithelial dysplasia and their progression to oral squamous cell carcinoma (OSCC) compared to normal oral mucosa. This study addresses this lacuna. Aims: To compare the expression of hTERT protein in oral epithelial dysplasia and OSCC with normal oral mucosa by Immunohistochemical method. Subjects and Methods: In this preliminary study, IHC was used to detect the expression of hTERT protein in OSCC (n = 20), oral epithelial dysplasia (n = 21) and normal oral mucosa (n = 10). The tissue localization of immunostain, cellular localization of immunostain, nature of stain, intensity of stain, percentage of cells stained with hTERT protein were studied. A total number of 100 cells were counted in each slide. Statistical Analysis: All the data were analyzed using SPSS software version 16.0. The tissue localization, cellular localization of cytoplasmic/nuclear/both of hTERT stain, staining intensity was compared across the groups using Pearson's Chi-square test. The mean percentage of cells stained for oral epithelial dysplasia, OSCC and normal oral mucosa were compared using analysis of variance (ANOVA). A P < 0.05 was considered to be statistically significant. Results: The mean hTERT positive cells in the study groups were as follows, 62.91% in normal oral mucosa samples, 77.06% in oral epithelial dysplasia cases, and 81.48% in OSCC. In 61.9% of oral epithelial dysplasia and 65% of OSCC in our study, staining was visualized within the nucleus predominantly in the dot like pattern. There was a statistically significant difference in the nature of nuclear stain between oral epithelial dysplasia and OSCC (P = 0.023). Conclusions: Our results suggests that the mean percentage of cells showing hTERT expression steadily increased from normal oral mucosa to oral epithelial dysplasia to OSCC. The steady trend of increase in the percentage of cells was evident in different grades of oral epithelial dysplasia group and OSCC. The nature of hTERT staining did show variations among the three groups and promise to be a potential surrogate marker for malignant transformation. Further studies using IHC on larger sample size and clinical follow-up of these patients will be ascertaining the full potential of hTERT as a surrogate marker of epithelial transformation. PMID:27194869

Expression of nestin, mesothelin and epithelial membrane antigen (EMA) in developing and adult human meninges and meningiomas.

PubMed

Petricevic, Josko; Forempoher, Gea; Ostojic, Ljerka; Mardesic-Brakus, Snjezana; Andjelinovic, Simun; Vukojevic, Katarina; Saraga-Babic, Mirna

2011-11-01

The spatial and temporal pattern of appearance of nestin, epithelial membrane antigen (EMA) and mesothelin proteins was immunohistochemically determined in the cells of normal developing and adult human meninges and meningiomas. Human meninges developed as two mesenchymal condensations in the head region. The simple squamous epithelium on the surface of leptomeninges developed during mesenchymal to epithelial transformation. Nestin appeared for the first time in week 7, EMA in week 8, while mesothelin appeared in week 22 of development. In the late fetal period and after birth, nestin expression decreased, whereas expression of EMA and mesothelin increased. EMA appeared in all surface epithelial cells and nodules, while mesothelin was found only in some of them. In adult meninges, all three proteins were predominantly localized in the surface epithelium and meningeal nodules. In meningothelial meningiomas (WHO grade I), EMA was detected in all tumor cells except in the endothelial cells, mesothelin characterized nests of tumor cells, while nestin was found predominantly in the walls of blood vessels. The distribution pattern of those proteins in normal meningeal and tumor cells indicates that nestin might characterize immature cells, while EMA and mesothelin appeared in maturing epithelial cells. Neoplastic transformation of these specific cell lineages contributes to the cell population in meningiomas. Copyright © 2010 Elsevier GmbH. All rights reserved.

Immunolocalization of osteopontin in dysplasias and squamous cell carcinomas arising from oral epithelium.

PubMed

Aravind, Thara; Janardhanan, Mahija; Rakesh, S; Savithri, Vindhya; Unnikrishnan, U G

2017-01-01

Early detection of oral squamous cell carcinoma (OSCC) remains one of the most efficient ways to ensure patient survival and improved quality of life. Although specific biomarkers related to OSCC have been investigated, a useful biomarker that assesses the transition potential of potentially malignant lesion to OSCC remains to be found. Osteopontin (OPN) has been recognized as an important factor in tumorigenesis and their expression in OSCC have been investigated earlier. In the present study, evaluation of OPN expression in premalignant and malignant lesions has been carried out to assess their possible role as a biomarker in the early diagnosis and prognosis of OSCC. The objective of this study is to evaluate the role of OPN as a biomarker in the diagnosis and prognosis of OSCC. The study group consisted of archival paraffin-embedded blocks of ten cases each of varying grades of OSCC, oral epithelial dysplasias and epithelial hyperplasias. Sections were subjected to immunohistochemical staining for the biomarker OPN. A positive OPN expression was noticed in epithelial dysplasias and SCC arising from the oral epithelium. A progressive increase in the intensity of staining was seen with increasing grades of dysplasias and a decrease in OPN expression with an increase in grades was observed in OSCC. The expression of OPN in full thickness of epithelium in severe dysplasias, carcinoma in situ, and in the superficial epithelium of OSCC suggest the possibility of considering OPN expression in full epithelial thickness in dysplasias as an indicator for malignant transformation.

Hedgehog signalling stimulates precursor cell accumulation and impairs epithelial maturation in the murine oesophagus.

PubMed

van Dop, Willemijn A; Rosekrans, Sanne L; Uhmann, Anja; Jaks, Viljar; Offerhaus, G Johan A; van den Bergh Weerman, Marius A; Kasper, Maria; Heijmans, Jarom; Hardwick, James C H; Verspaget, Hein W; Hommes, Daan W; Toftgård, Rune; Hahn, Heidi; van den Brink, Gijs R

2013-03-01

In the intestine Hedgehog (Hh) signalling is directed from epithelium to mesenchyme and negatively regulates epithelial precursor cell fate. The role of Hh signalling in the oesophagus has not been studied in vivo. Here the authors examined the role of Hh signalling in epithelial homeostasis of oesophagus. The authors used transgenic mice in which the Hh receptor Patched1 (Ptch1) could be conditionally inactivated in a body-wide manner and mice in which Gli1 could be induced specifically in the epithelium of the skin and oesophagus. Effects on epithelial homeostasis of the oesophagus were examined using immunohistochemistry, in situ hybridisation, transmission electron microscopy and real-time PCR. Hh signalling was examined in patients with oesophageal squamous cell carcinoma (SCC) by quantitative real-time PCR. Sonic Hh is signalled in an autocrine manner in the basal layer of the oesophagus. Activation of Hh signalling resulted in an expansion of the epithelial precursor cell compartment and failure of epithelial maturation and migration. Levels of Hh targets GLI1, HHIP and PTCH1 were increased in SCC compared with normal tissue from the same patients. Here the authors find that Hh signalling positively regulates the precursor cell compartment in the oesophageal epithelium in an autocrine manner. Since Hh signalling targets precursor cells in the oesophageal epithelium and signalling is increased in SCCs, Hh signalling may be involved in oesophageal SCC formation.

Multifocal epithelial hyperplasia: a forgotten condition in the elderly.

PubMed

Shamloo, Nafiseh; Mortazavi, Hamed; Taghavi, Nasim; Baharvand, Maryam

2016-01-01

Multifocal epithelial hyperplasia (MEH), also known as focal epithelial hyperplasia and Heck disease, is a relatively rare condition caused by the human papillomavirus. This case report describes a 92-year-old man who presented with multiple, asymptomatic, circumscribed, soft, flattened papules in different sizes on the retrocommissure of his lower lip. The lesions were of 2 months' duration and had the same coloration as the adjacent normal mucosa. Histopathologic examination showed orthokeratinized stratified squamous epithelium with acanthosis, some areas of club-shaped rete ridges, and a few superficial epithelial cells with koilocytic changes and a mitosoid-like appearance. A diagnosis of MEH was established. Although MEH tends to occur in the first 2 decades of life, it can be encountered in elderly patients as well.

MiR-141-3p is upregulated in esophageal squamous cell carcinoma and targets pleckstrin homology domain leucine-rich repeat protein phosphatase-2, a negative regulator of the PI3K/AKT pathway.

PubMed

Ishibashi, Osamu; Akagi, Ichiro; Ogawa, Yota; Inui, Takashi

2018-05-11

The phosphatidylinositol-3-kinase (PI3K)/AKT pathway is frequently activated in various human cancers and plays essential roles in their development and progression. Accumulating evidence suggests that dysregulated expression of microRNAs (miRNAs) is closely associated with cancer progression and metastasis. Here, we focused on miRNAs that could regulate genes related to the PI3K/AKT pathway in esophageal squamous cell carcinoma (ESCC). To identify upregulated miRNAs and their possible target genes in ESCC, we performed microarray-based integrative analyses of miRNA and mRNA expression levels in three human ESCC cell lines and a normal esophageal epithelial cell line. The miRNA microarray analysis revealed that miR-31-5p, miR-141-3p, miR-200b-3p, miR-200c-3p, and miR-205-5p were expressed at higher levels in the ESCC cell lines than the normal esophageal epithelial cell line. Bioinformatical analyses of mRNA microarray data identified several AKT/PI3K pathway-related genes as candidate targets of these miRNAs, which include tumor suppressors such as DNA-damage-inducible transcript 4 and pleckstrin homology domain leucine-rich repeat protein phosphatase-2 (PHLPP2). To validate the targets of relevant miRNAs experimentally, synthetic mimics of the miRNAs were transfected into the esophageal epithelial cell line. Here, we report that miR-141-3p suppress the expression of PHLPP2, a negative regulators of the AKT/PI3K pathway, as a target in ESCC. Copyright © 2018 Elsevier Inc. All rights reserved.

Immunocytochemical characterization of lung tumors in fine-needle aspiration. The use of cytokeratin monoclonal antibodies for the differential diagnosis of squamous cell carcinoma and adenocarcinoma.

PubMed

Bruderman, I; Cohen, R; Leitner, O; Ronah, R; Guber, A; Griffel, B; Geiger, B

1990-10-15

In the current study, immunocytochemical typing of intermediate filaments was used for a differential diagnosis of human lung tumors from transthoracic fine-needle aspiration biopsies (TFNAB). The authors have compared the cytologic diagnosis of 53 lung cancer cases with the immunofluorescence patterns obtained using a panel of monoclonal antibodies, five of which (KG 8.13, KM 4.62, Ks B.17, KS 8.12, KK 8.60) react with specific cytokeratin polypeptides and one with vimentin (VIM 13.2). Only in six of 23 samples cytologically diagnosed as squamous cell carcinoma did the immunocytochemical typing of cytokeratins (ICTC) confirm the cytologic diagnosis. In seven cases some of the tumor cells stained positively with antibody Ks B.17 specific for simple epithelial keratin (No: 18), suggesting the presence of some cells of glandular origin. In ten additional cases the ICTC was in conflict with the cytologic diagnosis of squamous cell carcinoma (i.e., antibodies Ks 8.12 and KK 8.60 were negative, and antibody Ks B.17, positive) supporting a diagnosis of adenocarcinoma. In 14 of 18 cases cytologically diagnosed as adenocarcinoma, the ICTC confirmed the diagnosis whereas in four cases additional presence of some squamous cells was noticed. The ICTC labeling of cases cytologically diagnosed as undifferentiated and large cell carcinomas was similar to that of the group of adenocarcinomas. Thus, the application of cytokeratin typing for TFNAB samples seems to provide a vital complementation to routine cytologic study, especially for cases cytologically diagnosed as squamous carcinoma.

Amyloid-producing odontogenic tumour (calcifying epithelial odontogenic tumour) in the mandible of a Bengal tiger (Panthera tigris tigris).

PubMed

Kang, M-S; Park, M-S; Kwon, S-W; Ma, S-A; Cho, D-Y; Kim, D-Y; Kim, Y

2006-01-01

A 13-year-old male tiger (Panthera tigris tigris) had a marked mandibular swelling noticed 12 months earlier and associated with progressive anorexia and weight loss. Radiological and post-mortem examination revealed a mass (13x15 cm) which was firm and poorly defined, with destruction of the adjacent bone tissue. Histologically, the mass was poorly demarcated, with infiltrative growth, and composed of nests, cords and islands of epithelial cells with characteristic basal cell features. Also observed were extensive squamous metaplasia, ghost cells, stellate reticulum, and fibroblastic connective tissue stroma containing inflammatory cells. A prominent feature of this tumour consisted of abundant nodular deposits of congophilic amyloid-like material with partial mineralization (Liesegang rings). Immunohistochemically, the neoplastic cells and the amyloid-like material were positive for pancytokeratin and negative for vimentin. The findings supported the diagnosis of an amyloid-producing odontogenic tumour (APOT), also known as calcifying epithelial odontogenic tumour in man and animals.

Cancer stem cells in head and neck squamous cell carcinoma: a review.

PubMed

Satpute, Pranali Shirish; Hazarey, Vinay; Ahmed, Riyaz; Yadav, Lalita

2013-01-01

Research indicates that a small population of cancer cells is highly tumorigenic, endowed with the capacity for self-renewal, and has the ability to differentiate into cells that constitute the bulk of tumors. These cells are considered the "drivers" of the tumorigenic process in some tumor types, and have been named cancer stem cells (CSC). Epithelial-mesenchymal transition (EMT) appears to be involved in the process leading to the acquisition of stemness by epithelial tumor cells. Through this process, cells acquire an invasive phenotype that may contribute to tumor recurrence and metastasis. CSC have been identified in human head and neck squamous cell carcinomas (HNSCC) using markers such as CD133 and CD44 expression, and aldehyde dehydrogenase (ALDH) activity. Head and neck cancer stem cells reside primarily in perivascular niches in the invasive fronts where endothelial-cell initiated events contribute to their survival and function. Clinically, CSC enrichment has been shown to be enhanced in recurrent disease, treatment failure and metastasis. CSC represent a novel target of study given their slow growth and innate mechanisms conferring treatment resistance. Further understanding of their unique phenotype may reveal potential molecular targets to improve therapeutic and survival outcomes in patients with HNSCC. Here, we discuss the state-of-the-knowledge on the pathobiology of cancer stem cells, with a focus on the impact of these cells on head and neck tumor progression, metastasis and recurrence due to treatment failure.

The prognostic role of the epithelial-mesenchymal transition markers E-cadherin and Slug in laryngeal squamous cell carcinoma.

PubMed

Cappellesso, Rocco; Marioni, Gino; Crescenzi, Marika; Giacomelli, Luciano; Guzzardo, Vincenza; Mussato, Alessio; Staffieri, Alberto; Martini, Alessandro; Blandamura, Stella; Fassina, Ambrogio

2015-10-01

Laryngeal squamous cell carcinoma (LSCC) prognosis is definitely related to lymph node metastasis. Epithelial-mesenchymal transition (EMT) allows neoplastic cells to gain the plasticity and motility required for tumour progression and metastasis. The aim of this study was to investigate the role of EMT in the prognosis of LSCC. Immunohistochemical analysis of E-cadherin, N-cadherin, Snail, Slug, ZEB1, and ZEB2 was performed in 37 consecutive LSCC cases. Low E-cadherin levels and high Slug levels correlated with both disease recurrence (P = 0.02 and P =0.01, respectively) and shorter disease-free survival (DFS) (P = 0.04 and P = 0.02, respectively). Relative expression levels of CDH1, SNAI2, miR-1 and the miR-200 family were also evaluated. CDH1, miR-200a and miR-200c down-regulation and SNAI2 overexpression were significantly associated with disease recurrence (P = 0.03, P = 0.02, P = 0.04, and P = 0.04, respectively). EMT increases tumour recurrence risk and shortens DFS in LSCC. E-cadherin and Slug immunohistochemical analysis could be useful for identifying patients requiring more aggressive treatment after surgery. © 2015 John Wiley & Sons Ltd.

Suppression of E-cadherin function drives the early stages of Ras-induced squamous cell carcinoma through up-regulation of FAK and Src

PubMed Central

Alt-Holland, Addy; Sowalsky, Adam; Szwec-Levin, Yonit; Shamis, Yulia; Hatch, Harold; Feig, Larry A.; Garlick, Jonathan A.

2011-01-01

Advanced stages of epithelial carcinogenesis involve the loss of intercellular adhesion, but it remains unclear how proteins that regulate alterations in cell-cell and cell-matrix adhesion are deregulated to promote the early stages of cancer development. To address this, a three-dimensional human tissue model that mimics the incipient stages of Squamous Cell Carcinoma (SCC) was used to study how E-cadherin suppression promotes tumor progression in Ras-expressing human keratinocytes. We found that E-cadherin suppression triggered elevated mRNA and protein expression levels of Focal Adhesion Kinase (FAK), and increased FAK and Src activities above the level seen in Ras-expressing E-cadherin-competent keratinocytes. sh-RNA-mediated depletion of FAK and Src restored E-cadherin expression levels by increasing its stability in the membrane, and blocked tumor cell invasion in tissues. Surface transplantation of these tissues to mice resulted in reversion of the tumor phenotype to low-grade tumor islands in contrast to control tissues that manifested an aggressive, high-grade SCC. These findings suggest that the tumor-promoting effect of E-cadherin suppression, a common event in SCC development, is exacerbated by enhanced E-cadherin degradation induced by elevated FAK and Src activities. Furthermore, they imply that targeting FAK or Src in human epithelial cells with neoplastic potential may inhibit the early stages of SCC. PMID:21716326

Establishment of a Novel Lingual Organoid Culture System: Generation of Organoids Having Mature Keratinized Epithelium from Adult Epithelial Stem Cells

NASA Astrophysics Data System (ADS)

Hisha, Hiroko; Tanaka, Toshihiro; Kanno, Shohei; Tokuyama, Yoko; Komai, Yoshihiro; Ohe, Shuichi; Yanai, Hirotsugu; Omachi, Taichi; Ueno, Hiroo

2013-11-01

Despite the strong need for the establishment of a lingual epithelial cell culture system, a simple and convenient culture method has not yet been established. Here, we report the establishment of a novel lingual epithelium organoid culture system using a three-dimensional matrix and growth factors. Histological analyses showed that the generated organoids had both a stratified squamous epithelial cell layer and a stratum corneum. Very recently, we showed via a multicolor lineage tracing method that Bmi1-positive stem cells exist at the base of the epithelial basal layer in the interpapillary pit. Using our new culture system, we found that organoids could be generated by single Bmi1-positive stem cells and that in the established organoids, multiple Bmi1-positive stem cells were generated at the outermost layer. Moreover, we observed that organoids harvested at an early point in culture could be engrafted and maturate in the tongue of recipient mice and that the organoids generated from carcinogen-treated mice had an abnormal morphology. Thus, this culture system presents valuable settings for studying not only the regulatory mechanisms of lingual epithelium but also lingual regeneration and carcinogenesis.

Human uterine cervical epithelial cells grown on permeable support--a new model for the study of differentiation.

PubMed

Gorodeski, G I; Romero, M F; Hopfer, U; Rorke, E; Utian, W H; Eckert, R L

1994-04-01

The purpose of the present study was to establish culture conditions for human uterine cervical epithelial cells on permeable support and to determine how it affects cervical cell differentiation. Human ectocervical epithelial cells (hECE), HPV-16 immortalized hECE cells (ECE16-1) and Caski cells were grown on collagen-coated filters. Culture conditions, density of cells in culture and expression of epithelial and cervical-cell phenotypic markers were determined and compared in cells grown on filter and on solid support. Compared with the latter, cultures on filter had a higher cell density, hECE cells stratified to 5-12 cell layers compared to 1-3 on solid support, and cells of all three types expressed intercellular tight junctions. The cytokeratin profiles revealed differences between the three cell types as well as differences within the same cell species when grown on filter, compared to solid support. Of particular importance was the finding of a higher expression of K-13 in hECE grown on filter compared to solid support; K-13 is a marker of ectocervical cell differentiation. The cytokeratin profiles of the cultured hECE, ECE16-1 and Caski cells resembled those of ectocervical, squamous metaplastic and endocervical epithelia, respectively. hECE and ECE16-1 expressed involucrin protein, the level of which in both was higher in cells grown on filter compared to solid support. Polarization of the cultures was determined by morphology (stratification of hECE cells, expression of pseudomicrovilli in the apical cell membrane), selective apical vs. basolateral secretion of [35S]methionine- and [35S]cysteine-, [3H]fucose- and [14C]glucosamine-labeled molecules, and positive short-circuit current (Isc) under voltage-clamp conditions. Confluency of the cultures was determined by measuring transepithelial unidirectional fluxes of inert molecules with different molecular weights (MWs) through the paracellular pathway, and by measuring transepithelial conductance. The results indicated transepithelial permeability of 7-22.10(-6) cm.sec-1, which was 5-100 fold smaller compared to blank inserts, with a cut-off MW of 40-70 kDa for hECE and Caski cells. Transepithelial conductance ranged 18.5 to 51.5 mS.cm-2, indicating a leaky but confluent epithelia. Collectively the results indicate the epithelial nature of the cells and their improved differentiation when grown on filter support; hECE is a model for ectocervical epithelium while ECE16-1 and Caski express phenotypic characteristics of squamous metaplastic cervical epithelium and endocervical epithelium respectively.

Salivary Chemical Factors in Relation with Oral Cancer in Smokers and Non-Smokers: a Literature Review.

PubMed

Nosratzehi, Tahereh

2017-12-01

Squamous cell carcinoma of oral cavity is of malignant tumors, which causes cancerous complications. DNA damage, mainly because of products of oxidative stress like reactive oxygen species, is a frequent mutagenic that triggers carcinoma. Smoking increases the probability of cancer incidence. Saliva is the first biological medium to interact with external compounds, especially smoking substances. The present study overviews the salivary level of some remarkable compounds in relation with smoking and squamous cell carcinoma. To collect data, English literature was searched in databases including PubMed, ScienceDirect and Google Scholar. The keywords used for search were as follows: 'Carcinoma, Squamous Cell', 'Smoking', 'Saliva', and 'Biomarkers'. The inclusion criteria were the presence of salivary chemical factors in relation with oral cancer and influence by smoking. Out of 239 found articles, only 56 were selected. Our results demonstrated the potential role of salivary biochemistry to predict and/or treat complications with cancer in both smoker and non-smoker individuals. Changes in concentrations of salivary chemicals including antioxidants, total antioxidant, glutathione and uric acid, epithelial growth factor, cytokine biomarkers, superoxide dismutase activity, and transcriptome were related to squamous cell carcinoma and could be used as potential biomarkers for cancer prognosis; moreover, enhancement of antioxidant level might be a potential treatment.

Comparative study of β-catenin and CD44 immunoexpression in oral lichen planus and squamous cell carcinoma.

PubMed

Zargaran, Massoumeh; Baghaei, Fahimeh; Moghimbeigi, Abbas

2018-04-24

Dysfunction of adhesion molecules is believed to play an early and important role in developing cancer. Accordingly, this study aims to compare beta-catenin (β-catenin) and CD44 expression in oral lichen planus (OLP) as a condition with malignant potential and oral squamous cell carcinoma (OSCC). β-Catenin and CD44 expression were evaluated in 15 patients with epithelial hyperplasia (group A), 20 OLP (group B), and 20 OSCC (group C) by immunohistochemistry. Quantitative and semi-quantitative evaluations revealed β-catenin, and CD44 membranous expression had significant differences among the three groups. Expression of these markers in the OSCC group decreased significantly compared to that of the OLP. Also, nuclear/cytoplasmic expression of β-catenin was significantly different among the three groups, considering that nuclear expression was not observed in any of the epithelial hyperplasia and OLP samples. According to the findings of this study, β-catenin and CD44 can differentiate between behavior of OLP and OSCC, while the precancerous nature of OLP and malignant transformation potential of it are not suggested. © 2018 The International Society of Dermatology.

Recent Changes of Classification for Squamous Intraepithelial Lesions of the Head and Neck.

PubMed

Cho, Kyung-Ja; Song, Joon Seon

2018-05-18

- Interpretation of atypical squamous lesions of the head and neck has always been a nettlesome task for pathologists. Moreover, many different grading systems for squamous intraepithelial lesions have been proposed in past decades. The recent World Health Organization 2017 classification presents 2 types of 2-tier systems for laryngeal and oral precursor lesions. - To review the recent changes in classification and the clinical significance for squamous intraepithelial lesions of the head and neck. - Personal experience and data from the literature. - The 2-tier grading system for laryngeal dysplasia, presented by World Health Organization in 2017, is expected to improve diagnostic reproducibility and clinical implication. However, the diagnostic criteria for low-grade dysplasia do not distinguish it clearly from basal cell hyperplasia. The World Health Organization 2017 classification of oral epithelial dysplasia remains unclear, and complicated and variable grading systems still make head and neck intraepithelial lesions difficult to interpret.

Serotonin disrupts esophageal mucosal integrity: an investigation using a stratified squamous epithelial model.

PubMed

Wu, Liping; Oshima, Tadayuki; Tomita, Toshihiko; Ohda, Yoshio; Fukui, Hirokazu; Watari, Jiro; Miwa, Hiroto

2016-11-01

Serotonin regulates gastrointestinal function, and mast cells are a potential nonneuronal source of serotonin in the esophagus. Tight junction (TJ) proteins in the esophageal epithelium contribute to the barrier function, and the serotonin signaling pathway may contribute to epithelial leakage in gastroesophageal reflux disease. Therefore, the aim of this study was to investigate the role of serotonin on barrier function, TJ proteins, and related signaling pathways. Normal primary human esophageal epithelial cells were cultured with use of an air-liquid interface system. Serotonin was added to the basolateral compartment, and transepithelial electrical resistance (TEER) was measured. The expression of TJ proteins and serotonin receptor 7 (5-HT 7 ) was assessed by Western blotting. The involvement of 5-HT 7 was assessed with use of an antagonist and an agonist. The underlying cellular signaling pathways were examined with use of specific blockers. Serotonin decreased TEER and reduced the expression of TJ proteins ZO-1, occludin, and claudin 1, but not claudin 4. A 5-HT 7 antagonist blocked the serotonin-induced decrease in TEER, and a 5-HT 7 agonist decreased TEER. Inhibition of p38 mitogen-activated protein kinase (MAPK) reduced the serotonin-induced decrease in TEER. Inhibition of p38 MAPK blocked the decrease of ZO-1 levels, whereas extracellular-signal-regulated kinase (ERK) inhibition blocked the decrease in occludin levels. Cell signaling pathway inhibitors had no effect on serotonin-induced alterations in claudin 1 and claudin 4 levels. Serotonin induced phosphorylation of p38 MAPK and ERK, and a 5-HT 7 antagonist partially blocked serotonin-induced phosphorylation of p38 MAPK but not that of ERK. Serotonin disrupted esophageal squamous epithelial barrier function by modulating the levels of TJ proteins. Serotonin signaling pathways may mediate the pathogenesis of gastroesophageal reflux disease.

Urinary Squamous Epithelial Cells Do Not Accurately Predict Urine Culture Contamination, but May Predict Urinalysis Performance in Predicting Bacteriuria.

PubMed

Mohr, Nicholas M; Harland, Karisa K; Crabb, Victoria; Mutnick, Rachel; Baumgartner, David; Spinosi, Stephanie; Haarstad, Michael; Ahmed, Azeemuddin; Schweizer, Marin; Faine, Brett

2016-03-01

The presence of squamous epithelial cells (SECs) has been advocated to identify urinary contamination despite a paucity of evidence supporting this practice. We sought to determine the value of using quantitative SECs as a predictor of urinalysis contamination. Retrospective cross-sectional study of adults (≥18 years old) presenting to a tertiary academic medical center who had urinalysis with microscopy and urine culture performed. Patients with missing or implausible demographic data were excluded (2.5% of total sample). The primary analysis aimed to determine an SEC threshold that predicted urine culture contamination using receiver operating characteristics (ROC) curve analysis. The a priori secondary analysis explored how demographic variables (age, sex, body mass index) may modify the SEC test performance and whether SECs impacted traditional urinalysis indicators of bacteriuria. A total of 19,328 records were included. ROC curve analysis demonstrated that SEC count was a poor predictor of urine culture contamination (area under the ROC curve = 0.680, 95% confidence interval [CI] = 0.671 to 0.689). In secondary analysis, the positive likelihood ratio (LR+) of predicting bacteriuria via urinalysis among noncontaminated specimens was 4.98 (95% CI = 4.59 to 5.40) in the absence of SECs, but the LR+ fell to 2.35 (95% CI = 2.17 to 2.54) for samples with more than 8 SECs/low-powered field (lpf). In an independent validation cohort, urinalysis samples with fewer than 8 SECs/lpf predicted bacteriuria better (sensitivity = 75%, specificity = 84%) than samples with more than 8 SECs/lpf (sensitivity = 86%, specificity = 70%; diagnostic odds ratio = 17.5 [14.9 to 20.7] vs. 8.7 [7.3 to 10.5]). Squamous epithelial cells are a poor predictor of urine culture contamination, but may predict poor predictive performance of traditional urinalysis measures. © 2016 by the Society for Academic Emergency Medicine.

Spontaneous Development of Cutaneous Squamous Cell Carcinoma in Mice with Cell-specific Deletion of Inhibitor of κB Kinase 2

PubMed Central

Kirkley, Kelly S; Walton, Kelly D; Duncan, Colleen; Tjalkens, Ronald B

2017-01-01

The deletion of NFκB in epithelial tissues by using skin-specific promoters can cause both tumor formation and severe inflammatory dermatitis, indicating that this signaling pathway is important for the maintenance of immune homeostasis in epithelial tissues. In the present study, we crossed mice transgenic for loxP-Ikbk2 and human Gfap-cre to selectively delete IKK2 in CNS astrocytes. Unexpectedly, a subset of mice developed severe and progressive skin lesions marked by hyperplasia, hyperkeratosis, dysplasia, inflammation, and neoplasia with a subset of lesions diagnosed as squamous cell carcinoma (SCC). The development of lesions was monitored over a 3.5-y period and over 4 filial generations. Average age of onset of was 4 mo of age with 19.5% of mice affected with frequency increasing in progressive generations. Lesion development appeared to correlate not only with unintended IKK2 deletion in GFAP expressing cells of the epidermis, but also with increased expression of TNF in lesioned skin. The skins changes described in these animals are similar to those in transgenic mice with an epidermis-specific deletion of NFκB and thus represents another genetic mouse model that can be used to study the role of NFκB signaling in regulating the development of SCC. PMID:28935002

Clinical laboratory urine analysis: comparison of the UriSed automated microscopic analyzer and the manual microscopy.

PubMed

Ma, Junlong; Wang, Chengbin; Yue, Jiaxin; Li, Mianyang; Zhang, Hongrui; Ma, Xiaojing; Li, Xincui; Xue, Dandan; Qing, Xiaoyan; Wang, Shengjiang; Xiang, Daijun; Cong, Yulong

2013-01-01

Several automated urine sediment analyzers have been introduced to clinical laboratories. Automated microscopic pattern recognition is a new technique for urine particle analysis. We evaluated the analytical and diagnostic performance of the UriSed automated microscopic analyzer and compared with manual microscopy for urine sediment analysis. Precision, linearity, carry-over, and method comparison were carried out. A total of 600 urine samples sent for urinalysis were assessed using the UriSed automated microscopic analyzer and manual microscopy. Within-run and between-run precision of the UriSed for red blood cells (RBC) and white blood cells (WBC) were acceptable at all levels (CV < 20%). Within-run and between-run imprecision of the UriSed testing for cast, squamous epithelial cells (EPI), and bacteria (BAC) were good at middle level and high level (CV < 20%). The linearity analysis revealed substantial agreement between the measured value and the theoretical value of the UriSed for RBC, WBC, cast, EPI, and BAC (r > 0.95). There was no carry-over. RBC, WBC, and squamous epithelial cells with sensitivities and specificities were more than 80% in this study. There is substantial agreement between the UriSed automated microscopic analyzer and the manual microscopy methods. The UriSed provides for a rapid turnaround time.

Trypsin impaired epithelial barrier function and induced IL-8 secretion through basolateral PAR-2: a lesson from a stratified squamous epithelial model.

PubMed

Shan, Jing; Oshima, Tadayuki; Chen, Xin; Fukui, Hirokazu; Watari, Jiro; Miwa, Hiroto

2012-11-15

Immune-mediated injury by the protease-activated receptor-2-interleukin-8 (PAR-2-IL8) pathway may underlie the development of gastroesophageal reflux disease (GERD). However, the localization of PAR-2 and the mechanism of PAR-2 activation remain unclear. This study aimed to address these questions on an esophageal stratified squamous epithelial model and in the human esophageal mucosa of GERD patients. Normal human esophageal epithelial cells were cultured with the air-liquid interface system to establish the model. SLIGKV-NH2 (PAR-2 synthetic agonist), trypsin (PAR-2 natural activator), and weak acid (pH 4, 5, and 6) were added to either the apical or basolateral compartment to evaluate their effects on transepithelial electrical resistance (TEER) and IL-8 production. PAR-2 localization was examined both in the cell model and biopsies from GERD patients by immunohistochemistry. Apical trypsin stimulation induced IL-8 accompanied by decreased TEER in vitro, whereas the effective concentration from the basolateral side was 10 times lower. SLIGKV-NH2 from basolateral but not apical stimulation induced IL-8 production. Apical weak acid stimulation did not influence TEER or IL-8 production. Immunohistochemistry showed intense reactivity of PAR-2 in the basal and suprabasal layers after stimulation with trypsin. A similar PAR-2 reactivity that was mainly located at the basal and suprabasal layers was detected in GERD patients. In conclusion, the activation of the PAR-2-IL-8 pathway probably occurred at the basal and suprabasal layers, while the esophageal epithelial barrier may influence the activation of PAR-2. Under proton pump inhibitor therapy, refluxed trypsin may remain active and be a potential agent in the pathogenesis of refractory GERD.

Submicrostructure and typing of female genital condylomata.

PubMed

He, Y C; Shen, L S; Xie, Z J; Yang, C L; Li, H; Zheng, Y; Zhu, G C; Zhao, S Z; Wang, C X; Zhang, J H

1993-04-01

Thirty biopsies from female genital condylomata were examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to study structural characteristics and typing of condylomata. It was found that cytoplasmic clearing was marked in acuminate condylomata, diffuse interstitial and epithelial proliferation in nodular condylomata (flat condylomata), and invagination of the lesions into the interstitial tissue or glandular ducts in endophytic condylomata. In nodular condylomata, SEM also showed some structural features similar to those of intra-epithelial neoplasia. Microridges on the surface of squamous cells had villiform of granular changes. On the surface of a percentage of squamous or columnar cells, there were holes with a diameter of about 3 to 5 microns. A number of giant cells were seen among other cells. The cervical squamatization zone contained groups of special cells covered with dense microvilli. TEM of nodular condylomata revealed some pictures resembling active proliferation of tumor cells, such as enlarged or irregular nuclei (large N/C ratio), evaginated or invaginated nuclear membranes, condensed chromatin attached to the inner part of the nuclear membrane, transparent nucleoplasm, and frequent nucleosomes and karyokinesis. Virus particles with the morphological characteristics of HPV (naked hexagon-like particles with an average diameter of 45-50 nm) were seen in some nuclei with markedly condensed chromatin. It is suggested that HPV-induced genital condylomata, especially nodular one (flat condylomata), entail a potential progression to malignancy.

A loss of profilin-1 in late-stage oral squamous cell carcinoma.

PubMed

Adami, Guy R; O'Callaghan, Thomas N; Kolokythas, Antonia; Cabay, Robert J; Zhou, Yalu; Schwartz, Joel L

2017-08-01

The genes for PFN1 and TMSB4 are both highly expressed in oral tissue and both encode actin monomer binding proteins thought to play a role in cell motility and possibly other crucial parts of tumor progression. Oral brush cytology of epithelium from oral squamous cell carcinoma (OSCC) was used to measure PFN1 and TMSB4 mRNA in OSCC, while immunohistochemical analysis of tissue was used to check protein levels. High but variable expression of mRNAs encoding these two proteins was observed suggesting they may contribute to tumor characteristics in a subset of OSCCs. Both proteins were highly expressed in normal appearing basal epithelium, in the cytoplasm, and perinuclear area, while expression was minimal in upper epithelial layers. In OSCCs, expression of these proteins varied. In tumors classified as later stage, based on size and/or lymph node involvement, PFN1 levels were lower in tumor epithelium. A control gene, KRT13, showed expression in normal differentiated basal and suprabasal oral mucosa epithelial cells and as reported was lost in OSCC cells. Loss of PFN1 in tumor cells has been associated with lymph node invasion and metastasis in other tumor types, strengthening the argument that the protein has the potential to be a tumor suppressor in late-stage OSCC. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Comparative study of frequency of micronuclei in normal, potentially malignant diseases and oral squamous cell carcinoma.

PubMed

Sangle, Varsha Ajit; Bijjaragi, Shobha; Shah, Nishat; Kangane, Suresh; Ghule, Hrishikesh M; Rani, Sr Ashwini

2016-01-01

The assessment of micronuclei (MN) in exfoliated oral epithelial cells is a promising tool for the study of epithelial carcinogens and can be used to detect chromosome breakage or mitotic interference, thought to be relevant to carcinogenesis. To detect MN in exfoliated oral mucosal cells in individuals using various tobacco forms and also to detect frequency of MN in premalignant lesions and conditions (potentially malignant diseases [PMD's]) and oral squamous cell carcinoma (OSCC). To correlate frequency of MN in oral exfoliated cells in clinically diagnosed cases of OSCC followed by a histopathological grading. A total of 90 subjects (30 smokeless tobacco users, 30 smokers and 30 nontobacco users) consisted of clinically diagnosed cases of PMD's and OSCC were selected for the study. Cytosmears from the groups were stained with rapid Papanicolaou stain. MN was identified according to the Tolbert et al. criteria. MN cells were found to be significantly higher in smokeless tobacco users than in smokers. The frequency of MN was three to four times higher in patients with OSCC as compared to patients in PMD's (P < 0.0001). The frequency of MN correlated with the histopathological grade was statistically significant. MN index can be used as a biomarker/screening test among the high-risk groups particularly the smokeless tobacco users and PMD's. MN can be a candidate to serve as a biomarker for prediction of the grade of OSCC.

In Vitro Detection of Characteristic Differences in Radiation Sensitivity of Female Genital Cancers

DOE Office of Scientific and Technical Information (OSTI.GOV)

LUDOVICI, PETER P.; MILLER, NORMAN F.

1962-01-01

BS>By a standardized assay technic in which cell monolayers were irradiated at different dose levels (100 to 1200 r) on the 4th culture day and cell counts carried out 4 days later, the radiation sensitivities of 37 cell strains, derived from female patients with various genital cancers and from normal individuals, were assessed. These 37 cell strains had certain patterns of radiation sensitivity which, in general, appear to be consistent with the generally accepted radiosensitivity of the tumors from which the cell strains arose. Cell strains from squamous-cell carcinomas of the cervix as a group were at least twice asmore » sensitive as those from other squamous-cell carcinomas of the female genital tract. Cell strains derived from carcinomas of the ovary, vagina, and vulva were almost equally resistant to radiation. As expected, cell strains derived from benign tissues were the most highly resistant to radiation, normal fibroblastic strains being more resistant than normal epithelial strains. (H.H.D.)« less

Productive Lifecycle of Human Papillomaviruses that Depends Upon Squamous Epithelial Differentiation

PubMed Central

Kajitani, Naoko; Satsuka, Ayano; Kawate, Akifumi; Sakai, Hiroyuki

2012-01-01

Human papillomaviruses (HPVs) target the stratified epidermis, and can causes diseases ranging from benign condylomas to malignant tumors. Infections of HPVs in the genital tract are among the most common sexually transmitted diseases, and a major risk factor for cervical cancer. The virus targets epithelial cells in the basal layer of the epithelium, while progeny virions egress from terminally differentiated cells in the cornified layer, the surface layer of the epithelium. In infected basal cells, the virus maintains its genomic DNA at low-copy numbers, at which the viral productive lifecycle cannot proceed. Progression of the productive lifecycle requires differentiation of the host cell, indicating that there is tight crosstalk between viral replication and host differentiation programs. In this review, we discuss the regulation of the HPV lifecycle controlled by the differentiation program of the host cells. PMID:22536200

CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma.

PubMed

Zhou, Jin; Wu, Zhong; Wong, Gabrielle; Pectasides, Eirini; Nagaraja, Ankur; Stachler, Matthew; Zhang, Haikuo; Chen, Ting; Zhang, Haisheng; Liu, Jie Bin; Xu, Xinsen; Sicinska, Ewa; Sanchez-Vega, Francisco; Rustgi, Anil K; Diehl, J Alan; Wong, Kwok-Kin; Bass, Adam J

2017-01-06

Oesophageal squamous cell carcinoma is a deadly disease where systemic therapy has relied upon empiric chemotherapy despite the presence of genomic alterations pointing to candidate therapeutic targets, including recurrent amplification of the gene encoding receptor tyrosine kinase epidermal growth factor receptor (EGFR). Here, we demonstrate that EGFR-targeting small-molecule inhibitors have efficacy in EGFR-amplified oesophageal squamous cell carcinoma (ESCC), but may become quickly ineffective. Resistance can occur following the emergence of epithelial-mesenchymal transition and by reactivation of the mitogen-activated protein kinase (MAPK) pathway following EGFR blockade. We demonstrate that blockade of this rebound activation with MEK (mitogen-activated protein kinase kinase) inhibition enhances EGFR inhibitor-induced apoptosis and cell cycle arrest, and delays resistance to EGFR monotherapy. Furthermore, genomic profiling shows that cell cycle regulators are altered in the majority of EGFR-amplified tumours and a combination of cyclin-dependent kinase 4/6 (CDK4/6) and EGFR inhibitors prevents the emergence of resistance in vitro and in vivo. These data suggest that upfront combination strategies targeting EGFR amplification, guided by adaptive pathway reactivation or by co-occurring genomic alterations, should be tested clinically.

Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration

PubMed Central

Giroux, Véronique; Lento, Ashley A.; Islam, Mirazul; Pitarresi, Jason R.; Kharbanda, Akriti; Hamilton, Kathryn E.; Whelan, Kelly A.; Long, Apple; Rhoades, Ben; Tang, Qiaosi; Nakagawa, Hiroshi; Lengner, Christopher J.; Bass, Adam J.; Wileyto, E. Paul; Klein-Szanto, Andres J.; Wang, Timothy C.; Rustgi, Anil K.

2017-01-01

The esophageal lumen is lined by a stratified squamous epithelium comprised of proliferative basal cells that differentiate while migrating toward the luminal surface and eventually desquamate. Rapid epithelial renewal occurs, but the specific cell of origin that supports this high proliferative demand remains unknown. Herein, we have described a long-lived progenitor cell population in the mouse esophageal epithelium that is characterized by expression of keratin 15 (Krt15). Genetic in vivo lineage tracing revealed that the Krt15 promoter marks a long-lived basal cell population able to self-renew, proliferate, and generate differentiated cells, consistent with a progenitor/stem cell population. Transcriptional profiling demonstrated that Krt15+ basal cells are molecularly distinct from Krt15– basal cells. Depletion of Krt15-derived cells resulted in decreased proliferation, thereby leading to atrophy of the esophageal epithelium. Further, Krt15+ cells were radioresistant and contributed to esophageal epithelial regeneration following radiation-induced injury. These results establish the presence of a long-lived and indispensable Krt15+ progenitor cell population that provides additional perspective on esophageal epithelial biology and the widely prevalent diseases that afflict this epithelium. PMID:28481227

Molecular profiling of tumour budding implicates TGFβ-mediated epithelial-mesenchymal transition as a therapeutic target in oral squamous cell carcinoma.

PubMed

Jensen, D H; Dabelsteen, E; Specht, L; Fiehn, A M K; Therkildsen, M H; Jønson, L; Vikesaa, J; Nielsen, F C; von Buchwald, C

2015-08-01

Although tumour budding is an adverse prognostic factor for many cancer types, the molecular mechanisms governing this phenomenon are incompletely understood. Therefore, understanding the molecular basis of tumour budding may provide new therapeutic and diagnostic options. We employ digital image analysis to demonstrate that the number of tumour buds in cytokeratin-stained sections correlates with patients having lymph node metastases at diagnosis. The tumour bud count was also a predictor of overall survival, independent of TNM stage. Tumour buds and paired central tumour areas were subsequently collected from oral squamous cell carcinoma (OSCC) specimens, using laser capture microdissection, and examined with RNA sequencing and miRNA-qPCR arrays. Compared with cells from the central parts of the tumours, budding cells exhibited a particular gene expression signature, comprising factors involved in epithelial-mesenchymal transition (EMT) and activated TGFβ signalling. Transcription factors ZEB1 and PRRX1 were up-regulated concomitantly with the decreased expression of mesenchymal-epithelial (MET) transcription factors (eg OVOL1) in addition to Krüppel-like factors and Grainyhead-like factors. Moreover, miR-200 family members were down-regulated in budding tumour cells. We used immunohistochemistry to validate five markers of the EMT/MET process in 199 OSCC tumours, as well as in situ hybridization in 20 OSCC samples. Given the strong relationship between tumour budding and the development of lymph node metastases and an adverse prognosis, therapeutics based on inhibiting the activation of TGFβ signalling may prove useful in the treatment of OSCC. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Proteins facilitating Escherichia coli O157 persistence at the bovine recto-anal junction (RAJ) squamous epithelial cells

USDA-ARS?s Scientific Manuscript database

Escherichia coli O157 (O157) persist at the recto-anal junction (RAJ) of gastrointestinal tracts (GIT) of cattle, the primary reservoirs of this human pathogen. We recently reported (Kudva et al., BMC Microbiol. 2012, 12: 103) that the previously identified and extensively documented principal O157...

Cancer of the Esophagus and Esophagogastric Junction: An Eighth Edition Staging Primer

PubMed Central

Rice, Thomas W.; Ishwaran, Hemant; Ferguson, Mark K.; Blackstone, Eugene H.; Goldstraw, Peter

2017-01-01

This primer for eighth edition staging of esophageal and esophagogastric epithelial cancers presents separate classifications for the clinical (cTNM), pathologic (pTNM), and postneoadjuvant pathologic (ypTNM) stage groups, which are no longer shared. For pTNM, pT1 has been subcategorized as pT1a and pT1b for the subgrouping pStage I adenocarcinoma and squamous cell carcinoma. A new, simplified esophagus-specific regional lymph node map has been introduced. Undifferentiated histologic grade (G4) has been eliminated; additional analysis is required to expose histopathologic cell type. Location has been removed as a category for pT2N0M0 squamous cell cancer. The definition of the esophagogastric junction has been revised. ypTNM stage groups are identical for both histopathologic cell types, unlike those for cTNM and pTNM. PMID:27810391

Immunolocalization of osteopontin in dysplasias and squamous cell carcinomas arising from oral epithelium

PubMed Central

Aravind, Thara; Janardhanan, Mahija; Rakesh, S; Savithri, Vindhya; Unnikrishnan, U G

2017-01-01

Background: Early detection of oral squamous cell carcinoma (OSCC) remains one of the most efficient ways to ensure patient survival and improved quality of life. Although specific biomarkers related to OSCC have been investigated, a useful biomarker that assesses the transition potential of potentially malignant lesion to OSCC remains to be found. Osteopontin (OPN) has been recognized as an important factor in tumorigenesis and their expression in OSCC have been investigated earlier. In the present study, evaluation of OPN expression in premalignant and malignant lesions has been carried out to assess their possible role as a biomarker in the early diagnosis and prognosis of OSCC. Objectives: The objective of this study is to evaluate the role of OPN as a biomarker in the diagnosis and prognosis of OSCC. Materials and Methods: The study group consisted of archival paraffin-embedded blocks of ten cases each of varying grades of OSCC, oral epithelial dysplasias and epithelial hyperplasias. Sections were subjected to immunohistochemical staining for the biomarker OPN. Results: A positive OPN expression was noticed in epithelial dysplasias and SCC arising from the oral epithelium. A progressive increase in the intensity of staining was seen with increasing grades of dysplasias and a decrease in OPN expression with an increase in grades was observed in OSCC. Conclusion: The expression of OPN in full thickness of epithelium in severe dysplasias, carcinoma in situ, and in the superficial epithelium of OSCC suggest the possibility of considering OPN expression in full epithelial thickness in dysplasias as an indicator for malignant transformation. PMID:28479681

Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents

PubMed Central

Szabo, Eva; Miller, Mark Steven; Lubet, Ronald A.; You, Ming; Wang, Yian

2017-01-01

Due to exposure to environmental toxicants, a “field cancerization” effect occurs in the lung resulting in the development of a field of initiated but morphologically normal appearing cells in the damaged epithelium of bronchial airways with dysregulated gene expression patterns. Using a mouse model of lung squamous cell carcinoma (SCC), we performed transcriptome sequencing (RNA-Seq) to profile bronchial airway gene expression and found activation of the PI3K and Myc signaling networks in cytologically normal bronchial airway epithelial cells of mice with preneopastic lung SCC lesions, which was reversed by treatment with the PI3K Inhibitor XL-147 and pioglitazone, respectively. Activated MYC signaling was also present in premalignant and tumor tissues from human lung SCC patients. In addition, we identified a key microRNA, mmu-miR-449c-5p, whose suppression significantly up-regulated Myc expression in the normal bronchial airway epithelial cells of mice with early stage SCC lesions. We developed a novel bronchial genomic classifier in mice and validated it in humans. In the classifier, Ppbp (pro-platelet basic protein) was overexpressed 115 fold in the bronchial airways of mice with preneoplastic lung SCC lesions. This is the first report that demonstrates Ppbp as a novel biomarker in the bronchial airway for lung cancer diagnosis. PMID:27935865

[Promoting effect of cyclin D1 overexpression on proliferation and epithelial mesenchymal transition of cervical squamous cell carcinoma SiHa cells].

PubMed

Wang, P; Liu, S; Cheng, B; Wu, X Z; Ding, S S; Xu, L; Liu, Y; Duan, L; Sun, S Z

2017-03-08

Objective: To study effects of cyclin D1 overexpression on the proliferation and differentiation of cervical squamous cell carcinoma SiHa cells and to investigate related signaling molecules. Methods: Primers were designed to amplify the full length of cyclin D1 gene and cyclin D1 gene was amplified by PCR for constructing pcDNA3.1 plasmid vector. The construct was then transfected into SiHa cells, and the cells with stable overexpression of cyclin D1 were established, cyclin D1 gene and protein expression were detected by RT-PCR and Western blot, respectively. Cell growth curve was documented by MTT assay. CK7, E-cadherin, vimentin, Snail gene and protein expression in transfected cells were detected by RT-PCR and Western blot. RT-PCR was used to detect the mRNA expression of proliferation and differentiation-related genes like CDK4, CDK2, p21, p27, cyclin E, Rb, E2F, E6/E7 and Ki-67. After synchronization of cells, RT-PCR was used to detect of cyclin D1 and p21 mRNA expression at different time points of the cell cycle. Results: The G-3 cells with cyclin D1 overexpression were successfully established. The growth curve and Ki-67 mRNA expression accelerated in G-3 cells.Vimentin and Snail expression significantly increased at both gene and protein levels, while E-cadherin, CK7 gene and protein expression significantly decreased, indicating epithelial mesenchymal transitionoccurred in G-3 cells.Meanwhile, mRNA expression of cyclin D1, CDK4, CDK2, p21, p27, cyclin E, E2F and Rb increased, while E6/E7 and p16 showed no significant change. The expression trends of p21 and cyclin D1 were almost identical with fluctuation at different time points in the cell cycle. Conclusions: Overexpression of cyclin D1 induced by gene transfection promotes proliferation and epithelial mesenchymal transition in SiHa cells.The process is accompanied by up-regulation of CDK4, CDK2, p21, p27 and cyclin E genes.p21 expression increases synchronously with cyclin D1, suggesting a regulatory role in epithelial mesenchymal transition by affecting expression of vimentin in G-3 cells.

Curli Temper Adherence of Escherichia coli O157:H7 to Squamous Epithelial Cells from the Bovine Recto-Anal Junction in a Strain-Dependent Manner

PubMed Central

Carter, Michelle Q.; Sharma, Vijay K.; Stasko, Judith A.; Giron, Jorge A.

2016-01-01

ABSTRACT Our recent studies have shown that intimin and the locus of enterocyte effacement-encoded proteins do not play a role in Escherichia coli O157:H7 (O157) adherence to the bovine recto-anal junction squamous epithelial (RSE) cells. To define factors that play a contributory role, we investigated the role of curli, fimbrial adhesins commonly implicated in adherence to various fomites and plant and human epithelial cells, in O157 adherence to RSE cells. Specifically, we examined (i) wild-type strains of O157; (ii) curli variants of O157 strains; (iii) isogenic curli deletion mutants of O157; and (iv) adherence inhibition of O157 using anti-curlin sera. Results of these experiments conducted under stringent conditions suggest that curli do not solely contribute to O157 adherence to RSE cells and in fact demonstrate a modulating effect on O157 adherence to RSE cells in contrast to HEp-2 cells (human epidermoid carcinoma of the larynx cells with HeLa contamination). The absence of curli and presence of blocking anti-curli antibodies enhanced O157-RSE cell interactions among some strains, thus alluding to a spatial, tempering effect of curli on O157 adherence to RSE cells when present. At the same time, the presence or absence of curli did not alter RSE cell adherence patterns of another O157 strain. These observations are at variance with the reported role of curli in O157 adherence to human cell lines such as HEp-2 and need to be factored in when developing anti-adherence modalities for preharvest control of O157 in cattle. IMPORTANCE This study demonstrated that O157 strains interact with epithelial cells in a host-specific manner. The fimbriae/adhesins that are significant for adherence to human cell lines may not have a role or may have a modulating role in O157 adherence to bovine cells. Targeting such adhesins may not prevent O157 attachment to bovine cells but instead may result in improved adherence. Hence, conducting host-specific evaluations is critical when selecting targets for O157 control strategies. PMID:27742683

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas.

PubMed

Campbell, Joshua D; Yau, Christina; Bowlby, Reanne; Liu, Yuexin; Brennan, Kevin; Fan, Huihui; Taylor, Alison M; Wang, Chen; Walter, Vonn; Akbani, Rehan; Byers, Lauren Averett; Creighton, Chad J; Coarfa, Cristian; Shih, Juliann; Cherniack, Andrew D; Gevaert, Olivier; Prunello, Marcos; Shen, Hui; Anur, Pavana; Chen, Jianhong; Cheng, Hui; Hayes, D Neil; Bullman, Susan; Pedamallu, Chandra Sekhar; Ojesina, Akinyemi I; Sadeghi, Sara; Mungall, Karen L; Robertson, A Gordon; Benz, Christopher; Schultz, Andre; Kanchi, Rupa S; Gay, Carl M; Hegde, Apurva; Diao, Lixia; Wang, Jing; Ma, Wencai; Sumazin, Pavel; Chiu, Hua-Sheng; Chen, Ting-Wen; Gunaratne, Preethi; Donehower, Larry; Rader, Janet S; Zuna, Rosemary; Al-Ahmadie, Hikmat; Lazar, Alexander J; Flores, Elsa R; Tsai, Kenneth Y; Zhou, Jane H; Rustgi, Anil K; Drill, Esther; Shen, Ronglei; Wong, Christopher K; Stuart, Joshua M; Laird, Peter W; Hoadley, Katherine A; Weinstein, John N; Peto, Myron; Pickering, Curtis R; Chen, Zhong; Van Waes, Carter

2018-04-03

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches. Published by Elsevier Inc.

Ichthyosis uteri with leiomyoma.

PubMed

Kanno, Kiyoshi; Kusakabe, Takashi; Takata, Megumi; Suzuki, Kazuo; Oowada, Makoto; Suzuki, Hiroshi

2016-11-01

A 58-year-old, postmenopausal, multiparous woman presented with a chief complaint of abnormal vaginal bleeding. Endometrial cytology was evaluated twice, revealing only squamous epithelial cells both times. Degenerated leiomyoma or uterine sarcoma was suspected from imaging findings, and total abdominal hysterectomy and bilateral salpingo-oophorectomy were therefore performed. However, histopathological examination revealed no signs of malignancy, and the patient was diagnosed as having ichthyosis uteri with uterine leiomyoma. No koilocytosis was evident, and immunostaining for p16 was also negative. Ichthyosis uteri is an extremely rare disease of unknown origin in which squamous metaplasia of the endometrium occurs across a wide area. Although regarded as a benign condition, cases have been reported in which the underlying condition was squamous cell carcinoma or endometrial adenocarcinoma. If ichthyosis uteri is present, a comprehensive approach is required, and the possibility of uterine malignancy should be considered. However, there may be no direct association between the malignant lesions and ichthyosis uteri. © 2016 Japan Society of Obstetrics and Gynecology.

Identification of unique expression signatures and therapeutic targets in esophageal squamous cell carcinoma

PubMed Central

2012-01-01

Background Esophageal squamous cell carcinoma (ESCC), the predominant histological subtype of esophageal cancer, is characterized by high mortality. Previous work identified important mRNA expression differences between normal and tumor cells; however, to date there are limited ex vivo studies examining expression changes occurring during normal esophageal squamous cell differentiation versus those associated with tumorigenesis. In this study, we used a unique tissue microdissection strategy and microarrays to measure gene expression profiles associated with cell differentiation versus tumorigenesis in twelve cases of patient-matched normal basal squamous epithelial cells (NB), normal differentiated squamous epithelium (ND), and squamous cell cancer. Class comparison and pathway analysis were used to compare NB versus tumor in a search for unique therapeutic targets. Results As a first step towards this goal, gene expression profiles and pathways were evaluated. Overall, ND expression patterns were markedly different from NB and tumor; whereas, tumor and NB were more closely related. Tumor showed a general decrease in differentially expressed genes relative to NB as opposed to ND that exhibited the opposite trend. FSH and IgG networks were most highly dysregulated in normal differentiation and tumorigenesis, respectively. DNA repair pathways were generally elevated in NB and tumor relative to ND indicating involvement in both normal and pathological growth. PDGF signaling pathway and 12 individual genes unique to the tumor/NB comparison were identified as therapeutic targets, and 10 associated ESCC gene-drug pairs were identified. We further examined the protein expression level and the distribution patterns of four genes: ODC1, POSTN, ASPA and IGF2BP3. Ultimately, three genes (ODC1, POSTN, ASPA) were verified to be dysregulated in the same pattern at both the mRNA and protein levels. Conclusions These data reveal insight into genes and molecular pathways mediating ESCC development and provide information potentially useful in designing novel therapeutic interventions for this tumor type. PMID:22280838

Salivary Chemical Factors in Relation with Oral Cancer in Smokers and Non-Smokers: a Literature Review

PubMed Central

Nosratzehi, Tahereh

2017-01-01

Squamous cell carcinoma of oral cavity is of malignant tumors, which causes cancerous complications. DNA damage, mainly because of products of oxidative stress like reactive oxygen species, is a frequent mutagenic that triggers carcinoma. Smoking increases the probability of cancer incidence. Saliva is the first biological medium to interact with external compounds, especially smoking substances. The present study overviews the salivary level of some remarkable compounds in relation with smoking and squamous cell carcinoma. To collect data, English literature was searched in databases including PubMed, ScienceDirect and Google Scholar. The keywords used for search were as follows: ‘Carcinoma, Squamous Cell’, ‘Smoking’, ‘Saliva’, and ‘Biomarkers‘. The inclusion criteria were the presence of salivary chemical factors in relation with oral cancer and influence by smoking. Out of 239 found articles, only 56 were selected. Our results demonstrated the potential role of salivary biochemistry to predict and/or treat complications with cancer in both smoker and non-smoker individuals. Changes in concentrations of salivary chemicals including antioxidants, total antioxidant, glutathione and uric acid, epithelial growth factor, cytokine biomarkers, superoxide dismutase activity, and transcriptome were related to squamous cell carcinoma and could be used as potential biomarkers for cancer prognosis; moreover, enhancement of antioxidant level might be a potential treatment. PMID:29201965

CD44 staining of cancer stem-like cells is influenced by down-regulation of CD44 variant isoforms and up-regulation of the standard CD44 isoform in the population of cells that have undergone epithelial-to-mesenchymal transition.

PubMed

Biddle, Adrian; Gammon, Luke; Fazil, Bilal; Mackenzie, Ian C

2013-01-01

CD44 is commonly used as a cell surface marker of cancer stem-like cells in epithelial tumours, and we have previously demonstrated the existence of two different CD44(high) cancer stem-like cell populations in squamous cell carcinoma, one having undergone epithelial-to-mesenchymal transition and the other maintaining an epithelial phenotype. Alternative splicing of CD44 variant exons generates a great many isoforms, and it is not known which isoforms are expressed on the surface of the two different cancer stem-like cell phenotypes. Here, we demonstrate that cancer stem-like cells with an epithelial phenotype predominantly express isoforms containing the variant exons, whereas the cancer stem-like cells that have undergone an epithelial-to-mesenchymal transition down-regulate these variant isoforms and up-regulate expression of the standard CD44 isoform that contains no variant exons. In addition, we find that enzymatic treatments used to dissociate cells from tissue culture or fresh tumour specimens cause destruction of variant CD44 isoforms at the cell surface whereas expression of the standard CD44 isoform is preserved. This results in enrichment within the CD44(high) population of cancer stem-like cells that have undergone an epithelial-to-mesenchymal transition and depletion from the CD44(high) population of cancer stem-like cells that maintain an epithelial phenotype, and therefore greatly effects the characteristics of any cancer stem-like cell population isolated based on expression of CD44. As well as effecting the CD44(high) population, enzymatic treatment also reduces the percentage of the total epithelial cancer cell population staining CD44-positive, with potential implications for studies that aim to use CD44-positive staining as a prognostic indicator. Analyses of the properties of cancer stem-like cells are largely dependent on the ability to accurately identify and assay these populations. It is therefore critical that consideration be given to use of multiple cancer stem-like cell markers and suitable procedures for cell isolation in order that the correct populations are assayed.

Variation of Keratin 7 Expression and Other Phenotypic Characteristics of Independent Isolates of Cadmium Transformed Human Urothelial Cells (UROtsa)

PubMed Central

Somji, Seema; Zhou, Xu Dong; Mehus, Aaron; Sens, Mary Ann; Garrett, Scott H.; Lutz, Krista L.; Dunlevy, Jane R.; Zheng, Yun; Sens, Donald. A.

2009-01-01

This laboratory has shown that a human urothelial cell line (UROtsa) transformed by cadmium (Cd+2) produced subcutaneous tumor heterotransplants that resemble human transitional cell carcinoma (TCC). In the present study, additional Cd+2 transformed cell lines were isolated to determine if independent exposures of the cell line to Cd+2 would result in malignantly transformed cell lines possessing similar phenotypic properties. Seven independent isolates were isolated and assessed for their doubling times, morphology, ability to heterotransplant subcutaneously and in the peritoneal cavity of nude mice and for the expression keratin 7. The 7 cell lines all displayed an epithelial morphology with no evidence of squamous differentiation. Doubling times were variable among the isolates, being significantly reduced or similar to the parental cells. All 7 isolates were able to form subcutaneous tumor heterotransplants with a TCC morphology and all heterotransplants displayed areas of squamous differentiation of the transitional cells. The degree of squamous differentiation varied among the isolates. In contrast to subcutaneous tumor formation, only 1 isolate of the Cd+2 transformed cells (UTCd#1) was able to effectively colonize multiple sites within the peritoneal cavity. An analysis of keratin 7 expression showed no correlation with squamous differentiation for the subcutaneous heterotransplants generated from the 7 cell lines. Keratin 7 was expressed in 6 of the 7 cell lines and their subcutaneous tumor heterotransplants. Keratin 7 was not expressed in the cell line that was able to form tumors within the peritoneal cavity. These results show that individual isolates of Cd+2 transformed cells have both similarities and differences in their phenotype. PMID:19921857

Epithelial morphogenesis of germline-derived pluripotent stem cells on organotypic skin equivalents in vitro.

PubMed

van de Kamp, Julia; Kramann, Rafael; Anraths, Julia; Schöler, Hans R; Ko, Kinarm; Knüchel, Ruth; Zenke, Martin; Neuss, Sabine; Schneider, Rebekka K

2012-03-01

For tissue engineering, cultivation of pluripotent stem cells on three-dimensional scaffolds allows the generation of organ-like structures. Previously, we have established an organotypic culture system of skin to induce epidermal differentiation in adult stem cells. Multipotent stem cells are not able to differentiate across germinal boundaries. In contrast, pluripotent stem cells readily differentiate into tissues of all three germ layers. Germline-derived pluripotent stem cells (gPS cells) can be generated by induction of pluripotency in mouse unipotent germline stem cells without the introduction of exogenous transcription factors. In the current study, we analyzed the influence of organotypic culture conditions of skin on the epithelial differentiation of gPS cells in comparison to the well-established HM1 ES cell line. Quantitative RT-PCR data of the pluripotency gene Oct4 showed that gPS cells are characterized by an accelerated Oct4-downregulation compared to HM1 ES cells. When subjected to the organotypic culture conditions of skin, gPS cells formed tubulocystic structures lined by stratified (CK5/6(+), CK14(+), CK8/18(-)) epithelia. HM1 ES cells formed only small tubulocystic structures lined by simple, CK8/18(+) epithelia. BMP-4, an epidermal morphogen, significantly enhanced the expression of epithelial markers in HM1 ES cells, but did not significantly affect the formation of complex (squamous) epithelia in gPS cells. In HM1 ES cells the differentiation into squamous epithelium was only inducible in the presence of mature dermal fibroblasts. Both pluripotent stem cell types spontaneously differentiated into mesodermal, endodermal and into neuroectodermal cells at low frequency, underlining their pluripotent differentiation capacity. Concluding, the organotypic culture conditions of skin induce a multilayered, stratified epithelium in gPS cells, in HM1 ES cells only in the presence of dermal fibroblasts. Thus, our data show that differentiation protocols strongly depend on the stem cell type and have to be modified for each specific stem cell type. Copyright © 2011 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Unusual recurrent tongue spindle cell carcinoma with marked anaplasia occurring at the site of glossectomy for a well-differentiated squamous cell carcinoma: A case report.

PubMed

Okuyama, Kohei; Fujita, Shuichi; Yanamoto, Souichi; Naruse, Tomofumi; Sakamoto, Yuki; Kawakita, Akiko; Omori, Keisuke; Tsuchihashi, Hiroki; Umeda, Masahiro

2017-09-01

Spindle cell carcinoma (SpCC), which predominantly arises in the oral, pharyngeal and laryngeal mucosal tissues, is composed of a mixture of squamous and sarcomatoid components. The present study describes the case of a 62-year-old woman with SpCC recurrence 4 years after an initial surgery to remove a well-differentiated primary squamous cell carcinoma (SCC) of the tongue. The recurrent tumor was spherical and located deep within the tongue tissue, which differs from the typical manifestation of ulcerated masses of the mucosa. The majority of cases of recurrence involving SpCC are associated with radiotherapeutic treatment of the primary malignancy; however, the patient in the present study had not received postoperative radiotherapy for SCC. Furthermore, the recurrent tumor in the present case exhibited marked anaplasia and sarcomatoid features, and the absence of SCC elements upon biopsy rendered histological diagnosis difficult. In summary, the present findings suggest that immunohistochemical examination and identification of SCC components are essential for ensuring the accuracy of the histological diagnosis of recurrent SpCC following a primary epithelial malignancy.

Unusual recurrent tongue spindle cell carcinoma with marked anaplasia occurring at the site of glossectomy for a well-differentiated squamous cell carcinoma: A case report

PubMed Central

Okuyama, Kohei; Fujita, Shuichi; Yanamoto, Souichi; Naruse, Tomofumi; Sakamoto, Yuki; Kawakita, Akiko; Omori, Keisuke; Tsuchihashi, Hiroki; Umeda, Masahiro

2017-01-01

Spindle cell carcinoma (SpCC), which predominantly arises in the oral, pharyngeal and laryngeal mucosal tissues, is composed of a mixture of squamous and sarcomatoid components. The present study describes the case of a 62-year-old woman with SpCC recurrence 4 years after an initial surgery to remove a well-differentiated primary squamous cell carcinoma (SCC) of the tongue. The recurrent tumor was spherical and located deep within the tongue tissue, which differs from the typical manifestation of ulcerated masses of the mucosa. The majority of cases of recurrence involving SpCC are associated with radiotherapeutic treatment of the primary malignancy; however, the patient in the present study had not received postoperative radiotherapy for SCC. Furthermore, the recurrent tumor in the present case exhibited marked anaplasia and sarcomatoid features, and the absence of SCC elements upon biopsy rendered histological diagnosis difficult. In summary, the present findings suggest that immunohistochemical examination and identification of SCC components are essential for ensuring the accuracy of the histological diagnosis of recurrent SpCC following a primary epithelial malignancy. PMID:28781811

Keratin expression profiling of transitional epithelium in the painful bladder syndrome/interstitial cystitis.

PubMed

Laguna, Pilar; Smedts, Frank; Nordling, Jörgen; Horn, Thomas; Bouchelouche, Kirsten; Hopman, Anton; de la Rosette, Jean

2006-01-01

Painful bladder syndrome/interstitial cystitis (PBS/IC) is a severely debilitating condition. Its cause is poorly understood; therapy is symptomatic and often unsuccessful. To study urothelial involvement, we characterized the keratin phenotype of bladder urothelium in 18 patients with PBS/IC using a panel of 11 keratin antibodies recognizing simple keratins found in columnar epithelia (keratins 7, 8, 18, and 20) and keratins associated with basal cell compartments of squamous epithelia (keratins 5, 13, 14, and 17). We also tested 2 antibodies recognizing more than 1 keratin also directed against basal cell compartments of squamous epithelia (D5/16 B4 and 34betaE12). Bladder urothelium in PBS/IC showed distinct differences in the profiles of keratins 7, 8, 14, 17, 18, and 20 compared with literature reports for normal bladder urothelium. These were characterized by a shift from the normal bladder urothelial keratin phenotype to a more squamous keratin profile, despite the lack of morphologic evidence of squamous epithelial differentiation and a loss of compartmentalization of keratin expression. The severity of these changes varied between biopsy specimens. Whether these changes are primary or secondary to another underlying condition remains to be determined.

Papilloma of lip associated with human papilloma viruses-32 infection in a child.

PubMed

Sabeena, Sasidharanpillai; Pallade, Sadashiva Rao; Kamath, Nutan; Mathew, Mary; Arunkumar, Govindakarnavar

2016-01-01

Squamous papilloma is the most common benign oral epithelial lesion, and it is well known to be associated with human papilloma virus 6 and 11. Here, we report a case of squamous papilloma associated with human papilloma viruses (HPV)-32 in a 4-year-old boy who presented with a verrucous lesion on the lower lip. HPV-32 is often associated with a rare benign condition focal epithelial hyperplasia (FEH). A limited number of lesions and the absence of characteristic histology ruled out FEH in our patient. To the best of our knowledge, the association of oral squamous papilloma with HPV-32 is hitherto unreported.

Morphology of the ampullae of Lorenzini in juvenile freshwater Carcharhinus leucas.

PubMed

Whitehead, Darryl L; Gauthier, Arnault R G; Mu, Erica W H; Bennett, Mike B; Tibbetts, Ian R

2015-05-01

Ampullae of Lorenzini were examined from juvenile Carcharhinus leucas (831-1,045 mm total length) captured from freshwater regions of the Brisbane River. The ampullary organ structure differs from all other previously described ampullae in the canal wall structure, the general shape of the ampullary canal, and the apically nucleated supportive cells. Ampullary pores of 140-205 µm in diameter are distributed over the surface of the head region with 2,681 and 2,913 pores present in two sharks that were studied in detail. The primary variation of the ampullary organs appears in the canal epithelial cells which occur as either flattened squamous epithelial cells or a second form of pseudostratified contour-ridged epithelial cells; both cell types appear to release material into the ampullary lumen. Secondarily, this ampullary canal varies due to involuted walls that form a clover-like canal wall structure. At the proximal end of the canal, contour-ridged cells abut a narrow region of cuboidal epithelial cells that verge on the constant, six alveolar sacs of the ampulla. The alveolar sacs contain numerous receptor and supportive cells bound by tight junctions and desmosomes. Pear-shaped receptor cells that possess a single apical kinocilium are connected basally by unmyelinated neural boutons. Opposed to previously described ampullae of Lorenzini, the supportive cells have an apical nucleus, possess a low number of microvilli, and form a unique, jagged alveolar wall. A centrally positioned centrum cap of cuboidal epithelial cells overlies a primary afferent lateral line nerve. © 2014 Wiley Periodicals, Inc.

Multimodality approach to optical early detection and mapping of oral neoplasia

NASA Astrophysics Data System (ADS)

Ahn, Yeh-Chan; Chung, Jungrae; Wilder-Smith, Petra; Chen, Zhongping

2011-07-01

Early detection of cancer remains the best way to ensure patient survival and quality of life. Squamous cell carcinoma is usually preceded by dysplasia presenting as white, red, or mixed red and white epithelial lesions on the oral mucosa (leukoplakia, erythroplakia). Dysplastic lesions in the form of erythroplakia can carry a risk for malignant conversion of 90%. A noninvasive diagnostic modality would enable monitoring of these lesions at regular intervals and detection of treatment needs at a very early, relatively harmless stage. The specific aim of this work was to test a multimodality approach [three-dimensional optical coherence tomography (OCT) and polarimetry] to noninvasive diagnosis of oral premalignancy and malignancy using the hamster cheek pouch model (nine hamsters). The results were compared to tissue histopathology. During carcinogenesis, epithelial down grow, eventual loss of basement membrane integrity, and subepithelial invasion were clearly visible with OCT. Polarimetry techniques identified a four to five times increased retardance in sites with squamous cell carcinoma, and two to three times greater retardance in dysplastic sites than in normal tissues. These techniques were particularly useful for mapping areas of field cancerization with multiple lesions, as well as lesion margins.

Histological and Ultrastructural Studies on the Conjunctiva of the Barred Owl (Strix varia)

PubMed Central

Jochems, Brian; Phillips, Thomas E.

2015-01-01

This report is the first characterization of the histology and ultrastructure of the barred owl conjunctiva. The inferior eyelid was dominated by a large disk-shaped plate covered by a non-keratinized stratified squamous or cuboidal epithelium of variable thickness. The apical surface of the plate epithelium varied from flat to long microvilli or even short cytoplasmic extensions similar to those seen in the third eyelid. All specimens had a few goblet cells filled with mucous secretory granules in the plate region. The underlying connective tissue was a dense fibroelastic stroma. Eosinophils were surprisingly common in the epithelial layer and underlying connective tissue in the plate and more distal orbital mucosal region. The orbital mucosa contained goblet cells with heterogeneous glycosylation patterns. The leading edge and marginal plait of the third eyelid are designed to collect fluid and particulate matter as they sweep across the surface of the eye. The palpebral conjunctival surface of the third eyelid was covered by an approximately five-cell-deep stratified squamous epithelium without goblet cells. The bulbar surface of the third eyelid was a bilayer of epithelial cells whose superficial cells have elaborate cytoplasmic tapering extensions reaching out 25 μm. Narrow cytofilia radiated outwards up to an additional 15–20 μm from the cytoplasmic extensions. Lectin labeling demonstrated heterogeneous glycosylation of the apical membrane specializations but only small amounts of glycoprotein-filled secretory granules in the third eyelid. PMID:26562834

Identification of host transcriptional networks showing concentration-dependent regulation by HPV16 E6 and E7 proteins in basal cervical squamous epithelial cells

PubMed Central

Smith, Stephen P.; Scarpini, Cinzia G.; Groves, Ian J.; Odle, Richard I.; Coleman, Nicholas

2016-01-01

Development of cervical squamous cell carcinoma requires increased expression of the major high-risk human-papillomavirus (HPV) oncogenes E6 and E7 in basal cervical epithelial cells. We used a systems biology approach to identify host transcriptional networks in such cells and study the concentration-dependent changes produced by HPV16-E6 and -E7 oncoproteins. We investigated sample sets derived from the W12 model of cervical neoplastic progression, for which high quality phenotype/genotype data were available. We defined a gene co-expression matrix containing a small number of highly-connected hub nodes that controlled large numbers of downstream genes (regulons), indicating the scale-free nature of host gene co-expression in W12. We identified a small number of ‘master regulators’ for which downstream effector genes were significantly associated with protein levels of HPV16 E6 (n = 7) or HPV16 E7 (n = 5). We validated our data by depleting E6/E7 in relevant cells and by functional analysis of selected genes in vitro. We conclude that the network of transcriptional interactions in HPV16-infected basal-type cervical epithelium is regulated in a concentration-dependent manner by E6/E7, via a limited number of central master-regulators. These effects are likely to be significant in cervical carcinogenesis, where there is competitive selection of cells with elevated expression of virus oncoproteins. PMID:27457222

Comparative study of frequency of micronuclei in normal, potentially malignant diseases and oral squamous cell carcinoma

PubMed Central

Sangle, Varsha Ajit; Bijjaragi, Shobha; Shah, Nishat; Kangane, Suresh; Ghule, Hrishikesh M.; Rani, SR Ashwini

2016-01-01

Context: The assessment of micronuclei (MN) in exfoliated oral epithelial cells is a promising tool for the study of epithelial carcinogens and can be used to detect chromosome breakage or mitotic interference, thought to be relevant to carcinogenesis. Aims: To detect MN in exfoliated oral mucosal cells in individuals using various tobacco forms and also to detect frequency of MN in premalignant lesions and conditions (potentially malignant diseases [PMD's]) and oral squamous cell carcinoma (OSCC). To correlate frequency of MN in oral exfoliated cells in clinically diagnosed cases of OSCC followed by a histopathological grading. Materials and Methods: A total of 90 subjects (30 smokeless tobacco users, 30 smokers and 30 nontobacco users) consisted of clinically diagnosed cases of PMD's and OSCC were selected for the study. Cytosmears from the groups were stained with rapid Papanicolaou stain. MN was identified according to the Tolbert et al. criteria. Results: MN cells were found to be significantly higher in smokeless tobacco users than in smokers. The frequency of MN was three to four times higher in patients with OSCC as compared to patients in PMD's (P < 0.0001). The frequency of MN correlated with the histopathological grade was statistically significant. Conclusion: MN index can be used as a biomarker/screening test among the high-risk groups particularly the smokeless tobacco users and PMD's. MN can be a candidate to serve as a biomarker for prediction of the grade of OSCC. PMID:27003966

Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells.

PubMed

Huang, Haishan; Zhu, Junlan; Li, Yang; Zhang, Liping; Gu, Jiayan; Xie, Qipeng; Jin, Honglei; Che, Xun; Li, Jingxia; Huang, Chao; Chen, Lung-Chi; Lyu, Jianxin; Gao, Jimin; Huang, Chuanshu

2016-10-02

Chronic lung inflammation is accepted as being associated with the development of lung cancer caused by nickel exposure. Therefore, identifying the molecular mechanisms that lead to a nickel-induced sustained inflammatory microenvironment that causes transformation of human bronchial epithelial cells is of high significance. In the current studies, we identified SQSTM1/p62 as a novel nickel-upregulated protein that is important for nickel-induced inflammatory TNF expression, subsequently resulting in transformation of human bronchial epithelial cells. We found that nickel exposure induced SQSTM1 protein upregulation in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The SQSTM1 upregulation was also observed in human lung squamous cell carcinoma. Further studies revealed that the knockdown of SQSTM1 expression dramatically inhibited transformation of human lung epithelial cells upon chronic nickel exposure, whereas ectopic expression of SQSTM1 promoted such transformation. Mechanistic studies showed that the SQSTM1 upregulation by nickel was the compromised result of upregulating SQSTM1 mRNA transcription and promoting SQSTM1 protein degradation. We demonstrated that nickel-initiated SQSTM1 protein degradation is mediated by macroautophagy/autophagy via an MTOR-ULK1-BECN1 axis, whereas RELA is important for SQSTM1 transcriptional upregulation following nickel exposure. Furthermore, SQSTM1 upregulation exhibited its promotion of nickel-induced cell transformation through exerting an impetus for nickel-induced inflammatory TNF mRNA stability. Consistently, the MTOR-ULK1-BECN1 autophagic cascade acted as an inhibitory effect on nickel-induced TNF expression and cell transformation. Collectively, our results demonstrate a novel SQSTM1 regulatory network that promotes a nickel-induced tumorigenic effect in human bronchial epithelial cells, which is negatively controlled by an autophagic cascade following nickel exposure.

Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells

PubMed Central

Huang, Haishan; Zhu, Junlan; Li, Yang; Zhang, Liping; Gu, Jiayan; Xie, Qipeng; Jin, Honglei; Che, Xun; Li, Jingxia; Huang, Chao; Chen, Lung-Chi; Lyu, Jianxin; Gao, Jimin; Huang, Chuanshu

2016-01-01

ABSTRACT Chronic lung inflammation is accepted as being associated with the development of lung cancer caused by nickel exposure. Therefore, identifying the molecular mechanisms that lead to a nickel-induced sustained inflammatory microenvironment that causes transformation of human bronchial epithelial cells is of high significance. In the current studies, we identified SQSTM1/p62 as a novel nickel-upregulated protein that is important for nickel-induced inflammatory TNF expression, subsequently resulting in transformation of human bronchial epithelial cells. We found that nickel exposure induced SQSTM1 protein upregulation in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The SQSTM1 upregulation was also observed in human lung squamous cell carcinoma. Further studies revealed that the knockdown of SQSTM1 expression dramatically inhibited transformation of human lung epithelial cells upon chronic nickel exposure, whereas ectopic expression of SQSTM1 promoted such transformation. Mechanistic studies showed that the SQSTM1 upregulation by nickel was the compromised result of upregulating SQSTM1 mRNA transcription and promoting SQSTM1 protein degradation. We demonstrated that nickel-initiated SQSTM1 protein degradation is mediated by macroautophagy/autophagy via an MTOR-ULK1-BECN1 axis, whereas RELA is important for SQSTM1 transcriptional upregulation following nickel exposure. Furthermore, SQSTM1 upregulation exhibited its promotion of nickel-induced cell transformation through exerting an impetus for nickel-induced inflammatory TNF mRNA stability. Consistently, the MTOR-ULK1-BECN1 autophagic cascade acted as an inhibitory effect on nickel-induced TNF expression and cell transformation. Collectively, our results demonstrate a novel SQSTM1 regulatory network that promotes a nickel-induced tumorigenic effect in human bronchial epithelial cells, which is negatively controlled by an autophagic cascade following nickel exposure. PMID:27467530

Ultrastructural nasal pathology in children chronically and sequentially exposed to air pollutants.

PubMed

Calderón-Garcidueñas, L; Valencia-Salazar, G; Rodríguez-Alcaraz, A; Gambling, T M; García, R; Osnaya, N; Villarreal-Calderón, A; Devlin, R B; Carson, J L

2001-02-01

Southwest Metropolitan Mexico City (SWMMC) children are repeatedly exposed to a complex mixture of air pollutants, including ozone, particulate matter, and aldehydes. Nasal biopsies taken from these children exhibit a wide range of histopathologic alterations: marked changes in ciliated and goblet cell populations, basal cell hyperplasia, squamous metaplasia, and mild dysplasias. We studied the ultrastructural features of 15 nasal biopsies obtained from clinically healthy children 4 to 15 yr of age, growing up in SWMMC. The results were compared with nasal biopsies from 11 children growing up in Veracruz and exposed to low pollutant levels. Ultrathin sections of nasal biopsies revealed an unremarkable mucociliary epithelium in control children, whereas SWMMC children showed an epithelium comprised of variable numbers of basal, ciliated, goblet, and squamous metaplastic as well as intermediate cells. Nascent ciliated cells, as evidenced by the presence of migratory kinetosomes, were common, as were ciliary abnormalities, including absent central microtubules, supernumerary central and peripheral tubules, ciliary microtubular discontinuities, and compound cilia. Dyskinesia associated with these abnormal cilia was suggested by the altered orientation of the central microtubules in closely adjacent cilia. A transudate was evident between epithelial cells, suggesting potential deficiencies in epithelial junction integrity. Particulate matter was present in heterolysosomal bodies in epithelial cells and it was also deposited in intercellular spaces. The severe structural alteration of the nasal epithelium together with the prominent acquired ciliary defects are likely the result of chronic airway injury in which ozone, particulate matter, and aldehydes are thought to play a crucial role. The nasal epithelium in SWMMC children is fundamentally disordered, and their mucociliary defense mechanisms are no longer intact. A compromised nasal epithelium has less ability to protect the lower respiratory tract and may potentially leave the distal acinar airways more vulnerable to reactive gases. Impairment of mucociliary clearance has the potential to increase the contact time between deposited mutagenic particulate matter and the epithelial surface, thus increasing the risk for nasal carcinogenesis. Chronic exposures to air pollutants affect the whole respiratory tract; the nasal epithelium is an accessible and valuable sentinel to monitor exposures to toxic or carcinogenic substances.

Generation of K14-E7/∆N87βcat double transgenic mice as a model of cervical cancer.

PubMed

Bulut, Gülay; Üren, Aykut

2015-01-01

Nearly all cervical cancers are initiated by a subset of high-risk human papilloma viruses (HPVs). However, cervical cancers develop only in a small fraction of women who are infected with these viruses. HPV is required, but not sufficient for developing cervical cancer. Activation of complementary signaling pathways appears to be necessary for malignant transformation of cervical epithelial cells that are immortalized by HPV. Here, we describe the creation and maintenance of a double transgenic mouse model that is based on constitutively active Wnt/β-catenin signaling in cervical epithelial cells expressing the HPV oncoprotein E7. These mice develop invasive cervical squamous carcinomas within 6 months with an average penetrance of 94 %.

Establishment of primary cultures of craniopharyngioma cells★

PubMed Central

Liu, Hao; Liu, Liang; Liu, Zhiyong; Li, Qiang; You, Chao; Xu, Jianguo

2012-01-01

Craniopharynigoma samples were collected from 36 patients. Out of the 36 samples, 29 achieved successful sub-culturing, with a success rate of 80.6%. Immunohistochemistry staining showed that cytokeratin-7 was positively expressed in the cytomembrane and cytoplasm of craniopharyngioma cells at 6-8 passages, confirming that all cultured cells were squamous epithelial cells. The doubling time of craniopharyngioma cells was 3 days, as confirmed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In this study, craniopharyngioma cells cultured in vitro were established; however, establishment of immortalized craniopharyngioma cell lines requires further research. PMID:25745451

Immunohistochemical study of p21 and Bcl-2 in leukoplakia, oral submucous fibrosis and oral squamous cell carcinoma.

PubMed

Sutariya, Rakesh V; Manjunatha, Bhari Sharanesha

2016-11-01

Oral Squamous cell carcinoma (OSCC) results from genetic damage, leading to uncontrolled cell proliferation of damaged cells and the cell death. In the course of its progression, visible changes are taking place at the cellular level (atypical) and the resultant at the tissue level (epithelial dysplasia). The Aim of the present study was to evaluate and compare the expressions of intensity of p21 and Bcl-2 in Leukoplakia, oralsubmucous fibrosis (OSMF) and oral squamous cell carcinoma. Total 60 cases, 30 cases of oral squamous cell carcinoma, 15 cases of oral submucous fibrosis and 15 cases of Leukoplakia were evaluated immunohistochemically for p21 and Bcl-2 expression. p21 showed positive expression in 13 (86.67%) cases out of 15 cases of OSMF, 12 (80%) cases of leukoplakia out of 15 cases and 24 (80%) cases out of 30 cases of OSCC. The Bcl-2 expression was positive in 13 (86.67%) cases of OSMF, all cases of Leukoplakia and 25 (83.33%) cases of OSCC. No statistical significance was noted in the expression of p21 and Bcl-2 positive expression between OSMF, Leukoplakia and OSCC. Statistical analysis for comparison of intensity of p21 expression in different grades of OSCC showed no significance. Statistical significance difference was found between the expressions of Bcl-2 in moderately and poorly differentiated SCC. The intensity of p21 and Bcl-2 expressions in different grades of OSCC indicates a key role in progression of oral neoplasia.

Squamous cell carcinoma – similarities and differences among anatomical sites

PubMed Central

Yan, Wusheng; Wistuba, Ignacio I; Emmert-Buck, Michael R; Erickson, Heidi S

2011-01-01

Squamous cell carcinoma (SCC) is an epithelial malignancy involving many anatomical sites and is the most common cancer capable of metastatic spread. Development of early diagnosis methods and novel therapeutics are important for prevention and mortality reduction. In this effort, numerous molecular alterations have been described in SCCs. SCCs share many phenotypic and molecular characteristics, but they have not been extensively compared. This article reviews SCC as a disease, including: epidemiology, pathology, risk factors, molecular characteristics, prognostic markers, targeted therapy, and a new approach to studying SCCs. Through this comparison, several themes are apparent. For example, HPV infection is a common risk factor among the four major SCCs (NMSC, HNSC, ESCC, and NSCLC) and molecular abnormalities in cell-cycle regulation and signal transduction predominate. These data reveal that the molecular insights, new markers, and drug targets discovered in individual SCCs may shed light on this type of cancer as a whole. PMID:21938273

Propagation of normal human epithelial cell populations using an in vivo culture system. Description and applications.

PubMed Central

Klein-Szanto, A. J.; Terzaghi, M.; Mirkin, L. D.; Martin, D.; Shiba, M.

1982-01-01

A new model using xenotransplanted human epithelia was developed for the study of toxic and carcinogenic effects of chemicals. Epithelial cells from the respiratory tract of 4 male and 3 female premature and fullterm fetuses were enzymatically removed and inoculated into deepithelialized rat tracheas. These were sealed at both ends and transplanted subcutaneously into nude mice. After 3-4 weeks, a normal mucociliary epithelium covered the tracheal lumen. At this stage the epithelial cells could be isolated again and transplanted into new denuded rat tracheas. This passaging could be repeated up to six times, each permitting an amplification factor of approximately 3. Tracheal transplants containing cells of human origin (in vivo Passages 2-4) were treated with 7,12-dimethylbenz(a)anthracene. Hyperplasias, squamous metaplasias, and dysplasias were seen 1-8 weeks after initiation of treatment, indicating that the responses of human and rodent epithelial cells to polycyclic aromatic hydrocarbons are similar. Initial experiments with skin and esophageal epithelia suggest that other covering epithelia could also be used in this fashion for evaluation of toxicants and carcinogens that are likely to come into contact with these tissues. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:6821529

Comparison of destructive periodontal disease in blue iris mink to PCB 126-induced mandibular and maxillary squamous epithelial proliferation in natural dark mink.

PubMed

Ellick, Rachel M; Fitzgerald, Scott D; Link, Jane E; Bursian, Steven J

2013-01-01

Mink (Mustela vison) exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-like chemicals have been reported to develop mandibular and maxillary squamous cell proliferation that results in the destruction of alveolar bone and eventual tooth loss. This jaw lesion has been reported in wild mink collected from areas contaminated with TCDD-like compounds and is a potential biomarker for exposure to these chemicals. The blue iris strain of domestic mink is prone to develop severe periodontal disease, which results in destruction of bone and tooth loss that is grossly similar to the lesion induced by exposure to TCDD-like chemicals. A histological assessment of jaws from blue iris mink and natural dark mink exposed to 3,3',4,4',5-pentachlorobiphenyl (PCB 126) was done to determine whether the oral lesions are similar. The jaw tissue from the blue iris mink had lesions indicative of lymphoplasmacytic gingivitis and osteomyelitis, caused by inflammation entering the dental sulcus, while the jaw tissue from the mink exposed to PCB 126 exhibited squamous epithelial proliferation. Therefore, it was determined that the tooth loss and bone destruction seen in these mink are of different origin despite the similarity of the gross clinical signs.

Integrin signalling regulates YAP and TAZ to control skin homeostasis.

PubMed

Elbediwy, Ahmed; Vincent-Mistiaen, Zoé I; Spencer-Dene, Bradley; Stone, Richard K; Boeing, Stefan; Wculek, Stefanie K; Cordero, Julia; Tan, Ee H; Ridgway, Rachel; Brunton, Val G; Sahai, Erik; Gerhardt, Holger; Behrens, Axel; Malanchi, Ilaria; Sansom, Owen J; Thompson, Barry J

2016-05-15

The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib. © 2016. Published by The Company of Biologists Ltd.

Integrin signalling regulates YAP and TAZ to control skin homeostasis

PubMed Central

Elbediwy, Ahmed; Vincent-Mistiaen, Zoé I.; Spencer-Dene, Bradley; Stone, Richard K.; Boeing, Stefan; Wculek, Stefanie K.; Cordero, Julia; Tan, Ee H.; Ridgway, Rachel; Brunton, Val G.; Sahai, Erik; Gerhardt, Holger; Behrens, Axel; Malanchi, Ilaria; Sansom, Owen J.; Thompson, Barry J.

2016-01-01

ABSTRACT The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib. PMID:26989177

Identification, expansion and characterization of cancer cells with stem cell properties from head and neck squamous cell carcinomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaseb, Hatem O.; Department of Clinical Pathology, National Cancer Institute; Fohrer-Ting, Helene

Head and neck squamous cell carcinoma (HNSCC) is a major public health concern. Recent data indicate the presence of cancer stem cells (CSC) in many solid tumors, including HNSCC. Here, we assessed the stem cell (SC) characteristics, including cell surface markers, radioresistance, chromosomal instability, and in vivo tumorigenic capacity of CSC isolated from HNSCC patient specimens. We show that spheroid enrichment of CSC from early and short-term HNSCC cell cultures was associated with increased expression of CD44, CD133, SOX2 and BMI1 compared with normal oral epithelial cells. On immunophenotyping, five of 12 SC/CSC markers were homogenously expressed in all tumormore » cultures, while one of 12 was negative, four of 12 showed variable expression, and two of the 12 were expressed heterogeneously. We showed that irradiated CSCs survived and retained their self-renewal capacity across different ionizing radiation (IR) regimens. Fluorescence in situ hybridization (FISH) analyses of parental and clonally-derived tumor cells revealed different chromosome copy numbers from cell to cell, suggesting the presence of chromosomal instability in HNSCC CSC. Further, our in vitro and in vivo mouse engraftment studies suggest that CD44+/CD66− is a promising, consistent biomarker combination for HNSCC CSC. Overall, our findings add further evidence to the proposed role of HNSCC CSCs in therapeutic resistance. - Highlights: • Spheroid enrichment selects cancer stem cells (CSC) from head & neck tumors (HNSCC). • Compared to normal epithelial cells, isolated CSC express increased SC/CSC markers. • Isolated CSC display enhanced radioresistance, clonogenicity and tumorigenicity. • HNSCC CSC express chromosomal instability. • CD44+/CD66− is a promising, consistent biomarker for HNSCC CSC.« less

IL17A Regulates Tumor Latency and Metastasis in Lung Adeno and Squamous SQ.2b and AD.1 Cancer.

PubMed

You, Ran; DeMayo, Francesco J; Liu, Jian; Cho, Sung-Nam; Burt, Bryan M; Creighton, Chad J; Casal, Roberto F; Lazarus, Donald R; Lu, Wen; Tung, Hui-Ying; Yuan, Xiaoyi; Hill-McALester, Andrea; Kim, Myunghoo; Perusich, Sarah; Cornwell, Loraine; Rosen, Daniel; Song, Li-Zhen; Paust, Silke; Diehl, Gretchen; Corry, David; Kheradmand, Farrah

2018-04-13

Somatic mutations can promote malignant transformation of airway epithelial cells and induce inflammatory responses directed against resultant tumors. Tumor-infiltrating T lymphocytes (TIL) in early-stage non-small cell lung cancer (NSCLC) secrete distinct proinflammatory cytokines, but the contribution of these TILs to tumor development and metastasis remains unknown. We show here that TILs in early-stage NSCLC are biased toward IL17A expression (Th17) when compared with adjacent tumor-free tissue, whereas Th17 cells are decreased in tumor infiltrating locoregional lymph nodes in advanced NSCLC. Mice in which Pten and Smad4 ( Pts4 d/d ) are deleted from airway epithelial cells develop spontaneous tumors, that share genetic signatures with squamous- (SQ.2b), and adeno- (AD.1) subtypes of human NSCLC. Pts4 d/d mice globally lacking in IL17a ( Pts4 d/d Il17a -/- ) showed decreased tumor latency and increased metastasis. Th17 cells were required for recruitment of CD103 + dendritic cells, and adoptive transfer of IL17a -sufficient CD4 + T cells reversed early tumor development and metastasis in Pts4 d/d Il17a -/- mice. Together, these findings support a key role for Th17 cells in TILs associated with the Pts4 d/d model of NSCLC and suggest therapeutic and biomarker strategies for human SQ2b and AD1 lung cancer. Cancer Immunol Res; 1-13. ©2018 AACR. ©2018 American Association for Cancer Research.

Caveolin-1 expression in oral lichen planus, dysplastic lesions and squamous cell carcinoma.

PubMed

Jaafari-Ashkavandi, Zohreh; Aslani, Ehsan

2017-07-01

Caveolin-1(Cav-1), the main part of caveolae structure, is supposed to play a role in pathogenesis of many human tumors. Since oral lichen planus (OLP) is considered as a potential premalignant disease, this study evaluated Cav-1 expression in OLP in comparison with benign hyperkeratosis, dysplastic epithelium and oral squamous cell carcinoma (OSCC), to investigate its possible role in pathogenesis and malignant transformation of OLP. In this cross-sectional retrospective study, immunohistochemical expression of Cav-1 in the epithelial component and stroma was evaluated in 81 samples, including 12 cases of hyperkeratosis, 24 OLP, 22 epithelial dysplasia, and 23 OSCC samples. Correlations between Cav-1 expression and clinicopathological variables were evaluated statistically. Positive Cav-1 staining was found in 58% of OLP, 91% of hyperkeratosis, 100% of epithelial dysplasia, and 95% of OSCC samples. OSCC showed the highest Cav-1 expression and OLP had the lowest (P=0.001). The intensity of staining was significantly increased in stepwise manner from OLP to OSCC (P=0.001). Expression of Cav-1 was related to the grade of samples in OSCC and dysplastic samples (P=0.04). Based on the findings, it was concluded that Cav-1 may play a role in the pathogenesis of OLP and carcinogenesis of SCC, but its role in malignant transformation of OLP is not confirmed. Further studies are needed to evaluate its potential therapeutic function in OLP and SCC. Copyright © 2017 Elsevier GmbH. All rights reserved.

Nrf2 regulates cellular behaviors and Notch signaling in oral squamous cell carcinoma cells.

PubMed

Fan, Hong; Paiboonrungruan, Chorlada; Zhang, Xinyan; Prigge, Justin R; Schmidt, Edward E; Sun, Zheng; Chen, Xiaoxin

2017-11-04

Oxidative stress is known to play a pivotal role in the development of oral squamous cell carcinoma (OSCC). We have demonstrated that activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway has chemopreventive effects against oxidative stress-associated OSCC. However, Nrf2 have dual roles in cancer development; while it prevents carcinogenesis of normal cells, hyperactive Nrf2 also promotes the survival of cancer cells. This study is aimed to understand the function of Nrf2 in regulating cellular behaviors of OSCC cells, and the potential mechanisms through which Nrf2 facilitates OSCC. We established the Nrf2-overexpressing and Nrf2-knockdown OSCC cell lines, and examined the function of Nrf2 in regulating cell proliferation, migration, invasion, cell cycle and colony formation. Our data showed that Nrf2 overexpression promoted cancer phenotypes in OSCC cells, whereas Nrf2 silencing inhibited these phenotypes. In addition, Nrf2 positively regulated Notch signaling pathway in OSCC cells in vitro. Consistent with this observation, Nrf2 activation in Keap1 -/- mice resulted in not only hyperproliferation of squamous epithelial cells in mouse tongue as evidenced by increased expression of PCNA, but also activation of Notch signaling in these cells as evidenced by increased expression of NICD1 and Hes1. In conclusion, Nrf2 regulates cancer behaviors and Notch signaling in OSCC cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Afatinib radiosensitizes head and neck squamous cell carcinoma cells by targeting cancer stem cells.

PubMed

Macha, Muzafar A; Rachagani, Satyanarayana; Qazi, Asif Khurshid; Jahan, Rahat; Gupta, Suprit; Patel, Anery; Seshacharyulu, Parthasarathy; Lin, Chi; Li, Sicong; Wang, Shuo; Verma, Vivek; Kishida, Shosei; Kishida, Michiko; Nakamura, Norifumi; Kibe, Toshiro; Lydiatt, William M; Smith, Russell B; Ganti, Apar K; Jones, Dwight T; Batra, Surinder K; Jain, Maneesh

2017-03-28

The dismal prognosis of locally advanced and metastatic squamous cell carcinoma of the head and neck (HNSCC) is primarily due to the development of resistance to chemoradiation therapy (CRT). Deregulation of Epidermal Growth Factor Receptor (EGFR) signaling is involved in HNSCC pathogenesis by regulating cell survival, cancer stem cells (CSCs), and resistance to CRT. Here we investigated the radiosensitizing activity of the pan-EGFR inhibitor afatinib in HNSCC in vitro and in vivo. Our results showed strong antiproliferative effects of afatinib in HNSCC SCC1 and SCC10B cells, compared to immortalized normal oral epithelial cells MOE1a and MOE1b. Comparative analysis revealed stronger antitumor effects with afatinib than observed with erlotinib. Furthermore, afatinib enhanced in vitro radiosensitivity of SCC1 and SCC10B cells by inducing mesenchymal to epithelial transition, G1 cell cycle arrest, and the attenuating ionizing radiation (IR)-induced activation of DNA double strand break repair (DSB) ATM/ATR/CHK2/BRCA1 pathway. Our studies also revealed the effect of afatinib on tumor sphere- and colony-forming capabilities of cancer stem cells (CSCs), and decreased IR-induced CSC population in SCC1 and SCC10B cells. Furthermore, we observed that a combination of afatinib with IR significantly reduced SCC1 xenograft tumors (median weight of 168.25 ± 20.85 mg; p = 0.05) compared to afatinib (280.07 ± 20.54 mg) or IR alone (324.91 ± 28.08 mg). Immunohistochemical analysis of SCC1 tumor xenografts demonstrated downregulation of the expression of IR-induced pEGFR1, ALDH1 and upregulation of phosphorylated γH2AX by afatinib. Overall, afatinib reduces tumorigenicity and radiosensitizes HNSCC cells. It holds promise for future clinical development as a novel radiosensitizer by improving CSC eradication.

Lactobacillus casei Strain Shirota Enhances the In Vitro Antiproliferative Effect of Geniposide in Human Oral Squamous Carcinoma HSC-3 Cells.

PubMed

Qian, Yu; Song, Jia-Le; Sun, Peng; Yi, Ruokun; Liu, Honglin; Feng, Xia; Park, Kun-Young; Zhao, Xin

2018-05-03

This study investigated the enhanced antiproliferative effect of Lactobacillus casei strain Shirota (LcS) on geniposide actions in human oral squamous carcinoma HSC-3 cells. An MTT assay, flow cytometry, qPCR assay, western blot and HPLC were used for this study. The concentration of 1.0 × 10⁶ CFU/mL of LcS had no effect on the HOK normal oral epithelial cells and HSC-3 cancer cells. The 25 and 50 µg/mL geniposide concentrations also had no impact on HOK normal oral epithelial cells, but they had remarkable inhibitory effects on the growth of HSC-3 cancer cells, which are enhanced in the presence of LcS. By the flow cytometry assay, the LcS-geniposide-H (1.0 × 10⁶ CFU/mL LcS and 50 µg/mL geniposide)-treated HSC-3 cancer cells had the largest number of cells undergoing apoptosis compared to cells treated with other combinationsand obviously more than cells treated with only geniposide-H (50 µg/mL geniposide). Geniposide-H could increase the mRNA and protein expressions of caspase-3, caspase-8, caspase-9, Bax, p53, p21, IκB-α, Fas, FasL, TIMP-1, and TIMP-2 as well as decrease those of Bcl-2, Bcl-xL, HIAP-1, HIAP-2, NF-κB, COX-2, iNOS, MMP-2, and MMP-9 compared to other groups of cells, and LcS further enhanced these changes, with results that are greater than for the cells treated with only a high concentration of geniposide. The results of this study show thatLcS enhanced the antiproliferative effect of geniposide in HSC-3 cancer cells.

In vitro epithelial differentiation of human induced pluripotent stem cells for vocal fold tissue engineering.

PubMed

Imaizumi, Mitsuyoshi; Sato, Yuka; Yang, David T; Thibeault, Susan L

2013-12-01

We determined the feasibility and optimization of differentiating human induced pluripotent stem cells (hiPS) into nonkeratinized stratified squamous epithelial cells for vocal fold engineering. hiPS were cultured and assessed for differentiation in 3 conditions: a 3-dimensional (3D) hyaluronic acid (HA) hydrogel scaffold, a 3D HA hydrogel scaffold with epidermal growth factor (EGF), and a 3D HA hydrogel scaffold cocultured with human vocal fold fibroblasts (hVFF). After 1, 2, and 4 weeks of cultivation, hiPS were selected for histology, immunohistochemistry, and/or transcript expression analysis. At 4 weeks, hiPS cultivated with hVFF or with EGF had significantly decreased levels of Oct 3/4, indicating loss of pluripotency. Immunofluorescence revealed the presence of pancytokeratin and of cytokeratin (CK) 13 and 14 epithelial-associated proteins at 4 weeks after cultivation in hiPS EGF and hiPS hVFF cultures. The transcript expression level of CK14 was significantly increased for hiPS hVFF cultures only and was measured concomitantly with cell morphology that was clearly cohesive and displayed a degree of nuclear polarity suggestive of epithelial differentiation. We found that hiPS cultivated in 3D HA hydrogel with hVFF demonstrated the most robust conversion evidence to date of epithelial differentiation. Further work is necessary to focus on amplification of these progenitors for application in vocal fold regenerative biology.

Electrophysiologic and morphologic effects of ophthalmic preparations on rabbit cornea epithelium.

PubMed

Burstein, N L; Klyce, S D

1977-10-01

The effects of several components of ophthalmic preparations on isolated rabbit cornea were studied by continuous electrophysiologic monitoring followed by fixation for scanning electron microscopy (SEM). Benzalkonium chloride (0.001 percent), thimerosal (0.0004 percent), and amphotericin B (0.0025 percent) all briefly increased ion transport, then greatly decreased epithelial resistance. Severe disruption of surface cell layers occurred simultaneously with resistance decrease. Silver nitrate (0.00017 percent) stimulated transport with less accompanying morphologic damage. Tetracaine (0.05 percent) disrupted epithelial function and caused exfoliation of several cell layers. Chlorobutanol (0.1 percent) produced a nearly complete loss of the squamous cell layer. Chloramphenicol, epinephrine, and pilocarpine produced minor changes in structure and electrophysiology at full clinical concentration. It was concluded that low concentrations of preservatives in ophthalmic preparations disrupt the barrier and transport properties of the corneal epithelium.

Nucleolar Organizer Regions in Oral Squamous Cell Carcinoma

PubMed Central

Moradzadeh Khiavi, Monir; Vosoughhosseini, Sepideh; Halimi, Monire; Mahmoudi, Seyyed Mostafa; Yarahmadi, Asghar

2012-01-01

Background and aims Several diagnostic methods are being employed to detect benign and malignant lesions, one of which is silver nitrate staining for organizer regions. The number of nucleolar organizing regions (NORs) can be used to show the degree of cell activity or metabolism in pathologic lesions. This study was designed to evaluate NORs as determi-nants of precancerous and squamous cell carcinoma. Materials and methods A silver colloid technique was applied on paraffin sections of 40 cases of oral squamous cell carcinoma and 25 cases of precancerous lesions; 15 specimens of normal epithelium were selected for the control group. After staining with silver nitrate, argyrophilic nucleolar organizer regions (AgNORs) were counted in 100 epithelial cells in three groups with the use of an oil immersion and ×1000 objective lens. One-way ANOVA and a post hoc Tukey test were used for statistical analysis. Results The mean numbers and standard deviations of AgNORs were 1.58 ± 0.76 in normal epithelium, 2.1 ± 1.05 in pre-cancerous lesions and 2.43 ±1.33 in squamous cell carcinoma (SCC). There were statistically significant differences in Ag-NORs numbers between the groups (P<0.001) and significant differences in precancerous lesions between dysplastic and non-dysplastic epithelia (P<0.001). The mean AgNORs count per nucleus increased from healthy epithelium to precancer-ous lesion to SCC. Conclusion This study suggests that the silver staining technique for the detection of NORs (AgNOR) can be used to distinguish precancerous lesions and benign and malignant lesions. PMID:22991629

HIV-associated hypertrophic herpes simplex genitalis with concomitant early invasive squamous cell carcinoma mimicking advanced genital cancer: case report and literature review.

PubMed

Strehl, Johanna D; Mehlhorn, Grit; Koch, Martin C; Harrer, Ellen G; Harrer, Thomas; Beckmann, Matthias W; Agaimy, Abbas

2012-05-01

Hypertrophic herpes simplex genitalis (HHSG) is an uncommon anogenital manifestation of herpes simplex virus (HSV) infection in immunocompromised patients. To date, 24 cases of HHSG have been reported; 23 of them were affected human immune deficiency virus (HIV) type 1-positive patients. We describe the case of a 44-year-old African HIV-1-positive woman who presented with painful ulcerated nodular lesions of the vulva and perianal area measuring up to 7 cm in diameter. Macroscopically, the lesions were highly suspicious of widely invasive cancer. The histologic workup of the resection specimen revealed patchy high-grade vulvar intraepithelial neoplasia Grade 3 (VIN 3) and 2 microscopic foci of superficially invasive squamous cell carcinoma. The nodular lesions were caused by massive tumefactive plasma cell-rich inflammatory infiltrates extending into the subcutis. Multinucleated herpes simplex virus 1 and herpes simplex virus 2-positive epithelial cells with glassy intranuclear inclusions were detected at the borders of the ulcerations, consistent with HHSG. Despite repeated surgery and medical treatment, the patient had 3 recurrences of HHSG within 18 months. The presence of intraepithelial neoplasia in HHSG lesions is relatively rare and has been described in 6 of 18 resected HHSG lesions in the literature so far. With regard to invasive malignancy, the present case is the first report of a superficially invasive squamous cell carcinoma associated with HHSG. Awareness of this condition is necessary to avoid misinterpretation of HHSG as widely invasive squamous cell carcinoma with the hazard of surgical and oncological overtreatment.

Reexcision Perineural Invasion and Epithelial Sheath Neuroma Possibly on a Spectrum of Postinjury Reactive Hyperplasia Mediated by IL-6.

PubMed

Wang, James Y; Nuovo, Gerard; Kline, Mitchell; Magro, Cynthia M

2017-01-01

Epithelial sheath neuroma is a rarely recognized but established entity in the medical literature. First described in 2000 by Requena et al, there have only been 7 published cases to date, mostly in female patients and presenting as symptomatic solitary lesions on the back without a known history of trauma. In 2006, Beer et al described and reviewed a dozen cases in which epithelial sheath neuroma-like features were seen in the advent of a surgical procedure, which was termed "re-excision perineural invasion" and attributed to possible eccrine duct implantation during surgery. Our case is a 66-year-old male patient who underwent an excision of a melanocytic neoplasm in which a reactive epithelial sheath neuroma was incidentally discovered in the excision specimen, adjacent to the biopsy site cicatrix. Histologically, there was benign cutaneous nerve hyperplasia with a proliferation of squamous epithelium in intimate apposition to the nerve bundles in the superficial dermis. We postulate that the process active in the formation of re-excision perineural invasion is the same as in epithelial sheath neuroma and that minor trauma not appreciable on histologic examination is responsible in the latter entity. We performed IL-6 staining and documented that IL-6 was upregulated at the interface of the nerve and reactive epithelium, but was absent in nerves distant from the site of surgery, suggesting that IL-6 may be essential to the lesion's development. The recognition of reactive epithelial sheath neuroma including the subcategory of re-excision perineural invasion is crucial for the dermatopathologist to prevent mislabeling this reactive entity as a perineural squamous cell carcinoma, which has clinical consequences for the patient such as wider re-excision and radiation treatment. Additionally, we have identified a potential pathophysiologic basis for this lesion.

Volumetric imaging of oral epithelial neoplasia by MPM-SHGM: epithelial connective tissue interface (Conference Presentation)

NASA Astrophysics Data System (ADS)

Pal, Rahul; Yang, Jinping; Qiu, Suimin; Resto, Vicente; McCammon, Susan; Vargas, Gracie

2016-03-01

The majority of oral cancers are comprised of oral squamous cell carcinoma in which neoplastic epithelial cells invade across the epithelial connective tissue interface (ECTI). Invasion is preceded by a multi-component process including epithelial hyperproliferation, loss of cell polarity, and remodeling of the extracellular matrix. Multiphoton Autofluorescence Microscopy (MPAM) and Second Harmonic Generation Microscopy (SHGM) show promise for revealing indicators of neoplasia. In particular, volumetric imaging by these methods can reveal aspects of the 3D microstructure that are not possible by other methods and which could both further our understanding of neoplastic transformation and be explored for development of diagnostic approaches in this disease having only 55% 5-year survival rate. MPAM-SHG were applied to reveal the 3D structure of the critical ECTI interface that plays an integral part toward invasion. Epithelial dysplasia was induced in an established hamster model. MPAM-SHGM was applied to lesion sites, using 780 nm excitation (450-600nm emission) for autofluroescence of cellular and extracellular components; 840 nm using 420 nm bandpass filter for SHG. The ECTI surface was identified as the interface at which SHG signal began following the epithelium and was modeled as a 3D surface using Matlab. ECTI surface area and cell features at sites of epithelial expansion where ECTI was altered were measured; Imaged sites were biopsied and processed for histology. ROC analysis using ECTI image metrics indicated the ability to delineate normal from neoplasia with high sensitivity and specificity and it is noteworthy that inflammation did not significantly alter diagnostic potential of MPAM-SHGM .

Keratin 5/14‑mediated cell differentiation and transformation are regulated by TAp63 and Notch‑1 in oral squamous cell carcinoma‑derived cells.

PubMed

Srivastava, Saumya S; Alam, Hunain; Patil, Sonam J; Shrinivasan, Rashmi; Raikundalia, Sweta; Chaudhari, Pratik Rajeev; Vaidya, Milind M

2018-05-01

Keratins 5/14 (K5/14) are intermediate filament proteins expressed in the basal layer of stratified epithelial cells and are known targets of p63. Previous research in our laboratory showed that upon K5/14 downregulation in oral squamous cell carcinoma (OSCC)‑derived cells, there was an increase in intracellular Notch‑1 levels and differentiation markers such as involucrin, keratin 1 and a decrease in tumorigenic potential in vivo. However, the molecules involved in the K14 regulated cell differentiation and transformation are not known to date. In order to understand the possible role of TAp63, we downregulated TAp63 in a K14‑knockdown background. We observed that there was a decrease in the expression of Notch‑1. Expression levels of differentiation markers such as involucrin, K1, loricrin and filaggrin were also decreased. Furthermore, TAp63 downregulation led to an increase in invasion, migration and in vivo tumorigenic potential of these cells. We observed a decrease in β‑catenin signaling in K14‑downregulated cells. Notably, when TAp63 was downregulated in K14‑knockdown cells, there was increase in non‑phospho β‑catenin levels. Hence, this study indicates that TAp63 plays an important role in K14‑downregulated cells possibly by regulating the Notch‑1 expression. K14 regulates the expression of TAp63 which in turn regulates expression of Notch‑1. The present study is a step forward in our quest to understand the functional significance of molecules that regulate the process of differentiation and tumorigenesis in stratified epithelial cells.

The Escherichia coli O157:H7 cattle immunoproteome includes outer membrane protein A (OmpA), a modulator of adherence to bovine rectoanal junction squamous epithelial (RSE) cells

USDA-ARS?s Scientific Manuscript database

Building on previous studies, we defined the repertoire of proteins comprising the antigenome of Escherichia coli (E. coli) O157 cultured in Dulbecco's Modified Eagles Medium (DMEM) supplemented with norepinephrine (NE; O157 protein-antigenome), a beta-adrenergic hormone that regulates E. coli O157 ...

Growth Arrest of Epithelial Cells during Measles Virus Infection Is Caused by Upregulation of Interferon Regulatory Factor 1

PubMed Central

Yokota, Shin-ichi; Okabayashi, Tamaki; Yokosawa, Noriko; Fujii, Nobuhiro

2004-01-01

Natural infection with measles virus (MeV) is initiated when the virus reaches epithelial cells in the respiratory tract, oropharynx, or conjunctivae. Human epithelial cells infected with MeV frequently show growth suppression. In this study, we investigated the possible mechanisms for this suppression. The bronchiolar epithelial cell A549 showed growth arrest in G0/G1 following MeV infection or treatment with gamma interferon (IFN-γ). IFN regulatory factor-1 (IRF-1) was upregulated during MeV infection, although A549 did not produce IFN-γ. Cells of the cervical squamous cell line SiHa persistently infected with various strains of MeV displayed slower growth than uninfected SiHa cells, although the growth rates varied depending on the MeV strain. Transfection of antisense-oriented IRF-1 cDNA released the MeV-infected SiHa cells from growth suppression. Although these infected cells did not produce IFN-γ and suppressed IFN-α/β-induced Jak1 phosphorylation, Jak1 was constitutively phosphorylated. The growth rates negatively correlated with levels of both IRF-1 expression and constitutively phosphorylated Jak1. These results indicate that MeV upregulates IRF-1 in a manner that is independent of IFN but dependent on the JAK/STAT pathway. This induction of IRF-1 appears to suppress cell growth, although the extent seems to vary among MeV strains. PMID:15078941

Down-regulation of Pax6 is associated with abnormal differentiation of corneal epithelial cells in severe ocular surface diseases

PubMed Central

Li, W; Chen, Y-T; Hayashida, Y; Blanco, G; Kheirkah, A; He, H; Chen, S-Y; Liu, C-Y; Tseng, SCG

2010-01-01

Pax6 is the universal master control gene for eye morphogenesis. Other than retina and lens, Pax6 also expressed in the ocular surface epithelium from early gestation until the postnatal stage, in which little is known about the function of Pax6. In this study, corneal pannus tissues from patients with ocular surface diseases such as Stevens–Johnson syndrome (SJS), chemical burn, aniridia and recurrent pterygium were investigated. Our results showed that normal ocular surface epithelial cells expressed Pax6. However, corneal pannus epithelial cells from the above patients showed a decline or absence of Pax6 expression, accompanied by a decline or absence of K12 keratin but an increase of K10 keratin and filaggrin expression. Pannus basal epithelial cells maintained nuclear p63 expression and showed activated proliferation, evidenced by positive Ki67 and K16 keratin staining. On 3T3 fibroblast feeder layers, Pax6 immunostaining was negative in clones generated from epithelial cells harvested from corneal pannus from SJS or aniridia, but positive in those from the normal limbal epithelium; whereas western blots showed that some epithelial clones expanded from pannus retained Pax6 expression. Transient transfection of an adenoviral vector carrying EGFP–Pax6 transgenes into these Pax6− clones increased both Pax6 and K12 keratin expression. These results indicate that Pax6 helps to maintain the normal corneal epithelial phenotype postnatally, and that down-regulation of Pax6 is associated with abnormal epidermal differentiation in severe ocular surface diseases. Reintroduction of activation of the Pax6 gene might be useful in treating squamous metaplasia of the ocular surface epithelium. PMID:18027901

The PDZ Ligand Domain of the Human Papillomavirus Type 16 E6 Protein Is Required for E6's Induction of Epithelial Hyperplasia In Vivo

PubMed Central

Nguyen, Marie L.; Nguyen, Minh M.; Lee, Denis; Griep, Anne E.; Lambert, Paul F.

2003-01-01

Human papillomaviruses (HPVs) are the causative agent of warts. Infections with high-risk HPVs are associated with anogenital and head and neck cancers. One of the viral genes responsible for HPV's oncogenic activity is E6. Mice expressing the HPV-16 E6 protein in their epidermis (K14E6WT) develop epithelial hyperplasia and squamous carcinomas. Numerous cellular proteins interact with E6, some of which can be grouped based on common amino acid motifs in their E6-binding domains. One such group, the PDZ partners, including hDLG, hSCRIBBLE, MUPP1, and MAGI, bind to the carboxy-terminal four amino acids of E6 through their PDZ domains. E6's interaction with the PDZ partners leads to their degradation. Additionally, E6's binding to PDZ proteins has been correlated with its ability to transform baby rat kidney cells in tissue culture and to confer tumorigenicity onto cells in xenograft experiments. To address whether the ability of E6 to bind PDZ domain partners is necessary for E6 to confer epithelial hyperproliferation in vivo, we generated transgenic mice that express in stratified squamous epithelia a mutant of E6 lacking the last six amino acids at its carboxyl terminus, E6Δ146-151, from the human keratin 14 (K14) promoter. The K14E6Δ146-151 mice exhibit a radiation response similar to that of the K14E6WT mice, demonstrating that this protein, as predicted, retains an ability to inactivate p53. However, the K14E6Δ146-151 mice fail to display epithelial hyperplasia. These results indicate that an interaction of E6 with PDZ partners is necessary for its induction of epithelial hyperplasia. PMID:12768014

Enhancement of cancer stem-like and epithelial−mesenchymal transdifferentiation property in oral epithelial cells with long-term nicotine exposure: Reversal by targeting SNAIL

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Cheng-Chia; School of Dentistry, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan

Cigarette smoking is one of the major risk factors in the development and further progression of tumorigenesis, including oral squamous cell carcinoma (OSCC). Recent studies suggest that interplay cancer stem-like cells (CSCs) and epithelial−mesenchymal transdifferentiation (EMT) properties are responsible for the tumor maintenance and metastasis in OSCC. The aim of the present study was to investigate the effects of long-term exposure with nicotine, a major component in cigarette, on CSCs and EMT characteristics. The possible reversal regulators were further explored in nicotine-induced CSCs and EMT properties in human oral epithelial (OE) cells. Long-term exposure with nicotine was demonstrated to up-regulatemore » ALDH1 population in normal gingival and primary OSCC OE cells dose-dependently. Moreover, long-term nicotine treatment was found to enhance the self-renewal sphere-forming ability and stemness gene signatures expression and EMT regulators in OE cells. The migration/cell invasiveness/anchorage independent growth and in vivo tumor growth by nude mice xenotransplantation assay was enhanced in long-term nicotine-stimulated OE cells. Knockdown of Snail in long-term nicotine-treated OE cells was found to reduce their CSCs properties. Therapeutic delivery of Si-Snail significantly blocked the xenograft tumorigenesis of long-term nicotine-treated OSCC cells and largely significantly improved the recipient survival. The present study demonstrated that the enrichment of CSCs coupled EMT property in oral epithelial cells induced by nicotine is critical for the development of OSCC tumorigenesis. Targeting Snail might offer a new strategy for the treatment of OSCC patients with smoking habit. -- Highlights: ► Sustained nicotine treatment induced CSCs properties of oral epithelial cells. ► Long-term nicotine treatment enhance EMT properties of oral epithelial cells. ► Long-term nicotine exposure increased tumorigenicity of oral epithelial cells. ► Si-Snail blocked xenograft tumorigenesis of long-term nicotine-treated OSCC cells.« less

CD44 Staining of Cancer Stem-Like Cells Is Influenced by Down-Regulation of CD44 Variant Isoforms and Up-Regulation of the Standard CD44 Isoform in the Population of Cells That Have Undergone Epithelial-to-Mesenchymal Transition

PubMed Central

Biddle, Adrian; Gammon, Luke; Fazil, Bilal; Mackenzie, Ian C.

2013-01-01

CD44 is commonly used as a cell surface marker of cancer stem-like cells in epithelial tumours, and we have previously demonstrated the existence of two different CD44high cancer stem-like cell populations in squamous cell carcinoma, one having undergone epithelial-to-mesenchymal transition and the other maintaining an epithelial phenotype. Alternative splicing of CD44 variant exons generates a great many isoforms, and it is not known which isoforms are expressed on the surface of the two different cancer stem-like cell phenotypes. Here, we demonstrate that cancer stem-like cells with an epithelial phenotype predominantly express isoforms containing the variant exons, whereas the cancer stem-like cells that have undergone an epithelial-to-mesenchymal transition down-regulate these variant isoforms and up-regulate expression of the standard CD44 isoform that contains no variant exons. In addition, we find that enzymatic treatments used to dissociate cells from tissue culture or fresh tumour specimens cause destruction of variant CD44 isoforms at the cell surface whereas expression of the standard CD44 isoform is preserved. This results in enrichment within the CD44high population of cancer stem-like cells that have undergone an epithelial-to-mesenchymal transition and depletion from the CD44high population of cancer stem-like cells that maintain an epithelial phenotype, and therefore greatly effects the characteristics of any cancer stem-like cell population isolated based on expression of CD44. As well as effecting the CD44high population, enzymatic treatment also reduces the percentage of the total epithelial cancer cell population staining CD44-positive, with potential implications for studies that aim to use CD44-positive staining as a prognostic indicator. Analyses of the properties of cancer stem-like cells are largely dependent on the ability to accurately identify and assay these populations. It is therefore critical that consideration be given to use of multiple cancer stem-like cell markers and suitable procedures for cell isolation in order that the correct populations are assayed. PMID:23437366

Combined excision, cryotherapy, and intraoperative mitomycin C (EXCRIM) for localized intraepithelial and squamous cell carcinoma of the conjunctiva.

PubMed

Sarici, Ahmet M; Arvas, Sema; Pazarli, Halit

2013-09-01

To report the results of patients undergoing combined excision, cryotherapy, and intraoperative mitomycin-C (EXCRIM) for primary ocular surface squamous neoplasia (OSSN) METHODS: A retrospective review of a non-comparative interventional case series. Histopathologically confirmed primary localized (less than four clock hours) OSSN treated with EXCRIM using adjuvant 0.02 % mitomycin-C (MMC) were included in the study. The main outcome measures were recurrence and complications related to MMC. The study enrolled 28 eyes of 28 patients with OSSN with a median age of 64.5 (range 43 to 84) years. The mean tumor size was 6.9 × 4.35 mm. There was corneal involvement in 23 of 28 (82 %). Seven patients (21 %) had delayed epithelial healing. Two of eight patients (25 %) with squamous cell carcinoma (SCC) had positive lateral margins. There were no recurrences over a mean follow-up of 49 months (range 24 to 96). The excision of OSSN combined with cryotherapy and intraoperative MMC is effective with a low recurrence rate. Long-term follow-up yielded favorable results.

No evidence for the presence of Epstein-Barr virus in squamous cell carcinoma of the mobile tongue.

PubMed

Wilms, Torben; Khan, Gulfaraz; Coates, Philip J; Sgaramella, Nicola; Fåhraeus, Robin; Hassani, Asma; Philip, Pretty S; Norberg Spaak, Lena; Califano, Luigi; Colella, Giuseppe; Olofsson, Katarina; Loizou, Christos; Franco, Renato; Nylander, Karin

2017-01-01

Squamous cell carcinoma of the head and neck (SCCHN) comprises a large group of cancers in the oral cavity and nasopharyngeal area that typically arise in older males in association with alcohol/tobacco usage. Within the oral cavity, the mobile tongue is the most common site for tumour development. The incidence of tongue squamous cell carcinoma (TSCC) is increasing in younger people, which has been suggested to associate with a viral aetiology. Two common human oncogenic viruses, human papilloma virus (HPV) and Epstein-Barr virus (EBV) are known causes of certain types of SCCHN, namely the oropharynx and nasopharynx, respectively. EBV infects most adults worldwide through oral transmission and establishes a latent infection, with sporadic productive viral replication and release of virus in the oral cavity throughout life. In view of the prevalence of EBV in the oral cavity and recent data indicating that it infects tongue epithelial cells and establishes latency, we examined 98 cases of primary squamous cell carcinoma of the mobile tongue and 15 cases of tonsillar squamous cell carcinoma for the presence of EBV-encoded RNAs (EBERs), EBV DNA and an EBV-encoded protein, EBNA-1. A commercially available in situ hybridisation kit targeting EBER transcripts (EBER-ISH) showed a positive signal in the cytoplasm and/or nuclei of tumour cells in 43% of TSCCs. However, application of control probes and RNase A digestion using in-house developed EBER-ISH showed identical EBER staining patterns, indicating non-specific signals. PCR analysis of the BamH1 W repeat sequences did not identify EBV genomes in tumour samples. Immunohistochemistry for EBNA-1 was also negative. These data exclude EBV as a potential player in TSCC in both old and young patients and highlight the importance of appropriate controls for EBER-ISH in investigating EBV in human diseases.

No evidence for the presence of Epstein-Barr virus in squamous cell carcinoma of the mobile tongue

PubMed Central

Wilms, Torben; Khan, Gulfaraz; Coates, Philip J.; Sgaramella, Nicola; Fåhraeus, Robin; Hassani, Asma; Philip, Pretty S.; Norberg Spaak, Lena; Califano, Luigi; Colella, Giuseppe; Olofsson, Katarina; Loizou, Christos; Franco, Renato

2017-01-01

Squamous cell carcinoma of the head and neck (SCCHN) comprises a large group of cancers in the oral cavity and nasopharyngeal area that typically arise in older males in association with alcohol/tobacco usage. Within the oral cavity, the mobile tongue is the most common site for tumour development. The incidence of tongue squamous cell carcinoma (TSCC) is increasing in younger people, which has been suggested to associate with a viral aetiology. Two common human oncogenic viruses, human papilloma virus (HPV) and Epstein-Barr virus (EBV) are known causes of certain types of SCCHN, namely the oropharynx and nasopharynx, respectively. EBV infects most adults worldwide through oral transmission and establishes a latent infection, with sporadic productive viral replication and release of virus in the oral cavity throughout life. In view of the prevalence of EBV in the oral cavity and recent data indicating that it infects tongue epithelial cells and establishes latency, we examined 98 cases of primary squamous cell carcinoma of the mobile tongue and 15 cases of tonsillar squamous cell carcinoma for the presence of EBV-encoded RNAs (EBERs), EBV DNA and an EBV-encoded protein, EBNA-1. A commercially available in situ hybridisation kit targeting EBER transcripts (EBER-ISH) showed a positive signal in the cytoplasm and/or nuclei of tumour cells in 43% of TSCCs. However, application of control probes and RNase A digestion using in-house developed EBER-ISH showed identical EBER staining patterns, indicating non-specific signals. PCR analysis of the BamH1 W repeat sequences did not identify EBV genomes in tumour samples. Immunohistochemistry for EBNA-1 was also negative. These data exclude EBV as a potential player in TSCC in both old and young patients and highlight the importance of appropriate controls for EBER-ISH in investigating EBV in human diseases. PMID:28926591

Loss of intercellular adhesion activates a transition from low- to high-grade human squamous cell carcinoma.

PubMed

Margulis, Alexander; Zhang, Weitian; Alt-Holland, Addy; Pawagi, Sujata; Prabhu, Padmaja; Cao, Jian; Zucker, Stanley; Pfeiffer, Laurence; Garfield, Jacqueline; Fusenig, Norbert E; Garlick, Jonathan A

2006-02-15

The relationship between loss of intercellular adhesion and the biologic properties of human squamous cell carcinoma is not well understood. We investigated how abrogation of E-cadherin-mediated adhesion influenced the behavior and phenotype of squamous cell carcinoma in 3D human tissues. Cell-cell adhesion was disrupted in early-stage epithelial tumor cells (HaCaT-II-4) through expression of a dominant-negative form of E-cadherin (H-2Kd-Ecad). Three-dimensional human tissue constructs harboring either H-2Kd-Ecad-expressing or control II-4 cells (pBabe, H-2Kd-EcadDeltaC25) were cultured at an air-liquid interface for 8 days and transplanted to nude mice; tumor phenotype was analyzed 2 days and 2 and 4 weeks later. H-2Kd-Ecad-expressing tumors demonstrated a switch to a high-grade aggressive tumor phenotype characterized by poorly differentiated tumor cells that infiltrated throughout the stroma. This high-grade carcinoma revealed elevated cell proliferation in a random pattern, loss of keratin 1 and diffuse deposition of laminin 5 gamma2 chain. When II-4 cell variants were seeded into type I collagen gels as an in vitro assay for cell migration, we found that only E-cadherin-deficient cells detached, migrated as single cells and expressed N-cadherin. Function-blocking studies demonstrated that this migration was matrix metalloproteinase-dependent, as GM-6001 and TIMP-2, but not TIMP-1, could block migration. Gene expression profiles revealed that E-cadherin-deficient II-4 cells demonstrated increased expression of proteases and cell-cell and cell-matrix proteins. These findings showed that loss of E-cadherin-mediated adhesion plays a causal role in the transition from low- to high-grade squamous cell carcinomas and that the absence of E-cadherin is an important prognostic marker in the progression of this disease.

Progression of abnormal MIB-1 staining patterns of reserve cells in cervical smears from women ultimately developing high grade squamous intraepithelial lesions.

PubMed

Siemens, Frederike C; van Haaften, Carolien; Kuijpers, Johan C; Helmerhorst, Theo J M; Boon, Mathilde E

2006-01-01

To assess, in a longitudinal study in women diagnosed with high grade squamous epithelial lesion (HSIL), the progression over time of proliferative activity in reserve cells using population screening cervical cytology specimens. Twenty consecutive, unselected patients with HSIL lesions were part of the national cervical screening program. From the archives, for each patient, the last prior normal population screening smear was included in the study. Concurrent sets of cervical smears from 80 age-matched women without pathology formed the controls. The original slides were stained using MIB-1 monoclonal antibody. The fraction of MIB-1-positive reserve cells was assessed using systematic random sampling and running progressive means assessment to ensure a sufficient sample size. The proliferation fraction in reserve cells of HSIL patients was significantly raised (mean, 65.0%; range, 53.5-94.1%; p < 0.01) as compared with that in concurrent controls (mean, 12.8%; range, 1.9-45.4%). Prior smears from HSIL patients, although without morphologic abnormalities, had abnormally high proliferation fractions (mean, 59.1%; range, 1.0-94.7%), significantly raised over those from concurrent controls (mean, 9.4%; range In population-based cervical smear screening, HSIL patients already have abnormally raised proliferation fractions of reserve cells, even without morphologic changes in squamous cells, 1-5 (mean, 3.6) years prior to diagnosis.

The notch pathway is activated in neoplastic progression in esophageal squamous cell carcinoma.

PubMed

Lubin, Daniel J; Mick, Rosemarie; Shroff, Stuti G; Stashek, Kristen; Furth, Emma E

2018-02-01

The Notch signaling pathway is integral to normal human development and homeostasis and has a deterministic function on cell differentiation. Recent studies suggest aberrant Notch signaling may contribute to neoplastic progression by an increase in stem cell survival, chemoresistance, and the promotion of epithelial-to-mesenchymal transition. The goals of our study were to determine, utilizing quantitative technologies, the expression of activated Notch 1 in esophageal squamous cell carcinoma (SCC) and to determine the relationship between Notch 1 expression and various clinicopathologic parameters. Immunohistochemical staining for Notch intracellular domain (NICD) was performed on 60 consecutive cases of esophageal squamous cell carcinoma, 42 cases of benign esophageal squamous epithelium, and 13 cases of eosinophilic esophagitis diagnosed in our department from 2007 through 2015, and exact nuclear staining and nuclear characteristics were graded using the Vectra imaging system. Clinicopathologic data (gender, age at diagnosis, smoking status, tumor grade, tumor stage, tumor location, and survival) were collected for each SCC case and these were correlated with NICD staining. Cases of esophageal SCC demonstrated significantly higher NICD staining compared to cases of benign and reactive esophageal epithelium (P=.003 and .005, respectively). Among cases of esophageal SCC, nuclear NICD staining was significantly correlated with both tumor grade and stage. Following classification and regression tree analysis, esophageal SCC patients with increased NICD expression were found to be more likely to die from their disease than those with lower levels of expression. Taken together, the findings suggest that increased Notch 1 may contribute to the development and aggressiveness of esophageal SCC. Copyright © 2017 Elsevier Inc. All rights reserved.

Anal Human Papillomavirus (HPV) Prevalences and Factors Associated with Abnormal Anal Cytology in HIV-Infected Women in an Urban Cohort from Rio de Janeiro, Brazil

PubMed Central

Luz, Paula M.; Lake, Jordan E.; Levi, José Eduardo; Coutinho, José Ricardo; de Andrade, Angela; Heinke, Thais; Derrico, Mônica; Veloso, Valdilea G.; Friedman, Ruth K.; Grinsztejn, Beatriz

2015-01-01

Abstract Identifying factors, including human papillomavirus (HPV) genotypes, associated with abnormal anal cytology in HIV-infected women have implications for anal squamous cell cancer (SCC) prevention in HIV-infected women. Anal and cervical samples were collected for cytology, and tested for high-(HR-HPV) and low-risk HPV (LR-HPV) genotypes in a cross-sectional analysis of the IPEC Women's HIV Cohort (Rio de Janeiro, Brazil). Multivariate log-binomial regression models estimated prevalence ratios for factors associated with abnormal anal cytology [≥atypical squamous cells of undetermined significance, (ASC-US)]. Characteristics of the 863 participants included: median age 42 years, 57% non-white, 79% current CD4+ T-cell count >350 cells/mm3, 53% HIV-1 viral load <50 copies/mL, median ART duration 5.8 years. Fifty-one percent of anal specimens contained ≥1 HR-HPV genotype; 31% had abnormal anal cytology [14% ASC-US, 11% low-grade squamous intra-epithelial lesion, (LSIL); 2% atypical squamous cells-cannot exclude high-grade SIL (ASC-H); 4% high-grade SIL/cancer (HSIL+)]. In multivariate analysis, cervical LSIL+, nadir CD4+ T-cell count ≤50 cells/mm3, HIV-1 viral load ≥50 copies/mL, and anal HPV 6, 11, 16, 18, 33, 45, 52, 56, and 58 were associated with ≥anal ASC-US (p<0.05). Abnormal anal cytology and HR-HPV prevalences were high. HIV-infected women with cervical LSIL+, low nadir CD4+ counts, or detectable HIV-1 viral loads should be a particular focus for enhanced anal SCC screening efforts. PMID:25361401

Assessment of Bax and Bcl-2 Immunoexpression in Patients with Oral Lichen Planus and Oral Squamous Cell Carcinoma

PubMed Central

Nafarzadeh, Shima; Jafari, Sina; Bijani, Ali

2013-01-01

Lichen planus (LP) is a chronic inflammatory disease of probable immune-based etiology. The pathogenesis of LP is unclear, but apoptotic changes in epidermal (epithelial) cells have been reported. Destruction of the basal cell layer is observed and many changes in cell proliferation, cell repair and cell death occur in the injured mucosal epithelium. The aim of this study was to evaluate and compare the expression of bax and bcl-2 in oral lichen planus (OLP), well differentiated oral squamous cell carcinoma (WOSCC) and normal mucosa. Sixty one paraffin-embedded biopsy including 11 cases of WOSCC, 30 cases of OLP (n=15 erosive OLP [OLP-E], n=15 reticular OLP [OLP-R]) and 20 normal mucosa were entered in our research. We used immunohistochemistry staining method for assessing bax and bcl-2 expression in epithelial layers. The percentage of stained cells was estimated in 5 randomized microscopic fields and classified as (-): 0%, (+) :< 10%, (++): 10-25%, (+++): 26-50%, (++++): > 50% positive cells. The data were analyzed with Mann-Whitney, Chi Square, and Kruskal-Wallis tests. Significant differences in bax expression were observed among OLP, WOSCC compared to normal mucosa (P=0.008). No significant difference in bax expression between OLP-E and OLP-R compared to WOSCC was seen (P>0.05). Bcl-2 was negative for all OLP and normal mucosa samples, and weak positivity was observed in WOSCC samples. According to the findings of our study, it may be possible to correlate the difference of bax and bcl-2 expression levels among the mentioned lesions to the malignant potential of OLP. PMID:24551804

Paracrine influence of human perivascular cells on the proliferation of adenocarcinoma alveolar epithelial cells.

PubMed

Kim, Eunbi; Na, Sunghun; An, Borim; Yang, Se-Ran; Kim, Woo Jin; Ha, Kwon-Soo; Han, Eun-Taek; Park, Won Sun; Lee, Chang-Min; Lee, Ji Yoon; Lee, Seung-Joon; Hong, Seok-Ho

2017-03-01

Understanding the crosstalk mechanisms between perivascular cells (PVCs) and cancer cells might be beneficial in preventing cancer development and metastasis. In this study, we investigated the paracrine influence of PVCs derived from human umbilical cords on the proliferation of lung adenocarcinoma epithelial cells (A549) and erythroleukemia cells (TF-1α and K562) in vitro using Transwell® co-culture systems. PVCs promoted the proliferation of A549 cells without inducing morphological changes, but had no effect on the proliferation of TF-1α and K562 cells. To identify the factors secreted from PVCs, conditioned media harvested from PVC cultures were analyzed by antibody arrays. We identified a set of cytokines, including persephin (PSPN), a neurotrophic factor, and a key regulator of oral squamous cell carcinoma progression. Supplementation with PSPN significantly increased the proliferation of A549 cells. These results suggested that PVCs produced a differential effect on the proliferation of cancer cells in a cell-type dependent manner. Further, secretome analyses of PVCs and the elucidation of the molecular mechanisms could facilitate the discovery of therapeutic target(s) for lung cancer.

THE NEOPLASTIC POTENTIALITIES OF MOUSE EMBRYO TISSUES

PubMed Central

Smith, William E.

1947-01-01

Epithelial tumors have been readily obtained by the implantation of embryo stomach tissue together with olive oil containing methylcholanthrene (with or without Scharlach R) in adult mice of homologous strain. The implanted tissue from the squamous portion of the stomach rapidly encysted the oil, and benign and malignant papillomas and squamous cell carcinomas soon arose from the stratified squamous lining of the cysts. Bits of the glandular portion of the stomach also formed cysts, but the gland cells underwent metaplasia in response to the carcinogen, altering first to transitional epithelium and then to a stratified squamous layer. So swiftly did these changes take place that nearly all of the tumors took origin from epithelium that had already become stratified and squamous, and the growths themselves were of this type. A single transitional cell carcinoma and an adenoacanthoma were procured, but no adenocarcinomas; nor did any benign papillomas develop, though they often resulted from the action of methylcholanthrene on the squamous portion of the embryo stomach. Search failed to disclose any distinctive precancerous changes in the gastric tissue. Five of the cancers were transplanted and they grew in every host. No tumors arose from any of the numerous control implants. Those consisting of glandular tissue formed cysts lined partly with columnar epithelium secreting mucus and partly with tubular glands equipped with chief and parietal cells in good condition. Pepsin and rennin were found in the fluid contained in these cysts, but no free hydrochloric acid. The enzymes were present also when the cysts contained methylcholanthrene and the glands had not yet been wholly replaced by metaplastic epithelium. The tumors appeared months sooner than when methylcholanthrene is injected into the stomach of adult animals or given by mouth; some of them were well established after 5 or 6 weeks. They arose regularly when the requisite experimental conditions were provided. The utilization of transplanted embryo tissue provides a means whereby gastric tumors free from bacterial infection can be procured swiftly and easily. PMID:19871629

Nipple adenoma arising from axillary accessory breast: a case report

PubMed Central

2012-01-01

Nipple adenoma is a relatively rare benign breast neoplasm, and cases of the disease arising from the axillary accessory breast have very seldom been reported in the English literature. We report a case of nipple adenoma arising from axillary accessory breast including clinical and pathological findings. An 82-year-old woman presented with the complaint of a small painful mass in the right axilla. Physical examination confirmed a well-defined eczematous crusted mass that was 8 mm in size. The diagnosis of nipple adenoma was made from an excisional specimen on the basis of characteristic histological findings. Microscopic structural features included a compact proliferation of small tubules lined by epithelial and myoepithelial cells, and the merging of glandular epithelial cells of the adenoma into squamous epithelial cells in the superficial epidermal layer. Because clinically nipple adenoma may resemble Paget’s disease and pathologically can be misinterpreted as tubular carcinoma, the correct identification of nipple adenoma is an important factor in the differential diagnosis for axillary tumor neoplasms. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1186821489769063 PMID:23186145

ΔNp63 versatilely regulates a broad NF-κB gene program and promotes squamous epithelial proliferation, migration and inflammation

PubMed Central

Yang, Xinping; Lu, Hai; Yan, Bin; Romano, Rose-Anne; Bian, Yansong; Friedman, Jay; Duggal, Praveen; Allen, Clint; Chuang, Ryan; Ehsanian, Reza; Si, Han; Sinha, Satrajit; Van Waes, Carter; Chen, Zhong

2012-01-01

Head and neck squamous cell carcinoma (HNSCC) and many epithelial malignancies exhibit increased proliferation, invasion and inflammation, concomitant with aberrant nuclear activation of TP53 and NF-κB family members ΔNp63, c-REL and RELA. However, the mechanisms of crosstalk by which these transcription factors coordinate gene expression and the malignant phenotype remain elusive. Here we demonstrate thatΔNp63 regulates a cohort of genes involved in cell growth, survival, adhesion and inflammation, which substantially overlaps with the NF-κB transcriptome. ΔNp63 with c-REL and/or RELA are recruited to form novel binding complexes on p63 or NF-κB/REL sites of multiple target gene promoters. Overexpressed ΔNp63- or TNF-α-induced NF-κB and inflammatory cytokine IL-8 reporter activation depended upon RELA/c-REL regulatory binding sites. Depletion of RELA or ΔNp63 by siRNA significantly inhibited NF-κB-specific, or TNF-α-induced IL-8 reporter activation. ΔNp63 siRNA significantly inhibited proliferation, survival, and migration by HNSCC cells in vitro. Consistent with the above, an increase in nuclear ΔNp63 accompanied by increased proliferation (Ki67), and adhesion (β4 integrin) markers, and induced inflammatory cell infiltration was observed throughout HNSCC specimens, when compared to the basilar pattern of protein expression and minimal inflammation seen in non-malignant mucosa. Further, overexpression of ΔNp63α in squamous epithelia in transgenic mice leads to increased suprabasilar c-REL, Ki-67, and cytokine expression, together with epidermal hyperplasia and diffuse inflammation, similar to HNSCC. Our study reveals ΔNp63 as a master transcription factor that in coordination with NF-κB/RELs, orchestrates a broad gene program promoting epidermal hyperplasia, inflammation, and the malignant phenotype of HNSCC. PMID:21576089

Molecular markers associated with development and progression of potentially premalignant oral epithelial lesions: Current knowledge and future implications.

PubMed

Nikitakis, Nikolaos G; Pentenero, Monica; Georgaki, Maria; Poh, Catherine F; Peterson, Douglas E; Edwards, Paul; Lingen, Mark; Sauk, John J

2018-06-01

Identification and management of potentially premalignant oral epithelial lesions (PPOELs) at highest risk of malignant transformation holds great promise for successful secondary prevention of oral squamous cell carcinoma, potentially reducing oral cancer morbidity and mortality. However, to date, neither clinical nor histopathologic validated risk predictors that can reliably predict which PPOELs will definitively progress to malignancy have been identified. In addition, the management of PPOELs remains a major challenge. Arguably, progress in the prevention and treatment of oral premalignancy and cancer will require improved understanding of the underlying molecular mechanisms, facilitating the discovery of diagnostic, prognostic, and predictive markers, as well as the identification of novel targeted therapeutics. This review provides a synopsis of the molecular biomarkers that have been studied in PPOELs and have been correlated with the presence and grade of dysplasia and/or their propensity to undergo malignant transformation to oral squamous cell carcinoma. The emphasis is on highlighting new emerging research fields, particularly epigenetic events, including methylation and micro-RNA regulation. Several promising biomarkers are highlighted. Current limitations and challenges are discussed. Recommendations for future focused research areas, to validate and promote clinically useful applications, are offered. Copyright © 2018 Elsevier Inc. All rights reserved.

Intraepidermal proliferation of Merkel cells within a seborrheic keratosis: Merkel cell carcinoma in situ or Merkel cell hyperplasia?

PubMed

McFalls, Jeanne; Okon, Lauren; Cannon, Sarah; Lee, Jason B

2017-05-01

Intradepidermal proliferation of Merkel cells without any dermal component has been interpreted as either a hyperplastic process secondary to chronic ultraviolet radiation or a neoplastic process, namely Merkel cell carcinoma (MCC) in situ. The recent criteria that have been proffered to diagnose MCC in situ, unfortunately, are identical to those that have been applied to Merkel cell hyperplasia in the past, posing a diagnostic quandary when faced with an intraepidermal proliferation of Merkel cells. Most previously reported cases of MCC in situ have occurred within associated epithelial lesion that includes solar (actinic) keratosis and squamous-cell carcinoma in situ. Similarly, Merkel cell hyperplasia has been reported to occur in association with a variety of epithelial lesions as well as on chronically sun-damaged skin. Herein, a case of an intraepidermal proliferation of Merkel cells within a seborrheic keratosis is presented accompanied by a discussion on whether the proliferation represents another case of Merkel cell carcinoma in situ or an incidental hyperplastic process on chronically sun-damaged skin. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Endorsing cellular competitiveness in aberrant epithelium of oral submucous fibrosis progression: neighbourhood analysis of immunohistochemical attributes.

PubMed

Anura, Anji; Kazi, Anees; Pal, Mousumi; Paul, Ranjan Rashmi; Sengupta, Sanghamitra; Chatterjee, Jyotirmoy

2018-04-23

Epithelial abnormality during the transformation of oral submucous fibrosis (OSF) into oral squamous cell carcinoma has been well studied and documented. However, the differential contribution of atrophy and hyperplasia for malignant potentiality of OSF is yet to be resolved. Existing diagnostic conjectures lack precise diagnostic attributes which may be effectively resolved by substantiation of specific molecular pathology signatures. Present study elucidates existence of cellular competitiveness in OSF conditions using computer-assisted neighbourhood analysis in quantitative immunohistochemistry (IHC) framework. The concept of field cancerization was contributory in finding correspondence among neighbouring cells of epithelial layers with reference to differential expression of cardinal cancer-related genes [c-Myc (oncogene), p53 (tumour suppressor), and HIF-1α (hypoxia regulator)] which are known to be important sensors in recognizing cellular competitive interface. Our analyses indicate that different states of OSF condition may be associated with different forms of competitiveness within epithelial neighbouring cells which might be responsible to shape the present and future of the pre-malignant condition. Analytical findings indicated association of atrophic epithelium with stress-driven competitive environment having low c-Myc, high-p53, and stable HIF-1α (the looser cells) which undergo apoptosis. Whereas, the cells with high c-Myc + (winner cells) give rise to hyperplastic epithelium via possible mutation in p53. The epithelial dysplasia plausibly occurs due to clonal expansion of c-Myc and p53 positive supercompetitor cells. Present study proposes quantitative IHC along with neighbourhood analysis which might help us to dig deeper on to the interaction among epithelial cell population to provide a better understanding of field cancerization and malignant transformation of pre-malignancy.

miR-654-5p Targets GRAP to Promote Proliferation, Metastasis, and Chemoresistance of Oral Squamous Cell Carcinoma Through Ras/MAPK Signaling.

PubMed

Lu, Meng; Wang, Chengyong; Chen, Weihui; Mao, Chuanqing; Wang, Jin

2018-04-01

Oral squamous cell carcinoma (OSCC) is characterized by rapid local migration and invasion. This study was aimed at clarifying the effect of miR-654-5p on progression of OSCC. miR-654-5p promoted proliferation, metastasis, and chemoresistance of OSCC in vitro and in vivo. Consistently, miR-654-5p was upregulated in late-stage OSCC and was correlated with poor prognosis of OSCC patients. Furthermore, miR-654-5p was mechanistically verified to target Grb-2-related adaptor protein (GRAP), accompanied by the activation of Ras/MAPK signaling and the facilitation of epithelial-mesenchymal transition in OSCC cells. GRAP was downregulated in T1-2 stage versus T3-4 stage head and neck squamous cell carcinoma (HNSC) and was negatively correlated with tumor-node-metastases (TNM) stage in HNSC patients based on The Cancer Genome Atlas (TCGA) analysis. In addition, GRAP was positively correlated with good prognosis in HNSC patients. Our findings suggest that the miR-654-5p/GRAP/Ras/Erk signaling pathway in OSCC cells might contribute to the underlying mechanism through which miR-654-5p participates in the regulation of OSCC progression. miR-654-5p, as a potential biomarker for the clinical diagnosis and prognosis of OSCC, may be an effective anticancer target for the treatment of OSCC.

Perforating elastic fibers ('elastic fiber trapping') in the differentiation of keratoacanthoma, conventional squamous cell carcinoma and pseudocarcinomatous epithelial hyperplasia.

PubMed

Shah, Kabeer; Kazlouskaya, Viktoryia; Lal, Karan; Molina, David; Elston, Dirk M

2014-02-01

Keratoacanthoma (KA), an epithelial neoplasm occurring in sun-exposed skin of the elderly, is considered a well-differentiated form of conventional squamous cell carcinoma (SCC) that often follows a course of spontaneous regression. Distinguishing KA from conventional SCC or pseudocarcinomatous epithelial hyperplasia ensures proper diagnosis, treatment and management. For some time, perforating elastic fibers have been utilized in differentiating KA from SCC. This phenomenon may also occur in association with scars and hypertrophic lupus erythematosus (LE). To assess the diagnostic utility of perforating elastic fibers, we compared their incidence in KA, SCC, scars with overlying pseudocarcinomatous hyperplasia, hypertrophic LE, hypertrophic lichen planus (LP) and lichen simplex chronicus (LSC). A retrospective case search identified 359 lesions and the presence of perforating elastic fibers was evaluated using routinely stained sections. This phenomenon was documented in all studied groups except hypertrophic LP. The incidence was found to be 71% in KA, 37% in SCC, and was lowest in inflammatory conditions with associated pseudocarcinomatous hyperplasia (hypertrophic LP 0%, hypertrophic LE 5.9% and LSC 28.2%). The observed frequency in pseudocarcinomatous hyperplasia overlying scars (57.8%) vs. KA (71%) was not statistically different. Although elastic fiber trapping has potential value as a diagnostic criterion for KA, dermatopathologists should consider its limitations. Its diagnostic utility was greatest in distinguishing KA from hypertrophic LE and hypertrophic LP. Conversely, elastic trapping is not helpful differentiating pseudocarcinomatous hyperplasia from recurrent/persistent KA following surgery. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Low Temperature Plasma Kills SCaBER Cancer Cells

NASA Astrophysics Data System (ADS)

Barekzi, Nazir; van Way, Lucas; Laroussi, Mounir

2013-09-01

Squamous cell carcinoma of the bladder is a rare type of bladder cancer that forms as a result of chronic irritation of the epithelial lining of the bladder. The cell line used in this study is SCaBER (ATCC® HTB-3™) derived from squamous cell carcinoma of the human urinary bladder. Current treatments of bladder cancer include surgery, radiation and chemotherapy. However, the cost of these treatments, the potential toxicity of the chemotherapeutic agents and the systemic side-effects warrant an alternative to current cancer treatment. This paper represents preliminary studies to determine the effects of biologically tolerant plasma (BTP) on a cell line of human bladder cancer cells. Previous work by our group using the plasma pencil revealed the efficacy of BTP on leukemia cells suspended in solution. Based on these earlier findings we hypothesized that the plasma exposure would elicit a similar programmed cell death in the SCaBER cells. Trypan blue exclusion and MTT assays revealed the cell killing after exposure to BTP. Our study indicates that low temperature plasma generated by ionizing helium gas and the reactive species may be a suitable and safe alternative for cancer therapy.

Senescence-Derived Extracellular Molecules as Modulators of Oral Cancer Development: A Mini-Review.

PubMed

Parkinson, Eric Kenneth; James, Emma L; Prime, Stephen S

2016-01-01

Oral cancers are predominantly oral squamous cell carcinomas (OSCCs) derived from keratinocytes, and there is now very detailed knowledge of the genetics and molecular biology of the epithelial tumourigenic component of these cancers, including the identification of cancer stem or tumour-initiating cells. Several key genetic alterations have been identified including the near ubiquitous loss of the CDKN2A/p16INK4A and p53 pathways and telomerase activation, together with frequent inactivation of the NOTCH1 canonical pathway either by somatic genetic alterations or by the presence of human papilloma virus. There is also evidence that OSCCs arise from a 'field' of altered cells and that malignant conversion takes place pre-dominantly at the microscopic level. However, in the last decade, it has been realised that tumour development and progression are influenced by the cells of the microenvironment with cross-talk between the epithelial (tumour) and mesenchymal components. OSCCs, especially those that have bypassed cellular senescence, produce an array of proteins and metabolites that induce cellular senescence in the normal surrounding cells; indeed, senescence is a common property of cancer-associated fibroblasts (CAFs). Cellular senescence is defined as an irreversible cell cycle arrest and is associated with the release of molecules known as the senescence-associated secretory phenotype that can selectively promote the growth of pre-neoplastic keratinocytes (osteopontin) and cancer invasion (transforming growth factor β, matrix metalloproteinases, interleukin 6 and lactate). In addition, both old and new work has shown that keratinocytes harbouring NOTCH loss-of-function mutations that lead to defective keratinocyte differentiation and loss of squamous epithelial barrier function may act as a tumour-promoting stimulus for initiated cells harbouring RAS pathway mutations by activating a wound response in the tumour mesenchyme. Thus, not all keratinocytes in the tumour tissue may be tumourigenic and may instead act as promoters of tumour growth and progression analogous to the much-studied CAFs which co-evolve with the genetically altered tumourigenic cells. This new data is discussed in relation to attempts to develop novel non-invasive diagnostics and therapeutics for oral cancer. © 2015 S. Karger AG, Basel.

The Role of BRCA1 in Normal Mammary Epithelial Development and Tumorigenesis.

DTIC Science & Technology

1999-06-01

addition, a hemangiosarcoma was found in one of the Brcal’’~p53~’~ mice. Cell lines were generated from each of these tumors. Generation and...19 10 45.2 23.8 2/9 0/5 Hemangiosarcoma Cerebellar developmental defect Adenocarcinoma of the Hardarian gland 3 2 1 5.9 3.9 2.0 2 4.8...17.4 0/2 Hemangiosarcoma 2 8.7 Squamous cell carcinoma 1 4.3 Benign spindle cell tumor 1 4.3 No visible or metastatic tumors at death 3 15.8 3 13.0

Pseudocarcinomatous hyperplasia in anaplastic large cell lymphoma, a mimicker of poorly differentiated squamous cell carcinoma: report of a case and review of the literature.

PubMed

Price, Alexandra; Miller, Jason H; Junkins-Hopkins, Jacqueline M

2015-11-01

Pseudocarcinomatous hyperplasia can occasionally be observed in biopsies of CD30-positive lymphoproliferative disorders. It is important to be cognizant of this association, because epithelial hyperproliferation can overshadow large atypical lymphoid cells, leading to an erroneous diagnosis of squamous cell carcinoma (SCC) or keratoacanthoma. Herein, we present a case of anaplastic large cell lymphoma (ALCL) with pseudocarcinomatous hyperplasia simulating a poorly differentiated carcinoma and review the literature on this subject. Immunohistochemical staining with p63 helped delineate the infiltrating tongues of pseudocarcinomatous hyperplasia from the malignant infiltrate. We present this case to raise awareness of the potential for pseudocarcinomatous hyperplasia to occur in the setting of CD30+ lymphoproliferative disorders. Clinicians and dermatopathologists should consider the possibility of ALCL or lymphomatoid papulosis when examining lesions with features of inflamed SCC, especially if the tumor presents on a site or in a patient that is not typical of SCC. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Lower gingival squamous cell carcinoma with brain metastasis during long-term cetuximab treatment: A case report.

PubMed

Naruse, Tomofumi; Tokuhisa, Mitsuko; Yanamoto, Souichi; Sakamoto, Yuki; Okuyama, Kohei; Tsuchihashi, Hiroki; Umeda, Masahiro

2018-05-01

Long-term cetuximab treatment can lead to acquired resistance, and tumor progression and/or new lesions often occur. The present report describes a case of lower gingival squamous cell carcinoma with brain metastasis during long-term cetuximab treatment in a 60-year-old man, including findings of an immunohistochemical study. The resected primary tumors, biopsy of the lung metastasis before administration of cetuximab, and brain metastasis specimens mediated by cetuximab were immunohistochemically examined. Histologically, the metastatic brain lesion showed hyperkeratinizing tumor cells with deeply stained irregular nuclei with necrotizing tumor cells, and a decrease in cell density was exhibited in part of the tumor nest. Moreover, the brain lesion was less malignant compared with the primary tumor and metastatic lung lesions. Immunohistochemically, the metastatic brain lesions showed low expression of epidermal growth factor receptor (EGFR) and high expression of N-cadherin compared with the primary tumor and metastatic lung lesions. These results suggest that acquired resistance to cetuximab may be associated with low EGFR expression and increased epithelial-to-mesenchymal transition potential.

Prognostic significance of phosphorylated RON in esophageal squamous cell carcinoma.

PubMed

Hui, Marco K C; Lai, Kenneth K Y; Chan, Kwok Wah; Luk, John M; Lee, Nikki P; Chung, Yvonne; Cheung, Leo C; Srivastava, Gopesh; Tsao, Sai Wah; Tang, Johnny C; Law, Simon

2012-09-01

Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer. RON is a transmembrane receptor overexpressed in various cancers; however, the clinical significance of its phosphorylated form (pRON) is not fully deciphered. This report is the first to investigate the expression and clinical significance of pRON in human ESCC. Quantitative polymerase chain reaction revealed an up-regulation of RON mRNA in 70% (7/10) of ESCC tissues when compared to the adjacent nontumor tissues. An overexpression of pRON protein was found in most of the ESCC cell lines studied (4/5) when compared to two non-neoplastic esophageal epithelial cells using immunoblot. In 64 ESCC tissues, pRON was localized at the cell membrane, cytoplasm and nucleus in 15 (23.4%), 63 (98.4%) and 61 (95.3%) cases using immunohistochemistry. Patients having high expression of cytoplasmic pRON significantly associated with shorter median survival when compared to those with low expression (25.41 months vs. 14.43 months), suggesting cytoplasmic pRON as a potential marker for poor prognosis in ESCC patients.

Micronuclei: An essential biomarker in oral exfoliated cells for grading of oral squamous cell carcinoma.

PubMed

Jadhav, Kiran; Gupta, Nidhi; Ahmed, Mujib Br

2011-01-01

Micronuclei in exfoliated oral epithelial cells have been shown in some studies to correlate with severity of this genotoxic damage. This severity can be measured in terms of grading of the lesions. To correlate frequency of micronuclei (MN) in oral exfoliated cells in clinically diagnosed cases of oral squamous cell carcinoma (OSCC) followed by a histopathological grading. The study subjects consisted of clinically diagnosed cases of OSCC. Healthy subjects without any tobacco consumption habits formed the control group. The cytosmears from both groups were stained with rapid Papanicolaou stain. MN were identified according to the criteria given by Countryman and Heddle with some modifications. The frequency of MN was three to four times higher in patients with OSCC as compared to patients in the control group and the difference was found to be highly significant. In 75% cases, the cytological grade as determined by the frequency of micronuclei correlated with the histopathological grade and this observation was statistically significant. MN can be a candidate to serve as a biomarker for prediction of the grade of OSCC.

Invasion-Related Factors as Potential Diagnostic and Therapeutic Targets in Oral Squamous Cell Carcinoma—A Review

PubMed Central

Siriwardena, Samadarani B. S. M.; Tsunematsu, Takaaki; Qi, Guangying; Ishimaru, Naozumi; Kudo, Yasusei

2018-01-01

It is well recognized that the presence of cervical lymph node metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC). In solid epithelial cancer, the first step during the process of metastasis is the invasion of cancer cells into the underlying stroma, breaching the basement membrane (BM)—the natural barrier between epithelium and the underlying extracellular matrix (ECM). The ability to invade and metastasize is a key hallmark of cancer progression, and the most complicated and least understood. These topics continue to be very active fields of cancer research. A number of processes, factors, and signaling pathways are involved in regulating invasion and metastasis. However, appropriate clinical trials for anti-cancer drugs targeting the invasion of OSCC are incomplete. In this review, we summarize the recent progress on invasion-related factors and emerging molecular determinants which can be used as potential for diagnostic and therapeutic targets in OSCC. PMID:29758011

Pattern of ophthalmic lesions at two histopathology centres in Ethiopia.

PubMed

Assegid, A

2001-05-01

To describe the distribution of ocular, orbital and eyelid lesions that required histopathologic analysis in Ethiopian children and adults. A retrospective study. Tikur Anbessa and Menelik II Teaching hospitals, Addis Ababa, Ethiopia, during 1995 and 1999 period. Two hundred and ninety ophthalmic specimens were examined, 20% of which came from children. Half of the lesions had epithelial origin, about 30% were malignant, 22.6% were benign and 16.4% were potentially malignant. Squamous cell carcinoma was the leading conjunctival (26%), eyelid (33%), orbital (33%) and ocular (20%) lesion among adults and elderly people whereas only 6% of eyelid lesion were basal cell carcinomas. In children the most frequent intra-ocular as well as orbital tumour was retinoblastoma, 39%, followed by miscellaneous benign lesions (24%). More than half of the request forms were incomplete. In Addis Ababa, squamous cell carcinoma and retinoblastoma should be considered when evaluating ophthalmic lesions in adults and children, respectively. Clinicians and pathologists should improve their communication by filling in request forms, providing clear reports and making dialogue.

Sequential pathological changes during malignant transformation of a craniopharyngioma: A case report and review of the literature

PubMed Central

Negoto, Tetsuya; Sakata, Kiyohiko; Aoki, Takachika; Orito, Kimihiko; Nakashima, Shinji; Hirohata, Masaru; Sugita, Yasuo; Morioka, Motohiro

2015-01-01

Background: Malignant transformation of craniopharyngiomas is quite rare, and the etiology of transformation remains unclear. The prognosis of malignantly transformed craniopharyngiomas is very poor. Case Description: A 36-year-old male had five craniotomies, five transsphenoidal surgeries, and two radiation treatments until 31 years of age after diagnosis of craniopharyngioma at 12 years of age. All serial pathological findings indicated adamantinomatous craniopharyngioma including those of a surgery performed for tumor regrowth at 31 years of age. However, when the tumor recurred approximately 5 years later, the pathological findings showed squamous metaplasia. The patient received CyberKnife surgery, but the tumor rapidly regrew within 4 months. The tumor was resected with the cavernous sinus via a dual approach: Transcranial and transsphenoidal surgery with an extracranial-intracranial bypass using the radial artery. Pathologic examination of a surgical specimen showed that it consisted primarily of squamous cells; the lamina propria was collapsed, and the tumor cells had enlarged nuclei and clarification of the nucleolus. The tumor was ultimately diagnosed as malignant transformation of craniopharyngioma. After surgery, he received combination chemotherapy (docetaxel, cisplatin, and fluorouracil). The tumor has been well controlled for more than 12 months. Conclusion: Serial pathological changes of the craniopharyngioma and a review of the 20 cases reported in the literature suggest that radiation of the squamous epithelial cell component of the craniopharyngioma led to malignant transformation via squamous metaplasia. We recommend aggressive surgical removal of craniopharyngiomas and avoidance of radiotherapy if possible. PMID:25883842

Defining the Interaction of HIV-1 with the Mucosal Barriers of the Female Reproductive Tract

PubMed Central

Carias, Ann M.; McCoombe, Scott; McRaven, Michael; Anderson, Meegan; Galloway, Nicole; Vandergrift, Nathan; Fought, Angela J.; Lurain, John; Duplantis, Maurice; Veazey, Ronald S.

2013-01-01

Worldwide, HIV-1 infects millions of people annually, the majority of whom are women. To establish infection in the female reproductive tract (FRT), HIV-1 in male ejaculate must overcome numerous innate and adaptive immune factors, traverse the genital epithelium, and establish infection in underlying CD4+ target cells. How the virus achieves this remains poorly defined. By utilizing a new technique, we define how HIV-1 interacts with different tissues of the FRT using human cervical explants and in vivo exposure in the rhesus macaque vaginal transmission model. Despite previous claims of the squamous epithelium being an efficient barrier to virus entry, we reveal that HIV-1 can penetrate both intact columnar and squamous epithelial barriers to depths where the virus can encounter potential target cells. In the squamous epithelium, we identify virus entry occurring through diffusive percolation, penetrating areas where cell junctions are absent. In the columnar epithelium, we illustrate that virus does not transverse barriers as well as previously thought due to mucus impediment. We also show a statistically significant correlation between the viral load of inocula and the ability of HIV-1 to pervade the squamous barrier. Overall, our results suggest a diffusive percolation mechanism for the initial events of HIV-1 entry. With these data, we also mathematically extrapolate the number of HIV-1 particles that penetrate the mucosa per coital act, providing a biological description of the mechanism for HIV-1 transmission during the acute and chronic stages of infection. PMID:23966398

Msx2 Prevents Stratified Squamous Epithelium Formation in the Enamel Organ.

PubMed

Nakatomi, M; Ida-Yonemochi, H; Nakatomi, C; Saito, K; Kenmotsu, S; Maas, R L; Ohshima, H

2018-06-01

Tooth enamel is manufactured by the inner enamel epithelium of the multilayered enamel organ. Msx2 loss-of-function mutation in a mouse model causes an abnormal accumulation of epithelial cells in the enamel organ, but the underlying mechanism by which Msx2 regulates amelogenesis is poorly understood. We therefore performed detailed histological and molecular analyses of Msx2 null mice. Msx2 null ameloblasts and stratum intermedium (SI) cells differentiated normally in the early stages of amelogenesis. However, during subsequent developmental stages, the outer enamel epithelium (OEE) became highly proliferative and transformed into a keratinized stratified squamous epithelium that ectopically expressed stratified squamous epithelium markers, including Heat shock protein 25, Loricrin, and Keratin 10. Moreover, expression of hair follicle-specific keratin genes such as Keratin 26 and Keratin 73 was upregulated in the enamel organ of Msx2 mutants. With the accumulation of keratin in the stellate reticulum (SR) region and subsequent odontogenic cyst formation, SI cells gradually lost the ability to differentiate, and the expression of Sox2 and Notch1 was downregulated, leading to ameloblast depolarization. As a consequence, the organization of the Msx2 mutant enamel organ became disturbed and enamel failed to form in the normal location. Instead, there was ectopic mineralization that likely occurred within the SR. In summary, we show that during amelogenesis, Msx2 executes a bipartite function, repressing the transformation of OEE into a keratinized stratified squamous epithelium while simultaneously promoting the development of a properly differentiated enamel organ competent for enamel formation.

Ultrastructural analysis of oral exfoliated epithelial cells of tobacco smokers and betel nut chewers: A scanning electron microscopy study.

PubMed

Khan, Sameera Shamim; Shreedhar, Balasundari; Kamboj, Mala

2016-01-01

The study was undertaken to correlate epithelial surface pattern changes of oral exfoliated cells of tobacco smokers and betel nut chewers and also to compare them with patients of oral squamous cell carcinoma (OSCC) and healthy individuals. In this cross-sectional study, a total of fifty persons were included in the study, out of which thirty formed the study group (15 each tobacco smokers and betel nut chewers) and twenty formed the control group (ten each of OSCC patients - positive control and ten normal buccal mucosa - negative control). Their oral exfoliated cells were scraped, fixed, and studied under scanning electron microscope (SEM). The statistical analysis was determined using ANOVA, Tukey honestly significant difference, Chi-square test, and statistical SPASS software, P < 0.05. OSCC, Individual cell modifications, intercellular relationships and surface characteristics observed by scanning electron microscopy between OSCC, tobacco smokers, betel nut chewers compared to normal oral mucosa have been tabulated. In normal oral mucosa, cell surface morphology depends on the state of keratinization of the tissue. Thus, it could prove helpful in detecting any carcinomatous change at its incipient stage and also give an insight into the ultra-structural details of cellular differentiations in epithelial tissues.

Morphological characterization of sprouting and intussusceptive angiogenesis by SEM in oral squamous cell carcinoma.

PubMed

Oliveira de Oliveira, Laura Beatriz; Faccin Bampi, Vinícius; Ferreira Gomes, Carolina; Braga da Silva, Jefferson Luis; Encarnação Fiala Rechsteiner, Sandra Mara

2014-01-01

The word angiogenesis indicates the formation of new vascular segments from existing vessels such as capillaries and venules. Blood vessel formation in tumors is the result of rapid, disorganized vascular growth through two distinct mechanisms: sprouting and intussusceptive angiogenesis. The objective of this study was to elucidate the morphological aspects of these two vascular growth mechanisms in oral squamous cell carcinoma induced in hamster buccal pouch. Eight Syrian golden hamsters had their right buccal pouch treated with DMBA 0.5% and 10% carbamide peroxide for 90 days in order to produce squamous cell carcinoma in this site. Next, buccal pouches of the animals were submitted to the vascular corrosion technique and then analyzed by scanning electron microscopy. The vascular figures of sprouts were observed in the entire vascular network of the buccal pouches, as opposed to the intussusceptive angiogenesis that was predominantly observed in the sub-epithelial network. It was possible to differentiate the figures of sprouts from artifacts by the analysis of the blind ending of these structures. Intussusceptive angiogenesis was identified by the presence of holes trespassing the lumen of the capillaries. Vascular expansion occurred through intussusceptive angiogenesis in two ways: by the fusion of the pillars to form a new capillary and, by increasing the girth of the pillar to form meshes. The method of corrosion associated with scanning electron microscopy proved to be an excellent tool to study the two types of angiogenesis in oral squamous cell carcinoma in the hamster buccal pouch. © 2013 Wiley Periodicals, Inc.

Non-invasive label-free investigation and typing of head and neck cancers by multimodal nonlinear microscopy

NASA Astrophysics Data System (ADS)

Meyer, Tobias; Vogler, Nadine; Dietzek, Benjamin; Akimov, Denis; Inhestern, Johanna; Guntinas-Lichius, Orlando; Popp, Jürgen

2012-06-01

Early detection and typing of tumors is pressing matter in clinical research with important impacts for prognosis and successful treatment. Currently, staining is the golden standard in histopathology but requires surgical removal of tissue. In order to avoid resection of non-diseased tissue a non-invasive real-time imaging method is required which can be applied ideally intrasurgically. In this proceeding a combination of second harmonic generation (SHG), two photon excited fluorescence (TPEF) and coherent anti-Stokes Raman (CARS) imaging has been employed to investigate tissue sections of head and neck carcinomas focussing on laryngeal carcinoma. Primary laryngeal and other head and neck carcinomas consist to 99% of squamous cell carcinoma. By fusing the various imaging methods it is possible to measure the thickness of the epithelial cell layer as a marker for dysplastic or cancerous tissue degradation and to differentiate keratinizing and nonkeratininzing squamous cell carcinomas (SCC). As nonkeratinizing SCCs of the oropharynx correlate with a human papillomavirus (HPV) infection as a subentity of head and neck cancer, and HPV related tumors are associated with a better clinical prognosis, the differentiation between keratinizing and non-keratinizing forms of SCCs is of high diagnostic value. TPEF is capable of displaying cell nuclei, therefore, morphologic information as cell density, cell to cytoplasm ratio, size and shape of cell nuclei can be obtained. SHG - on the other hand - selectively reveals the collagen matrix of the connective tissue, which is useful for determination of tumor-islets boundaries within epithelial tissue - a prerequisite for precise resection. Finally CARS in the CH-stretching region visualizes the lipid content of the tissue, which can be correlated with the dysplastic grade of the tissue.

Collecting Tumor Samples From Patients With Gynecological Tumors

ClinicalTrials.gov

2016-10-26

Borderline Ovarian Clear Cell Tumor; Borderline Ovarian Serous Tumor; Cervical Adenocarcinoma; Cervical Adenosquamous Carcinoma; Cervical Small Cell Carcinoma; Cervical Squamous Cell Carcinoma, Not Otherwise Specified; Childhood Embryonal Rhabdomyosarcoma; Childhood Malignant Ovarian Germ Cell Tumor; Endometrioid Stromal Sarcoma; Gestational Trophoblastic Tumor; Malignant Mesothelioma; Malignant Ovarian Epithelial Tumor; Melanoma; Neoplasm of Uncertain Malignant Potential; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Paget Disease of the Vulva; Recurrent Cervical Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Ovarian Germ Cell Tumor; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Recurrent Vaginal Carcinoma; Recurrent Vulvar Carcinoma; Stage I Ovarian Cancer; Stage I Uterine Corpus Cancer; Stage I Vaginal Cancer; Stage I Vulvar Cancer; Stage IA Cervical Cancer; Stage IA Fallopian Tube Cancer; Stage IA Ovarian Cancer; Stage IA Ovarian Germ Cell Tumor; Stage IB Cervical Cancer; Stage IB Fallopian Tube Cancer; Stage IB Ovarian Cancer; Stage IB Ovarian Germ Cell Tumor; Stage IC Fallopian Tube Cancer; Stage IC Ovarian Cancer; Stage IC Ovarian Germ Cell Tumor; Stage II Ovarian Cancer; Stage II Uterine Corpus Cancer; Stage II Vaginal Cancer; Stage II Vulvar Cancer; Stage IIA Cervical Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIA Ovarian Germ Cell Tumor; Stage IIB Cervical Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIB Ovarian Germ Cell Tumor; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIC Ovarian Germ Cell Tumor; Stage III Borderline Ovarian Surface Epithelial-Stromal Tumor; Stage III Cervical Cancer; Stage III Uterine Corpus Cancer; Stage III Vaginal Cancer; Stage III Vulvar Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Ovarian Germ Cell Tumor; Stage IIIC Primary Peritoneal Cancer; Stage IV Borderline Ovarian Surface Epithelial-Stromal Tumor; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Stage IV Uterine Corpus Cancer; Stage IVA Cervical Cancer; Stage IVA Vaginal Cancer; Stage IVB Cervical Cancer; Stage IVB Vaginal Cancer; Stage IVB Vulvar Cancer; Uterine Corpus Cancer; Uterine Corpus Leiomyosarcoma; Vulvar Squamous Cell Carcinoma

Prepare to Care, A Supported Self-Management Intervention for Head and Neck Cancer CaregiversHead and Neck Cancer

ClinicalTrials.gov

2018-04-26

Caregiver; Malignant Head and Neck Neoplasm; Paranasal Sinus Squamous Cell Carcinoma; Salivary Gland Squamous Cell Carcinoma; Stage I Hypopharyngeal Squamous Cell Carcinoma; Stage I Laryngeal Squamous Cell Carcinoma; Stage I Lip and Oral Cavity Squamous Cell Carcinoma; Stage I Oropharyngeal Squamous Cell Carcinoma; Stage II Hypopharyngeal Squamous Cell Carcinoma; Stage II Laryngeal Squamous Cell Carcinoma; Stage II Lip and Oral Cavity Squamous Cell Carcinoma; Stage II Oropharyngeal Squamous Cell Carcinoma; Stage III Hypopharyngeal Squamous Cell Carcinoma; Stage III Laryngeal Squamous Cell Carcinoma; Stage III Lip and Oral Cavity Squamous Cell Carcinoma; Stage III Oropharyngeal Squamous Cell Carcinoma; Stage IV Hypopharyngeal Squamous Cell Carcinoma; Stage IV Laryngeal Squamous Cell Carcinoma; Stage IV Lip and Oral Cavity Squamous Cell Carcinoma; Stage IV Oropharyngeal Squamous Cell Carcinoma; Stage IVA Hypopharyngeal Squamous Cell Carcinoma; Stage IVA Laryngeal Squamous Cell Carcinoma; Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma; Stage IVA Oropharyngeal Squamous Cell Carcinoma; Stage IVB Hypopharyngeal Squamous Cell Carcinoma; Stage IVB Laryngeal Squamous Cell Carcinoma; Stage IVB Lip and Oral Cavity Squamous Cell Carcinoma; Stage IVB Oropharyngeal Squamous Cell Carcinoma; Stage IVC Hypopharyngeal Squamous Cell Carcinoma; Stage IVC Laryngeal Squamous Cell Carcinoma; Stage IVC Lip and Oral Cavity Squamous Cell Carcinoma; Stage IVC Oropharyngeal Squamous Cell Carcinoma

Connective tissue growth factor activates pluripotency genes and mesenchymal-epithelial transition in head and neck cancer cells.

PubMed

Chang, Cheng-Chi; Hsu, Wen-Hao; Wang, Chen-Chien; Chou, Chun-Hung; Kuo, Mark Yen-Ping; Lin, Been-Ren; Chen, Szu-Ta; Tai, Shyh-Kuan; Kuo, Min-Liang; Yang, Muh-Hwa

2013-07-01

The epithelial-mesenchymal transition (EMT) is a key mechanism in both embryonic development and cancer metastasis. The EMT introduces stem-like properties to cancer cells. However, during somatic cell reprogramming, mesenchymal-epithelial transition (MET), the reverse process of EMT, is a crucial step toward pluripotency. Connective tissue growth factor (CTGF) is a multifunctional secreted protein that acts as either an oncoprotein or a tumor suppressor among different cancers. Here, we show that in head and neck squamous cell carcinoma (HNSCC), CTGF promotes the MET and reduces invasiveness. Moreover, we found that CTGF enhances the stem-like properties of HNSCC cells and increases the expression of multiple pluripotency genes. Mechanistic studies showed that CTGF induces c-Jun expression through αvβ3 integrin and that c-Jun directly activates the transcription of the pluripotency genes NANOG, SOX2, and POU5F1. Knockdown of CTGF in TW2.6 cells was shown to reduce tumor formation and attenuate E-cadherin expression in xenotransplanted tumors. In HNSCC patient samples, CTGF expression was positively correlated with the levels of CDH1, NANOG, SOX2, and POU5F1. Coexpression of CTGF and the pluripotency genes was found to be associated with a worse prognosis. These findings are valuable in elucidating the interplay between epithelial plasticity and stem-like properties during cancer progression and provide useful information for developing a novel classification system and therapeutic strategies for HNSCC. ©2013 AACR.

NOTCH pathway inactivation promotes bladder cancer progression

PubMed Central

Maraver, Antonio; Fernandez-Marcos, Pablo J.; Cash, Timothy P.; Mendez-Pertuz, Marinela; Dueñas, Marta; Maietta, Paolo; Martinelli, Paola; Muñoz-Martin, Maribel; Martínez-Fernández, Mónica; Cañamero, Marta; Roncador, Giovanna; Martinez-Torrecuadrada, Jorge L.; Grivas, Dimitrios; de la Pompa, Jose Luis; Valencia, Alfonso; Paramio, Jesús M.; Real, Francisco X.; Serrano, Manuel

2015-01-01

NOTCH signaling suppresses tumor growth and proliferation in several types of stratified epithelia. Here, we show that missense mutations in NOTCH1 and NOTCH2 found in human bladder cancers result in loss of function. In murine models, genetic ablation of the NOTCH pathway accelerated bladder tumorigenesis and promoted the formation of squamous cell carcinomas, with areas of mesenchymal features. Using bladder cancer cells, we determined that the NOTCH pathway stabilizes the epithelial phenotype through its effector HES1 and, consequently, loss of NOTCH activity favors the process of epithelial-mesenchymal transition. Evaluation of human bladder cancer samples revealed that tumors with low levels of HES1 present mesenchymal features and are more aggressive. Together, our results indicate that NOTCH serves as a tumor suppressor in the bladder and that loss of this pathway promotes mesenchymal and invasive features. PMID:25574842

Human papillomavirus molecular biology.

PubMed

Harden, Mallory E; Munger, Karl

Human papillomaviruses are small DNA viruses with a tropism for squamous epithelia. A unique aspect of human papillomavirus molecular biology involves dependence on the differentiation status of the host epithelial cell to complete the viral lifecycle. A small group of these viruses are the etiologic agents of several types of human cancers, including oral and anogenital tract carcinomas. This review focuses on the basic molecular biology of human papillomaviruses. Copyright © 2016 Elsevier B.V. All rights reserved.

p16INK4A expression as biomarker for HPV 16-related vulvar neoplasias.

PubMed

Riethdorf, Sabine; Neffen, Eduardo F; Cviko, Aida; Löning, Thomas; Crum, Christopher P; Riethdorf, Lutz

2004-12-01

Up-regulation of p16INK4A is associated with high-risk human papillomavirus (HPV) in preinvasive and invasive cervical neoplasia. However, its expression in vulvar carcinomas, which have a diverse pathogenesis, has not been extensively studied. One hundred seventy-seven vulvar intraepithelial neoplasms (VIN), squamous cell carcinomas (SCC), and benign squamous epithelia were analyzed for p16 expression. RNA/RNA in situ hybridization was used to detect HPV 16 E6/E7 transcripts in 112. Ninety-five percent of VIN 3 and basaloid or warty SCCs (76/80) and 4% of keratinizing SCC (2/48) were moderately to strongly immunopositive for p16, which localized to nucleus and cytoplasm; 52/58 analyzed (90%) contained HPV 16 transcripts. The positive predictive value (PPV) of moderate to strong diffuse p16 immunostaining and HPV positivity for the diagnosis of VIN 3 and of basaloid or warty SCC was 97% and 95%, respectively. Conversely, 94% of keratinizing SCC contained heterogeneous staining, and when present, it was strictly cytoplasmic and frequently localized to the cells at the epithelial-stromal interface. Benign squamous epithelia were p16 negative, with the exception of lichen sclerosus, which contained focal and heterogeneously p16 positive in 42%. As in the cervix, intense diffuse p16 expression supports an HPV-related neoplastic process in vulvar neoplasia, irrespective of the level of differentiation. Up-regulation of p16 at the epithelial-stromal interface in HPV negative keratinizing SCCs is consistent with an HPV-independent response to alterations associated with invasion. These disparate patterns of p16 expression underscore 2 different mechanisms for p16 expression in HPV-related and HPV-unrelated vulvar carcinomas.

The dynamics of the oesophageal squamous epithelium 'normalisation' process in patients with gastro-oesophageal reflux disease treated with long-term acid suppression or anti-reflux surgery.

PubMed

Mastracci, L; Fiocca, R; Engström, C; Attwood, S; Ell, C; Galmiche, J P; Hatlebakk, J G; Långström, G; Eklund, S; Lind, T; Lundell, L

2017-05-01

Proton pump inhibitors and laparoscopic anti-reflux surgery (LARS) offer long-term symptom control to patients with gastro-oesophageal reflux disease (GERD). To evaluate the process of 'normalisation' of the squamous epithelium morphology of the distal oesophagus on these therapies. In the LOTUS trial, 554 patients with chronic GERD were randomised to receive either esomeprazole (20-40 mg daily) or LARS. After 5 years, 372 patients remained in the study (esomeprazole, 192; LARS, 180). Biopsies were taken at the Z-line and 2 cm above, at baseline, 1, 3 and 5 years. A severity score was calculated based on: papillae elongation, basal cell hyperplasia, intercellular space dilatations and eosinophilic infiltration. The epithelial proliferative activity was assessed by Ki-67 immunohistochemistry. A gradual improvement in all variables over 5 years was noted in both groups, at both the Z-line and 2 cm above. The severity score decreased from baseline at each subsequent time point in both groups (P < 0.001, all comparisons), attaining a normal level by 5 years. Corresponding decreases in Ki-67 expression were observed (P < 0.001, all comparisons). No significant differences were found between esomeprazole treatment and LARS. Neither baseline severity score nor Ki-67 expression predicted the risk of treatment failure. Five years of treatment is generally required before squamous epithelial cell morphology and proliferation are 'normalised' in patients with chronic GERD, despite endoscopic and symptomatic disease control. Control of the acid component of the refluxate seems to play the predominant role in restoring tissue morphology. © 2017 John Wiley & Sons Ltd.

Proteins other than the locus of enterocyte effacement-encoded proteins contribute to Escherichia coli O157:H7 adherence to bovine rectoanal junction stratified squamous epithelial cells

PubMed Central

2012-01-01

Background In this study, we present evidence that proteins encoded by the Locus of Enterocyte Effacement (LEE), considered critical for Escherichia coli O157 (O157) adherence to follicle-associated epithelial (FAE) cells at the bovine recto-anal junction (RAJ), do not appear to contribute to O157 adherence to squamous epithelial (RSE) cells also constituting this primary site of O157 colonization in cattle. Results Antisera targeting intimin-γ, the primary O157 adhesin, and other essential LEE proteins failed to block O157 adherence to RSE cells, when this pathogen was grown in DMEM, a culture medium that enhances expression of LEE proteins. In addition, RSE adherence of a DMEM-grown-O157 mutant lacking the intimin protein was comparable to that seen with its wild-type parent O157 strain grown in the same media. These adherence patterns were in complete contrast to that observed with HEp-2 cells (the adherence to which is mediated by intimin-γ), assayed under same conditions. This suggested that proteins other than intimin-γ that contribute to adherence to RSE cells are expressed by this pathogen during growth in DMEM. To identify such proteins, we defined the proteome of DMEM-grown-O157 (DMEM-proteome). GeLC-MS/MS revealed that the O157 DMEM-proteome comprised 684 proteins including several components of the cattle and human O157 immunome, orthologs of adhesins, hypothetical secreted and outer membrane proteins, in addition to the known virulence and LEE proteins. Bioinformatics-based analysis of the components of the O157 DMEM proteome revealed several new O157-specific proteins with adhesin potential. Conclusion Proteins other than LEE and intimin-γ proteins are involved in O157 adherence to RSE cells at the bovine RAJ. Such proteins, with adhesin potential, are expressed by this human pathogen during growth in DMEM. Ongoing experiments to evaluate their role in RSE adherence should provide both valuable insights into the O157-RSE interactions and new targets for more efficacious anti-adhesion O157 vaccines. PMID:22691138

Ovarian teratoma displaying a wide variety of tissue components in a broiler chicken (Gallus Domesticus): morphological heterogeneity of pluripotential germ cell during tumorigenesis.

PubMed

Ohfuji, S

2016-01-01

Spontaneous ovarian teratoma was found in a seven-week-old female Chunky broiler chicken that was slaughtered for food. On post-mortem inspection, a spherical tumor mass attaching to a juvenile ovary was found in the abdominal cavity. Histopathologically, the tumor was comprised of immature mesenchymal stroma and a variety of mature tissue elements of mesodermal and ectodermal origin. In addition, there were multiple indistinguishable tissue elements, which showed no malignant cytological features but were unidentifiable as to corresponding embryological layer of origin. These heterogeneous teratoma tissues consisted of a variety of glandular, cystic, duct-like, and tubular structures, some of which exhibited a lining by a mixture of both keratinizing/non-keratinizing stratified squamous epithelial cells and cuboidal/columnar epithelial cells. The ovarian tetatoma was considered a benign and congenital one. The highly diverse differentiation of the teratoma might have manifested a morphological aspect of intrinsic character of the pluripotential germ cells during tumorigenesis.

The predictive role of E2-EPF ubiquitin carrier protein in esophageal squamous cell carcinoma.

PubMed

Chen, Miao-Fen; Lee, Kuan-Der; Lu, Ming-Shian; Chen, Chih-Cheng; Hsieh, Ming-Ju; Liu, Yun-Hen; Lin, Paul-Yang; Chen, Wen-Cheng

2009-03-01

The ubiquitin proteasome pathway has been implicated in carcinogenesis. However, the role of E2-EPF ubiquitin carrier protein (UCP) in esophageal cancer remains relatively unstudied. In the study, we examined the mRNA level of circulating tumor cells from 60 esophageal cancer patients by membrane arrays consisting of a panel of potential markers including UCP, compared to 40 normal populations. The predictive capacity of UCP was also assessed by immunohistochemical staining of a retrospective series of 84 biopsied esophageal squamous cell carcinomas in relation to clinical outcome. In addition, we studied in vitro biological changes including tumor growth, metastatic capacity, and the sensitivity to irradiation and cisplatin, after experimental manipulation of UCP expression in esophageal cancer cells. By the data of 25-gene membrane array analysis, UCP was the only factor significantly associated with the extent of tumor burden in esophageal cancer patients. Our immunochemistry findings further indicate that UCP positivity was linked to poor response to neoadjuvant therapy and worse survival. In cell culture, inhibited UCP significantly decrease tumor growth and the capacity for metastasis. The epithelial-mesenchymal transition (EMT) induced by VHL/HIF-1alpha-TGF-beta1 pathway might be the underlying mechanism responsible to the more aggressive tumor growth in UCP-positive esophageal cancer. Our results suggest that UCP was significantly associated with poor prognosis of esophageal cancer and may be a new molecular target for therapeutic intervention for esophageal squamous cell carcinoma.

SUZ12 is a novel putative oncogene promoting tumorigenesis in head and neck squamous cell carcinoma.

PubMed

Wu, Yaping; Hu, Huijun; Zhang, Wei; Li, Zhongwu; Diao, Pengfei; Wang, Dongmiao; Zhang, Wei; Wang, Yanling; Yang, Jianrong; Cheng, Jie

2018-04-18

The suppressor of zest 12 (SUZ12), one of the core polycomb repressive complex 2 (PRC2) components, has increasingly appreciated as a key mediator during human tumorigenesis. However, its expression pattern and oncogenic roles in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored yet. Here, we sought to determine its expression pattern, clinicopathological significance and biological roles in HNSCC. Through data mining and interrogation from multiple publicly available databases, our bioinformatics analyses revealed that SUZ12 mRNA was significantly overexpressed in multiple HNSCC patient cohorts. Moreover, SUZ12 protein was markedly up-regulated in primary HNSCC samples from our patient cohort as assessed by immunohistochemical staining and its overexpression significantly associated with cervical node metastasis and reduced overall and disease-free survival. In the 4-nitroquinoline 1-oxide (4NQO)-induced HNSCC mouse model, increased SUZ12 immunostaining was observed along with disease progression from epithelial hyperplasia to squamous cell carcinoma in tongue. Furthermore, shRNA-mediated SUZ12 knock-down significantly inhibited cell proliferation, migration and invasion in HNSCC cells, and resulted in compromised tumour growth in vivo. Collectively, our data reveal that SUZ12 might serve as a putative oncogene by promoting cell proliferation, migration and invasion, and also a novel biomarker with diagnostic and prognostic significance for HNSCC. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Ganetespib Window of Opportunity Study in Head and Neck Cancers

ClinicalTrials.gov

2016-07-22

Stage I Hypopharyngeal Squamous Cell Carcinoma; Stage I Laryngeal Squamous Cell Carcinoma; Stage I Oral Cavity Squamous Cell Carcinoma; Stage I Oropharyngeal Squamous Cell Carcinoma; Stage II Hypopharyngeal Squamous Cell Carcinoma; Stage II Laryngeal Squamous Cell Carcinoma; Stage II Oral Cavity Squamous Cell Carcinoma; Stage II Oropharyngeal Squamous Cell Carcinoma; Stage III Hypopharyngeal Squamous Cell Carcinoma; Stage III Laryngeal Squamous Cell Carcinoma; Stage III Oral Cavity Squamous Cell Carcinoma; Stage III Oropharyngeal Squamous Cell Carcinoma; Stage IVA Hypopharyngeal Squamous Cell Carcinoma; Stage IVA Laryngeal Squamous Cell Carcinoma; Stage IVA Oral Cavity Squamous Cell Carcinoma; Stage IVA Oropharyngeal Squamous Cell Carcinoma

Generation of organotypic raft cultures from primary human keratinocytes.

PubMed

Anacker, Daniel; Moody, Cary

2012-02-22

The development of organotypic epithelial raft cultures has provided researchers with an efficient in vitro system that faithfully recapitulates epithelial differentiation. There are many uses for this system. For instance, the ability to grow three-dimensional organotypic raft cultures of keratinocytes has been an important milestone in the study of human papillomavirus (HPV)(1). The life cycle of HPV is tightly linked to the differentiation of squamous epithelium(2). Organotypic epithelial raft cultures as demonstrated here reproduce the entire papillomavirus life cycle, including virus production(3,4,5). In addition, these raft cultures exhibit dysplastic lesions similar to those observed upon in vivo infection with HPV. Hence this system can also be used to study epithelial cell cancers, as well as the effect of drugs on epithelial cell differentiation in general. Originally developed by Asselineau and Prunieras(6) and modified by Kopan et al.(7), the organotypic epithelial raft culture system has matured into a general, relatively easy culture model, which involves the growth of cells on collagen plugs maintained at an air-liquid interface (Figure 1A). Over the course of 10-14 days, the cells stratify and differentiate, forming a full thickness epithelium that produces differentiation-specific cytokeratins. Harvested rafts can be examined histologically, as well as by standard molecular and biochemical techniques. In this article, we describe a method for the generation of raft cultures from primary human keratinocytes. The same technique can be used with established epithelial cell lines, and can easily be adapted for use with epithelial tissue from normal or diseased biopsies(8). Many viruses target either the cutaneous or mucosal epithelium as part of their replicative life cycle. Over the past several years, the feasibility of using organotypic raft cultures as a method of studying virus-host cell interactions has been shown for several herpesviruses, as well as adenoviruses, parvoviruses, and poxviruses(9). Organotypic raft cultures can thus be adapted to examine viral pathogenesis, and are the only means to test novel antiviral agents for those viruses that are not cultivable in permanent cell lines.

Metformin inhibits the radiation-induced invasive phenotype of esophageal squamous cell carcinoma.

PubMed

Nakayama, Akira; Ninomiya, Itasu; Harada, Shinichi; Tsukada, Tomoya; Okamoto, Koichi; Nakanuma, Shinichi; Sakai, Seisho; Makino, Isamu; Kinoshita, Jun; Hayashi, Hironori; Oyama, Katsunobu; Miyashita, Tomoharu; Tajima, Hidehiro; Takamura, Hiroyuki; Fushida, Sachio; Ohta, Tetsuo

2016-11-01

Esophageal cancer is one of the most aggressive tumor types because of its invasiveness and metastatic potential. Several reports have described an association between increased invasiveness after ionizing radiation (IR) treatment and epithelial-to-mesenchymal transition (EMT). The biguanide metformin is reported to prevent transforming growth factor-β (TGF-β)-induced EMT and proliferation of cancer. This study examined whether IR induces EMT and promotes the invasive potential of TE-9 esophageal squamous cell carcinoma cells and the effect of metformin on IR-induced EMT. After IR exposure, TE-9 cells showed a spindle-shaped morphology and lost cell-cell adhesion. Immunoblotting showed that IR induced expression of mesenchymal markers (vimentin and N-cadherin), transcription factors (Slug, Snail, and Twist), and matrix metalloproteinases. A scratch wound assay and Matrigel invasion assay showed that IR enhanced the invasive potential and migratory capacity of TE-9 cells. Expression of hypoxia-related factor-1α and TGF-β was increased after IR. IR also induced phosphorylation of Smad2 and Smad3. Metformin inhibited radiation-induced EMT-like morphological changes, and enhanced invasion and migration of TE-9 cells. Metformin inhibited IR-induced phosphorylation of Smad2 and Smad3. Although phosphorylation of AMP-activated protein kinase was enhanced by IR and metformin, phosphorylation of mammalian target of rapamycin was enhanced by IR and suppressed by metformin. These results indicated that metformin suppressed IR-induced EMT via suppression of the TGF-β-Smad phosphorylation pathway, and a part of the non-Smad pathway. Metformin might be useful to prevent IR-induced invasion and metastasis of esophageal squamous cell carcinoma.

COPD and squamous cell lung cancer: aberrant inflammation and immunity is the common link.

PubMed

Bozinovski, Steven; Vlahos, Ross; Anthony, Desiree; McQualter, Jonathan; Anderson, Gary; Irving, Louis; Steinfort, Daniel

2016-02-01

Cigarette smoking has reached epidemic proportions within many regions of the world and remains the highest risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Squamous cell lung cancer is commonly detected in heavy smokers, where the risk of developing lung cancer is not solely defined by tobacco consumption. Although therapies that target common driver mutations in adenocarcinomas are showing some promise, they are proving ineffective in smoking-related squamous cell lung cancer. Since COPD is characterized by an excessive inflammatory and oxidative stress response, this review details how aberrant innate, adaptive and systemic inflammatory processes can contribute to lung cancer susceptibility in COPD. Activated leukocytes release increasing levels of proteases and free radicals as COPD progresses and tertiary lymphoid aggregates accumulate with increasing severity. Reactive oxygen species promote formation of reactive carbonyls that are not only tumourigenic through initiating DNA damage, but can directly alter the function of regulatory proteins involved in host immunity and tumour suppressor functions. Systemic inflammation is also markedly increased during infective exacerbations in COPD and the interplay between tumour-promoting serum amyloid A (SAA) and IL-17A is discussed. SAA is also an endogenous allosteric modifier of FPR2 expressed on immune and epithelial cells, and the therapeutic potential of targeting this receptor is proposed as a novel strategy for COPD-lung cancer overlap. © 2015 The British Pharmacological Society.

Squamous Cell Carcinoma Antigen 2 (SCCA2, SERPINB4): An Emerging Biomarker for Skin Inflammatory Diseases.

PubMed

Izuhara, Kenji; Yamaguchi, Yukie; Ohta, Shoichiro; Nunomura, Satoshi; Nanri, Yasuhiro; Azuma, Yoshinori; Nomura, Noriko; Noguchi, Yasuhiko; Aihara, Michiko

2018-04-06

Squamous cell carcinoma antigens 1 and 2 (SCCA1 and 2, SERPIN B3 and B4), members of the ovalbumin serpin (ov-serpin)/clade B serpin family, were originally discovered as tumor-specific antigens and are used as tumor markers for various kinds of squamous cell carcinomas. Recently, our understanding of the underlying mechanisms of how SCCA1/2 enhance tumor growth has greatly increased. Moreover, it has been shown that SCCA1/2 are involved in the pathogenesis of several inflammatory diseases: asthma, psoriasis, and atopic dermatitis (AD). IL-22 and IL-17, signature cytokines of type 17 inflammation, as well as IL-4 and IL-13, signature cytokines of type 2 inflammation, both of which are positively correlated with the pathogenesis of psoriasis and allergic diseases, respectively, can induce expression of SCCA1/2 in airway epithelial cells and/or keratinocytes, leading to high expression of SCCA1/2 in these diseases. Based on these findings, several trials have been performed to examine the potential of applying SCCA1/2 to biomarkers for these diseases. The findings show that SCCA2 is useful to aid diagnosis, estimate clinical severity and disease type, and assess responses to treatment in psoriasis and AD. These results suggest that SCCA2 has emerged as a novel biomarker for skin inflammatory diseases.

Effects of Cetuximab and Erlotinib on the behaviour of cancer stem cells in head and neck squamous cell carcinoma.

PubMed

Setúbal Destro Rodrigues, Maria Fernanda; Gammon, Luke; Rahman, Muhammad M; Biddle, Adrian; Nunes, Fabio Daumas; Mackenzie, Ian C

2018-03-02

The therapeutic responses of many solid tumours to chemo- and radio-therapies are far from fully effective but therapies targeting malignancy-related cellular changes show promise for further control. In head and neck squamous cell carcinoma, the epidermal growth factor receptor (EGFR) is commonly overexpressed and investigation of agents that block this receptor indicate a limited response when used alone but an ability to enhance the actions of other drugs. The hierarchical stem cell patterns present in tumours generate cellular heterogeneity and this is further complicated by cancer stem cells (CSC) shifting between epithelial (Epi-CSC) and mesenchymal (EMT-CSC) states. To clarify how such heterogeneity influences responses to EGFR blocking, we examined the effects of Cetuximab and Erlotinib on the cell sub-populations in HNSCC cell lines. These agents reduced cell proliferation for all subpopulations but induced little cell death. They did however induce large shifts of cells between the EMT-CSC, Epi-CSC and differentiating cell compartments. Loss of EMT-CSCs reduced cell motility and is expected to reduce invasion and metastasis. EGFR blocking also induced shifts of Epi-CSCs into the differentiating cell compartment which typically has greater sensitivity to chemo/radiation, an effect expected to enhance the overall response of tumour cell populations to adjunctive therapies.

Effects of Cetuximab and Erlotinib on the behaviour of cancer stem cells in head and neck squamous cell carcinoma

PubMed Central

Setúbal Destro Rodrigues, Maria Fernanda; Gammon, Luke; Rahman, Muhammad M.; Biddle, Adrian; Nunes, Fabio Daumas; Mackenzie, Ian C.

2018-01-01

The therapeutic responses of many solid tumours to chemo- and radio-therapies are far from fully effective but therapies targeting malignancy-related cellular changes show promise for further control. In head and neck squamous cell carcinoma, the epidermal growth factor receptor (EGFR) is commonly overexpressed and investigation of agents that block this receptor indicate a limited response when used alone but an ability to enhance the actions of other drugs. The hierarchical stem cell patterns present in tumours generate cellular heterogeneity and this is further complicated by cancer stem cells (CSC) shifting between epithelial (Epi-CSC) and mesenchymal (EMT-CSC) states. To clarify how such heterogeneity influences responses to EGFR blocking, we examined the effects of Cetuximab and Erlotinib on the cell sub-populations in HNSCC cell lines. These agents reduced cell proliferation for all subpopulations but induced little cell death. They did however induce large shifts of cells between the EMT-CSC, Epi-CSC and differentiating cell compartments. Loss of EMT-CSCs reduced cell motility and is expected to reduce invasion and metastasis. EGFR blocking also induced shifts of Epi-CSCs into the differentiating cell compartment which typically has greater sensitivity to chemo/radiation, an effect expected to enhance the overall response of tumour cell populations to adjunctive therapies. PMID:29568372

[Human papilloma virus and its association with oral cancer].

PubMed

Bologna-Molina, Ronell E; Castañeda-Castaneira, Raúl E; Molina-Frechero, Nelly; Pérez-Rodríguez, Eréndira

2006-01-01

Oral cancer it a pathology of multifactorial etiology, where some factors such as age, sex, race, genetic predisposition, nutrition, and the use of tobacco and alcohol have a bearing on. In the last years, some authors showed the implication of the human papilloma virus (HPV) in the development of precarcinogenic lesions and of oral squamous cell carcinoma. The infection by HPV has been associated to hyperplastic epithelial lesions, papilloma and warty carcinoma in skin and in different types of mucosa, including the anus-genital, cervical, urethral, tracheobronchial, nasal, laryngeal and oral mucosa tracts. The viral high-risk geno-types (oncogenic) such as 16, 18, 31, 33 and 35 are frequently associated to leukoplakia and squamous carcinoma. An association of HPV with oral squamous carcinoma in patients that consume tobacco and alcohol has been fundamentally established. It is important to study and to frequently review the role that viral infections and cancer have, and maybe in the future, it would be possible to create a vaccine that diminishes the frequency of oncological problems.

Lymphomatoid papulosis with pseudocarcinomatous hyperplasia in a 7-year-old girl: a case report.

PubMed

Xiong, Jingshu; Ma, Yiping; Chen, Hao; Xu, Xiulian; Sun, Jianfang

2016-05-01

Lymphomatoid papulosis (LyP) belongs to the group of cutaneous CD30+ lymphoproliferative disorders. Pseudocarcinomatous hyperplasia has rarely been reported in patients with LyP. In this report, we describe a case of LyP presenting as pseudocarcinomatous hyperplasia. The patient was a 7-year-old girl who presented with a recurrent papulonodular eruption on her face and trunk for 2 months. Histopathologic examination revealed an irregular growth of hyperkeratotic epidermis into the whole dermal layer with marked nests of squamous cells in the background of diffuse atypical lymphoid cells, eosinophils and neutrophils. The large atypical cells were positive for CD30 and CD3, but negative for CD4, CD5, CD8, CD20 and CD56. A TCR-γ clone was identified by polymerase chain reaction (PCR). The correct diagnosis in cases of LyP with overlying pseudocarcinomatous epithelial hyperplasia can be very difficult both clinically and histopathologically. Clinical and histopathologic characteristics should be integrated to avoid an erroneous diagnosis of squamous cell carcinoma or keratoacanthoma. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Clinical significance of the correlation between PLCE 1 and PRKCA in esophageal inflammation and esophageal carcinoma

PubMed Central

Ma, Ming; Zhang, Shanshan; Zhang, Yongmeng; Yuan, Ming; Liu, Bing; Yang, Yiqiong; Cui, Wen; Ansong, Emmanuel; Dong, Huali; Macias, Virgilia; Yang, Wancai

2017-01-01

Esophagitis and Barrett's esophagus are linked to esophageal squamous cell carcinoma and adenocarcinoma, respectively. However, the underlying mechanisms are still unclear. This study analyzed the expression levels of and correlation between PLCE1 and PRKCA in human esophagitis, carcinogen NMBA-induced rat esophagus, PLCE1 genetic deficient mouse esophageal epithelial tissues and human esophageal cancer cell line, integrated with Online oncology data sets. We found that the expression levels of both PLCE1 and PRKCA were significantly elevated in human esophagitis, esophageal squamous cell carcinoma, Barrett's esophagus, esophageal adenocarcinoma and in NMBA-treated rat esophageal epithelia. However, PRKCA and cytokines were significantly downregulated in PLCE1-deficient mouse esophageal epithelia, and knockdown of PLCE1 in human esophageal cancer cells led to reduction of PRKCA and cytokines. Finally, high expression of both PLCE1 and PRKCA is significantly associated with poor outcomes of the patients with esophageal cancers. In conclusion, this study defined the initiation and progression of esophageal inflammation and malignant transformation, in which the positive correlation of PLCE1 and PRKCA exhibits critical clinical significance. PMID:28402280

Bacteria on Urine Microscopy Is Not Associated with Systemic Infection in Patients with Obstructing Urolithiasis.

PubMed

Cheung, Felix; Loeb, Charles A; Croglio, Michael P; Waltzer, Wayne C; Weissbart, Steven J

2017-09-01

Determining whether bacterial presence in urine microscopy represents infection is important as ureteral stent placement is indicated in patients with obstructing urolithiasis and infection. We aim to investigate whether the presence of bacteria on urine microscopy is associated with other markers of infection in patients with obstructing urolithiasis presenting to the emergency room. We performed a cross-sectional study of 199 patients with obstructing urolithiasis and divided patients into two groups according to the presence of bacteria on urine microscopy. The primary outcome was serum white blood cell count and secondary outcomes were objective fever, subjective fever, tachycardia, pyuria, and final urine culture. Univariate and multivariate analysis were used to assess whether the presence of bacteria on microscopy was associated with other markers of infection. The study included 72 patients in the bacteriuria group and 127 without bacteriuria. On univariate analysis, the presence of bacteria was not associated with leukocytosis, objective fever, or subjective fever, but it was associated with gender (p < 0.001), pyuria (p < 0.001), positive nitrites (p = 0.001), positive leukocyte esterase (p < 0.001), and squamous epithelial cells (p = 0.002). In a multilinear regression model including the presence of squamous cells, age, and sex, the presence of bacteriuria was not related to serum white blood cell count (coefficient -0.47; 95% confidence interval [CI] -1.1, 0.2; p = 0.17), heart rate (coefficient 0.85; 95% CI -2.5, 4.2; p = 0.62), presence of subjective or objective fever (odds ratio [OR] 1.5; 95% CI 0.8, 3.1; p = 0.18), or the presence of squamous epithelial cells (coefficient -4.4; 95% CI -10, 1.2; p = 0.12). However, the presence of bacteriuria was related to only the degree of pyuria (coefficient 16.4; 95% CI 9.6, 23.3; p < 0.001). Bacteria on urine microscopy is not associated with other markers of systemic infection and may largely represent a contaminant. Renal colic may be a risk factor for providing a contaminated urine specimen.

Evaluation of a new automated microscopy urine sediment analyser - sediMAX conTRUST®.

PubMed

Bogaert, Laura; Peeters, Bart; Billen, Jaak

2017-04-01

This study evaluated the performance of the stand-alone sediMAX conTRUST (77Elektronika, Budapest, Hungary) analyser as an alternative to microscopic analysis of urine. The validation included a precision, carry-over, categorical correlation and diagnostic performance study with manual phase-contrast microscopy as reference method. A total of 260 routine urine samples were assessed. The within-run precision was much better at higher concentrations than at very low concentrations. The precision met our predefined limits for all the elements at the different concentrations, with the exception of the lowest RBC, the WBC, pathological casts and crystals count. There was no sample carry-over. The analyser showed good categorical agreement with manual microscopy for RBC and WBC counts, moderate agreement for yeast cells, crystals and squamous epithelial cells and bad agreement for non-squamous epithelial cells, bacteria and casts. Diagnostic performance was satisfying only for RBC, WBC and yeast cells. The number of false negative results was acceptable (≤4%) for all elements after connecting the sediMAX conTRUST with an automatic strip reader (AutionMAX) and after implementation of review rules. We conclude that the sediMAX conTRUST should be used as a screening tool in combination with an automatic strip reader, for the identification of normal samples. Therefore, adequate review rules should be defined. Manual microscopy is still required in 'flagged' pathological samples. Despite the poor analytical performance on pathological samples, the images on the screen can be used for interpretation without the microscope and can be stored as PDF-documents for archiving the results.

Afatinib radiosensitizes head and neck squamous cell carcinoma cells by targeting cancer stem cells

PubMed Central

Macha, Muzafar A; Rachagani, Satyanarayana; Qazi, Asif Khurshid; Jahan, Rahat; Gupta, Suprit; Patel, Anery; Seshacharyulu, Parthasarathy; Lin, Chi; Li, Sicong; Wang, Shuo; Verma, Vivek; Kishida, Shosei; Kishida, Michiko; Nakamura, Norifumi; Kibe, Toshiro; Lydiatt, William M; Smith, Russell B; Ganti, Apar K; Jones, Dwight T; Batra, Surinder K; Jain, Maneesh

2017-01-01

The dismal prognosis of locally advanced and metastatic squamous cell carcinoma of the head and neck (HNSCC) is primarily due to the development of resistance to chemoradiation therapy (CRT). Deregulation of Epidermal Growth Factor Receptor (EGFR) signaling is involved in HNSCC pathogenesis by regulating cell survival, cancer stem cells (CSCs), and resistance to CRT. Here we investigated the radiosensitizing activity of the pan-EGFR inhibitor afatinib in HNSCC in vitro and in vivo. Our results showed strong antiproliferative effects of afatinib in HNSCC SCC1 and SCC10B cells, compared to immortalized normal oral epithelial cells MOE1a and MOE1b. Comparative analysis revealed stronger antitumor effects with afatinib than observed with erlotinib. Furthermore, afatinib enhanced in vitro radiosensitivity of SCC1 and SCC10B cells by inducing mesenchymal to epithelial transition, G1 cell cycle arrest, and the attenuating ionizing radiation (IR)-induced activation of DNA double strand break repair (DSB) ATM/ATR/CHK2/BRCA1 pathway. Our studies also revealed the effect of afatinib on tumor sphere- and colony-forming capabilities of cancer stem cells (CSCs), and decreased IR-induced CSC population in SCC1 and SCC10B cells. Furthermore, we observed that a combination of afatinib with IR significantly reduced SCC1 xenograft tumors (median weight of 168.25 ± 20.85 mg; p = 0.05) compared to afatinib (280.07 ± 20.54 mg) or IR alone (324.91 ± 28.08 mg). Immunohistochemical analysis of SCC1 tumor xenografts demonstrated downregulation of the expression of IR-induced pEGFR1, ALDH1 and upregulation of phosphorylated γH2AX by afatinib. Overall, afatinib reduces tumorigenicity and radiosensitizes HNSCC cells. It holds promise for future clinical development as a novel radiosensitizer by improving CSC eradication. PMID:28423495

GATA3 Expression in Normal Skin and in Benign and Malignant Epidermal and Cutaneous Adnexal Neoplasms

PubMed Central

de Peralta-Venturina, Mariza N.; Balzer, Bonnie L.; Frishberg, David P.

2015-01-01

Abstract: Initial investigations reported GATA3 to be a sensitive and relatively specific marker for mammary and urothelial carcinomas. Recently, GATA3 expression has been described in several other epithelial tumors. However, there has been only limited investigation of GATA3 expression in cutaneous epithelial tumors. The objective of this study was to examine the immunohistochemical expression of GATA3 in a wide variety of cutaneous epithelial neoplasms. GATA3 expression was evaluated in 99 benign and 63 malignant cutaneous epithelial tumors. GATA3 was consistently and usually strongly expressed in clear cell acanthoma, trichofolliculoma, trichoepithelioma, trichilemmoma, sebaceous adenoma, sebaceoma, apocrine hidrocystoma, apocrine tubular papillary adenoma, hidradenoma papilliferum, and syringocystadenoma papilliferum. Hidradenomas exhibited variable positive staining. Most poromas, syringomas, chondroid syringomas, cylindromas, and spiradenomas were negative or only focally and weakly positive. Focal staining was present in all pilomatrixomas. Thirteen of 14 basal cell carcinomas, 21 of 24 squamous carcinomas, and all 6 sebaceous carcinomas exhibited positive staining. The 1 apocrine carcinoma, both mucinous carcinomas, and 2 of 3 microcystic adnexal carcinomas also exhibited positive staining, whereas the 1 eccrine porocarcinoma and the 1 adenoid cystic carcinoma were negative. One of 11 Merkel cell carcinomas exhibited focal weak staining. Our findings demonstrate that GATA3 is expressed in a wide variety of benign and malignant cutaneous epithelial neoplasms. In addition to carcinomas of breast and urothelial origin and other more recently described GATA3-positive tumors, the differential diagnosis of a metastatic tumor of unknown primary origin that expresses GATA3 should also include a carcinoma of cutaneous epithelial origin. PMID:26595821

GATA3 Expression in Normal Skin and in Benign and Malignant Epidermal and Cutaneous Adnexal Neoplasms.

PubMed

Mertens, Richard B; de Peralta-Venturina, Mariza N; Balzer, Bonnie L; Frishberg, David P

2015-12-01

Initial investigations reported GATA3 to be a sensitive and relatively specific marker for mammary and urothelial carcinomas. Recently, GATA3 expression has been described in several other epithelial tumors. However, there has been only limited investigation of GATA3 expression in cutaneous epithelial tumors. The objective of this study was to examine the immunohistochemical expression of GATA3 in a wide variety of cutaneous epithelial neoplasms. GATA3 expression was evaluated in 99 benign and 63 malignant cutaneous epithelial tumors. GATA3 was consistently and usually strongly expressed in clear cell acanthoma, trichofolliculoma, trichoepithelioma, trichilemmoma, sebaceous adenoma, sebaceoma, apocrine hidrocystoma, apocrine tubular papillary adenoma, hidradenoma papilliferum, and syringocystadenoma papilliferum. Hidradenomas exhibited variable positive staining. Most poromas, syringomas, chondroid syringomas, cylindromas, and spiradenomas were negative or only focally and weakly positive. Focal staining was present in all pilomatrixomas. Thirteen of 14 basal cell carcinomas, 21 of 24 squamous carcinomas, and all 6 sebaceous carcinomas exhibited positive staining. The 1 apocrine carcinoma, both mucinous carcinomas, and 2 of 3 microcystic adnexal carcinomas also exhibited positive staining, whereas the 1 eccrine porocarcinoma and the 1 adenoid cystic carcinoma were negative. One of 11 Merkel cell carcinomas exhibited focal weak staining. Our findings demonstrate that GATA3 is expressed in a wide variety of benign and malignant cutaneous epithelial neoplasms. In addition to carcinomas of breast and urothelial origin and other more recently described GATA3-positive tumors, the differential diagnosis of a metastatic tumor of unknown primary origin that expresses GATA3 should also include a carcinoma of cutaneous epithelial origin.

Differential roles of kallikrein-related peptidase 6 in malignant transformation and ΔNp63β-mediated epithelial-mesenchymal transition of oral squamous cell carcinoma.

PubMed

Kaneko, Naoki; Kawano, Shintaro; Yasuda, Kaori; Hashiguchi, Yuma; Sakamoto, Taiki; Matsubara, Ryota; Goto, Yuichi; Jinno, Teppei; Maruse, Yasuyuki; Morioka, Masahiko; Hattori, Taichi; Tanaka, Shoichi; Tanaka, Hideaki; Kiyoshima, Tamotsu; Nakamura, Seiji

2017-12-01

We previously reported that epithelial-to-mesenchymal transition (EMT) was mediated by ΔNp63β in oral squamous cell carcinoma (OSCC). In this study, DNA microarray analyses were performed using ΔNp63β-overexpressing OSCC cells to identify genes associated with ΔNp63β-mediated EMT. Thereby, we focused on kallikrein-related peptidase (KLK) 6, most up-regulated following ΔNp63β-overexpression, that activates protease-activated receptors (PARs). In RT-PCR analyses, ΔNp63 was positively associated with KLK6 and PAR2 and negatively with PAR1 in OSCC cells. By ΔNp63 knockdown, KLK6 and PAR2 expression was decreased and PAR1 was increased. Furthermore, KLK6 knockdown led to enhancing migration and invasion, and inhibiting proliferation, suggesting EMT-phenotypes. Although, in the KLK6 or PAR2 knockdown cells, phosphorylation of ERK was reduced, it was restored in the KLK6 knockdown OSCC cells treated with recombinant KLK6 proteins. Immunohistochemistry showed ΔNp63, KLK6, and PAR2 were more strongly expressed in the epithelial dysplasia and central region of OSCC than normal oral epithelium, whereas PAR1 expression was undetectable. Interestingly, at the invasive front of OSCC, ΔNp63, KLK6, and PAR2 were reduced, but PAR1 was elevated. In addition, the OSCC patients with decreasing KLK6 expression at the invasive front had more unfavourable prognosis. These results suggested differential roles of KLK6 in malignant transformation and EMT; high ΔNp63β expression up-regulates KLK6-PAR2 and down-regulates PAR1, inducing malignant transformation in oral epithelium with stimulating proliferation through ERK signal activation. Moreover, KLK6-PAR2 expression is down-regulated and PAR1 is up-regulated when ΔNp63β expression is decreased, leading to EMT with enhancing migration and invasion through ERK signal reduction at the invasive front. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Imaging of oral pathological tissue using optical coherence tomography

NASA Astrophysics Data System (ADS)

Canjau, Silvana; Todea, Carmen; Sinescu, Cosmin; Duma, Virgil-Florin; Topala, Florin I.; Podoleanu, Adrian G.

2014-01-01

Oral squamous cell carcinoma (OSCC) constitutes 90% of oral cancer. Early detection is a cornerstone to improve survival. Interaction of light with tissues may highlight changes in tissue structure and metabolism. We propose optical coherence tomography (OCT), as a non-invasive diagnosis method, being a new high-resolution optical technique that permits tri-dimensional (3-D), real-time imaging of near surface abnormalities in complex tissues. In this study half of the excisional biopsy was directed to the pathologist and the other half was assigned for OCT investigation. Histopathology validated the results. Areas of OSCC of the buccal mucosa were identified in the OCT images. The elements obserced included extensive epithelial down-growth, the disruption of the basement membrane, with areas of erosion, an epithelial layer that was highly variable in thickness and invasion into the sub-epithelial layers. Therefore, OCT appears to be a highly promising imaging modality.

The Type 7 Serotonin Receptor, 5-HT7, Is Essential in the Mammary Gland for Regulation of Mammary Epithelial Structure and Function

PubMed Central

Pai, Vaibhav P.; Hernandez, Laura L.; Stull, Malinda A.; Horseman, Nelson D.

2015-01-01

Autocrine-paracrine activity of serotonin (5-hydroxytryptamine, 5-HT) is a crucial homeostatic parameter in mammary gland development during lactation and involution. Published studies suggested that the 5-HT7 receptor type was important for mediating several effects of 5-HT in the mammary epithelium. Here, using 5-HT7 receptor-null (HT7KO) mice we attempt to understand the role of this receptor in mediating 5-HT actions within the mammary gland. We demonstrate for the first time that HT7KO dams are inefficient at sustaining their pups. Histologically, the HT7KO mammary epithelium shows a significant deviation from the normal secretory epithelium in morphological architecture, reduced secretory vesicles, and numerous multinucleated epithelial cells with atypically displaced nuclei, during lactation. Mammary epithelial cells in HT7KO dams also display an inability to transition from lactation to involution as normally seen by transition from a columnar to a squamous cell configuration, along with alveolar cell apoptosis and cell shedding. Our results show that 5-HT7 is required for multiple actions of 5-HT in the mammary glands including core functions that contribute to changes in cell shape and cell turnover, as well as specialized secretory functions. Understanding these actions may provide new interventions to improve lactation performance and treat diseases such as mastitis and breast cancer. PMID:25664318

Crystal violet stain as a selective stain for the assessment of mitotic figures in oral epithelial dysplasia and oral squamous cell carcinoma.

PubMed

Jadhav, Kiran B; Ahmed Mujib, B R; Gupta, Nidhi

2012-01-01

Assessment of mitotic figures (MFs) is routinely practiced as prognostic indicator in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC), but identification of MFs poses a problem in terms of staining characteristics. To evaluate effectiveness of crystal violet stain for staining of MFs and its comparison with hematoxylin and eosin (H and E) stain. Study sample includes archival tissues embedded in paraffin blocks diagnosed as OED (n = 30) and OSCC (n = 30). The control group comprised of tissue specimen from oral mucosa of healthy volunteers (n = 30). Two serial sections of each tissue specimen were stained separately with H and E stain and 1% crystal violet stain. The stained sections were observed under microscope for identification and counting of MFs. Data obtained was statistically analyzed by using the Man-Whitney U test. A significant increase in number of MFs was observed in OED and OSCC in comparison with normal oral mucosa. There was a highly significant increase in number of MFs in crystal violet stained tissue sections when compared with H and E stain. Metaphase is the most commonly observed phase of mitosis in crystal violet stain when compared with H and E stain for all three groups. Crystal violet stain can be considered as selective stain for mitotic figures.

Intratumoral PV701 in Treating Patients With Advanced or Recurrent Unresectable Squamous Cell Carcinoma of the Head and Neck

ClinicalTrials.gov

2013-01-23

Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Salivary Gland Squamous Cell Carcinoma; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity

miR-300 inhibits epithelial to mesenchymal transition and metastasis by targeting Twist in human epithelial cancer

PubMed Central

2014-01-01

Background Epithelial-to-mesenchymal transition (EMT) is a key step of the progression of tumor cell metastasis. Recent work has demonstrated some miRNAs play critical roles in EMT. In this study, we focused on the roles of miR-300 in regulating EMT. Methods The expression levels of miR-300 were examined in epithelial carcinoma cells that underwent an EMT using quantitative reverse transcription-PCR. The role of miR-300 in EMT was investigated by transfection of the miR-300 mimic or inhibitor in natural epithelial-mesenchymal phenotype cell line pairs and in transforming growth factor (TGF) beta-induced EMT cell models. A luciferase reporter assay and a rescue experiment were conducted to confirm the target gene of miR-300. The efficacy of miR-300 against tumor invasion and metastasis was evaluated both in vitro and in vivo. Correlation analysis between miR-300 expression and the expression levels of its target gene, as well as tumor metastasis was performed in specimens from patients with head and neck squamous cell carcinoma (HNSCC). Results MiR-300 was found down-regulated in the HNSCC cells and breast cancer cells that underwent EMT. Ectopic expression of miR-300 effectively blocked TGF-beta-induced EMT and reversed the phenotype of EMT in HN-12 and MDA-MB-231 cells, but inhibition of miR-300 in the epithelial phenotype cells, HN-4 and MCF-7 cells, could induce EMT. The luciferase reporter assay and the rescue assay results showed that miR-300 directly targets the 3′UTR of Twist. Enforced miR-300 expression suppressed cell invasion in vitro and experimental metastasis in vivo. Clinically, miR-300 expression was found inversely correlated with Twist expression and reduced miR-300 was associated with metastasis in patient specimens. Conclusions Down-regulation of miR-300 is required for EMT initiation and maintenance. MiR-300 may negatively regulate EMT by direct targeting Twist and therefore inhibit cancer cell invasion and metastasis, which implicates miR-300 as an attractive candidate for cancer therapy. PMID:24885626

miR-300 inhibits epithelial to mesenchymal transition and metastasis by targeting Twist in human epithelial cancer.

PubMed

Yu, Jingshuang; Xie, Furong; Bao, Xin; Chen, Wantao; Xu, Qin

2014-05-24

Epithelial-to-mesenchymal transition (EMT) is a key step of the progression of tumor cell metastasis. Recent work has demonstrated some miRNAs play critical roles in EMT. In this study, we focused on the roles of miR-300 in regulating EMT. The expression levels of miR-300 were examined in epithelial carcinoma cells that underwent an EMT using quantitative reverse transcription-PCR. The role of miR-300 in EMT was investigated by transfection of the miR-300 mimic or inhibitor in natural epithelial-mesenchymal phenotype cell line pairs and in transforming growth factor (TGF) beta-induced EMT cell models. A luciferase reporter assay and a rescue experiment were conducted to confirm the target gene of miR-300. The efficacy of miR-300 against tumor invasion and metastasis was evaluated both in vitro and in vivo. Correlation analysis between miR-300 expression and the expression levels of its target gene, as well as tumor metastasis was performed in specimens from patients with head and neck squamous cell carcinoma (HNSCC). MiR-300 was found down-regulated in the HNSCC cells and breast cancer cells that underwent EMT. Ectopic expression of miR-300 effectively blocked TGF-beta-induced EMT and reversed the phenotype of EMT in HN-12 and MDA-MB-231 cells, but inhibition of miR-300 in the epithelial phenotype cells, HN-4 and MCF-7 cells, could induce EMT. The luciferase reporter assay and the rescue assay results showed that miR-300 directly targets the 3'UTR of Twist. Enforced miR-300 expression suppressed cell invasion in vitro and experimental metastasis in vivo. Clinically, miR-300 expression was found inversely correlated with Twist expression and reduced miR-300 was associated with metastasis in patient specimens. Down-regulation of miR-300 is required for EMT initiation and maintenance. MiR-300 may negatively regulate EMT by direct targeting Twist and therefore inhibit cancer cell invasion and metastasis, which implicates miR-300 as an attractive candidate for cancer therapy.

Oral Rigosertib for Squamous Cell Carcinoma

ClinicalTrials.gov

2017-06-22

Head and Neck Squamous Cell Carcinoma; Anal Squamous Cell Carcinoma; Lung Squamous Cell Carcinoma; Cervical Squamous Cell Carcinoma; Esophageal Squamous Cell Carcinoma; Skin Squamous Cell Carcinoma; Penile Squamous Cell Carcinoma

Penile warty mucoepidermoid carcinoma with features of stratified mucin-producing intra-epithelial lesion and invasive stratified mucin-producing carcinoma.

PubMed

Yorita, Kenji; Kuroda, Naoto; Naroda, Takushi; Tamura, Masato; Ohe, Chisato; Divatia, Mukul; Amin, Mahul B; Cubilla, Antonio L; Kazakov, Dimitry V; Hes, Ondrej; Michal, Michael; Michal, Michal

2018-04-01

Stratified mucin-producing intra-epithelial lesion (SMILE) and invasive stratified mucin-producing carcinoma (ISMC) are recently described cervical and penile lesions. We report an unusual case of mixed variant of penile squamous cell carcinomas with warty, usual and mucoepidermoid SMILE/ISMC features. A 62-year-old Japanese man had a glans penis lesion of one-and-a-half years' duration, suggesting malignancy. Partial penectomy and left inguinal lymphadenectomy were performed. Pathological evaluation revealed a mixed squamous cell carcinoma with warty, mucinous and usual features. The mucinous component resembled mucoepidermoid carcinoma (MEC) and SMILE/ISMC. Glandular differentiation was absent. All the diverse tumour components were negative for p16, which was confirmed by negative human papillomavirus (HPV) genotyping. The mucinous component was diffusely positive for cytokeratin 7 and largely negative for cytokeratin 5 and p63. Fluorescence in-situ hybridisation did not detect rearrangement in the MAML2 or EWSR1 genes. The tumour was pathological stage pT2, pN1 (AJCC prognostic stage group IIIA) and was disease-free 26 months after surgery. The lack of glands in the mucinous areas suggested that MEC should be separated from adenosquamous carcinoma (ASC). Penile SMILE/ISMC may occur without dependence upon HPV status. Further studies will be necessary to determine the pathogenesis and definition of penile SMILE/ISMC, the presence of true MEC arising from the glans penis and the clinicopathological differences of penile ASC, MEC and SMILE/ISMC. Herein, we refer to the SMILE-like penile lesion as 'mucinous penile intra-epithelial neoplasia'. © 2017 John Wiley & Sons Ltd.

CD40 Ligand Is Increased in Mast Cells in Psoriasis and Actinic Keratosis but Less So in Epithelial Skin Carcinomas.

PubMed

Haimakainen, Salla; Kaukinen, Antti P; Suttle, Mireille-Maria; Pelkonen, Jukka; Harvima, Ilkka T

2017-03-16

The expression of CD40 ligand (CD40L) in mast cells was investigated in biopsies from lesional and non-lesional skin samples of patients with psoriasis, actinic keratosis (AK), basal cell carcinoma, and squamous cell carcinoma using a sequential double-staining technique. The percentage of CD40L + mast cells was higher in the lesional than in the non-lesional skin (p < .003). Interestingly, this percentage was lower in both carcinomas than in psoriasis and actinic keratosis (p < .025). Cells immunopositive for CD40 receptor were increased in all lesion types but especially so in carcinomas. The results suggest a dysregulated anti-tumoral immune response by mast cell CD40L in skin carcinomas.

Grover Disease With Epidermal Dysmaturation Pattern: a Common Histopathologic Finding.

PubMed

Aljarbou, Ohoud Z; Asgari, Masoud; Al-Saidi, Nagla; Silloca-Cabana, Elizabeth O; Alathamneh, Mamoun; Sangueza, Omar

2018-02-06

Grover disease is an entity whose diagnosis is based on clinicopathologic correlation. Histopathologically, focal acantholysis is the most common finding. In some cases, there is prominent squamous atypia which can prove to be very challenging and the lesion may be confused with an epidermal neoplasm. To report on atypical histopathological changes in Grover disease and to provide helpful clues to differentiate between the epidermal atypia seen in some cases of Grover disease and epithelial neoplasms. We analyzed 33 cases of Grover disease histologically diagnosed at Wake Forest Baptist Medical Center, NC, between 2011 and 2017. Atypical changes in keratinocytes were defined as epithelial buds, nuclear pleomorphism, and dyskeratosis in all layers of epidermis or altered granular layer. Twenty cases (64%) showed foci with alteration of the normal keratinocytic maturation, whereas 18 cases demonstrated nuclear pleomorphism. Buds of epithelial cells emanating from the basal layer of the epidermis and granular cell alteration was present in 19 cases. The findings especially the presence of an altered granular layer may represent a diagnostic clue in cases of Grover disease with atypical changes.

Epithelial alterations adjacent to invasive squamous carcinoma of the vulva.

PubMed

Gómez Rueda, N; García, A; Vighi, S; Belardi, M G; Cardinal, L; di Paola, G

1994-07-01

The slides of 64 vulvectomy specimens from vulvar squamous carcinoma were reviewed in order to study the histopathologic changes adjacent to the neoplasia. Normal epithelium was found in 7 cases (11%) and epithelial alterations adjacent to carcinoma in 59 (89%). The epithelial alterations found were: nonneoplastic epithelial disorder (NNDV) in 38 cases (59%) and vulvar intraepithelial neoplasia (VIN) in 19 (30%). The distribution of NNDV was: 20 cases of epithelial hyperplasia (EH) (31%), 6 of lichen sclerosus (9%) and 12 of the mixed type (19%). Sixteen cases of VIN 3 (25%) were undifferentiated, and three cases were differentiated VIN. Eighteen of 19 VIN cases were associated with NNDV, and 8 cases of undifferentiated VIN were associated with human papillomavirus infection. There was no apparent relationship between the associated lesions and tumor size, depth of invasion, lymph node metastases and clinical stage. Nevertheless, we found a significantly higher frequency of associated lesions in poorly differentiated tumors (P > .01). The most important finding was a high association between EH (50%) and VIN (30%) with carcinoma. VIN cases were almost always (95%) associated with EH.

Morphological and histochemical characterization of the mucosa of the digestive tract in Engraulis anchoita.

PubMed

Díaz, A O; García, A M; Devincenti, C V; Goldemberg, A L

2003-12-01

The histomorphological aspects as well as the histochemical content and distribution of glycoproteins (GPs) in the mucosa of the digestive tract of the anchovy Engraulis anchoita were studied. The buccopharyngeal cavity is lined by a squamous stratified epithelium with mucous superficial cells; the oesophagus shows two zones, cranial with a squamous stratified epithelium with mucous superficial cells and caudal with a columnar secretory epithelium. Finally, the stomach presents both the cranial and pyloric portion lined with a simple columnar epithelium. Tubular branched glands, formed by a single type of glandular cell, located along the stomach, are more numerous in the cranial portion. The GPs were identified with (1) oxidizable vicinal diols; (2) sialic acids and some of their chain variants, C7 or C9; (3) sialic acid residues with O-acyl substitution at C7 or C8; (4) carboxyl groups and (5) sulphate groups. Histochemical tests showed that the buccopharyngeal cavity presented the largest amount of the different types of mucosubstances. Epithelial secretory cells were found in the oesophagus, which synthesized a large quantity of sialosulphoglycoproteins likely to be related to a protective role. The surface epithelium of the stomach synthesizes and secretes acid and neutral GPs, probably related to the movement of fluids and to the absorption of easily digested substrates, respectively. Although great differences exist between different species, in E. anchoita as in other fish species, the wall of the digestive tract is composed of the four layers classically described for vertebrates. The GPs secreted by the epithelial cells are suggested to be important for the protection and inhibition of microorganisms. In addition, they are involved in enzymatic digestion of food, absorptive functions and lubrication of the alimentary tract.

Epithelial expression of extracellular matrix metalloproteinase inducer/CD147 and matrix metalloproteinase-2 in neoplasms and precursor lesions derived from cutaneous squamous cells: An immunohistochemical study.

PubMed

Ayva, Sebnem Kupana; Karabulut, Ayse Anil; Akatli, Ayşe Nur; Atasoy, Pinar; Bozdogan, Onder

2013-10-01

Extracellular matrix metalloproteinase inducer (CD147) is a transmembrane glycoprotein involved in the regulation of matrix metalloproteinases (MMPs). The study investigated CD147 and MMP-2 expression in epidermis of cutaneous squamous lesions. CD147 and MMP-2 expressions were evaluated immunohistochemically in 44 specimens: 18 actinic keratoses (AK), 6 squamous cell carcinomas in situ (SCCIS), 13 squamous cell carcinomas (SCC; peritumoral and invasive portions assessed), and 7 normal skins. Patterns of expression were assessed, with MMP-2 in nuclei (MMP-2n) and cytoplasm (MMP-2c) evaluated separately. The expression of each marker was quantified using a calculated immunohistochemical/histologic score (H-score). Correlations were analyzed for the marker H-scores in each study group. Associations between H-scores and histopathologic parameters were also evaluated. CD147 H-score was the highest in SCC (invasive islands), followed by AK, SCCIS, and control specimens, respectively. MMP-2n and MMP-2c H-scores were the highest in AK, followed by SCCIS, SCC, and control specimens, respectively. MMP-2c and MMP-2n H-scores were significantly higher in peritumoral epidermis than in invasive islands of SCC. MMP-2c and CD147 H-scores were positively correlated in the peritumoral SCCs. CD147 H-score was positively correlated with tumor differentiation in SCC. The findings suggest that overexpression of CD147 plays a role in the development of SCC. Copyright © 2013 Elsevier GmbH. All rights reserved.

Soy Isoflavones in Preventing Head and Neck Cancer Recurrence in Patients With Stage I-IV Head and Neck Cancer Undergoing Surgery

ClinicalTrials.gov

2016-09-01

Recurrent Hypopharyngeal Squamous Cell Carcinoma; Recurrent Laryngeal Squamous Cell Carcinoma; Recurrent Laryngeal Verrucous Carcinoma; Recurrent Lip and Oral Cavity Squamous Cell Carcinoma; Recurrent Oral Cavity Verrucous Carcinoma; Recurrent Oropharyngeal Squamous Cell Carcinoma; Stage I Hypopharyngeal Squamous Cell Carcinoma; Stage I Laryngeal Squamous Cell Carcinoma; Stage I Laryngeal Verrucous Carcinoma; Stage I Lip and Oral Cavity Squamous Cell Carcinoma; Stage I Oral Cavity Verrucous Carcinoma; Stage I Oropharyngeal Squamous Cell Carcinoma; Stage II Hypopharyngeal Squamous Cell Carcinoma; Stage II Laryngeal Squamous Cell Carcinoma; Stage II Laryngeal Verrucous Carcinoma; Stage II Lip and Oral Cavity Squamous Cell Carcinoma; Stage II Oral Cavity Verrucous Carcinoma; Stage II Oropharyngeal Squamous Cell Carcinoma; Stage III Hypopharyngeal Squamous Cell Carcinoma; Stage III Laryngeal Squamous Cell Carcinoma; Stage III Laryngeal Verrucous Carcinoma; Stage III Lip and Oral Cavity Squamous Cell Carcinoma; Stage III Oral Cavity Verrucous Carcinoma; Stage III Oropharyngeal Squamous Cell Carcinoma; Stage IV Hypopharyngeal Squamous Cell Carcinoma; Stage IVA Laryngeal Squamous Cell Carcinoma; Stage IVA Laryngeal Verrucous Carcinoma; Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma; Stage IVA Oral Cavity Verrucous Carcinoma; Stage IVA Oropharyngeal Squamous Cell Carcinoma; Tongue Carcinoma

Durvalumab Before Surgery in Treating Patients With Oral Cavity or Oropharynx Cancer

ClinicalTrials.gov

2017-12-20

Human Papillomavirus Infection; Stage I Oral Cavity Squamous Cell Carcinoma; Stage I Oropharyngeal Squamous Cell Carcinoma; Stage II Oral Cavity Squamous Cell Carcinoma; Stage II Oropharyngeal Squamous Cell Carcinoma; Stage III Oral Cavity Squamous Cell Carcinoma; Stage III Oropharyngeal Squamous Cell Carcinoma; Stage IVA Oral Cavity Squamous Cell Carcinoma; Stage IVA Oropharyngeal Squamous Cell Carcinoma; Stage IVB Oral Cavity Squamous Cell Carcinoma; Stage IVB Oropharyngeal Squamous Cell Carcinoma; Stage IVC Oropharyngeal Squamous Cell Carcinoma

Temsirolimus With or Without Cetuximab in Patients With Recurrent and/or Metastatic Head and Neck Cancer Who Did Not Respond to Previous Therapy

ClinicalTrials.gov

2017-02-23

Recurrent Hypopharyngeal Squamous Cell Carcinoma; Recurrent Laryngeal Squamous Cell Carcinoma; Recurrent Laryngeal Verrucous Carcinoma; Recurrent Lip and Oral Cavity Squamous Cell Carcinoma; Recurrent Metastatic Squamous Cell Carcinoma in the Neck With Occult Primary; Recurrent Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Recurrent Nasopharyngeal Keratinizing Squamous Cell Carcinoma; Recurrent Oral Cavity Verrucous Carcinoma; Recurrent Oropharyngeal Squamous Cell Carcinoma; Recurrent Salivary Gland Carcinoma; Salivary Gland Squamous Cell Carcinoma; Squamous Cell Carcinoma Metastatic in the Neck With Occult Primary; Stage IV Hypopharyngeal Squamous Cell Carcinoma; Stage IV Nasopharyngeal Keratinizing Squamous Cell Carcinoma; Stage IVA Laryngeal Squamous Cell Carcinoma; Stage IVA Laryngeal Verrucous Carcinoma; Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma; Stage IVA Major Salivary Gland Carcinoma; Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage IVA Oral Cavity Verrucous Carcinoma; Stage IVA Oropharyngeal Squamous Cell Carcinoma; Stage IVB Laryngeal Squamous Cell Carcinoma; Stage IVB Laryngeal Verrucous Carcinoma; Stage IVB Lip and Oral Cavity Squamous Cell Carcinoma; Stage IVB Major Salivary Gland Carcinoma; Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage IVB Oral Cavity Verrucous Carcinoma; Stage IVB Oropharyngeal Squamous Cell Carcinoma; Stage IVC Laryngeal Squamous Cell Carcinoma; Stage IVC Laryngeal Verrucous Carcinoma; Stage IVC Lip and Oral Cavity Squamous Cell Carcinoma; Stage IVC Major Salivary Gland Carcinoma; Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage IVC Oral Cavity Verrucous Carcinoma; Stage IVC Oropharyngeal Squamous Cell Carcinoma; Tongue Carcinoma

Human Papillomavirus Promotes Epstein-Barr Virus Maintenance and Lytic Reactivation in Immortalized Oral Keratinocytes

PubMed Central

Makielski, Kathleen R.; Lee, Denis; Lorenz, Laurel D.; Nawandar, Dhananjay M.; Chiu, Ya- Fang; Kenney, Shannon C.; Lambert, Paul F.

2016-01-01

Epstein-Barr virus and human papillomaviruses are human tumor viruses that infect and replicate in upper aerodigestive tract epithelia and cause head and neck cancers. The productive phases of both viruses are tied to stratified epithelia highlighting the possibility that these viruses may affect each other’s life cycles. Our lab has established an in vitro model system to test the effects of EBV and HPV co-infection in stratified squamous oral epithelial cells. Our results indicate that HPV increases maintenance of the EBV genome in the co-infected cells and promotes lytic reactivation of EBV in upper layers of stratified epithelium. Expression of the HPV oncogenes E6 and E7 were found to be necessary and sufficient to account for HPV-mediated lytic reactivation of EBV. Our findings indicate that HPV increases the capacity of epithelial cells to support the EBV life cycle, which could in turn increase EBV-mediated pathogenesis in the oral cavity. PMID:27179345

Crystalline structure of pulverized dental calculus induces cell death in oral epithelial cells.

PubMed

Ziauddin, S M; Yoshimura, A; Montenegro Raudales, J L; Ozaki, Y; Higuchi, K; Ukai, T; Kaneko, T; Miyazaki, T; Latz, E; Hara, Y

2018-06-01

Dental calculus is a mineralized deposit attached to the tooth surface. We have shown that cellular uptake of dental calculus triggers nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, leading to the processing of the interleukin-1β precursor into its mature form in mouse and human phagocytes. The activation of the NLRP3 inflammasome also induced a lytic form of programmed cell death, pyroptosis, in these cells. However, the effects of dental calculus on other cell types in periodontal tissue have not been investigated. The aim of this study was to determine whether dental calculus can induce cell death in oral epithelial cells. HSC-2 human oral squamous carcinoma cells, HOMK107 human primary oral epithelial cells and immortalized mouse macrophages were exposed to dental calculus or 1 of its components, hydroxyapatite crystals. For inhibition assays, the cells were exposed to dental calculus in the presence or absence of cytochalasin D (endocytosis inhibitor), z-YVAD-fmk (caspase-1 inhibitor) or glyburide (NLRP3 inflammasome inhibitor). Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) release and staining with propidium iodide. Tumor necrosis factor-α production was quantified by enzyme-linked immunosorbent assay. Oral epithelial barrier function was examined by permeability assay. Dental calculus induced cell death in HSC-2 cells, as judged by LDH release and propidium iodide staining. Dental calculus also induced LDH release from HOMK107 cells. Following heat treatment, dental calculus lost its capacity to induce tumor necrosis factor-α in mouse macrophages, but could induce LDH release in HSC-2 cells, indicating a major role of inorganic components in cell death. Hydroxyapatite crystals also induced cell death in both HSC-2 and HOMK107 cells, as judged by LDH release, indicating the capacity of crystal particles to induce cell death. Cell death induced by dental calculus was significantly inhibited by cytochalasin D, z-YVAD-fmk and glyburide, indicating NLRP3 inflammasome involvement. In permeability assays, dental calculus attenuated the barrier function of HSC-2 cell monolayers. Dental calculus induces pyroptotic cell death in human oral epithelial cells and the crystalline structure plays a major role in this process. Oral epithelial cell death induced by dental calculus might be important for the etiology of periodontitis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sorafenib Tosylate, Cisplatin, and Docetaxel in Treating Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

ClinicalTrials.gov

2018-05-22

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Salivary Gland Cancer; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Oral Cavity Squamous Cell Carcinoma; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Salivary Gland Cancer; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Salivary Gland Cancer; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer; Untreated Metastatic Squamous Neck Cancer With Occult Primary

Entolimod in Treating Patients With Stage III-IV Squamous Cell Head and Neck Cancer Receiving Cisplatin and Radiation Therapy

ClinicalTrials.gov

2013-12-10

Mucositis; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer

Cisplatin With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Recurrent or Metastatic Head and Neck Cancer

ClinicalTrials.gov

2017-03-22

Recurrent Hypopharyngeal Squamous Cell Carcinoma; Recurrent Laryngeal Squamous Cell Carcinoma; Recurrent Laryngeal Verrucous Carcinoma; Recurrent Lip and Oral Cavity Squamous Cell Carcinoma; Recurrent Metastatic Squamous Cell Carcinoma in the Neck With Occult Primary; Recurrent Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Recurrent Oral Cavity Verrucous Carcinoma; Recurrent Oropharyngeal Squamous Cell Carcinoma; Squamous Cell Carcinoma Metastatic in the Neck With Occult Primary; Stage IV Hypopharyngeal Squamous Cell Carcinoma; Stage IVA Laryngeal Squamous Cell Carcinoma; Stage IVA Laryngeal Verrucous Carcinoma; Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma; Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage IVA Oral Cavity Verrucous Carcinoma; Stage IVA Oropharyngeal Squamous Cell Carcinoma; Stage IVB Laryngeal Squamous Cell Carcinoma; Stage IVB Laryngeal Verrucous Carcinoma; Stage IVB Lip and Oral Cavity Squamous Cell Carcinoma; Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage IVB Oral Cavity Verrucous Carcinoma; Stage IVB Oropharyngeal Squamous Cell Carcinoma; Stage IVC Laryngeal Squamous Cell Carcinoma; Stage IVC Laryngeal Verrucous Carcinoma; Stage IVC Lip and Oral Cavity Squamous Cell Carcinoma; Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage IVC Oral Cavity Verrucous Carcinoma; Stage IVC Oropharyngeal Squamous Cell Carcinoma; Tongue Carcinoma

Micronuclei: An essential biomarker in oral exfoliated cells for grading of oral squamous cell carcinoma

PubMed Central

Jadhav, Kiran; Gupta, Nidhi; Ahmed, Mujib BR

2011-01-01

Background: Micronuclei in exfoliated oral epithelial cells have been shown in some studies to correlate with severity of this genotoxic damage. This severity can be measured in terms of grading of the lesions. Aim: To correlate frequency of micronuclei (MN) in oral exfoliated cells in clinically diagnosed cases of oral squamous cell carcinoma (OSCC) followed by a histopathological grading. Materials and Methods: The study subjects consisted of clinically diagnosed cases of OSCC. Healthy subjects without any tobacco consumption habits formed the control group. The cytosmears from both groups were stained with rapid Papanicolaou stain. MN were identified according to the criteria given by Countryman and Heddle with some modifications. Results: The frequency of MN was three to four times higher in patients with OSCC as compared to patients in the control group and the difference was found to be highly significant. In 75% cases, the cytological grade as determined by the frequency of micronuclei correlated with the histopathological grade and this observation was statistically significant. Conclusions: MN can be a candidate to serve as a biomarker for prediction of the grade of OSCC. PMID:21552400

Molecular Histopathology Using Gold Nanorods and Optical Coherence Tomography

PubMed Central

Prabhulkar, Shradha; Matthews, Jared; Rawal, Siddarth; Awdeh, Richard M.

2013-01-01

Purpose. To examine the novel application of a commercially available optical coherence tomography (OCT) system toward molecular histopathology using gold nanorod (GNR) linked antibodies as a functionalized contrast agent to evaluate ocular surface squamous neoplasia (OSSN). Methods. GNRs were synthesized and covalently attached to anti–glucose transporter-1 (GLUT-1) antibodies via carbodiimide chemistry. Three specimens from each of three distinct categories of human conjunctival tissue were selected for analysis, including conjunctiva without epithelial atypia (controls); conjunctival intraepithelial neoplasia, carcinoma in situ (CIS); and conjunctival squamous cell carcinoma (SCC). Tissue sections were incubated initially with GNR tagged anti–GLUT-1 antibodies and then with a fluorescent-tagged secondary antibody. Immunofluorescence and OCT imaging of the tissue was performed and the results were correlated to the light microscopic findings on traditional hemotoxyin and eosin stained sections. Results. No binding of the functionalized GNRs was observed within the epithelium of three normal conjunctiva controls. While immunofluorescence disclosed variable binding of the functionalized GNRs to atypical epithelial cells in all six cases of OSSN, the enhancement of the OCT signal in three cases of CIS was insufficient to distinguish these specimens from normal controls. In two of three cases of SCC, binding of functionalized GNRs was sufficient to produce an increased scattering effect on OCT in areas correlating to atypical epithelial cells which stained intensely on immunofluorescence imaging. Binding of functionalized GNRs was sufficient to produce an increased scattering effect on OCT in areas correlating to regions of erythrocytes and hemorrhage which stained intensely on immunofluorescence imaging within all nine tested samples. Conclusions. We have demonstrated the use of OCT for molecular histopathology using functionalized gold nanorods in the setting of OSSN. Our results suggest a threshold concentration of functionalized GNRs within tissue is required to achieve a detectable enhancement in scattering of the OCT signal. PMID:23307958

Molecular Analysis of Non-Small Cell Lung Cancer (NSCLC) Identifies Subsets with Different Sensitivity to Insulin like Growth Factor I Receptor (IGF-IR) Inhibition

PubMed Central

Gualberto, Antonio; Dolled-Filhart, Marisa; Gustavson, Mark; Christiansen, Jason; Wang, Yu-Fen; Hixon, Mary L.; Reynolds, Jennifer; McDonald, Sandra; Ang, Agnes; Rimm, David L.; Langer, Corey J.; Blakely, Johnetta; Garland, Linda; Paz-Ares, Luis G.; Karp, Daniel D.; Lee, Adrian V.

2010-01-01

Purpose Identify molecular determinants of sensitivity of NSCLC to anti-insulin like growth factor receptor (IGF-IR) therapy. Experimental Design 216 tumor samples were investigated. 165 consisted of retrospective analyses of banked tissue and an additional 51 were from patients enrolled in a phase 2 study of figitumumab (F), a monoclonal antibody against the IGF-IR, in stage IIIb/IV NSCLC. Biomarkers assessed included IGF-IR, EGFR, IGF-2, IGF-2R, IRS-1, IRS-2, vimentin and E-cadherin. Sub-cellular localization of IRS-1 and phosphorylation levels of MAPK and Akt1 were also analyzed. Results IGF-IR was differentially expressed across histological subtypes (P=0.04), with highest levels observed in squamous cell tumors. Elevated IGF-IR expression was also observed in a small number of squamous cell tumors responding to chemotherapy combined with F (p=0.008). Since no other biomarker/response interaction was observed using classical histological sub-typing, a molecular approach was undertaken to segment NSCLC into mechanism-based subpopulations. Principal component analysis and unsupervised Bayesian clustering identified 3 NSCLC subsets that resembled the steps of the epithelial-to-mesenchymal transition: E-cadherin high/IRS-1 low (Epithelial-like), E-cadherin intermediate/IRS-1 high (Transitional) and E-cadherin low/IRS-1 low (Mesenchymal-like). Several markers of the IGF-IR pathway were over-expressed in the Transitional subset. Furthermore, a higher response rate to the combination of chemotherapy and F was observed in Transitional tumors (71%) compared to those in the Mesenchymal-like subset (32%, p=0.03). Only one Epithelial-like tumor was identified in the phase 2 study, suggesting that advanced NSCLC has undergone significant de-differentiation at diagnosis. Conclusion NSCLC comprises molecular subsets with differential sensitivity to IGF-IR inhibition. PMID:20670944

Talactoferrin in Treating Patients With Relapsed or Refractory Non-Small Cell Lung Cancer or Squamous Cell Head and Neck Cancer

ClinicalTrials.gov

2016-07-30

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Non-small Cell Lung Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Salivary Gland Cancer; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Salivary Gland Cancer; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Salivary Gland Cancer; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer

Sunitinib, Cetuximab, and Radiation Therapy in Treating Patients With Locally Advanced or Recurrent Squamous Cell Carcinoma of the Head and Neck

ClinicalTrials.gov

2013-07-01

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Tongue Cancer; Untreated Metastatic Squamous Neck Cancer With Occult Primary

Phase II Randomized Trial of the Combination of Cetuximab and Sorafenib or Single Agent Cetuximab

ClinicalTrials.gov

2017-12-28

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Salivary Gland Cancer; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Salivary Gland Cancer; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Salivary Gland Cancer; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer; Untreated Metastatic Squamous Neck Cancer With Occult Primary

Detection of Papillomavirus DNA in Cutaneous Squamous Cell Carcinoma and Multiple Papillomas in Captive Reptiles.

PubMed

Eleni, C; Corteggio, A; Altamura, G; Meoli, R; Cocumelli, C; Rossi, G; Friedrich, K G; Di Cerbo, P; Borzacchiello, G

2017-07-01

Papillomaviruses (PVs) are small, non-enveloped DNA viruses that cause mucocutaneous tumours including squamous cell carcinoma (SCC) in man. In animals, evidence supports a causal role for PVs in the development of cutaneous and oral SCC in some species. In reptiles, three cases of papilloma or fibropapilloma have been associated with PV infection, but no association has been reported to date with SCC. Two cases of cutaneous epithelial tumours, multiple papillomas in a spiny-tailed lizard (Uromastyx acanthinura) and SCC in a Dumeril's boa (Acrantophis dumerili), were investigated by polymerase chain reaction. PV DNA was amplified from samples of both lesions. Typical microscopical features suggestive of PV infection (e.g. the presence of koilocytes) were observed in the lesions from the spiny-tailed lizard. This is the first report of an association between PV and SCC in reptiles. Further studies are needed to better clarify the role of PVs in these species and to characterize the PV strains involved. Copyright © 2017 Elsevier Ltd. All rights reserved.

PI3K Inhibitor BKM120 and Cetuximab in Treating Patients With Recurrent or Metastatic Head and Neck Cancer

ClinicalTrials.gov

2017-05-22

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Salivary Gland Cancer; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Salivary Gland Cancer; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Salivary Gland Cancer; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer

Altered gene expression in conjunctival squamous cell carcinoma.

PubMed

Mahale, Alka; Alkatan, Hind; Alwadani, Saeed; Othman, Maha; Suarez, Maria J; Price, Antoinette; Al-Hussain, Hailah; Jastaneiah, Sabah; Yu, Wayne; Maktabi, Azza; Deepak, Edward P; Eberhart, Charles G; Asnaghi, Laura

2016-05-01

Conjunctival squamous cell carcinoma is a malignancy of the ocular surface. The molecular drivers responsible for the development and progression of this disease are not well understood. We therefore compared the transcriptional profiles of eight snap-frozen conjunctival squamous cell carcinomas and one in situ lesion with normal conjunctival specimens in order to identify diagnostic markers or therapeutic targets. RNA was analyzed using oligonucleotide microarrays, and a wide range of transcripts with altered expression identified, including many dysregulated in carcinomas arising at other sites. Among the upregulated genes, we observed more than 30-fold induction of the matrix metalloproteinases, MMP-9 and MMP-11, as well as a prominent increase in the mRNA level of a calcium-binding protein important for the intracellular calcium signaling, S100A2, which was induced over 20-fold in the tumor cohort. Clusterin was the most downregulated gene, with an approximately 180-fold reduction in the mRNA expression. These alterations were all confirmed by qPCR in the samples used for initial microarray analysis. In addition, immunohistochemical analysis confirmed the overexpression of MMP-11 and S100A2, as well as reductions in clusterin, in several independent in situ carcinomas of conjunctiva. These data identify a number of alterations, including upregulation of MMP-9, MMP-11, and S100A2, as well as downregulation of clusterin, associated with epithelial tumorigenesis in the ocular surface.

Ficlatuzumab With or Without Cetuximab in Treating Patients With Cetuximab-Resistant, Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

ClinicalTrials.gov

2018-02-02

Head and Neck Basaloid Carcinoma; Recurrent Head and Neck Squamous Cell Carcinoma; Recurrent Oropharyngeal Squamous Cell Carcinoma; Squamous Cell Carcinoma of Unknown Primary Origin; Stage IV Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IV Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IV Nasopharyngeal Keratinizing Squamous Cell Carcinoma AJCC v7; Stage IV Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVA Nasopharyngeal Keratinizing Squamous Cell Carcinoma AJCC v7; Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVB Nasopharyngeal Keratinizing Squamous Cell Carcinoma AJCC v7; Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVC Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVC Nasopharyngeal Keratinizing Squamous Cell Carcinoma AJCC v7; Stage IVC Oropharyngeal Squamous Cell Carcinoma AJCC v7; Head and Neck Cancer; Oropharyngeal Cancer; HNSCC

Evidence for mesenchymal-like sub-populations within squamous cell carcinomas possessing chemoresistance and phenotypic plasticity.

PubMed

Basu, D; Nguyen, T-T K; Montone, K T; Zhang, G; Wang, L-P; Diehl, J A; Rustgi, A K; Lee, J T; Weinstein, G S; Herlyn, M

2010-07-22

Variable drug responses among malignant cells within individual tumors may represent a barrier to their eradication using chemotherapy. Carcinoma cells expressing mesenchymal markers resist conventional and epidermal growth factor receptor (EGFR)-targeted chemotherapy. In this study, we evaluated whether mesenchymal-like sub-populations within human squamous cell carcinomas (SCCs) with predominantly epithelial features contribute to overall therapy resistance. We identified a mesenchymal-like subset expressing low E-cadherin (Ecad-lo) and high vimentin within the upper aerodigestive tract SCCs. This subset was both isolated from the cell lines and was identified in xenografts and primary clinical specimens. The Ecad-lo subset contained more low-turnover cells, correlating with resistance to the conventional chemotherapeutic paclitaxel in vitro. Epidermal growth factor induced less stimulation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways in Ecad-lo cells, which was likely due to lower EGFR expression in this subset and correlated with in vivo resistance to the EGFR-targeted antibody, cetuximab. The Ecad-lo and high E-cadherin subsets were dynamic in phenotype, showing the capacity to repopulate each other from single-cell clones. Taken together, these results provide evidence for a low-turnover, mesenchymal-like sub-population in SCCs with diminished EGFR pathway function and intrinsic resistance to conventional and EGFR-targeted chemotherapies.

Upper aerodigestive tract cancer and the lung: a tale of two aspirations.

PubMed

Vaideeswar, P; Ghodke, R

2012-01-01

Patients with upper aerodigestive epithelial cancers frequently develop second primary cancers due to common risk factors or develop distant metastases depending on the locoregional status of the primary tumor. In most instances, the organ affected is the lung. Pulmonary spread usually occurs due to hematogenous or lymphatic dissemination. The following is a report of two patients with upper aerodigestive tract squamous cell carcinomas who developed lung metastases due to aspiration, a route not well documented in recent literature.

TWIST and p-Akt immunoexpression in normal oral epithelium oral dysplasia and in oral squamous cell carcinoma

PubMed Central

Yamamoto, Fernanda-Paula; Corrêa Pontes, Flávia-Sirotheau; Cury, Sérgio-Elias; Fonseca, Felipe-Paiva; Rebelo-Pontes, Hélder; Pinto-Júnior, Décio-dos Santos

2012-01-01

Objectives: The aim of this study was to evaluate the immunoexpression of TWIST and p-Akt proteins in oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC), correlating their expressions with the histological features of the lesions. Study design: Immunohistochemical studies were carried out on 10 normal oral epithelium, 30 OL and 20 OSCC formalin-fixed, paraffin-embedded tissue samples. Immunoperoxidase reactions for TWIST and p-Akt proteins were applied on the specimens and the positivity of the reactions was calculated for 1000 epithelial cells. Results: Kruskal-Wallis and Dunn’s post tests revealed a significant difference in TWIST and p-Akt immunoexpression among normal oral mucosa, OL and OSCC. In addition, a significant positive correlation was found between TWIST and p-Akt expressions according to the Pearson’s correlation test. Conclusions: The results obtained in the current study suggest that TWIST and p-Akt may participate of the multi-step process of oral carcinogenesis since its early stages. Key words: Oral cancer, oral leukoplakia, dysplasia, immunohistochemistry. PMID:21743395

Analysis of clonality and HPV infection in benign, hyperplastic, premalignant, and malignant lesions of the vulvar mucosa.

PubMed

Ueda, Yutaka; Enomoto, Takayuki; Miyatake, Takashi; Shroyer, Kenneth R; Yoshizaki, Tatsuo; Kanao, Hiroyuki; Ueno, Yuko; Sun, Hongbo; Nakashima, Ryuichi; Yoshino, Kiyoshi; Kimura, Toshihiro; Haba, Tomoko; Wakasa, Kenichi; Murata, Yuji

2004-08-01

To elucidate the pathogenesis of vulvar carcinomas, we studied clonality and human papillomavirus (HPV) infection in vulvar epithelial diseases. Monoclonal composition was demonstrated in all 9 invasive tumors (squamous cell carcinoma [SCC], 6; basal cell carcinoma, 1; malignant melanoma, 2), 15 of 20 cases of vulvar intraepithelial neoplasia (VIN), 7 of 9 cases of Paget disease, 2 of 6 cases of lichen sclerosus (LS), and 2 of 3 cases of squamous cell hyperplasia (SCH); high-risk type HPV was revealed in 5 of 6 SCCs and 17 of 20 VINs. These observations might imply that a subset of cases of LS and SCH result from a neoplastic proliferation, similar to VINs but not related to infection with high-risk type HPV. In 1 case of SCC with concurrent VIN 3 in an adjacent lesion, both lesions showed the same pattern of X chromosome inactivation and the presence of HPV-16 in episomal and integrated forms, suggesting that monoclonal expansion triggered by high-risk type HPV integration is an early event for carcinogenesis of HPV-associated SCC.

Radiation Therapy With or Without Cisplatin in Treating Patients With Stage III-IV Squamous Cell Carcinoma of the Head and Neck Who Have Undergone Surgery

ClinicalTrials.gov

2017-12-07

Head and Neck Squamous Cell Carcinoma; Laryngeal Squamous Cell Carcinoma, Spindle Cell Variant; Stage III Hypopharyngeal Squamous Cell Carcinoma; Stage III Laryngeal Squamous Cell Carcinoma; Stage III Laryngeal Verrucous Carcinoma; Stage III Oral Cavity Squamous Cell Carcinoma; Stage III Oral Cavity Verrucous Carcinoma; Stage III Oropharyngeal Squamous Cell Carcinoma; Stage IVA Hypopharyngeal Squamous Cell Carcinoma; Stage IVA Laryngeal Squamous Cell Carcinoma; Stage IVA Laryngeal Verrucous Carcinoma; Stage IVA Oral Cavity Squamous Cell Carcinoma; Stage IVA Oral Cavity Verrucous Carcinoma; Stage IVA Oropharyngeal Squamous Cell Carcinoma

Cetuximab & Nivolumab in Patients With Recurrent/Metastatic Head & Neck Squamous Cell Carcinoma

ClinicalTrials.gov

2018-06-13

Squamous Cell Carcinoma of the Oropharynx; Squamous Cell Carcinoma of the Larynx; Squamous Cell Carcinoma of the Oral Cavity; Squamous Cell Carcinoma of the Hypopharynx; Squamous Cell Carcinoma of the Paranasal Sinus; Head and Neck Squamous Cell Carcinoma; Squamous Cell Cancer; Head and Neck Carcinoma

Down regulation of E-Cadherin (ECAD) - a predictor for occult metastatic disease in sentinel node biopsy of early squamous cell carcinomas of the oral cavity and oropharynx.

PubMed

Huber, Gerhard F; Züllig, Lena; Soltermann, Alex; Roessle, Matthias; Graf, Nicole; Haerle, Stephan K; Studer, Gabriela; Jochum, Wolfram; Moch, Holger; Stoeckli, Sandro J

2011-06-03

Prognostic factors in predicting occult lymph node metastasis in patients with head and neck squamous-cell carcinoma (HNSCC) are necessary to improve the results of the sentinel lymph node procedure in this tumour type. The E-Cadherin glycoprotein is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections. To determine the value of the molecular marker E-Cadherin in predicting regional metastatic disease. E-Cadherin expression in tumour tissue of 120 patients with HNSCC of the oral cavity and oropharynx were evaluated using the tissue microarray technique. 110 tumours were located in the oral cavity (91.7%; mostly tongue), 10 tumours in the oropharynx (8.3%). Intensity of E-Cadherin expression was quantified by the Intensity Reactivity Score (IRS). These results were correlated with the lymph node status of biopsied sentinel lymph nodes. Univariate and multivariate analysis was used to determine statistical significance. pT-stage, gender, tumour side and location did not correlate with lymph node metastasis. Differentiation grade (p = 0.018) and down regulation of E-Cadherin expression significantly correlate with positive lymph node status (p = 0.005) in univariate and multivariate analysis. These data suggest that loss of E-cadherin expression is associated with increased lymhogeneous metastasis of HNSCC. E-cadherin immunohistochemistry may be used as a predictor for lymph node metastasis in squamous cell carcinoma of the oral cavity and oropharynx. 2b.

Onalespib in Treating Patients With Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck Receiving Radiation Therapy and Cisplatin

ClinicalTrials.gov

2018-04-23

Stage III Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage III Laryngeal Squamous Cell Carcinoma AJCC v6 and v7; Stage III Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7

Phase 1b Food Based Modulation of Biomarkers in Human Tissues at High-Risk for Oral Cancer.

ClinicalTrials.gov

2018-03-05

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Salivary Gland Squamous Cell Carcinoma; Stage 0 Hypopharyngeal Cancer; Stage 0 Laryngeal Cancer; Stage 0 Lip and Oral Cavity Cancer; Stage 0 Nasopharyngeal Cancer; Stage 0 Oropharyngeal Cancer; Stage 0 Paranasal Sinus and Nasal Cavity Cancer; Stage I Salivary Gland Cancer; Stage I Squamous Cell Carcinoma of the Hypopharynx; Stage I Squamous Cell Carcinoma of the Larynx; Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage I Squamous Cell Carcinoma of the Nasopharynx; Stage I Squamous Cell Carcinoma of the Oropharynx; Stage I Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage I Verrucous Carcinoma of the Larynx; Stage I Verrucous Carcinoma of the Oral Cavity; Stage II Salivary Gland Cancer; Stage II Squamous Cell Carcinoma of the Hypopharynx; Stage II Squamous Cell Carcinoma of the Larynx; Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage II Squamous Cell Carcinoma of the Nasopharynx; Stage II Squamous Cell Carcinoma of the Oropharynx; Stage II Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage II Verrucous Carcinoma of the Larynx; Stage II Verrucous Carcinoma of the Oral Cavity; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Salivary Gland Cancer; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Oral Cavity Squamous Cell Carcinoma; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Nasal Cavity and Paranasal Sinus Cancer; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Salivary Gland Cancer; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Oral Cavity Squamous Cell Carcinoma; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Salivary Gland Cancer; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Oral Cavity Squamous Cell Carcinoma; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Paranasal Sinus and Nasal Cavity Squamous Cell Carcinoma; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer

Identification of a Novel Proto-oncogenic Network in Head and Neck Squamous Cell Carcinoma

PubMed Central

Georgy, Smitha R.; Cangkrama, Michael; Srivastava, Seema; Partridge, Darren; Auden, Alana; Dworkin, Sebastian; McLean, Catriona A.; Darido, Charbel

2015-01-01

Background: The developmental transcription factor Grainyhead-like 3 (GRHL3) plays a critical tumor suppressor role in the mammalian epidermis through direct regulation of PTEN and the PI3K/AKT/mTOR signaling pathway. GRHL3 is highly expressed in all tissues derived from the surface ectoderm, including the oral cavity, raising a question about its potential role in suppression of head and neck squamous cell carcinoma (HNSCC). Methods: We explored the tumor suppressor role of Grhl3 in HNSCC using a conditional knockout (Grhl3 ∆/– /K14Cre +) mouse line (n = 26) exposed to an oral chemical carcinogen. We defined the proto-oncogenic pathway activated in the HNSCC derived from these mice and assessed it in primary human HNSCC samples, normal oral epithelial cell lines carrying shRNA to GRHL3, and human HNSCC cell lines. Data were analyzed with two-sided chi square and Student’s t tests. Results: Deletion of Grhl3 in oral epithelium in mice did not perturb PTEN/PI3K/AKT/mTOR signaling, but instead evoked loss of GSK3B expression, resulting in stabilization and accumulation of c-MYC and aggressive HNSCC. This molecular signature was also evident in a subset of primary human HNSCC and HNSCC cell lines. Loss of Gsk3b in mice, independent of Grhl3, predisposed to chemical-induced HNSCC. Restoration of GSK3B expression blocked proliferation of normal oral epithelial cell lines carrying shRNA to GRHL3 (cell no., Day 8: Scramble ctl, 616±21.8 x 103 vs GRHL3-kd, 1194±44 X 103, P < .001; GRHL3-kd vs GRHL3-kd + GSK3B, 800±98.84 X 103, P = .003) and human HNSCC cells. Conclusions: We defined a novel molecular signature in mammalian HNSCC, suggesting new treatment strategies targeting the GRHL3/GSK3B/c-MYC proto-oncogenic network. PMID:26063791

Electronic cigarettes induce DNA strand breaks and cell death independently of nicotine in cell lines.

PubMed

Yu, Vicky; Rahimy, Mehran; Korrapati, Avinaash; Xuan, Yinan; Zou, Angela E; Krishnan, Aswini R; Tsui, Tzuhan; Aguilera, Joseph A; Advani, Sunil; Crotty Alexander, Laura E; Brumund, Kevin T; Wang-Rodriguez, Jessica; Ongkeko, Weg M

2016-01-01

Evaluate the cytotoxicity and genotoxicity of short- and long-term e-cigarette vapor exposure on a panel of normal epithelial and head and neck squamous cell carcinoma (HNSCC) cell lines. HaCaT, UMSCC10B, and HN30 were treated with nicotine-containing and nicotine-free vapor extract from two popular e-cigarette brands for periods ranging from 48 h to 8 weeks. Cytotoxicity was assessed using Annexin V flow cytometric analysis, trypan blue exclusion, and clonogenic assays. Genotoxicity in the form of DNA strand breaks was quantified using the neutral comet assay and γ-H2AX immunostaining. E-cigarette-exposed cells showed significantly reduced cell viability and clonogenic survival, along with increased rates of apoptosis and necrosis, regardless of e-cigarette vapor nicotine content. They also exhibited significantly increased comet tail length and accumulation of γ-H2AX foci, demonstrating increased DNA strand breaks. E-cigarette vapor, both with and without nicotine, is cytotoxic to epithelial cell lines and is a DNA strand break-inducing agent. Further assessment of the potential carcinogenic effects of e-cigarette vapor is urgently needed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Menadione (Vitamin K3) induces apoptosis of human oral cancer cells and reduces their metastatic potential by modulating the expression of epithelial to mesenchymal transition markers and inhibiting migration.

PubMed

Suresh, Shruthy; Raghu, Dinesh; Karunagaran, Devarajan

2013-01-01

Oral cancer is one of the most commonly occurring cancers worldwide, decreasing the patient's survival rate due to tumor recurrence and metastasis. Menadione (Vitamin K3) is known to exhibit cytotoxicity in various cancer cells but the present study focused on its effects on viability, apoptosis, epithelial to mesenchymal transition (EMT), anchorage independent growth and migration of oral cancer cells. The results show that menadione is more cytotoxic to SAS (oral squamous carcinoma) cells but not to non-tumorigenic HEK293 and HaCaT cells. Menadione treatment increased the expression of pro-apoptotic proteins, Bax and p53, with a concurrent decrease in anti-apoptotic proteins, Bcl-2 and p65. Menadione induced the expression of E-cadherin but reduced the expression of EMT markers, vimentin and fibronectin. Menadione also inhibited anchorage independent growth and migration in SAS cells. These findings reveal and confirm that menadione is a potential candidate in oral cancer therapy as it exhibits cytotoxic, antineoplastic and antimigratory effects besides effectively blocking EMT in oral cancer cells.

Electronic cigarettes induce DNA strand breaks and cell death independently of nicotine in cell lines

PubMed Central

Yu, Vicky; Rahimy, Mehran; Korrapati, Avinaash; Xuan, Yinan; Zou, Angela E.; Krishnan, Aswini R.; Tsui, Tzuhan; Aguilera, Joseph A.; Advani, Sunil; Crotty Alexander, Laura E.; Brumund, Kevin T.; Wang-Rodriguez, Jessica

2016-01-01

Objectives Evaluate the cytotoxicity and genotoxicity of short- and long-term e-cigarette vapor exposure on a panel of normal epithelial and head and neck squamous cell carcinoma (HNSCC) cell lines. Materials and Methods HaCaT, UMSCC10B, and HN30 were treated with nicotine-containing and nicotine-free vapor extract from two popular e-cigarette brands for periods ranging from 48 hours to 8 weeks. Cytotoxicity was assessed using Annexin V flow cytometric analysis, trypan blue exclusion, and clonogenic assays. Genotoxicity in the form of DNA strand breaks was quantified using the neutral comet assay and γ-H2AX immunostaining. Results E-cigarette-exposed cells showed significantly reduced cell viability and clonogenic survival, along with increased rates of apoptosis and necrosis, regardless of e-cigarette vapor nicotine content. They also exhibited significantly increased comet tail length and accumulation of γ-H2AX foci, demonstrating increased DNA strand breaks. Conclusion E-cigarette vapor, both with and without nicotine, is cytotoxic to epithelial cell lines and is a DNA strand break-inducing agent. Further assessment of the potential carcinogenic effects of e-cigarette vapor is urgently needed. PMID:26547127

Radiation Therapy With Durvalumab or Cetuximab in Treating Patients With Stage III-IVB Head and Neck Cancer Who Cannot Take Cisplatin

ClinicalTrials.gov

2018-06-15

Head and Neck Squamous Cell Carcinoma; Stage III Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage III Laryngeal Squamous Cell Carcinoma AJCC v6 and v7; Stage III Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7

Cisplatin, Intensity-Modulated Radiation Therapy, and Pembrolizumab in Treating Patients With Stage III-IV Head and Neck Squamous Cell Carcinoma

ClinicalTrials.gov

2018-05-18

CDKN2A-p16 Negative; Stage III Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage III Laryngeal Squamous Cell Carcinoma AJCC v6 and v7; Stage III Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7

Colonization of the Stratified Squamous Epithelium of the Nonsecreting Area of Horse Stomach by Lactobacilli

PubMed Central

Yuki, Norikatsu; Shimazaki, Tomoko; Kushiro, Akira; Watanabe, Koichi; Uchida, Kazumi; Yuyama, Teruhiko; Morotomi, Masami

2000-01-01

Selective adhesion to only certain epithelia is particularly common among the bacterial members of the indigenous microflora of mammals. We have found that the stratified squamous epithelium of the nonsecreting area of horse stomach is colonized by gram-positive rods. The microscopic features of a dense layer of these bacteria on the epithelium were found to be similar to those reported in mice, rats, and swine. Adhering microorganisms were isolated and identified as Lactobacillus salivarius, L. crispatus, L. reuteri, and L. agilis by DNA-DNA hybridization and 16S rRNA gene sequencing techniques. These lactobacilli associated with the horse, except for L. reuteri, were found to adhere to horse epithelial cells in vitro but not to those of rats. A symbiotic relationship of these lactobacilli with the horse is suggested. PMID:11055960

Erlotinib, Docetaxel, and Radiation Therapy in Treating Patients With Locally Advanced Head and Neck Cancer

ClinicalTrials.gov

2014-06-05

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer; Untreated Metastatic Squamous Neck Cancer With Occult Primary

Fibronectin Modulates Cell Adhesion and Signaling to Promote Single Cell Migration of Highly Invasive Oral Squamous Cell Carcinoma

PubMed Central

Ramos, Grasieli de Oliveira; Bernardi, Lisiane; Lauxen, Isabel; Sant’Ana Filho, Manoel; Horwitz, Alan Rick; Lamers, Marcelo Lazzaron

2016-01-01

Cell migration is regulated by adhesion to the extracellular matrix (ECM) through integrins and activation of small RhoGTPases, such as RhoA and Rac1, resulting in changes to actomyosin organization. During invasion, epithelial-derived tumor cells switch from laminin-enriched basal membrane to collagen and fibronectin-enriched connective tissue. How this switch affects the tumor migration is still unclear. We tested the hypothesis that ECM dictates the invasiveness of Oral Squamous Cell Carcinoma (OSCC). We analyzed the migratory properties of two OSCC lines, a low invasive cell line with high e-cadherin levels (Linv/HE-cad) or a highly invasive cell line with low e-cadherin levels (Hinv/LE-cad), plated on different ECM components. Compared to laminin, fibronectin induced non-directional collective migration and decreased RhoA activity in Linv/HE-cad OSCC. For Hinv/LE-cad OSCC, fibronectin increased Rac1 activity and induced smaller adhesions, resulting in a fast single cell migration in both 2D and 3D environments. Consistent with these observations, human OSCC biopsies exhibited similar changes in cell-ECM adhesion distribution at the invasive front of the tumor, where cells encounter fibronectin. Our results indicate that ECM composition might induce a switch from collective to single cell migration according to tumor invasiveness due to changes in cell-ECM adhesion and the resulting signaling pathways that alter actomyosin organization. PMID:26978651

Clinical implication of elevated human cervical cancer oncogene-1 expression in esophageal squamous cell carcinoma.

PubMed

Liu, Ying; Li, Ke; Ren, Zhonghai; Li, Shenglei; Zhang, Hongyan; Fan, Qingxia

2012-07-01

The human cervical cancer oncogene 1 (HCCR-1), a novel human oncoprotein, has been shown to be upregulated in various human tumors and plays a critical role in tumorigenesis and tumor progression. Here, the authors investigated HCCR-1 level in esophageal squamous cell carcinoma (ESCC) tissues and assessed the correlation between HCCR-1 level and prognosis of the patients with ESCC. HCCR-1 levels were investigated by immunohistochemistry, in situ hybridization, real-time quantitative RT-PCR and Western blotting methods; Kaplan-Meier curve was used to evaluate the prognostic value of HCCR-1 level in patients with ESCC using log-rank test. HCCR-1 displayed high levels in ESCC tissues compared to squamous dysplasia tissues and normal esophageal epithelial tissues. No significant correlation was observed between the levels of HCCR-1 mRNA and protein and gender and age (all p>0.05) but obviously related to histological grade, clinical stage, and lymph node metastasis (all p<0.001). Moreover, the survival rate of the patients with low HCCR-1 levels was higher than that of the patients with high HCCR-1 levels (both p<0.05). These data demonstrate that HCCR-1 may be used as a novel predictor for the prognosis of the patients with ESCC.

Differential expression of GSK3β and pS9GSK3β in normal human tissues: can pS9GSK3β be an epithelial marker?

PubMed

Lee, Hojung; Ro, Jae Y

2015-01-01

Glycogen synthase kinase 3β (GSK3β) and phosphorylated GSK3β at Ser9 (pS9GSK3β) are crucial in cellular proliferation and metabolism. GSK3β and pS9GSK3β are deregulated in many diseases including tumors. Data on altered expression of GSK3β and pS9GSK3β are mainly limited to tumor tissues, thus the expression of GSK3β and pS9GSK3β in normal human tissue has been largely unknown. Thus, we examined the immunohistochemical localization of GSK3β and pS9GSK3β in human fetal and adult tissues, and also compared the expression pattern of GSK3β and pS9GSK3β with that of the CK7 and CK20. We found GSK3β expression in neurons of brain, myenteric plexus in gastrointestinal tract, squamous epithelium of skin, and mammary gland. The expression of pS9GSK3β was restricted to the epithelial cells of breast and pancreaticobiliary duct, distal nephron of kidney, gastrointestinal tract, fallopian tube, epididymis, secretory cell of prostatic gland, and umbrella cell of urinary tract. The staining pattern of pS9GSK3β and CK7 was overlapped in most organs except for gastrointestinal tract where CK7 was negative and CK20 was positive. Our results show that the expression of GSK3β may be associated with differentiation of ectodermal derived tissues and pS9GSK3β with that of epithelial cells of endodermal derived tissues in human. In addition, the expression of pS9GSK3β in the selective epithelial cells may indicate its association with secretory or barrier function of specific cells and may serve as another immunohistochemical marker for epithelial cells.

Chemotherapy With or Without Bevacizumab in Treating Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

ClinicalTrials.gov

2018-06-19

Recurrent Hypopharyngeal Squamous Cell Carcinoma; Recurrent Laryngeal Squamous Cell Carcinoma; Recurrent Laryngeal Verrucous Carcinoma; Recurrent Lip and Oral Cavity Squamous Cell Carcinoma; Recurrent Metastatic Squamous Cell Carcinoma in the Neck With Occult Primary; Recurrent Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Recurrent Oral Cavity Verrucous Carcinoma; Recurrent Oropharyngeal Squamous Cell Carcinoma; Recurrent Salivary Gland Carcinoma; Salivary Gland Squamous Cell Carcinoma; Squamous Cell Carcinoma Metastatic in the Neck With Occult Primary; Stage IV Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage IV Major Salivary Gland Cancer AJCC v7; Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Laryngeal Verrucous Carcinoma AJCC v7; Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVA Major Salivary Gland Cancer AJCC v7; Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVA Oral Cavity Cancer AJCC v6 and v7; Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Laryngeal Verrucous Carcinoma AJCC v7; Stage IVB Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVB Major Salivary Gland Cancer AJCC v7; Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVB Oral Cavity Cancer AJCC v6 and v7; Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVC Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVC Laryngeal Verrucous Carcinoma AJCC v7; Stage IVC Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVC Major Salivary Gland Cancer AJCC v7; Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVC Oral Cavity Cancer AJCC v6 and v7; Stage IVC Oropharyngeal Squamous Cell Carcinoma AJCC v7; Tongue Carcinoma; Untreated Metastatic Squamous Cell Carcinoma to Neck With Occult Primary

Aberrant Epithelial-Mesenchymal Hedgehog Signaling Characterizes Barrett's Metaplasia

PubMed Central

Wang, David H.; Clemons, Nicholas J.; Miyashita, Tomoharu; Dupuy, Adam J.; Zhang, Wei; Szczepny, Anette; Corcoran-Schwartz, Ian M.; Wilburn, Daniel L.; Montgomery, Elizabeth A.; Wang, Jean S.; Jenkins, Nancy A.; Copeland, Neal A.; Harmon, John W.; Phillips, Wayne A.; Watkins, D. Neil

2010-01-01

Background & Aims The molecular mechanism underlying epithelial metaplasia in Barrett's esophagus remains unknown. Recognizing that Hedgehog signaling is required for early esophageal development, we sought to determine if the Hedgehog pathway is reactivated in Barrett's esophagus, and if genes downstream of the pathway could promote columnar differentiation of esophageal epithelium. Methods Immunohistochemistry, immunofluorescence, and quantitative real-time PCR were used to analyze clinical specimens, human esophageal cell lines, and mouse esophagi. Human esophageal squamous epithelial (HET-1A) and adenocarcinoma (OE33) cells were subjected to acid treatment and used in transfection experiments. Swiss Webster mice were used in a surgical model of bile reflux injury. An in vivo transplant culture system was created using esophageal epithelium from Sonic hedgehog transgenic mice. Results Marked upregulation of Hedgehog ligand expression, which can be induced by acid or bile exposure, occurs frequently in Barrett's epithelium and is associated with stromal expression of the Hedgehog target genes PTCH1 and BMP4. BMP4 signaling induces expression of SOX9, an intestinal crypt transcription factor, which is highly expressed in Barrett's epithelium. We further show that expression of DMBT1, the human homologue of the columnar cell factor Hensin, occurs in Barrett's epithelium and is induced by SOX9. Finally, transgenic expression of Sonic hedgehog in mouse esophageal epithelium induces expression of stromal Bmp4, epithelial Sox9 and columnar cytokeratins. Conclusions Epithelial Hedgehog ligand expression may contribute to the initiation of Barrett's esophagus through induction of stromal BMP4, which triggers reprogramming of esophageal epithelium in favor of a columnar phenotype. PMID:20138038

Donor-derived stem-cells and epithelial mesenchymal transition in squamous cell carcinoma in transplant recipients.

PubMed

Verneuil, Laurence; Leboeuf, Christophe; Bousquet, Guilhem; Brugiere, Charlotte; Elbouchtaoui, Morad; Plassa, Louis-François; Peraldi, Marie-Noelle; Lebbé, Celeste; Ratajczak, Philippe; Janin, Anne

2015-12-08

Skin squamous-cell-carcinoma (SCC), is the main complication in long-term kidney-transplant recipients, and it can include donor-derived cells. Preclinical models demonstrated the involvement of epithelial mesenchymal transition (EMT) in the progression of skin SCC, and the role of Snail, an EMT transcription factor, in cancer stem-cell survival and expansion.Here, we studied stem-cells and EMT expression in SCCs and concomitant actinic keratoses (AK) in kidney-transplant recipients. In SCC and AK in 3 female recipients of male kidney-transplants, donor-derived Y chromosome in epidermal stem cells was assessed using combined XY-FISH/CD133 immunostaining, and digital-droplet-PCR on laser-microdissected CD133 expressing epidermal cells.For EMT study, double immunostainings of CD133 with vimentin or snail and slug, electron microscopy and immunostainings of keratinocytes junctions were performed. Digital droplet PCR was used to check CDH1 (E-cadherin) expression level in laser-microdissected cells co-expressing CD133 and vimentin or snail and slug.The numbers of Y-chromosome were assessed using digital droplet PCR in laser-microdissected cells co-expressing CD133 and vimentin, or snail and slug, and in CD133 positive cells not expressing any EMT maker. We identified donor-derived stem-cells in basal layers and invasive areas in all skin SCCs and in concomitant AKs, but not in surrounding normal skin.The donor-derived stem-cells expressed the EMT markers, vimentin, snail and slug in SCCs but not in AKs. The expression of the EMT transcription factor, SNAI1, was higher in stem-cells when they expressed vimentin. They were located in invasive areas of SCCs. In these areas, the expressions of claudin-1 and desmoglein 1 were reduced or absent, and within the basal layer there were features of basal membrane disappearance.Donor-derived stem cells were in larger numbers in stem cells co-expressing vimentin or snail and slug than in stem cells not expressing any EMT marker. We identified here donor-derived stem cells within skin SCC in kidney-transplant recipients. They were located in invasive areas of SCC and had EMT characteristics.

ACTOplus Met XR in Treating Patients With Stage I-IV Oral Cavity or Oropharynx Cancer Undergoing Definitive Treatment

ClinicalTrials.gov

2018-03-02

Oral Cavity Neoplasm; Oropharyngeal Neoplasm; Stage I Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage I Oropharyngeal Squamous Cell Carcinoma AJCC v6 and v7; Stage II Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage II Oropharyngeal Squamous Cell Carcinoma AJCC v6 and v7; Stage III Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IV Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IV Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVC Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVC Oropharyngeal Squamous Cell Carcinoma AJCC v7

Selenomethionine in Reducing Mucositis in Patients With Locally Advanced Head and Neck Cancer Who Are Receiving Cisplatin and Radiation Therapy

ClinicalTrials.gov

2014-08-08

Chemotherapeutic Agent Toxicity; Mucositis; Radiation Toxicity; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Xerostomia

VX-970, Cisplatin, and Radiation Therapy in Treating Patients With Locally Advanced HPV-Negative Head and Neck Squamous Cell Carcinoma

ClinicalTrials.gov

2018-06-11

Head and Neck Squamous Cell Carcinoma; Human Papillomavirus Negative; Stage III Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v6 and v7; Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IV Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IV Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVC Oropharyngeal Squamous Cell Carcinoma AJCC v7

FRMD4A upregulation in human squamous cell carcinoma promotes tumor growth and metastasis and is associated with poor prognosis.

PubMed

Goldie, Stephen J; Mulder, Klaas W; Tan, David Wei-Min; Lyons, Scott K; Sims, Andrew H; Watt, Fiona M

2012-07-01

New therapeutic strategies are needed to improve treatment of head and neck squamous cell carcinoma (HNSCC), an aggressive tumor with poor survival rates. FRMD4A is a human epidermal stem cell marker implicated previously in epithelial polarity that is upregulated in SCC cells. Here, we report that FRMD4A upregulation occurs in primary human HNSCCs where high expression levels correlate with increased risks of relapse. FRMD4A silencing decreased growth and metastasis of human SCC xenografts in skin and tongue, reduced SCC proliferation and intercellular adhesion, and stimulated caspase-3 activity and expression of terminal differentiation markers. Notably, FRMD4A attenuation caused nuclear accumulation of YAP, suggesting a potential role for FRMD4A in Hippo signaling. Treatment with the HSP90 inhibitor 17-DMAG or ligation of CD44 with hyaluronan caused nuclear depletion of FRMD4A, nuclear accumulation of YAP and reduced SCC growth and metastasis. Together, our findings suggest FRMD4A as a novel candidate therapeutic target in HNSCC based on the key role in metastatic growth we have identified. ©2012 AACR.

Regulation of tumor progression via the Snail-RKIP signaling pathway by nicotine exposure in head and neck squamous cell carcinoma.

PubMed

Nieh, Shin; Jao, Shu-Wen; Yang, Chin-Yuh; Lin, Yaoh-Shiang; Tseng, Yi-Han; Liu, Chia-Lin; Lee, Tsai-Yu; Liu, Tsung-Yun; Chu, Yueng-Hsiang; Chen, Su-Feng

2015-12-01

Recent studies suggest that long-term exposure of the carcinogen 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK) found in tobacco smoke is involved in the progression of head and neck squamous cell carcinoma (HNSCC). The underlying nicotine-mediated mechanism remains unclear. An analysis of SCC-25 and Fadu cells with or without NNK exposure focusing on the evaluation of migration and invasion abilities, the expression of epithelial-mesenchymal transition, drug-resistance-related genes, properties of cancer stem cells (CSCs), and anti-apoptosis was performed. Long-term NNK exposure enhances migration and invasion with morphological alterations in a dose-dependently manner. Furthermore, NNK exposure also upregulates Snail, promotes sphere-forming ability, and overexpresses aldehyde dehydrogenase 1 (ALDH1), Nanog, OCT4, ABCG2, and MDR1. The current study confirmed that long-term NNK exposure plays a role in HNSCC by increasing anti-apoptosis and therapeutic resistance via the Snail-RKIP signaling pathway. Our data also suggest that α7 nicotinic acetylcholine receptor (α7-nAChR) inhibition or targeting Snail may provide a feasible rationale for preventing the progression of HNSCC. © 2015 Wiley Periodicals, Inc.

Expression of cytosolic malic enzyme (ME1) is associated with disease progression in human oral squamous cell carcinoma.

PubMed

Nakashima, Chie; Yamamoto, Kazuhiko; Fujiwara-Tani, Rina; Luo, Yi; Matsushima, Sayako; Fujii, Kiyomu; Ohmori, Hitoshi; Sasahira, Tomonori; Sasaki, Takamitsu; Kitadai, Yasuhiko; Kirita, Tadaaki; Kuniyasu, Hiroki

2018-06-01

Malic enzyme 1 (ME1) is a multifunctional protein involved in glycolysis, the citric acid cycle, NADPH production, glutamine metabolism, and lipogenesis. It is overexpressed in various cancers. We examined the expression of ME1 in 119 oral squamous cell carcinomas (OSCCs) using immunohistochemistry. Malic enzyme 1 expression was moderate to strong in 57 (48%) OSCCs and correlated with pT, pN, clinical stage, and histological grade. In 37 cases with prognostic evaluation, moderate to strong ME1 expression indicated a worse prognosis than did weak ME1 expression. Malic enzyme 1 knockdown or inactivation by lanthanide inhibited cell proliferation and motility and suppressed the epithelial-mesenchymal transition in HSC3 human OSCC cells. Knockdown of ME1 also shifted energy metabolism from aerobic glycolysis and lactate fermentation to mitochondrial oxidative phosphorylation, and the redox status from reductive to oxidative. In a mouse tumor model, lanthanide suppressed tumor growth and increased survival time. These findings reveal that ME1 is a valid target for molecular therapy in OSCC. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

KH-type splicing regulatory protein is involved in esophageal squamous cell carcinoma progression.

PubMed

Fujita, Yuji; Masuda, Kiyoshi; Hamada, Junichi; Shoda, Katsutoshi; Naruto, Takuya; Hamada, Satoshi; Miyakami, Yuko; Kohmoto, Tomohiro; Watanabe, Miki; Takahashi, Rizu; Tange, Shoichiro; Saito, Masako; Kudo, Yasusei; Fujiwara, Hitoshi; Ichikawa, Daisuke; Tangoku, Akira; Otsuji, Eigo; Imoto, Issei

2017-11-24

KH-type splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein, which is involved in several post-transcriptional aspects of RNA metabolism, including microRNA (miRNA) biogenesis. It affects distinct cell functions in different tissues and can have an impact on various pathological conditions. In the present study, we investigated the oncogenic functions of KHSRP and their underlying mechanisms in the pathogenesis of esophageal squamous cell carcinoma (ESCC). KHSRP expression levels were elevated in ESCC tumors when compared with those in non-tumorous tissues by immunohistochemistry, and cytoplasmic KHSRP overexpression was found to be an independent prognosticator for worse overall survival in a cohort of 104 patients with ESCC. KHSRP knockdown inhibited growth, migration, and invasion of ESCC cells. KHSRP knockdown also inhibited the maturation of cancer-associated miRNAs, such as miR-21, miR-130b, and miR-301, and induced the expression of their target mRNAs, such as BMP6, PDCD4, and TIMP3, resulting in the inhibition of epithelial-to-mesenchymal transition. Our findings uncover a novel oncogenic function of KHSRP in esophageal tumorigenesis and implicate its use as a marker for prognostic evaluation and as a putative therapeutic target in ESCC.

Expression of matrix metalloproteinases (MMP-1 and -2) and their inhibitors (TIMP-1, -2 and -3) in oral lichen planus, dysplasia, squamous cell carcinoma and lymph node metastasis.

PubMed Central

Sutinen, M.; Kainulainen, T.; Hurskainen, T.; Vesterlund, E.; Alexander, J. P.; Overall, C. M.; Sorsa, T.; Salo, T.

1998-01-01

Although matrix metalloproteinases (MMPs) are among the potential key mediators of cancer invasion, their involvement in premalignant lesions and conditions is not clarified. Therefore, we studied, using in situ hybridization, immunohistochemistry and zymography the expression and distribution of MMP-1 and -2, and their tissue inhibitors (TIMPs -1, -2 and -3) in oral squamous cell carcinomas (SCC) and lymph node metastases as well as in oral lichen planus, epithelial dysplasias and normal buccal mucosa. In oral SCC and lymph node metastasis, MMP-1 mRNA was detected in fibroblastic cells of tumoral stroma. In two out of ten carcinomas studied, the peripheral cells of neoplastic islands were also positive. MMP-2 mRNA expression was noted in fibroblasts surrounding the carcinoma cells, and no signal in carcinoma cells was detected. A clear TIMP-3 mRNA expression was seen in stromal cells surrounding the neoplastic islands in all SCCs and lymph node metastases studied. TIMP-1 mRNA was detected in some stromal cells surrounding the neoplastic islands, whereas the mRNA expression for TIMP-2 was negligible. On the other hand, expression of MMPs and TIMPs was consistently low in oral epithelial dysplasias, lichen planus and normal mucosa. In certain epithelial dysplasias and lichen planus, MMP-1 and -2 mRNA expressions were detected in few fibroblasts under the basement membrane zone, but normal mucosa was completely negative. In SCC and lymph node metastasis, a detectable immunostaining for MMP-1 in stromal cells and in some carcinoma cells was observed. MMP-2 immunoreactivity was detected in the peripheral cell layer in neoplastic islands and in some fibroblast-like cells of tumoral stroma. Immunostaining for TIMP-3 was detected in stromal cells surrounding the neoplastic islands. A weak positive staining for TIMP-1 was located in tumoral stroma, whereas the immunostaining for TIMP-2 was negative. Using zymography, elevated levels of MMP-2 and MMP-9 were observed in carcinoma samples in comparison with lichen planus or normal oral mucosa. Our results indicate that the studied MMPs and TIMPs are clearly up-regulated during invasion in oral SCC. However, there was also a clear, although weak, up-regulation of the expression of the MMPs but not TIMPs in some of the lichen planus and dysplastic lesions. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:9649139

Cisplatin and Radiation Therapy With or Without Erlotinib Hydrochloride in Treating Patients With Stage III or Stage IV Head and Neck Cancer

ClinicalTrials.gov

2013-05-08

Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx

Morphometric computer-assisted image analysis of epithelial cells in different grades of oral squamous cell carcinoma.

PubMed

Ananjan, Chatterjee; Jyothi, Mahadesh; Laxmidevi, B L; Gopinathan, Pillai Arun; Nazir, Salroo Humaira; Pradeep, L

2018-01-01

Oral squamous cell carcinoma (OSCC) accounts 94% of all malignant lesions in the oral cavity. In the assessment of OSCC, nowadays the WHO grading system has been followed widely but due to its subjectivity, investigators applied the sophisticated technique of computer-assisted image analysis in the grading of carcinoma in larynx, lungs, esophagus, and cervix to make it more objective. Access, analyze, and compare the cellular area (CA); cytoplasmic area (Cyt A); nuclear area (NA); nuclear perimeter (NP); nuclear form factor (NF); and nuclear-cytoplasmic ratio (N/C) of the cells in different grades of OSCC. Fifty OSCC cases were obtained and stained with hematoxylin and eosin which were graded according to the WHO classification. The sections were subjected to morphometric analysis to analyze all the morphometric parameters in different grades of OSCC and subjected to one-way ANOVA statistical analysis. CA and Cyt A decreased from normal mucosa with dedifferentiation of OSCC. The NA and NP increased in carcinoma group when compared to normal mucosa but decreased with dedifferentiation of OSCC (P < 0.05). NF had no significance with normal mucosa and different grades of OSCC (P > 0.05), while N/C ratio increased from normal mucosa through increasing grades of OSCC, reaching the highest value in poorly differentiated squamous cell carcinoma (P < 0.05). Both cellular and nuclear variables provide a more accurate indication of tumor aggressiveness than any single parameter. Morphometric analysis can be a reliable tool to determine objectively the degree of malignancy at the invasive tumor front.

Circulating Tumor DNA in Predicting Outcomes in Patients With Stage IV Head and Neck Cancer or Stage III-IV Non-small Cell Lung Cancer

ClinicalTrials.gov

2018-01-12

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Salivary Gland Squamous Cell Carcinoma; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Salivary Gland Cancer; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Salivary Gland Cancer; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Salivary Gland Cancer; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer; Untreated Metastatic Squamous Neck Cancer With Occult Primary

A Comparative Immunohistochemical Study of Anal Canal Epithelium in Humans and Swine, Focusing on the Anal Transitional Zone Epithelium and the Anal Glands.

PubMed

Muranaka, Futoshi; Nakajima, Tomoyuki; Iwaya, Mai; Ishii, Keiko; Higuchi, Kayoko; Ogiwara, Naoko; Miyagawa, Shinichi; Ota, Hiroyoshi

2018-05-01

To better understand the cellular origins and differentiation of anal canal epithelial neoplasms, the immunohistochemical profiles of the anal canal epithelium in humans and swine were evaluated. Formalin-fixed tissue sections were immunostained for mucin (MUC: MUC2, MUC5AC, MUC5B), desmoglein 3 (DGS3), p63, CDX2, SOX2, and α-smooth muscle actin (α-SMA). The anal transitional zone (ATZ) epithelium covered the anal sinus and consisted of a stratified epithelium with mucous cells interspersed within the surface lining. Anal glands opened into the anal sinus. Ducts and acini of intraepithelial or periepithelial mucous type were the main structures of human anal glands, whereas those of swine were compound tubuloacinar mixed glands. Distal to the ATZ epithelium, non-keratinized stratified squamous epithelium merged with the keratinized stratified squamous epithelium of the perianal skin. MUC5AC expression predominated over MUC5B expression in the ATZ epithelium, while MUC5B expression was higher in the anal glands. SOX2 was positive in the ATZ epithelium, anal glands, and squamous epithelium except in the perianal skin. In humans, DGS3 was expressed in the ATZ epithelium, anal gland ducts, and squamous epithelium. p63 was detected in the ATZ epithelium, anal glands, and squamous epithelium. Myoepithelial cells positive for α-SMA and p63 were present in the anal glands of swine. Colorectal columnar cells were MUC5B + /MUC2 + /CDX2 + /MUC5AC - /SOX2 - . The ATZ epithelium seems to be a distinctive epithelium, with morphological and functional features allowing smooth defecation. The MUC5AC + /SOX2 + /MUC2 - /CDX2 - profile of the ATZ epithelium and anal glands is a useful feature for diagnosing adenocarcinoma arising from these regions. Anat Rec, 301:796-805, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

SB-715992 in Treating Patients With Recurrent or Metastatic Head and Neck Cancer

ClinicalTrials.gov

2017-01-13

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Stage IVA Salivary Gland Cancer; Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Salivary Gland Cancer; Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Salivary Gland Cancer; Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity

Effects of overnight refrigeration on the microscopic evaluation of sputum.

PubMed Central

Penn, R L; Silberman, R

1984-01-01

Microscopic evaluation of sputum permits selection of specimens suitable for culture, assessment of likely pathogens, and the best interpretation of culture results. We prospectively evaluated 50 sputum specimens which were promptly submitted to our clinical laboratory; smears and cultures were performed both immediately and after 20 h of refrigeration. Specimens were grouped according to the numbers of squamous epithelial cells and neutrophils per low-power field present on coded Gram-stained smears. The numbers of bacteria in five oil immersion fields were used to characterize smears for predominant, mixed, or scanty forms. After refrigeration, only three specimens changed group from a definite loss of squamous epithelial cells, and only two changed group from a definite loss of neutrophils. Based on cellular composition, the majority of samples would have been processed identically both before and after refrigeration. In contrast, organism forms detected on smears and their relative quantities were dramatically altered after refrigeration. A predominant smear form was gained in 11 and lost in 8 refrigerated specimens. The frequent changes on smears observed overall resulted from both increases and decreases in numbers of bacteria and yeasts. The majority of sputum culture results were insignificantly affected by the refrigeration of specimens. We conclude that 20 h of refrigeration renders sputum useless for the microscopic evaluation of potential pathogens and the subsequent interpretation of culture results. However, overnight refrigeration does not affect the determination from smears of sputum suitability for culture based on cellular composition. PMID:6699145

Tumor suppressor Lzap regulates cell cycle progression, doming and zebrafish epiboly

PubMed Central

Liu, Dan; Wang, Wen-Der; Melville, David B.; Cha, Yong I.; Yin, Zhirong; Issaeva, Natalia; Knapik, Ela W.; Yarbrough, Wendell G.

2012-01-01

Initial stages of embryonic development rely on rapid, synchronized cell divisions of the fertilized egg followed by a set of morphogenetic movements collectively called epiboly and gastrulation. Lzap is a putative tumor suppressor whose expression is lost in 30% of head and neck squamous cell carcinomas. Lzap activities include regulation of cell cycle progression and response to therapeutic agents. Here we explore developmental roles of the lzap gene during zebrafish morphogenesis. Lzap is highly conserved among vertebrates and is maternally deposited. Expression is initially ubiquitous during gastrulation, and later becomes more prominent in the pharyngeal arches, digestive tract and brain. Antisense morpholino-mediated depletion of Lzap resulted in delayed cell divisions and apoptosis during blastomere formation, resulting in fewer, larger cells. Cell cycle analysis suggested that Lzap loss in early embryonic cells resulted in a G2/M arrest. Furthermore, the Lzap-deficient embryos failed to initiate epiboly – the earliest morphogenetic movement in animal development – which has been shown to be dependent on cell adhesion and migration of epithelial sheets. Our results strongly implicate Lzap in regulation of cell cycle progression, adhesion and migratory activity of epithelial cell sheets during early development. These functions provide further insight into Lzap activity that may contribute not only to development, but also to tumor formation. PMID:21523853

Commensal Bacteria Modulate Innate Immune Responses of Vaginal Epithelial Cell Multilayer Cultures

PubMed Central

Rose, William A.; McGowin, Chris L.; Spagnuolo, Rae Ann; Eaves-Pyles, Tonyia D.; Popov, Vsevolod L.; Pyles, Richard B.

2012-01-01

The human vaginal microbiome plays a critical but poorly defined role in reproductive health. Vaginal microbiome alterations are associated with increased susceptibility to sexually-transmitted infections (STI) possibly due to related changes in innate defense responses from epithelial cells. Study of the impact of commensal bacteria on the vaginal mucosal surface has been hindered by current vaginal epithelial cell (VEC) culture systems that lack an appropriate interface between the apical surface of stratified squamous epithelium and the air-filled vaginal lumen. Therefore we developed a reproducible multilayer VEC culture system with an apical (luminal) air-interface that supported colonization with selected commensal bacteria. Multilayer VEC developed tight-junctions and other hallmarks of the vaginal mucosa including predictable proinflammatory cytokine secretion following TLR stimulation. Colonization of multilayers by common vaginal commensals including Lactobacillus crispatus, L. jensenii, and L. rhamnosus led to intimate associations with the VEC exclusively on the apical surface. Vaginal commensals did not trigger cytokine secretion but Staphylococcus epidermidis, a skin commensal, was inflammatory. Lactobacilli reduced cytokine secretion in an isolate-specific fashion following TLR stimulation. This tempering of inflammation offers a potential explanation for increased susceptibility to STI in the absence of common commensals and has implications for testing of potential STI preventatives. PMID:22412914

Targeting c-Myc: JQ1 as a promising option for c-Myc-amplified esophageal squamous cell carcinoma.

PubMed

Wang, Jingyuan; Liu, Zhentao; Wang, Ziqi; Wang, Shubin; Chen, Zuhua; Li, Zhongwu; Zhang, Mengqi; Zou, Jianling; Dong, Bin; Gao, Jing; Shen, Lin

2018-04-10

c-Myc amplification-induced cell cycle dysregulation is a common cause for esophageal squamous cell carcinoma (ESCC), but no approved targeted drug is available so far. The bromodomain inhibitor JQ1, which targets c-Myc, exerts anti-tumor activity in multiple cancers. However, the role of JQ1 in ESCC remains unknown. In this study, we reported that JQ1 had potent anti-proliferative effects on ESCC cells in both time- and dose-dependent manners by inducing cell cycle arrest at G1 phase, cell apoptosis, and the mesenchymal-epithelial transition. Follow-up studies revealed that both c-Myc/cyclin/Rb and PI3K/AKT signaling pathways were inactivated by JQ1, as indicated by the downregulation of c-Myc, cyclin A/E, and phosphorylated Rb, AKT and S6. Tumor suppression induced by JQ1 in c-Myc amplified or highly expressed xenografts was higher than that in xenografts with low expression, suggesting its potential role in prediction. In conclusion, targeting c-Myc by JQ1 could cause significant tumor suppression in ESCC both in vitro and in vivo. Also, c-Myc amplification or high expression might serve as a potential biomarker and provide a promising therapeutic option for ESCC. Copyright © 2018 Elsevier B.V. All rights reserved.

Parenteral Nutrition for Patients Treated for Locally Advanced Inoperable Tumors of the Head and Neck

ClinicalTrials.gov

2018-03-28

Squamous Cell Carcinoma of the Hypopharynx Stage III; Squamous Cell Carcinoma of the Hypopharynx Stage IV; Laryngeal Squamous Cell Carcinoma Stage III; Laryngeal Squamous Cell Carcinoma Stage IV; Oropharyngeal Squamous Cell Carcinoma Stage III; Oropharyngeal Squamous Cell Carcinoma Stage IV; Squamous Cell Carcinoma of the Oral Cavity Stage III; Squamous Cell Carcinoma of the Oral Cavity Stage IV; Locally Advanced Malignant Neoplasm

Photodynamic Therapy With HPPH in Treating Patients With Squamous Cell Carcinoma of the Oral Cavity

ClinicalTrials.gov

2016-04-19

Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage I Squamous Cell Carcinoma of the Oropharynx; Stage I Verrucous Carcinoma of the Oral Cavity; Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage II Squamous Cell Carcinoma of the Oropharynx; Stage II Verrucous Carcinoma of the Oral Cavity; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Verrucous Carcinoma of the Oral Cavity

Different immunohistochemical and ultrastructural phenotypes of squamous differentiation in bladder cancer.

PubMed

Gaisa, Nadine T; Braunschweig, Till; Reimer, Nina; Bornemann, Jörg; Eltze, Elke; Siegert, Sabine; Toma, Marieta; Villa, Luigi; Hartmann, Arndt; Knuechel, Ruth

2011-03-01

Besides worse prognosis of bladder cancer with squamous differentiation (pure squamous cell carcinoma (SCC) or mixed urothelial carcinoma (UC/SCC)), high-grade non-keratinising squamous differentiation is difficult to identify in haematoxylin-eosin stainings. This study aims to validate routine immunohistochemical markers for squamous differentiation in a larger cohort of patients. Tissue microarrays of 89 pure SCCs and mixed UC/SCCs, 66 urothelial carcinomas (UC), precursor lesions and normal urothelium were stained for cytokeratin (CK) 5/6, CK 5/14, CK 7, CK 20 and uroplakin III. Electron microscopy was performed to confirm the differentiation. Pure SCCs displayed staining throughout the epithelium for CK 5/6 (76.6% (36/47)) and CK 5/14 (95.8% (46/48)), focal staining for CK 7 (28.9% (13/45)) and no staining for CK 20 and uroplakin III (both 0% (0/48)). UCs exhibited a basal or diffuse staining for CK 5/6 (30.2% (16/53)) and CK 5/14 (57.1% (32/56)), focal positivity for CK 7 (83.6% (46/55)), CK 20 (50.9% (29/57)) and uroplakin III (21.8% (12/55)). Each marker discriminated SCC and UC significantly (p < 0.01). A third subgroup rarely showed full epithelial staining for CK 5/6 (14.3% (1/7)) and CK 5/14 (28.6% (2/7)), focal staining for CK 7 (85.7% (6/7)) and no staining for CK 20 and uroplakin III (both 0% (0/7)). Electron microscopy could prove both, SCC and UC characteristics, revealing a transient type. A staining pattern with CK 5/6- and CK 5/14-positivity plus CK 20- and uroplakin III-negativity identified squamous differentiation in bladder tumours and revealed a third type of squamous transdifferentiation.

Radiation Therapy With Cisplatin, Docetaxel, or Cetuximab After Surgery in Treating Patients With Stage III-IV Squamous Cell Head and Neck Cancer

ClinicalTrials.gov

2017-05-18

Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Tongue Cancer

Acquisition cancer stemness, mesenchymal transdifferentiation, and chemoresistance properties by chronic exposure of oral epithelial cells to arecoline.

PubMed

Wang, Tung Yuan; Peng, Chih-Yu; Lee, Shiuan-Shinn; Chou, Ming-Yung; Yu, Cheng-Chia; Chang, Yu-Chao

2016-12-20

Oral squamous cell carcinoma (OSCC), one of the most deadliest malignancies in the world, is caused primarily by areca nut chewing in Southeast Asia. The mechanisms by which areca nut participates in OSCC tumorigenesis are not well understood. In this study, we investigated the effects of low dose long-term arecoline (10 μg/mL, 90-days), a major areca nut alkaloid, on enhancement cancer stemness of human oral epithelial (OE) cells. OE cells with chronic arecoline exposure resulted in increased ALDH1 population, CD44 positivity, stemness-related transcription factors (Oct4, Nanog, and Sox2), epithelial-mesenchymal transdifferentiation (EMT) traits, chemoresistance, migration/invasiveness/anchorage independent growth and in vivo tumor growth as compared to their untreated controls. Mechanistically, ectopic miR-145 over-expression in chronic arecoline-exposed OE (AOE) cells inhibited the cancer stemness and xenografic. In AOE cells, luciferase reporter assays further revealed that miR-145 directly targets the 3' UTR regions of Oct4 and Sox2 and overexpression of Sox2/Oct4 effectively reversed miR-145-regulated cancer stemness-associated phenomenas. Additionally, clinical results further revealed that Sox2 and Oct4 expression was inversely correlated with miR-145 in the tissues of areca quid chewing-associated OSCC patients. This study hence attempts to provide novel insight into areca nut-induced oral carcinogenesis and new intervention for the treatment of OSCC patients, especially in areca nut users.

Lenalidomide and Cetuximab in Treating Patients With Advanced Colorectal Cancer or Head and Neck Cancer

ClinicalTrials.gov

2018-05-23

Recurrent Colon Carcinoma; Recurrent Hypopharyngeal Squamous Cell Carcinoma; Recurrent Laryngeal Squamous Cell Carcinoma; Recurrent Laryngeal Verrucous Carcinoma; Recurrent Lip and Oral Cavity Squamous Cell Carcinoma; Recurrent Metastatic Squamous Cell Carcinoma in the Neck With Occult Primary; Recurrent Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Recurrent Nasopharyngeal Keratinizing Squamous Cell Carcinoma; Recurrent Oral Cavity Verrucous Carcinoma; Recurrent Oropharyngeal Squamous Cell Carcinoma; Recurrent Rectal Carcinoma; Recurrent Salivary Gland Carcinoma; Salivary Gland Squamous Cell Carcinoma; Squamous Cell Carcinoma Metastatic in the Neck With Occult Primary; Stage IV Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage IV Nasopharyngeal Keratinizing Squamous Cell Carcinoma AJCC v7; Stage IVA Colon Cancer AJCC v7; Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Laryngeal Verrucous Carcinoma AJCC v7; Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVA Major Salivary Gland Cancer AJCC v7; Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVA Oral Cavity Cancer AJCC v6 and v7; Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Rectal Cancer AJCC v7; Stage IVB Colon Cancer AJCC v7; Stage IVB Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Laryngeal Verrucous Carcinoma AJCC v7; Stage IVB Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVB Major Salivary Gland Cancer AJCC v7; Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVB Oral Cavity Cancer AJCC v6 and v7; Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Rectal Cancer AJCC v7; Stage IVC Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVC Laryngeal Verrucous Carcinoma AJCC v7; Stage IVC Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVC Major Salivary Gland Cancer AJCC v7; Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVC Oral Cavity Cancer AJCC v6 and v7; Stage IVC Oropharyngeal Squamous Cell Carcinoma AJCC v7; Tongue Carcinoma; Untreated Metastatic Squamous Cell Carcinoma to Neck With Occult Primary

Fosaprepitant Dimeglumine, Palonosetron Hydrochloride, and Dexamethasone in Preventing Nausea and Vomiting Caused by Cisplatin in Patients With Stage III or Stage IV Head and Neck Cancer Undergoing Chemotherapy and Radiation Therapy

ClinicalTrials.gov

2017-04-13

Nausea and Vomiting; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx

Induction Chemotherapy With TP+5-FU or TP+Cetuximab Followed by Radioimmuptherapy for Locally Advanced or Not Resectable SCCHNN

ClinicalTrials.gov

2017-06-26

Squamous Cell Carcinoma of the Hypopharynx Stage III; Squamous Cell Carcinoma of the Hypopharynx Stage IV; Squamous Cell Carcinoma of the Larynx Stage III; Squamous Cell Carcinoma of the Larynx Stage IV; Squamous Cell Carcinoma of the Oropharynx Stage III; Squamous Cell Carcinoma of the Oropharynx Stage IV; Squamous Cell Carcinoma of the Oral Cavity Stage III; Squamous Cell Carcinoma of the Oral Cavity Stage IV

Ipilimumab, Cetuximab, and Intensity-Modulated Radiation Therapy in Treating Patients With Previously Untreated Stage III-IVB Head and Neck Cancer

ClinicalTrials.gov

2018-05-23

Stage III Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage III Laryngeal Squamous Cell Carcinoma AJCC v6 and v7; Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7

Associations of P16INK4a promoter hypermethylation with squamous intra-epithelial lesion, cervical cancer and their clinicopathological features: a meta-analysis

PubMed Central

Cui, Ning-hua; Zhang, Shuai; Wang, Chen; Zheng, Fang

2017-01-01

To assess the associations of P16INK4a methylation status with low-grade squamous intra-epithelial lesion (LSIL), high-grade squamous intra-epithelial lesion (HSIL), cervical cancer (CC) and their clinicopathological features, a meta-analysis with 29 eligible studies was conducted. Pooled odds ratios (ORs) with their 95% confidence intervals (CIs) were estimated to assess the strength of the associations. Heterogeneity, sensitivity of pooled results and publication bias were also evaluated. Overall, there was an increasing trend of P16INK4a hypermethylation rates among LSIL (21.4%), HSIL (30.9%) and CC (35.0%) specimens. P16INK4a hypermethylation was significantly associated with the increased risk of LSIL, HSIL and CC, with the pooled ORs of 3.26 (95% CI: 1.86-5.71), 5.80 (95% CI: 3.80-8.84) and 12.17 (95% CI: 5.86-25.27), respectively. A significant association was also found between P16INK4a hypermethylation and smoking habit (OR = 3.88, 95% CI: 2.13-7.08). Taken together, meta-analysis results support P16INK4a hypermethylation as an epigenetic marker for the progression of cervical carcinogenesis. PMID:27669738

Summer Research Paper

NASA Technical Reports Server (NTRS)

Patel, Zarana

2011-01-01

Certain populations such as chemotherapy patients and atomic bomb survivors have been exposed to ionizing radiation and experience tissue damage and cancer initiation and progression. One cancer that can be initiated from radiation is esophageal squamous cell carcinoma (ESCC), an epithelial cancer that has a survival rate as low as 20%. Researchers have found that when protein tyrosine kinase receptors (RPTK) activate oncogenes, they can create epithelial tumors and cause deadly cancers like ESCC. The RPTK family has one group, MET, that has only two receptors, MET and RON, present in the human body. MET s ligand is the hepatocyte growth factor (HGF) and RON's ligand is the macrophage-stimulating protein (MSP-1). Both HGF and MSP-1 have been shown to activate their receptors and are implicated in certain processes. Since radiation damages cells throughout the biological system, researchers are investigating whether or not HGF and MSP-1 protects or kills certain normal and cancerous cells by being part of cell recovery processes. One research group recently reviewed that the HGF-MET pathway has an important role in the embryonic development in the liver, migration of myogenic precursor cells, regulation of epithelial morphogenesis and growth, and regeneration and protection in tissues. In addition, since the RON receptor is more commonly expressed in cells of epithelial origin, and when activated is part of epithelial cell matrix invasion, dissociation, and migration processes, scientists conclude that RON might be one of the factors causing epithelial cancer initiation in the biological system. In order to examine HGF and MSP-1 s effect on cancer initiation and progression we used two immortalized esophageal epithelial cell lines. One is a normal human cell line (EPC2-hTERT), while the other had a p53 mutation at the 175th amino acid position (EPC2-hTERT-p53(sup R175H)). For this investigation, we used 0(control), 2, and 4 Gray doses of gamma (Cs137) radiation and selected various concentrations from 0-100 ng/mL of HGF and MSP-1 in our assays. Since the HGF and MSP-1 pathways have proliferative roles in epithelial cells, we conducted the MTT proliferation assay to see if either drug enhances or inhibits cell proliferation over time. Also, a MTT cytotoxicity assay was necessary to observe whether the drugs are protecting the cells from radiation and if a trend is occurring depending upon the amount of dose added. In addition, a wound healing assay was done since both drugs have been to known to promote cell motility. Since cell damage occurs when radiation is added, apoptosis and micronuclei assays are vital to see if HGF and MSP-1 increase or decrease cell death and damage in normal and pre-cancerous cells and by how much based on the radiation dosage. Overall, we used the MTT, wound healing, apoptosis and micronuclei assays to investigate the effects ofHGF and MSP-1 on irradiated esophageal epithelial cells.

Prevalence of abnormal Pap smears in a consecutive and previously unscreened population in Romania.

PubMed

Stolnicu, Simona; Musca, Simona; Micu, Dorian; Micu, Luminita; Moldovan, Cosmin; Puscasiu, Lucian

2014-02-01

To determine the prevalence of abnormal cervical smears in a previously unscreened and asymptomatic population in Romania and to compare the data with those from other countries in Europe. In a retrospective study, data were reviewed from smears obtained from women in Romania who had been referred to the gynecologist between January 2006 and December 2011. The smears were collected through 3 regional opportunistic programs of cervical screening and were classified according to the Bethesda system. During the study period, 50536 smear tests were carried out. Of these, 100 smears (0.2%) were unsatisfactory and excluded from the study. Among the remaining 50436 smears, 2965 patients (5.9%) had abnormal epithelial changes. Most of the abnormal smears were represented by atypical squamous cells of undetermined significance (2.6% of all smears). The data confirmed that there is a high prevalence of high-grade intraepithelial squamous-type lesions (0.9% of all smears) in Romania, and of abnormal smears in women younger than 25years of age (14.0% of all abnormal smears). The data show that there is a high prevalence of epithelial abnormalities among cervical smears in Romania compared with other European countries that run a national screening program. © 2013.

Craniopharyngioma

PubMed Central

Garnett, Matthew R; Puget, Stéphanie; Grill, Jacques; Sainte-Rose, Christian

2007-01-01

Craniopharyngiomas are benign slow growing tumours that are located within the sellar and para sellar region of the central nervous system. The point prevalence of this tumour is approximately 2/100,000. The onset of symptoms is normally insidious with most patients at diagnosis having neurological (headaches, visual disturbances) and endocrine (growth retardation, delayed puberty) dysfunctions. Craniopharyngiomas are thought to arise from epithelial remnants of the craniopharyngeal duct or Rathke's pouch (adamantinomatous type) or from metaplasia of squamous epithelial cell rests that are remnants of the part of the stomadeum that contributed to the buccal mucosa (squamous papillary type). The neuroradiological diagnosis is mainly based on the three components of the tumour (cystic, solid and calcified) in the characteristic sellar/para sellar location. Definitive diagnosis is made following histological examination of a surgical specimen. The differential diagnosis includes other tumours in this region (pituitary adenoma), infectious or inflammatory processes (eosinophilic granuloma), vascular malformations (aneurysm) and congenital anomalies (Rathke's cleft cyst). The current treatment is gross total excision of the tumour, if there is no hypothalamic invasion or, in the presence of hypothalamic invasion, a sub-total resection with post-operative radiotherapy. Endocrine disturbances are normally permanent and need careful replacement. Overall, there is an 80% 5 year survival, though this can be associated with marked morbidity (hypothalamic dysfunction, altered neuropsychological profile). PMID:17425791

Immunohistochemical study on the expression of matrix metalloproteinase 2 and high-risk human papilloma virus in the malignant progression of papillomas

PubMed Central

Lee, Ho-Jin

2013-01-01

Objectives Papilloma frequently develops as a benign tumor of the head and neck area, but its potential for malignant transformation has yet to be studied. This study aims to provide basic information for papillomas using the immunohistochemical staining of matrix metalloproteinase 2 (MMP-2) and human papilloma virus (HPV) 16 and 18. Materials and Methods To evaluate the malignant transformation of papillomas, the selected tissue samples were serially diagnosed with pre-cancerous papilloma (with epithelial dysplasia, pseudo-epitheliomatous hyperplasia) or malignant lesion (squamous cell carcinoma, SCC) after the first diagnosis (squamous papilloma, inverted papilloma). The selected tissues were stained with an antibody to MMP-2 and HPV 16-E7, HPV 18-L1. A statistical analysis was performed according to each transformation step. Results The epithelial layer of papilloma and pre-cancerous papilloma lesions had a similar MMP-2 expression, but that of the malignant lesion had a significantly increased MMP-2 expression. HPV 16 and 18 infection rates were 28.6%, 33.3% and 63.6% in papillomas, pre-cancerous papilloma lesions, and SCC. Conclusions A relatively high MMP-2 expression and HPV 16 or 18 infection of papillomas may be associated with early events in the multistep processes of malignant transformation of papillomas. PMID:24471049

Bupropion Hydrochloride or Patient's Choice for Smoking Cessation in Patients With Squamous Cell Head and Neck Cancer Undergoing Radiation Therapy With or Without Chemotherapy

ClinicalTrials.gov

2017-12-20

Current Smoker; Head and Neck Squamous Cell Carcinoma; Hypopharyngeal Squamous Cell Carcinoma; Laryngeal Squamous Cell Carcinoma; Nasopharyngeal Carcinoma; Oral Cavity Squamous Cell Carcinoma; Oropharyngeal Squamous Cell Carcinoma

Gefitinib and Radiation Therapy With or Without Cisplatin in Treating Patients With Stage III or Stage IV Head and Neck Cancer

ClinicalTrials.gov

2013-01-24

Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Oropharynx

Differential cytotoxicity of long-chain bases for human oral gingival epithelial keratinocytes, oral fibroblasts, and dendritic cells.

PubMed

Mehalick, Leslie A; Poulsen, Christopher; Fischer, Carol L; Lanzel, Emily A; Bates, Amber M; Walters, Katherine S; Cavanaugh, Joseph E; Guthmiller, Janet M; Johnson, Georgia K; Wertz, Philip W; Brogden, Kim A

2015-12-01

Long-chain bases, found in the oral cavity, have potent antimicrobial activity against oral pathogens. In an article associated with this dataset, Poulson and colleagues determined the cytotoxicities of long-chain bases (sphingosine, dihydrosphingosine, and phytosphingosine) for human oral gingival epithelial (GE) keratinocytes, oral gingival fibroblasts (GF), dendritic cells (DC), and squamous cell carcinoma (SCC) cell lines [1]. Poulson and colleagues found that GE keratinocytes were more resistant to long-chain bases as compared to GF, DC, and SCC cell lines [1]. In this study, we assess the susceptibility of DC to lower concentrations of long chain bases. 0.2-10.0 µM long-chain bases and GML were not cytotoxic to DC; 40.0-80.0 µM long-chain bases, but not GML, were cytotoxic for DC; and 80.0 µM long-chain bases were cytotoxic to DC and induced cellular damage and death in less than 20 mins. Overall, the LD50 of long-chain bases for GE keratinocytes, GF, and DC were considerably higher than their minimal inhibitory concentrations for oral pathogens, a finding important to pursuing their future potential in treating periodontal and oral infections.

Combined detection of Twist1, Snail1 and squamous cell carcinoma antigen for the prognostic evaluation of invasion and metastasis in cervical squamous cell carcinoma.

PubMed

Yang, Huilun; Hu, Haiyang; Gou, Yanling; Hu, Yuhong; Li, Hui; Zhao, Hongwei; Wang, Beidi; Li, Peiling; Zhang, Zongfeng

2018-04-01

Cervical cancer is one of the most common malignant tumours of the female reproductive system, ranking second only to breast cancer in morbidity worldwide. Essential features of the progression of cervical cancer are invasion and metastasis, which are closely related to disease prognosis and mortality rate. At the present time there is no effective method to evaluate cancer invasion and metastasis before surgery. Here we report our study on molecular changes in biopsy tissue for the prognostic evaluation of cancer invasion and metastasis. Expression of the epithelial-mesenchymal transition-inducing transcription factors Twist1 and Snail1 was detected by immunohistochemistry in 32 normal, 36 low-grade squamous intraepithelial neoplasia (LSIL), 54 high-grade squamous intraepithelial neoplasia (HSIL) and 320 cervical squamous cell carcinoma (CSCC) samples. The correlation between the expression of Twist1, Snail1 and squamous cell carcinoma antigen (SCCA) in CSCC tissues and clinical pathology results was evaluated. A transwell migration and invasion assay was used to explore the roles of Twist1 and Snail1 in the invasion of cancer cells. Lymph node metastasis and lymphovascular space invasion (LVSI) rates for the following groups were analysed: SCCA(+) group, Twist1(+) group, Snail1(+) group, Twist1(+)Snail1(+)group, Twist1(+)SCCA(+)group, Snail1(+)SCCA(+)group and Twist1(+)Snail1(+)SCCA(+) group. The expression of Twist1 and Snail1 was significantly upregulated in HSIL and CSCC (p < 0.05). Twist1 and Snail1 expression levels were associated with LVSI, lymph node metastasis and histological grade (p < 0.05) but not with age or FIGO stage (p > 0.05). The expression of SCCA was associated with LVSI, lymph node metastasis, FIGO stage and histological grade (p < 0.05) but not with age (p > 0.05). Twist1 was an independent factor contributing to the invasion ability of cervical cancer cells. In addition, the positive rate of lymph node metastasis and LVSI was higher in the Twist1(+)Snail1(+)SCCA(+) group than in the SCCA(+) group, Twist1(+) group and Snail1(+) group, respectively (p < 0.05). Combined detection of Twist1 and Snail1 in SCCA-positive biopsy specimens may be a potential method for evaluating the invasion and metastasis of CSCC prior to surgery.

Characterization of the Influence of Semen-Derived Enhancer of Virus Infection on the Interaction of HIV-1 with Female Reproductive Tract Tissues

PubMed Central

Allen, Shannon A.; Carias, Ann M.; Anderson, Meegan R.; Okocha, Eneniziaogochukwu A.; Benning, Lorie; McRaven, Michael D.; Kelley, Z L.; Lurain, John; Veazey, Ronald S.

2015-01-01

ABSTRACT The majority of human immunodeficiency virus type 1 (HIV-1) transmission events occur in women when semen harboring infectious virus is deposited onto the mucosal barriers of the vaginal, ectocervical, and endocervical epithelia. Seminal factors such as semen-derived enhancer of virus infection (SEVI) fibrils were previously shown to greatly enhance the infectivity of HIV-1 in cell culture systems. However, when SEVI is intravaginally applied to living animals, there is no effect on vaginal transmission. To define how SEVI might function in the context of sexual transmission, we applied HIV-1 and SEVI to intact human and rhesus macaque reproductive tract tissues to determine how it influences virus interactions with these barriers. We show that SEVI binds HIV-1 and sequesters most virions to the luminal surface of the stratified squamous epithelium, significantly reducing the number of virions that penetrated the tissue. In the simple columnar epithelium, SEVI was no longer fibrillar in structure and was detached from virions but allowed significantly deeper epithelial virus penetration. These observations reveal that the action of SEVI in intact tissues is very different in the anatomical context of sexual transmission and begin to explain the lack of stimulation of infection observed in the highly relevant mucosal transmission model. IMPORTANCE The most common mode of HIV-1 transmission in women occurs via genital exposure to the semen of HIV-infected men. A productive infection requires the virus to penetrate female reproductive tract epithelial barriers to infect underlying target cells. Certain factors identified within semen, termed semen-derived enhancers of virus infection (SEVI), have been shown to significantly enhance HIV-1 infectivity in cell culture. However, when applied to the genital tracts of living female macaques, SEVI did not enhance virus transmission. Here we show that SEVI functions very differently in the context of intact mucosal tissues. SEVI decreases HIV-1 penetration of squamous epithelial barriers in humans and macaques. At the mucus-coated columnar epithelial barrier, the HIV-1/SEVI interaction is disrupted. These observations suggest that SEVI may not play a significant stimulatory role in the efficiency of male-to-female sexual transmission of HIV. PMID:25740984

[S100A7 promotes the metastasis and epithelial-mesenchymal transition on HeLa and CaSki cells].

PubMed

Tian, T; Hua, Z; Wang, L Z; Wang, X Y; Chen, H Y; Liu, Z H; Cui, Z M

2018-02-25

Objective: To elucidate the impact of over-expression of S100A7 on migration, invasion, proliferation, cell cycle, and epithelial-mesenchymal transition (EMT) in human cervical cancer HeLa and CaSki cells. Methods: (1) Immunohistochemistry of SP was used to examine the expression of S100A7 in 40 cases of squamous cervical cancer tissues and 20 cases of normal cervical tissues. (2) The vectors of pLVX-IRES-Neo-S100A7 and pLVX-IRES-Neo were used to transfect human cervical cancer HeLa and CaSki cells, and the positive clones were screened and identified. Next, transwell migration assay, cell counting kit-8 (CCK-8) assay and fluorescence activating cell sorter (FACS) were used to detect the effect of S100A7-overexpression on the migration, invasion, proliferation and cell cycle of cervical cancer cells. Furthermore, western blot was performed to observe the expression of epithelial marker (E-cadherin) and mesenchymal markers (N-cadherin, vimentin, and fibronectin) of EMT. Results: (1) S100A7 expression was significantly higher in cervical squamous cancer tissues (median 91.6) than that in normal cervical tissues (median 52.1; Z=- 2.948, P= 0.003) . (2) Stable S100A7-overexpressed cells were established using lentiviral-mediated gene delivery in HeLa and CaSki cells. S100A7 was detected by real-time quantitative reverse transcription PCR, S100A7 mRNA of S100A7-overexpressed cells were 119±3 and 177±16, increased significantly compared with control groups of median ( P< 0.01) . Compared with the control cells, the number of S100A7-overexpressed HeLa and CaSki cells that passed the transwell membrane assay were increased significanatly (572±51 vs 337±25, P< 0.01; 100±8 vs 41±4, P< 0.01) .Matrigel invasion assay showed that the number of S100A7-overexpressed HeLa and CaSki cells that passed the transwell membrane were respectively 441±15 and 110±14, elevated significantly compared with control cells (156±21 and 59±7; P< 0.05) . However, S100A7 overexpression didn't influence the proliferation and cell cycle progression of HeLa and CaSki cells ( P> 0.05) . Expression of E-cadherin was dramatically decreased, while N-cadherin, vimentin, and fibronectin increased in S100A7-overexpressed cells. Conclusion: S100A7 enhances the migration, invasion and EMT of HeLa cells and CaSki cells, and may be plays an important role in the development of cervical cancer.

Clinicopahological features of superficial basaloid squamous cell carcinoma of the esophagus.

PubMed

Oguma, J; Ozawa, S; Kazuno, A; Nitta, M; Ninomiya, Y; Tomita, S

2017-12-01

Basaloid squamous cell carcinoma (BSC) of the esophagus is classified as an epithelial malignant tumor and is a rare variant of squamous cell carcinoma (SCC). Most previous reports have suggested that advanced BSC has a poorer prognosis than typical SCC because of its high biological malignancy, but the biological activity of superficial BSC remains unclear. Twenty cases of superficial BSC, which underwent surgical resection in Tokai University Hospital between January 2004 and December 2013, were analyzed retrospectively. Among these cases, 19 cases with a T1 depth of invasion (BSC group) were compared with 180 cases of SCC that were resected during the same period and were pathologically diagnosed as T1 (SCC group). The frequency of lymph node metastasis in the T1 BSC group was significantly lower (2 patients, 11%) than that in the SCC group (84 patients, 47%) (P = 0.005). The frequency of lymphatic invasion in the BSC group was also lower (9 patients, 47%) than that in the SCC group (131 patients, 73%) (P = 0.021). The pathological type of the metastatic lymph node was BSC in all the superficial BSC cases with lymph node metastasis. This study demonstrated that lymph node metastasis was less likely to occur in cases with superficial BSC than in cases with superficial SCC. © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Erlotinib Hydrochloride and Radiation Therapy in Stage III-IV Squamous Cell Cancer of the Head and Neck

ClinicalTrials.gov

2012-10-30

Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity

Down regulation of E-Cadherin (ECAD) - a predictor for occult metastatic disease in sentinel node biopsy of early squamous cell carcinomas of the oral cavity and oropharynx

PubMed Central

2011-01-01

Background Prognostic factors in predicting occult lymph node metastasis in patients with head and neck squamous-cell carcinoma (HNSCC) are necessary to improve the results of the sentinel lymph node procedure in this tumour type. The E-Cadherin glycoprotein is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections. Objectives To determine the value of the molecular marker E-Cadherin in predicting regional metastatic disease. Methods E-Cadherin expression in tumour tissue of 120 patients with HNSCC of the oral cavity and oropharynx were evaluated using the tissue microarray technique. 110 tumours were located in the oral cavity (91.7%; mostly tongue), 10 tumours in the oropharynx (8.3%). Intensity of E-Cadherin expression was quantified by the Intensity Reactivity Score (IRS). These results were correlated with the lymph node status of biopsied sentinel lymph nodes. Univariate and multivariate analysis was used to determine statistical significance. Results pT-stage, gender, tumour side and location did not correlate with lymph node metastasis. Differentiation grade (p = 0.018) and down regulation of E-Cadherin expression significantly correlate with positive lymph node status (p = 0.005) in univariate and multivariate analysis. Conclusion These data suggest that loss of E-cadherin expression is associated with increased lymhogeneous metastasis of HNSCC. E-cadherin immunohistochemistry may be used as a predictor for lymph node metastasis in squamous cell carcinoma of the oral cavity and oropharynx. Level of evidence: 2b PMID:21639893

Immunohistochemical Study of Laminin-332 γ2 Chain and MMP-9 in High Risk of Malignant Transformation Oral Lesions and OSCC.

PubMed

Silva, Eline Manhães Reid; Freitas, Vanessa Morais; Bautz, Willian Grassi; de Barros, Liliana Aparecida Pimenta; da Gama de Souza, Letícia Nogueira

2018-01-01

Oral squamous cell carcinoma is associated with alterations in basement membrane. Laminin-332 is present in basal lamina and performs multiple biologic effects by γ2 chain. Matrix metalloproteinase acts disrupting extracellular components and was related to poor prognosis in cancer. Here, molecular profile of laminin-332 γ2 chain and matrix metalloproteinase-9 was assessed in oral lesions. The expression of laminin-332 γ2 chain and matrix metalloproteinase-9 (MMP-9) was examined by immunohistochemistry in 10 patients with high risk of malignant transformation oral lesions and 26 cases of oral squamous cell carcinoma (OSCC). Associations between microscopic and clinicopathologic features were established. Immunostaining of laminin-332 γ2 chain in high risk oral lesions was most detected in basement membrane which is continuous, while the majority of OSCC cases showed a discontinuous membrane (P = 0.001). It was observed a positive reaction for γ2 chain in invasive fronts and a higher expression in epithelial compartment of smoking patients with OSCC (P < 0.0001). In epithelium, MMP-9 expression was presented in all layers with no difference between lesions. However, an elevated immunostaining in stromal cells was associated with male patients (P = 0.0054), older than 60 years (P = 0.0101) and with OSCC. Present study results support the hypothesis of changes in molecules expression in high risk oral lesions and oral squamous cell carcinoma. A relation between clinical and molecule profile was observed. Those molecules may represent a useful tool to predict oral cancer behaviour.

Histopathology of malignant salivary gland tumours.

PubMed

Seifert, G

1992-07-01

This report is based upon the Salivary Gland Register in Hamburg and on the second revised edition of the WHO Histological Typing of Salivary Gland Tumours. The group of malignant salivary gland tumours contains carcinomas, malignant non-epithelial tumours, malignant lymphomas and secondary tumours. The various carcinomas are classified in a continuous separate listing because the different types are distinguished not only by histopathology, but also by differences in prognosis and treatment. The term "tumour" is replaced by "carcinoma" in two entities: acinic cell carcinoma and mucoepidermoid carcinoma. New entities are: polymorphous low-grade adenocarcinoma, basal cell adenocarcinoma, salivary duct carcinoma and malignant myoepithelioma. Carcinoma in pleomorphic adenoma can be distinguished as non-invasive and invasive carcinoma, and carcinosarcoma. Malignant non-epithelial tumours are mostly malignant fibrous histiocytoma, malignant schwannoma and rhabdomyosarcoma. The large majority of malignant lymphomas are non-Hodgkin-lymphomas with high differentiation. Many lymphomas are associated with chronic immunosialadenitis (Sjögren's syndrome). Secondary tumours are mostly metastases from primary squamous cell carcinomas or from melanomas of the skin (head and neck area). Haematogeneous metastases are very rare (mainly from lung, kidney or breast).

Cetuximab and Radiation Therapy in Treating Patients With Stage III-IV Head and Neck Cancer

ClinicalTrials.gov

2017-11-15

Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Verrucous Carcinoma of the Larynx; Tongue Cancer

Paclitaxel and Carboplatin Before Radiation Therapy With Paclitaxel in Treating HPV-Positive Patients With Stage III-IV Oropharynx, Hypopharynx, or Larynx Cancer

ClinicalTrials.gov

2017-04-19

Human Papilloma Virus Infection; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Verrucous Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Verrucous Carcinoma of the Larynx

Phase I Study of IMRT and Molecular-Image Guided Adaptive Radiation Therapy for Advanced HNSCC

ClinicalTrials.gov

2016-10-27

Salivary Gland Squamous Cell Carcinoma; Stage II Salivary Gland Cancer; Stage II Squamous Cell Carcinoma of the Hypopharynx; Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage II Squamous Cell Carcinoma of the Oropharynx; Stage II Verrucous Carcinoma of the Oral Cavity; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Verrucous Carcinoma of the Oral Cavity

Transoral Robotic Surgery in Treating Patients With Benign or Stage I-IV Head and Neck Cancer

ClinicalTrials.gov

2014-11-07

Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage I Adenoid Cystic Carcinoma of the Oral Cavity; Stage I Lymphoepithelioma of the Nasopharynx; Stage I Lymphoepithelioma of the Oropharynx; Stage I Mucoepidermoid Carcinoma of the Oral Cavity; Stage I Squamous Cell Carcinoma of the Hypopharynx; Stage I Squamous Cell Carcinoma of the Larynx; Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage I Squamous Cell Carcinoma of the Nasopharynx; Stage I Squamous Cell Carcinoma of the Oropharynx; Stage I Verrucous Carcinoma of the Larynx; Stage I Verrucous Carcinoma of the Oral Cavity; Stage II Adenoid Cystic Carcinoma of the Oral Cavity; Stage II Lymphoepithelioma of the Nasopharynx; Stage II Lymphoepithelioma of the Oropharynx; Stage II Mucoepidermoid Carcinoma of the Oral Cavity; Stage II Squamous Cell Carcinoma of the Hypopharynx; Stage II Squamous Cell Carcinoma of the Larynx; Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage II Squamous Cell Carcinoma of the Nasopharynx; Stage II Squamous Cell Carcinoma of the Oropharynx; Stage II Verrucous Carcinoma of the Larynx; Stage II Verrucous Carcinoma of the Oral Cavity; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Lymphoepithelioma of the Nasopharynx; Stage III Lymphoepithelioma of the Oropharynx; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity

Fractionated Ionizing Radiation Promotes Epithelial-Mesenchymal Transition in Human Esophageal Cancer Cells through PTEN Deficiency-Mediated Akt Activation.

PubMed

He, Enhui; Pan, Fei; Li, Guangchao; Li, Jingjing

2015-01-01

In some esophageal cancer patients, radiotherapy may not prevent distant metastasis thus resulting in poor survival. The underlying mechanism of metastasis in these patients is not well established. In this study, we have demonstrated that ionizing radiation may induce epithelial-mesenchymal transition (EMT) accompanied with increased cell migration and invasion, through downregulation of phosphatase and tensin homolog (PTEN), and activation of Akt/GSK-3β/Snail signaling. We developed a radioresistant (RR) esophageal squamous cancer cell line, KYSE-150/RR, by fractionated ionizing radiation (IR) treatment, and confirmed its radioresistance using a clonogenic survival assay. We found that the KYSE-150/RR cell line displayed typical morphological and molecular characteristics of EMT. In comparison to the parental cells, KYSE-150/RR cells showed an increase in post-IR colony survival, migration, and invasiveness. Furthermore, a decrease in PTEN in KYSE-150/RR cells was observed. We postulated that over-expression of PTEN may induce mesenchymal-epithelial transition in KYSE-150/RR cells and restore IR-induced increase of cell migration. Mechanistically, fractionated IR inhibits expression of PTEN, which leads to activation of Akt/GSK-3β signaling and is associated with the elevated levels of Snail protein, a transcription factor involved in EMT. Correspondingly, treatment with LY294002, a phosphatidylinositol-3-kinase inhibitor, mimicked PTEN overexpression effect in KYSE-150/RR cells, further suggesting a role for the Akt/GSK-3β/Snail signaling in effects mediated through PTEN. Together, these results strongly suggest that fractionated IR-mediated EMT in KYSE-150/RR cells is through PTEN-dependent pathways, highlighting a direct proinvasive effect of radiation treatment on tumor cells.

Immunohistochemical study of integrin α₅β₁, fibronectin, and Bcl-2 in normal oral mucosa, inflammatory fibroepithelial hyperplasia, oral epithelial dysplasia, and oral squamous cell carcinoma.

PubMed

Núñez, Manuel Antonio Gordón; de Matos, Felipe Rodrigues; Freitas, Roseana de Almeida; Galvão, Hébel Cavalcanti

2013-07-01

The objective of this study was to compare the immunoexpression of integrin α₅β₁, fibronectin, and the Bcl-2 protein in normal oral mucosa (NOM), inflammatory fibroepithelial hyperplasia (IFH), oral epithelial dysplasia (OED), and oral squamous cell carcinoma (OSCC). Eleven cases of NOM, 16 IFH, 20 OED, and 27 OSCC were selected for analysis of the immunoexpression of integrin α₅β₁, fibronectin, and bcl-2 protein. There was an association between the intensity and location of the integrin α₅β₁ expression, especially in the OSCC, that 48.1% of cases showed weak immunoreactivity and 40.7% in the suprabasal layer (P < 0.05). There was an association between the pattern and distribution of fibronectin expression in basement membrane, where 90% of NOM showed a pattern of linear continuous and 80% of OED exhibited focal distribution (P < 0.05). The fibronectin expression in connective tissue was predominantly intense with an association of staining pattern among the different specimens, where 37% of OSCC showed a reticular pattern (P < 0.05). There was an association of bcl-2 protein among the types of specimens, especially in IFH and OSCC, where 100% of the cases exhibited scores 1 of staining (P < 0.05). Within this context, the interaction of integrin α₅β₁ with its main ligand in the extracellular matrix, fibronectin, is suggested to influence the survival of tumor cells and to favor their proliferation by modulating apoptosis through the upregulation of antiapoptotic proteins or the suppression of apoptotic mediators.

A rare case of anal carcinosarcoma with human papilloma virus infection in both biphasic tumor elements: An immunohistochemical, molecular and ultrastructural study.

PubMed

Hickman, Richard A; Bradshaw, Azore-Dee; Cassai, Nicholas; Neto, Antonio Galvao; Zhou, David; Fu, Tinghao; Lee, Peng; Pei, Zhiheng; Wieczorek, Rosemary

2016-12-01

Carcinosarcoma of the anus is rare and has yet to be reportedly associated with the keratinocyte-specific Human Papilloma Virus (HPV). We describe a case of anal carcinosarcoma with HPV infection in both the epithelial and mesenchymal components of the tumor by immunohistochemistry, chromogenic in-situ hybridization (CISH) and further supported by electron microscopy (EM). Microscopic examination of the tumor showed nests of poorly-differentiated invasive squamous cell carcinoma with basaloid features intermixed with a hypercellular, atypical spindle cell proliferation. Immunohistochemistry demonstrated that the epithelial component was positive for AE1/AE3, p63, CK5/6 and p16, whilst the mesenchymal component was positive for smooth muscle actin, vimentin, and focally positive for desmin and p16, consistent with carcinosarcoma. The tumor was negative for GATA-3, CK7 and CK20. CISH demonstrated that the tumor was positive for high risk HPV (subtype 16/18) in both tumor components. EM further supported the presence of intracellular virus particles (~50 nm) that is compatible with HPV infection. Infection of both epithelial and mesenchymal tumor components by HPV has not been previously observed in the gastrointestinal tract. This finding may represent initial epithelial HPV infection with subsequent divergent tumoral differentiation and suggests the presence of viral replication in both biphasic tumor components.

Nature of "basal" and "reserve" cells in oviductal and cervical epithelium in man.

PubMed Central

Peters, W M

1986-01-01

The epithelium of the human fallopian tube (oviduct) and cervix were studied by histological, immunohistological, and ultrastructural methods with a view to establishing the nature of the so called "basal" and "reserve" cells. The results indicated that the "basal" cells of the oviductal epithelia were T lymphocytes, with a predominance of T cytotoxic and suppressor cells. A more heterogeneous inflammatory cell population was present in cervical epithelium, although once again T cytotoxic and suppressor cells were the most numerous subtype. The intraepithelial inflammatory cells were quite distinct from the cells commonly referred to as "reserve" cells (reserve cell hyperplasia), which have epithelial characteristics. The origin of the "reserve" cells is unclear, but they seem to arise within the epithelium. They probably represent an early sign of squamous metaplasia. The lymphoid tissue of fallopian tube and endocervix shows similarities with that of the endometrium and mucosal associated lymphoid tissue in general. Images PMID:2937810

Safety Study of SEA-CD40 in Cancer Patients

ClinicalTrials.gov

2018-06-21

Cancer; Carcinoma; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Hematologic Malignancies; Hodgkin Disease; Lymphoma; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Melanoma; Neoplasms; Neoplasm Metastasis; Neoplasms, Head and Neck; Neoplasms, Squamous Cell; Non-Small Cell Lung Cancer; Non-Small Cell Lung Cancer Metastatic; Non-small Cell Carcinoma; Squamous Cell Cancer; Squamous Cell Carcinoma; Squamous Cell Carcinoma of the Head and Neck; Squamous Cell Neoplasm; Lymphoma, Non-Hodgkin

TCDD alters medial epithelial cell differentiation during palatogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abbott, B.D.; Birnbaum, L.S.

1989-06-15

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widely distributed, persistent environmental contaminant that is teratogenic in mice, where it induces hydronephrosis and cleft palate. The incidence of clefting has been shown to be dose dependent after exposure on either gestation Day (GD) 10 or 12, although the embryo is more susceptible on GD 12. TCDD-exposed palatal shelves meet but do not fuse, and programmed cell death of the medial epithelial cells is inhibited. The mechanism of action through which TCDD alters the program of medial cell development has not been examined in earlier studies, and it is not known whether the mechanism ismore » the same regardless of the dose or developmental stage of exposure. In this study, C57BL/6N mice, a strain sensitive to TCDD, were dosed orally on GD 10 or 12 with 0, 6, 12, 24, or 30 micrograms/kg body wt, in 10 ml corn oil/kg. Embryonic palatal shelves were examined on GD 14, 15, or 16. The degree of palatal closure, epithelial surface morphology, and cellular ultrastructure, the incorporation of (3H)TdR, the expression of EGF receptors, and the binding of 125I-EGF were assessed. After exposure on GD 10 or 12, TCDD altered the differentiation pathway of the medial epithelial cells. The palatal shelves were of normal size and overall morphology, but fusion of the medial epithelia of the opposing shelves did not occur. TCDD prevented programmed cell death of the medial peridermal cells. The expression of EGF receptors by medial cells continued through Day 16 and the receptors were able to bind ligand. The medial cells differentiated into a stratified, squamous, keratinizing epithelium. The shift in phenotype to an oral-like epithelium occurred after exposure on either GD 10 or 12. At the lower dose (6 micrograms/kg), fewer cleft palates were produced, but those shelves which did respond had a fully expressed shift in differentiation.« less

Freeze-Dried Black Raspberries in Preventing Oral Cancer Recurrence in High-Risk Appalachian Patients Previously Treated With Surgery For Oral Cancer

ClinicalTrials.gov

2018-03-04

Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage I Squamous Cell Carcinoma of the Oropharynx; Stage I Verrucous Carcinoma of the Oral Cavity; Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage II Squamous Cell Carcinoma of the Oropharynx; Stage II Verrucous Carcinoma of the Oral Cavity; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer

Transforming Growth Factor-β1 activates ΔNp63/c-Myc to promote Oral Squamous cell carcinoma

PubMed Central

Hu, Lihua; Li, Zhi; Liu, Jingpeng; Wang, Chunling; Nawshad, Ali

2016-01-01

Objective During the development of oral squamous cell carcinoma (OSCC), the transformed epithelial cells undergo increased proliferation resulting in tumor growth and invasion. Interestingly, throughout all phases of differentiation and progression of OSCC, TGFβ1 induces cell cycle arrest/apoptosis, however; the role of TGFβ1 in promoting cancer cell proliferation has not been explored in detail. The purpose of this study was to identify the effect of TGFβ1 on OSCC cell proliferation. Methods Using both human OSCC samples and cell lines (UMSCC38 and UMSCC 11B), we employed biochemical experiments to show protein, mRNA, gene expression and protein-DNA interactions during OSCC progression. Results Our results showed that TGFβ1 increased OSCC cell proliferation by up-regulating the expression of ΔNp63 and c-Myc oncogenes. While the basal OSCC cell proliferation is sustained by activating ΔNp63, increased induction of c-Myc causes unregulated OSCC cell proliferation. Following induction of the cell cycle by ΔNp63 and c-Myc, cancer cells that halt c-Myc activity undergo EMT/invasion while those that continue to express ΔNp63/c-Myc undergo unlimited progression through the cell cycle. Conclusion We conclude that OSCC proliferation is manifested by the induction of c-Myc in response to TGFβ1 signaling, which is essential for OSCC growth. Our data highlights the potential role of TGFβ1 in the induction of cancer progression and invasion of OSCC. PMID:27567435

Synergistic function of Smad4 and PTEN in suppressing forestomach squamous cell carcinoma in the mouse.

PubMed

Teng, Yan; Sun, An-Na; Pan, Xiao-Chen; Yang, Guan; Yang, Lei-Lei; Wang, Ming-Rong; Yang, Xiao

2006-07-15

The genetic bases underlying esophageal tumorigenesis are poorly understood. Our previous studies have shown that coordinated deletion of the Smad4 and PTEN genes results in accelerated hair loss and skin tumor formation in mice. Herein, we exemplify that the concomitant inactivation of Smad4 and PTEN accelerates spontaneous forestomach carcinogenesis at complete penetrance during the first 2 months of age. All of the forestomach tumors were invasive squamous cell carcinomas (SCCs), which recapitulated the natural history and pathologic features of human esophageal SCCs. A small population of the SCC lesions was accompanied by adenocarcinomas at the adjacent submucosa region in the double mutant mice. The rapid progression of forestomach tumor formation in the Smad4 and PTEN double knockout mice corresponded to a dramatic increase in esophageal and forestomach epithelial proliferation. The decreased expression of p27, p21, and p16 together with the overexpression of cyclin D1 contributed cooperatively to the accelerated forestomach tumorigenesis in the double mutant mice. Our results point strongly to the crucial relevance of synergy between Smad4 and PTEN to suppress forestomach tumorigenesis through the cooperative induction of cell cycle inhibitors.

Tumours and dysplasias of the mammary gland

PubMed Central

Hampe, J. F.; Misdorp, W.

1974-01-01

As mammary tumours occur frequently in the dog and cat but rarely in other domestic animals, only the tumours of these two species are classified. The epithelial tumours are termed “complex” when they consist of cells resembling both secretory and myoepithelial cells: these tumours are biologically less malignant than tumours of the “simple” type in which only one of these kinds of cell is present. The carcinomas are subdivided into adenocarcinoma, solid carcinoma, spindle cell carcinoma, anaplastic carcinoma, squamous cell carcinoma, and mucinous carcinoma. The term “carcinosarcoma or malignant mixed tumour” was used only when there were cells morphologically resembling not only one or both of the epithelial components but also connective tissue cells with their products of differentiation. The benign tumours are classed as adenoma, papilloma, fibroadenoma, or benign soft tissue tumour. The dysplasias are described under the following headings: cyst, adenosis, regular typical epithelial proliferation in ducts and lobules (epitheliosis), duct ectasia, fibrosclerosis, and lobular hyperplasia. ImagesFig. 41Fig. 42Fig. 43Fig. 44Fig. 5Fig. 6Fig. 7Fig. 8Fig. 13Fig. 14Fig. 15Fig. 16Fig. 45Fig. 46Fig. 47Fig. 48Fig. 17Fig. 18Fig. 19Fig. 20Fig. 25Fig. 26Fig. 27Fig. 28Fig. 29Fig. 30Fig. 31Fig. 32Fig. 21Fig. 22Fig. 23Fig. 24Fig. 37Fig. 38Fig. 39Fig. 40Fig. 9Fig. 10Fig. 11Fig. 12Fig. 1Fig. 2Fig. 3Fig. 4Fig. 33Fig. 34Fig. 35Fig. 36 PMID:4371737

Elevated Src family kinase activity stabilizes E-cadherin-based junctions and collective movement of head and neck squamous cell carcinomas

PubMed Central

Veracini, Laurence; Grall, Dominique; Schaub, Sébastien; Divonne, Stéphanie Beghelli-de la Forest; Etienne-Grimaldi, Marie-Christine; Milano, Gérard; Bozec, Alexandre; Babin, Emmanuel; Sudaka, Anne; Thariat, Juliette; Van Obberghen-Schilling, Ellen

2015-01-01

EGF receptor (EGFR) overexpression is thought to drive head and neck carcinogenesis however clinical responses to EGFR-targeting agents have been modest and alternate targets are actively sought to improve results. Src family kinases (SFKs), reported to act downstream of EGFR are among the alternative targets for which increased expression or activity in epithelial tumors is commonly associated to the dissolution of E-cadherin-based junctions and acquisition of a mesenchymal-like phenotype. Robust expression of total and activated Src was observed in advanced stage head and neck tumors (N=60) and in head and neck squamous cell carcinoma lines. In cultured cancer cells Src co-localized with E-cadherin in cell-cell junctions and its phosphorylation on Y419 was both constitutive and independent of EGFR activation. Selective inhibition of SFKs with SU6656 delocalized E-cadherin and disrupted cellular junctions without affecting E-cadherin expression and this effect was phenocopied by knockdown of Src or Yes. These findings reveal an EGFR-independent role for SFKs in the maintenance of intercellular junctions, which likely contributes to the cohesive invasion E-cadherin-positive cells in advanced tumors. Further, they highlight the need for a deeper comprehension of molecular pathways that drive collective cell invasion, in absence of mesenchymal transition, in order to combat tumor spread. PMID:25779657

Focus on the role of the CXCL12/CXCR4 chemokine axis in head and neck squamous cell carcinoma.

PubMed

Albert, Sébastien; Riveiro, Maria Eugenia; Halimi, Caroline; Hourseau, Muriel; Couvelard, Anne; Serova, Maria; Barry, Béatrix; Raymond, Eric; Faivre, Sandrine

2013-12-01

The human chemokine system includes approximately 48 chemokines and 19 chemokine receptors. The CXCL12/CXCR4 system is one of the most frequently studied that is also found overexpressed in a large variety of tumors. The CXCL12/CXCR4 axis has been increasingly identified as an important target in cancer growth, metastasis, relapse, and resistance to therapy. In this review, we highlight current knowledge of the molecular mechanisms involving chemokines CXCL12/CXCR4 and their consequences in head and neck squamous cell carcinoma (HNSCC). Overexpression of CXCL12/CXCR4 in HNSCC appears to activate cellular functions, including motility, invasion, and metastatic processes. Current findings suggest that CXCR4 and epithelial-mesenchymal transition markers are associated with tumor aggressiveness and a poor prognosis, and may be suitable biomarkers for head and neck tumors with high metastatic potential. Furthermore, knowledge of the role of CXCR4 in HNSCC could influence the development of new targeted therapies for treatment, aimed at improving the prognosis of this disease. Copyright © 2013 Wiley Periodicals, Inc., A Wiley Company.

Organization of Human Papillomavirus Productive Cycle during Neoplastic Progression Provides a Basis for Selection of Diagnostic Markers

PubMed Central

Middleton, Kate; Peh, Woei; Southern, Shirley; Griffin, Heather; Sotlar, Karl; Nakahara, Tomomi; El-Sherif, Amira; Morris, Lesley; Seth, Rashmi; Hibma, Merilyn; Jenkins, David; Lambert, Paul; Coleman, Nicholas; Doorbar, John

2003-01-01

The productive cycle of human papillomaviruses (HPVs) can be divided into discrete phases. Cell proliferation and episomal maintenance in the lower epithelial layers are followed by genome amplification and the expression of capsid proteins. These events, which occur in all productive infections, can be distinguished by using antibodies to viral gene products or to surrogate markers of their expression. Here we have compared precancerous lesions caused by HPV type 16 (HPV16) with lesions caused by HPV types that are not generally associated with human cancer. These include HPV2 and HPV11, which are related to HPV16 (supergroup A), as well as HPV1 and HPV65, which are evolutionarily divergent (supergroups E and B). HPV16-induced low-grade squamous intraepithelial lesions (CIN1) are productive infections which resemble those caused by other HPV types. During progression to cancer, however, the activation of late events is delayed, and the thickness of the proliferative compartment is progressively increased. In many HPV16-induced high-grade squamous intraepithelial lesions (CIN3), late events are restricted to small areas close to the epithelial surface. Such heterogeneity in the organization of the productive cycle was seen only in lesions caused by HPV16 and was not apparent when lesions caused by other HPV types were compared. By contrast, the order in which events in the productive cycle were initiated was invariant and did not depend on the infecting HPV type or the severity of disease. The distribution of viral gene products in the infected cervix depends on the extent to which the virus can complete its productive cycle, which in turn reflects the severity of cervical neoplasia. It appears from our work that the presence of such proteins in cells at the epithelial surface allows the severity of the underlying disease to be predicted and that markers of viral gene expression may improve cervical screening. PMID:12970404

Evaluation of AgNORs in Oral Potentially Malignant Lesions.

PubMed

Tomazelli, Karin Berria; Modolo, Filipe; Rivero, Elena Riet Correa

2015-01-01

Oral squamous cell carcinoma (OSCC) is usually preceded by detectable mucosal changes, as leukoplakias and erythroplakia. Histologically, these lesions can range from hyperkeratosis and acanthosis to epithelial dysplasia and even OSCC. The aim of this study was to investigate the proliferative activity, using AgNORs quantification proteins, in low- and high-risk oral epithelial dysplasia, OSCC, and nondysplastic epithelium (inflammatory fibrous hyperplasia). The sample was divided into 4 groups: G1: 10 cases of inflammatory fibrous hyperplasia (IFH), G2: 11 cases of low-risk epithelial dysplasia (LD), G3: 10 cases of high-risk epithelial dysplasia (HD), and G4: 11 cases of OSCC. The quantitative analysis was performed using an image processing software in photomicrographs at 1000x magnification. The one-way ANOVA was used for comparison of the mean AgNORs counts between the study groups. The mean AgNORs count was significantly higher (P ≤ 0.01) in OSCC when compared to IFH and the LD; however, it was not statistically different from HD. The mean number of LD was significantly lower than the HD and OSCC, with no difference related to IFH. AgNORs quantification can be an important and cheap method to help in the determination of the degree of epithelial dysplasia and, consequently, in the analysis of their potential for malignant transformation.

Radiation Therapy and Docetaxel in Treating Patients With HPV-Related Oropharyngeal Cancer

ClinicalTrials.gov

2017-11-14

Human Papillomavirus Infection; Stage I Oropharyngeal Squamous Cell Carcinoma; Stage II Oropharyngeal Squamous Cell Carcinoma; Stage III Oropharyngeal Squamous Cell Carcinoma; Stage IVA Oropharyngeal Squamous Cell Carcinoma; Stage IVB Oropharyngeal Squamous Cell Carcinoma

L-lysine in Treating Oral Mucositis in Patients Undergoing Radiation Therapy With or Without Chemotherapy For Head and Neck Cancer

ClinicalTrials.gov

2013-05-15

Mucositis; Oral Complications of Chemotherapy; Oral Complications of Radiation Therapy; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage I Adenoid Cystic Carcinoma of the Oral Cavity; Stage I Basal Cell Carcinoma of the Lip; Stage I Lymphoepithelioma of the Nasopharynx; Stage I Lymphoepithelioma of the Oropharynx; Stage I Mucoepidermoid Carcinoma of the Oral Cavity; Stage I Salivary Gland Cancer; Stage I Squamous Cell Carcinoma of the Hypopharynx; Stage I Squamous Cell Carcinoma of the Larynx; Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage I Squamous Cell Carcinoma of the Nasopharynx; Stage I Squamous Cell Carcinoma of the Oropharynx; Stage I Verrucous Carcinoma of the Larynx; Stage I Verrucous Carcinoma of the Oral Cavity; Stage II Adenoid Cystic Carcinoma of the Oral Cavity; Stage II Basal Cell Carcinoma of the Lip; Stage II Lymphoepithelioma of the Nasopharynx; Stage II Lymphoepithelioma of the Oropharynx; Stage II Mucoepidermoid Carcinoma of the Oral Cavity; Stage II Salivary Gland Cancer; Stage II Squamous Cell Carcinoma of the Hypopharynx; Stage II Squamous Cell Carcinoma of the Larynx; Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage II Squamous Cell Carcinoma of the Nasopharynx; Stage II Squamous Cell Carcinoma of the Oropharynx; Stage II Verrucous Carcinoma of the Larynx; Stage II Verrucous Carcinoma of the Oral Cavity; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Basal Cell Carcinoma of the Lip; Stage III Lymphoepithelioma of the Nasopharynx; Stage III Lymphoepithelioma of the Oropharynx; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity

Paclitaxel Albumin-Stabilized Nanoparticle Formulation and Carboplatin Followed By Chemoradiation in Treating Patients With Recurrent Head and Neck Cancer

ClinicalTrials.gov

2017-05-22

Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Tongue Cancer

deltaNp63 Has a Role in Maintaining Epithelial Integrity in Airway Epithelium

PubMed Central

Arason, Ari Jon; Jonsdottir, Hulda R.; Halldorsson, Skarphedinn; Benediktsdottir, Berglind Eva; Bergthorsson, Jon Thor; Ingthorsson, Saevar; Baldursson, Olafur; Sinha, Satrajit; Gudjonsson, Thorarinn; Magnusson, Magnus K.

2014-01-01

The upper airways are lined with a pseudostratified bronchial epithelium that forms a barrier against unwanted substances in breathing air. The transcription factor p63, which is important for stratification of skin epithelium, has been shown to be expressed in basal cells of the lungs and its ΔN isoform is recognized as a key player in squamous cell lung cancer. However, the role of p63 in formation and maintenance of bronchial epithelia is largely unknown. The objective of the current study was to determine the expression pattern of the ΔN and TA isoforms of p63 and the role of p63 in the development and maintenance of pseudostratified lung epithelium in situ and in culture. We used a human bronchial epithelial cell line with basal cell characteristics (VA10) to model bronchial epithelium in an air-liquid interface culture (ALI) and performed a lentiviral-based silencing of p63 to characterize the functional and phenotypic consequences of p63 loss. We demonstrate that ΔNp63 is the major isoform in the human lung and its expression was exclusively found in the basal cells lining the basement membrane of the bronchial epithelium. Knockdown of p63 affected proliferation and migration of VA10 cells and facilitated cellular senescence. Expression of p63 is critical for epithelial repair as demonstrated by wound healing assays. Importantly, generation of pseudostratified VA10 epithelium in the ALI setup depended on p63 expression and goblet cell differentiation, which can be induced by IL-13 stimulation, was abolished by the p63 knockdown. After knockdown of p63 in primary bronchial epithelial cells they did not proliferate and showed marked senescence. We conclude that these results strongly implicate p63 in the formation and maintenance of differentiated pseudostratified bronchial epithelium. PMID:24533135

deltaNp63 has a role in maintaining epithelial integrity in airway epithelium.

PubMed

Arason, Ari Jon; Jonsdottir, Hulda R; Halldorsson, Skarphedinn; Benediktsdottir, Berglind Eva; Bergthorsson, Jon Thor; Ingthorsson, Saevar; Baldursson, Olafur; Sinha, Satrajit; Gudjonsson, Thorarinn; Magnusson, Magnus K

2014-01-01

The upper airways are lined with a pseudostratified bronchial epithelium that forms a barrier against unwanted substances in breathing air. The transcription factor p63, which is important for stratification of skin epithelium, has been shown to be expressed in basal cells of the lungs and its ΔN isoform is recognized as a key player in squamous cell lung cancer. However, the role of p63 in formation and maintenance of bronchial epithelia is largely unknown. The objective of the current study was to determine the expression pattern of the ΔN and TA isoforms of p63 and the role of p63 in the development and maintenance of pseudostratified lung epithelium in situ and in culture. We used a human bronchial epithelial cell line with basal cell characteristics (VA10) to model bronchial epithelium in an air-liquid interface culture (ALI) and performed a lentiviral-based silencing of p63 to characterize the functional and phenotypic consequences of p63 loss. We demonstrate that ΔNp63 is the major isoform in the human lung and its expression was exclusively found in the basal cells lining the basement membrane of the bronchial epithelium. Knockdown of p63 affected proliferation and migration of VA10 cells and facilitated cellular senescence. Expression of p63 is critical for epithelial repair as demonstrated by wound healing assays. Importantly, generation of pseudostratified VA10 epithelium in the ALI setup depended on p63 expression and goblet cell differentiation, which can be induced by IL-13 stimulation, was abolished by the p63 knockdown. After knockdown of p63 in primary bronchial epithelial cells they did not proliferate and showed marked senescence. We conclude that these results strongly implicate p63 in the formation and maintenance of differentiated pseudostratified bronchial epithelium.

Comparative Analysis of Super-Shedder Strains of Escherichia coli O157:H7 Reveals Distinctive Genomic Features and a Strongly Aggregative Adherent Phenotype on Bovine Rectoanal Junction Squamous Epithelial Cells

PubMed Central

Cote, Rebecca; Katani, Robab; Moreau, Matthew R.; Kudva, Indira T.; Arthur, Terrance M.; DebRoy, Chitrita; Mwangi, Michael M.; Albert, Istvan; Raygoza Garay, Juan Antonio; Li, Lingling; Brandl, Maria T.; Carter, Michelle Q.; Kapur, Vivek

2015-01-01

Shiga toxin-producing Escherichia coli O157:H7 (O157) are significant foodborne pathogens and pose a serious threat to public health worldwide. The major reservoirs of O157 are asymptomatic cattle which harbor the organism in the terminal recto-anal junction (RAJ). Some colonized animals, referred to as “super-shedders” (SS), are known to shed O157 in exceptionally large numbers (>104 CFU/g of feces). Recent studies suggest that SS cattle play a major role in the prevalence and transmission of O157, but little is known about the molecular mechanisms associated with super-shedding. Whole genome sequence analysis of an SS O157 strain (SS17) revealed a genome of 5,523,849 bp chromosome with 5,430 open reading frames and two plasmids, pO157 and pSS17, of 94,645 bp and 37,446 bp, respectively. Comparative analyses showed that SS17 is clustered with spinach-associated O157 outbreak strains, and belongs to the lineage I/II, clade 8, D group, and genotype 1, a subgroup of O157 with predicted hyper-virulence. A large number of non-synonymous SNPs and other polymorphisms were identified in SS17 as compared with other O157 strains (EC4115, EDL933, Sakai, TW14359), including in key adherence- and virulence-related loci. Phenotypic analyses revealed a distinctive and strongly adherent aggregative phenotype of SS17 on bovine RAJ stratified squamous epithelial (RSE) cells that was conserved amongst other SS isolates. Molecular genetic and functional analyses of defined mutants of SS17 suggested that the strongly adherent aggregative phenotype amongst SS isolates is LEE-independent, and likely results from a novel mechanism. Taken together, our study provides a rational framework for investigating the molecular mechanisms associated with SS, and strong evidence that SS O157 isolates have distinctive features and use a LEE-independent mechanism for hyper-adherence to bovine rectal epithelial cells. PMID:25664460

KH-type splicing regulatory protein is involved in esophageal squamous cell carcinoma progression

PubMed Central

Shoda, Katsutoshi; Naruto, Takuya; Hamada, Satoshi; Miyakami, Yuko; Kohmoto, Tomohiro; Watanabe, Miki; Takahashi, Rizu; Tange, Shoichiro; Saito, Masako; Kudo, Yasusei; Fujiwara, Hitoshi; Ichikawa, Daisuke; Tangoku, Akira; Otsuji, Eigo; Imoto, Issei

2017-01-01

KH-type splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein, which is involved in several post-transcriptional aspects of RNA metabolism, including microRNA (miRNA) biogenesis. It affects distinct cell functions in different tissues and can have an impact on various pathological conditions. In the present study, we investigated the oncogenic functions of KHSRP and their underlying mechanisms in the pathogenesis of esophageal squamous cell carcinoma (ESCC). KHSRP expression levels were elevated in ESCC tumors when compared with those in non-tumorous tissues by immunohistochemistry, and cytoplasmic KHSRP overexpression was found to be an independent prognosticator for worse overall survival in a cohort of 104 patients with ESCC. KHSRP knockdown inhibited growth, migration, and invasion of ESCC cells. KHSRP knockdown also inhibited the maturation of cancer-associated miRNAs, such as miR-21, miR-130b, and miR-301, and induced the expression of their target mRNAs, such as BMP6, PDCD4, and TIMP3, resulting in the inhibition of epithelial-to-mesenchymal transition. Our findings uncover a novel oncogenic function of KHSRP in esophageal tumorigenesis and implicate its use as a marker for prognostic evaluation and as a putative therapeutic target in ESCC. PMID:29254151

Immunohistochemical study of DNA topoisomerase I, DNA topoisomerase II alpha, p53, and Ki-67 in oral preneoplastic lesions and oral squamous cell carcinomas.

PubMed

Hafian, Hilal; Venteo, Lydie; Sukhanova, Alyona; Nabiev, Igor; Lefevre, Benoît; Pluot, Michel

2004-06-01

Human DNA topoisomerase I (topo I) is the molecular target of the camptothecin group of anticancer drugs. Laboratory studies have shown that the cellular response to topo I-targeted drugs depends on the topo I expression and DNA replication rate and the apoptotic pathway activity. In this study, we tested potential indicators of the sensitivity of topo I-targeted drugs in 36 cases of oral squamous cell carcinoma (OSCC). Formalin-fixed, paraffin-embedded tissue sections were immunostained with monoclonal antibodies against Ki-67, p53, and topo I, and with polyclonal antibodies against DNA topoisomerase II-alpha (topo II-alpha). These markers were also tested in 18 epithelial hyperplastic lesions and 18 mild dysplasias. Immunostaining was quantified by the percentage of stained nuclei in each sample (the labeling index); 200 immunoreactive epithelial nuclei were counted per case for each antibody. The results support the possibility of using topo II-alpha staining for assessing the proliferative activity. High expression of topo II-alpha and topo I in OSCCs suggests that they may serve as potential indicators of sensitivity to topo I inhibitors. However, the apoptotic pathway assessed by p53 immunostaining was found to be uninformative. Analysis of the relationship between immunohistochemical results and clinical and pathologic parameters (the T and N stages and differentiation) showed that only the differentiation parameter correlated with the topo I expression rate. Thus, significant increase in the topo I expression in the poorly differentiated OSCCs suggests their higher sensitivity to drug treatment.

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts.

PubMed

Kretschmer, Inga; Freudenberger, Till; Twarock, Sören; Yamaguchi, Yu; Grandoch, Maria; Fischer, Jens W

2016-02-19

The aim of this study was to characterize the interaction of KYSE-410, an esophageal squamous cell carcinoma cell line, and fibroblasts with respect to the extracellular matrix component hyaluronan (HA) and chemokine expression. KYSE-410 cells induced the mRNA expression of HA synthase 2 (Has2) in normal skin fibroblasts (SF) only in direct co-cultures. Parallel to Has2 mRNA, Has2 antisense RNA (Has2os2) was up-regulated in co-cultures. Knockdown of LEF1, a downstream target of Wnt signaling, abrogated Has2 and Has2os2 induction. After knockdown of Has2 in SF, significantly less α-smooth muscle actin expression was detected in co-cultures. Moreover, it was investigated whether the phenotype of KYSE-410 was affected in co-culture with SF and whether Has2 knockdown in SF had an impact on KYSE-410 cells in co-culture. However, no effects on epithelial-mesenchymal transition markers, proliferation, and migration were detected. In addition to Has2 mRNA, the chemokine CCL5 was up-regulated and CCL11 was down-regulated in SF in co-culture. Furthermore, co-cultures of KYSE-410 cells and cancer-associated fibroblasts (CAF) were investigated. Similar to SF, Has2 and Ccl5 were up-regulated and Ccl11 was down-regulated in CAF in co-culture. Importantly and in contrast to SF, inhibiting HA synthesis by 4-methylumbelliferone abrogated the effect of co-culture on Ccl5 in CAF. Moreover, HA was found to promote adhesion of CD4(+) but not CD8(+) cells to xenogaft tumor tissues. In conclusion, direct co-culture of esophageal squamous cell carcinoma and fibroblasts induced stromal HA synthesis via Wnt/LEF1 and altered the chemokine profile of stromal fibroblasts, which in turn may affect the tumor immune response. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts*

PubMed Central

Kretschmer, Inga; Freudenberger, Till; Twarock, Sören; Yamaguchi, Yu; Grandoch, Maria; Fischer, Jens W.

2016-01-01

The aim of this study was to characterize the interaction of KYSE-410, an esophageal squamous cell carcinoma cell line, and fibroblasts with respect to the extracellular matrix component hyaluronan (HA) and chemokine expression. KYSE-410 cells induced the mRNA expression of HA synthase 2 (Has2) in normal skin fibroblasts (SF) only in direct co-cultures. Parallel to Has2 mRNA, Has2 antisense RNA (Has2os2) was up-regulated in co-cultures. Knockdown of LEF1, a downstream target of Wnt signaling, abrogated Has2 and Has2os2 induction. After knockdown of Has2 in SF, significantly less α-smooth muscle actin expression was detected in co-cultures. Moreover, it was investigated whether the phenotype of KYSE-410 was affected in co-culture with SF and whether Has2 knockdown in SF had an impact on KYSE-410 cells in co-culture. However, no effects on epithelial-mesenchymal transition markers, proliferation, and migration were detected. In addition to Has2 mRNA, the chemokine CCL5 was up-regulated and CCL11 was down-regulated in SF in co-culture. Furthermore, co-cultures of KYSE-410 cells and cancer-associated fibroblasts (CAF) were investigated. Similar to SF, Has2 and Ccl5 were up-regulated and Ccl11 was down-regulated in CAF in co-culture. Importantly and in contrast to SF, inhibiting HA synthesis by 4-methylumbelliferone abrogated the effect of co-culture on Ccl5 in CAF. Moreover, HA was found to promote adhesion of CD4+ but not CD8+ cells to xenogaft tumor tissues. In conclusion, direct co-culture of esophageal squamous cell carcinoma and fibroblasts induced stromal HA synthesis via Wnt/LEF1 and altered the chemokine profile of stromal fibroblasts, which in turn may affect the tumor immune response. PMID:26699196

Depsipeptide in Unresectable Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

ClinicalTrials.gov

2015-04-29

Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Oropharynx

Sulforaphane targets cancer stemness and tumor initiating properties in oral squamous cell carcinomas via miR-200c induction.

PubMed

Liu, Chia-Ming; Peng, Chih-Yu; Liao, Yi-Wen; Lu, Ming-Yi; Tsai, Meng-Lun; Yeh, Jung-Chun; Yu, Chuan-Hang; Yu, Cheng-Chia

2017-01-01

Cancer stem cells (CSCs) are deemed as the driving force of tumorigenesis in oral squamous cell carcinomas (OSCCs). In this study, we investigated the chemotherapeutic effect of sulforaphane, a dietary component from broccoli sprouts, on targeting OSCC-CSCs. The effect of sulforaphane on normal oral epithelial cells (SG) and sphere-forming OSCC-CSCs isolated from SAS and GNM cells was examined. ALDH1 activity and CD44 positivity of OSCC-CSCs with sulforaphane treatment was assessed by flow cytometry analysis. In vitro and in vivo tumorigenicity assays of OSCC-CSCs with sulforaphane treatment were presented. We observed that the sulforaphane dose-dependently eliminated the proliferation rate of OSCC-CSCs, whereas the inhibition on SG cells proliferation was limited. Cancer stemness properties including self-renewal, CD44 positivity, and ALDH1 activity were also decreased in OSCC-CSCs with different doses of sulforaphane treatment. Moreover, sulforaphane treatment of OSCC-CSCs decreased the migration, invasion, clonogenicity, and in vivo tumorigenicity of xenograghts. Sulforaphane treatment resulted in a dose-dependent increase in the levels of tumor suppressive miR200c. These lines of evidence suggest that sulforaphane can suppress the cancer stemness and tumor-initiating properties in OSCC-CSCs both in vitro and in vivo. Copyright © 2016. Published by Elsevier B.V.

Identification of differentially expressed genes in human lung squamous cell carcinoma using suppression subtractive hybridization.

PubMed

Sun, Wenyue; Zhang, Kaitai; Zhang, Xinyu; Lei, Wendong; Xiao, Ting; Ma, Jinfang; Guo, Suping; Shao, Shujuan; Zhang, Husheng; Liu, Yan; Yuan, Jinsong; Hu, Zhi; Ma, Ying; Feng, Xiaoli; Hu, Songnian; Zhou, Jun; Cheng, Shujun; Gao, Yanning

2004-08-20

Lung cancer is one of the major causes of cancer-related deaths. Over the past decade, much has been known about the molecular changes associated with lung carcinogenesis; however, our understanding to lung tumorigenesis is still incomplete. To identify genes that are differentially expressed in squamous cell carcinoma (SCC) of the lung, we compared the expression profiles between primarily cultured SCC tumor cells and bronchial epithelial cells derived from morphologically normal bronchial epithelium of the same patient. Using suppression subtractive hybridization (SSH), two cDNA libraries containing up- and down-regulated genes in the tumor cells were constructed, named as LCTP and LCBP. The two libraries comprise 258 known genes and 133 unknown genes in total. The known up-regulated genes in the library LCTP represented a variety of functional groups; including metabolism-, cell adhesion and migration-, signal transduction-, and anti-apoptosis-related genes. Using semi-quantitative reverse transcription-polymerase chain reaction, seven genes chosen randomly from the LCTP were analyzed in the tumor tissue paired with its corresponding adjacent normal lung tissue derived from 16 cases of the SCC. Among them, the IQGAP1, RAP1GDS1, PAICS, MLF1, and MARK1 genes showed a consistent expression pattern with that of the SSH analysis. Identification and further characterization of these genes may allow a better understanding of lung carcinogenesis.

Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis

PubMed Central

Sales, Katiuchia Uzzun; Friis, Stine; Konkel, Joanne E.; Godiksen, Sine; Hatakeyama, Marcia; Hansen, Karina K.; Rogatto, Silvia Regina; Szabo, Roman; Vogel, Lotte K.; Chen, Wanjun; Gutkind, J. Silvio; Bugge, Thomas H.

2014-01-01

The membrane-anchored serine protease, matriptase, is consistently dysregulated in a range of human carcinomas, and high matriptase activity correlates with poor prognosis. Furthermore, matriptase is unique among tumor-associated proteases in that epithelial stem cell expression of the protease suffices to induce malignant transformation. Here, we use genetic epistasis analysis to identify proteinase-activated receptor (PAR)-2-dependent inflammatory signaling as an essential component of matriptase-mediated oncogenesis. In cell-based assays, matriptase was a potent activator of PAR-2, and PAR-2 activation by matriptase caused robust induction of NFκB through Gαi. Importantly, genetic elimination of PAR-2 from mice completely prevented matriptase-induced pre-malignant progression, including inflammatory cytokine production, inflammatory cell recruitment, epidermal hyperplasia, and dermal fibrosis. Selective ablation of PAR-2 from bone marrow-derived cells did not prevent matriptase-driven pre-malignant progression, indicating that matriptase activates keratinocyte stem cell PAR-2 to elicit its pro-inflammatory and pro-tumorigenic effects. When combined with previous studies, our data suggest that dual induction of PAR-2-NFκB inflammatory signaling and PI3K-Akt-mTor survival/proliferative signaling underlies the transforming potential of matriptase and may contribute to pro-tumorigenic signaling in human epithelial carcinogenesis. PMID:24469043

Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis.

PubMed

Sales, K U; Friis, S; Konkel, J E; Godiksen, S; Hatakeyama, M; Hansen, K K; Rogatto, S R; Szabo, R; Vogel, L K; Chen, W; Gutkind, J S; Bugge, T H

2015-01-15

The membrane-anchored serine protease, matriptase, is consistently dysregulated in a range of human carcinomas, and high matriptase activity correlates with poor prognosis. Furthermore, matriptase is unique among tumor-associated proteases in that epithelial stem cell expression of the protease suffices to induce malignant transformation. Here, we use genetic epistasis analysis to identify proteinase-activated receptor (PAR)-2-dependent inflammatory signaling as an essential component of matriptase-mediated oncogenesis. In cell-based assays, matriptase was a potent activator of PAR-2, and PAR-2 activation by matriptase caused robust induction of nuclear factor (NF)κB through Gαi. Importantly, genetic elimination of PAR-2 from mice completely prevented matriptase-induced pre-malignant progression, including inflammatory cytokine production, inflammatory cell recruitment, epidermal hyperplasia and dermal fibrosis. Selective ablation of PAR-2 from bone marrow-derived cells did not prevent matriptase-driven pre-malignant progression, indicating that matriptase activates keratinocyte stem cell PAR-2 to elicit its pro-inflammatory and pro-tumorigenic effects. When combined with previous studies, our data suggest that dual induction of PAR-2-NFκB inflammatory signaling and PI3K-Akt-mTor survival/proliferative signaling underlies the transforming potential of matriptase and may contribute to pro-tumorigenic signaling in human epithelial carcinogenesis.

Phase I/II Study of Postoperative Adjuvant Chemoradiation for Advanced-Stage Cutaneous Squamous Cell Carcinoma of the Head and Neck (cSCCHN)

ClinicalTrials.gov

2014-11-17

Recurrent Skin Cancer; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Squamous Cell Carcinoma of the Skin; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity

Erlotinib and Radiation Therapy With or Without Cisplatin in Treating Patients With Mouth or Throat Cancer

ClinicalTrials.gov

2013-09-27

Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage II Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Oropharynx

Everolimus, Erlotinib Hydrochloride, and Radiation Therapy in Treating Patients With Recurrent Head and Neck Cancer Previously Treated With Radiation Therapy

ClinicalTrials.gov

2016-03-01

Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Tongue Cancer

In situ hybridization analysis of human papillomavirus DNA in oral mucosal lesions.

PubMed

Zeuss, M S; Miller, C S; White, D K

1991-06-01

Commercial biotinylated DNA probes specific for human papillomavirus (HPV) types 6 and 11; 16 and 18; and 31, 33, and 35 were used for in situ hybridization analysis of 105 oral mucosal specimens from 5 cases of verruca vulgaris, 15 cases of condyloma acuminatum, 30 cases of squamous papilloma, 20 cases of hyperkeratosis/acanthosis, 15 cases of epithelial dysplasia, 5 cases of carcinoma in situ, and 15 cases of squamous cell carcinoma. Positive hybridization signals were found in 26 specimens (24.8%). Only HPV-6/11 was detected. HPV DNA occurred significantly more often (p less than 0.005, chi-square analysis) in condyloma acuminatum (100%) and verruca vulgaris (100%) than squamous papilloma (13.3%), hyperkeratotic/acanthotic lesions (10%), and malignant and premalignant lesions (0%). The tongue (19.1%) and labial epithelium (17.1%) were infected most frequently. Nuclear reaction products indicating HPV infection were associated primarily with koilocytes. These results demonstrate the usefulness of commercial biotinylated probes for HPV DNA analysis in routine paraffin-embedded lesion specimens. They confirm HPV involvement in benign lesions of the oral mucosa but fail to associate HPV infection with oral cancer and precancer.

Bevacizumab, Fluorouracil, and Hydroxyurea Plus Radiation Therapy in Treating Patients With Advanced Head and Neck Cancer

ClinicalTrials.gov

2013-02-06

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Basal Cell Carcinoma of the Lip; Stage III Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage III Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage III Lymphoepithelioma of the Nasopharynx; Stage III Lymphoepithelioma of the Oropharynx; Stage III Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Untreated Metastatic Squamous Neck Cancer With Occult Primary

Squamous metaplasia of the rete ovarii in a Zebu cow

PubMed Central

2012-01-01

Background Stratified keratinizing squamous epithelium in the ovary has been associated with the diagnosis of ovarian teratoma in cows. Recently, the diagnosis of “epidermoid cyst” has been proposed. A case of squamous metaplasia of the rete ovarii in a Zebu cow is described in this report. Case presentation A crossbreed Zebu cow had both ovaries enlarged with multiple cysts. Most cysts were lined by well differentiated keratinizing stratified squamous epithelium and filled with keratinized lamellar material. Some cysts were lined by an epithelial layer that ranged from single cuboidal, double cuboidal epithelium, stratified non keratinized epithelium, and areas of keratinizing stratified squamous epithelium. Single or double layered cuboidal epithelia of the cysts expressed low molecular weight cytokeratin 7, whose expression was absent in the keratinizing stratified squamous epithelia of same cysts. Conversely, high molecular weight cytokeratins 1, 5, 10, and 14 were strongly expressed by the keratinizing stratified epithelium. Conclusion Squamous metaplasia of the rete ovarii was diagnosed. Squamous metaplasia of the rete ovarii, may account for some of the previously described squamous lesions in the ovary, which may have been misinterpreted as teratoma or epidermoid cysts. PMID:23217175

Identification of a Novel Proto-oncogenic Network in Head and Neck Squamous Cell Carcinoma.

PubMed

Georgy, Smitha R; Cangkrama, Michael; Srivastava, Seema; Partridge, Darren; Auden, Alana; Dworkin, Sebastian; McLean, Catriona A; Jane, Stephen M; Darido, Charbel

2015-09-01

The developmental transcription factor Grainyhead-like 3 (GRHL3) plays a critical tumor suppressor role in the mammalian epidermis through direct regulation of PTEN and the PI3K/AKT/mTOR signaling pathway. GRHL3 is highly expressed in all tissues derived from the surface ectoderm, including the oral cavity, raising a question about its potential role in suppression of head and neck squamous cell carcinoma (HNSCC). We explored the tumor suppressor role of Grhl3 in HNSCC using a conditional knockout (Grhl3 (∆/-) /K14Cre (+) ) mouse line (n = 26) exposed to an oral chemical carcinogen. We defined the proto-oncogenic pathway activated in the HNSCC derived from these mice and assessed it in primary human HNSCC samples, normal oral epithelial cell lines carrying shRNA to GRHL3, and human HNSCC cell lines. Data were analyzed with two-sided chi square and Student's t tests. Deletion of Grhl3 in oral epithelium in mice did not perturb PTEN/PI3K/AKT/mTOR signaling, but instead evoked loss of GSK3B expression, resulting in stabilization and accumulation of c-MYC and aggressive HNSCC. This molecular signature was also evident in a subset of primary human HNSCC and HNSCC cell lines. Loss of Gsk3b in mice, independent of Grhl3, predisposed to chemical-induced HNSCC. Restoration of GSK3B expression blocked proliferation of normal oral epithelial cell lines carrying shRNA to GRHL3 (cell no., Day 8: Scramble ctl, 616±21.8 x 10(3) vs GRHL3-kd, 1194±44 X 10(3), P < .001; GRHL3-kd vs GRHL3-kd + GSK3B, 800±98.84 X 10(3), P = .003) and human HNSCC cells. We defined a novel molecular signature in mammalian HNSCC, suggesting new treatment strategies targeting the GRHL3/GSK3B/c-MYC proto-oncogenic network. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

[Papilloma of the lacrimal sac].

PubMed

Burduk, Paweł K; Seredyka-Burduk, Małgorzata; Kaźmierczak, Wojciech; Dalke, Krzysztof; Marszałek, Andrzej

2013-01-01

The benign lesions of the lacrimal sac are very rare. The most typical epithelial tumor is squamous papilloma. This tumors often present with symptoms of dacryostenosis and dacriocystitis. Human papillomavirus (HPV) infection is known to be causative agent in the development of epithelial tumor. Lacrimal sac tumors could transform to malignant neoplasms, especially if they are developed of coexisting HPV infection. We present a patient with a squamous papilloma of the lacrimal sac and discussed the method of treatment. The patient was suffered from epiphora and recurrent dacriocystitis. An endoscopic surgery with dacriocystorhinostomy and local resection of the tumor could be an effective method of choice. The usage of a shaver for wide removal of the lacrimal sac wall is recommended to prevent local recurrence. The histopathology examination showed squamous papilloma. The patient is free of the disease over 8 months of follow up. Primary lacrimal sac papilloma require long term follow up for recurrence or malignant transformation. HPV infection could be associated with the development of lacrimal sac papillomas. Copyright © 2012 Polish Otorhinolaryngology - Head and Neck Surgery Society. Published by Elsevier Urban & Partner Sp. z.o.o. All rights reserved.

Acetylcysteine Rinse in Reducing Saliva Thickness and Mucositis in Patients With Head and Neck Cancer Undergoing Radiation Therapy

ClinicalTrials.gov

2018-04-17

Mucositis; Oral Complications; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage I Adenoid Cystic Carcinoma of the Oral Cavity; Stage I Basal Cell Carcinoma of the Lip; Stage I Lymphoepithelioma of the Nasopharynx; Stage I Lymphoepithelioma of the Oropharynx; Stage I Mucoepidermoid Carcinoma of the Oral Cavity; Stage I Salivary Gland Cancer; Stage I Squamous Cell Carcinoma of the Larynx; Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage I Squamous Cell Carcinoma of the Nasopharynx; Stage I Squamous Cell Carcinoma of the Oropharynx; Stage I Verrucous Carcinoma of the Larynx; Stage I Verrucous Carcinoma of the Oral Cavity; Stage II Adenoid Cystic Carcinoma of the Oral Cavity; Stage II Basal Cell Carcinoma of the Lip; Stage II Lymphoepithelioma of the Nasopharynx; Stage II Lymphoepithelioma of the Oropharynx; Stage II Mucoepidermoid Carcinoma of the Oral Cavity; Stage II Salivary Gland Cancer; Stage II Squamous Cell Carcinoma of the Larynx; Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage II Squamous Cell Carcinoma of the Nasopharynx; Stage II Squamous Cell Carcinoma of the Oropharynx; Stage II Verrucous Carcinoma of the Larynx; Stage II Verrucous Carcinoma of the Oral Cavity; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Basal Cell Carcinoma of the Lip; Stage III Lymphoepithelioma of the Nasopharynx; Stage III Lymphoepithelioma of the Oropharynx; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Adenoid Cystic Carcinoma of the Oral Cavity; Stage IVA Basal Cell Carcinoma of the Lip; Stage IVA Lymphoepithelioma of the Oropharynx; Stage IVA Mucoepidermoid Carcinoma of the Oral Cavity; Stage IVA Salivary Gland Cancer; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Adenoid Cystic Carcinoma of the Oral Cavity; Stage IVB Basal Cell Carcinoma of the Lip; Stage IVB Lymphoepithelioma of the Oropharynx; Stage IVB Mucoepidermoid Carcinoma of the Oral Cavity; Stage IVB Salivary Gland Cancer; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Adenoid Cystic Carcinoma of the Oral Cavity; Stage IVC Basal Cell Carcinoma of the Lip; Stage IVC Lymphoepithelioma of the Oropharynx; Stage IVC Mucoepidermoid Carcinoma of the Oral Cavity; Stage IVC Salivary Gland Cancer; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer

Actinic lesions in fishermen’s lower lip: clinical, cytopathological and histopathologic analysis

PubMed Central

Piñera-Marques, Karine; Lorenço, Silvia Vanessa; da Silva, Luiz Fernando Ferraz; Sotto, Mirian Nacagami; Carneiro, Paulo Campos

2010-01-01

INTRODUCTION Actinic cheilitis (AC) is considered to be a pre-malignant lesion or an incipient and superficial form of lip squamous cell carcinoma. It is commonly found in individuals whose occupational activities are related to chronic sun exposure and the definitive diagnosis is performed with biopsy. Althoug Exfoliative cytology has been used as a screening procedure to evaluate cancer of the oral cavity no studies have proposed the use of exfoliative cytologic analysis to evaluate and diagnose AC. OBJECTIVE The purpose of this study was to evaluate lower lip lesions on fishermen related to chronic solar exposure using clinical, cytologic and histopathologic analyses. PATIENTS AND METHODS Smears taken from the vermilion of the lower lips of 125 fishermen and 30 control individuals were subjected to cytologic analysis. RESULTS The harvested cells were sufficient for cytologic analysis in 83.2% of the samples. Sixteen fishermen exhibited prominent lower lip lesions that justified biopsy and histological studies. In total, 4 specimens were malignant (3.2%), and 12 displayed epithelial dysplasia, demonstrating that the prevalence of epithelial dysplasia and malignant lesions was high among the fishermen population. These conditions were strongly associated with infiltration and blurring of the vermilion margin of the lower lip. CONCLUSION The cytologic analysis was not useful for detecting epithelial dysplasia or malignant alterations. PMID:20454492

Bardoxolone methyl induces apoptosis and autophagy and inhibits epithelial-to-mesenchymal transition and stemness in esophageal squamous cancer cells.

PubMed

Wang, Yan-Yang; Yang, Yin-Xue; Zhao, Ren; Pan, Shu-Ting; Zhe, Hong; He, Zhi-Xu; Duan, Wei; Zhang, Xueji; Yang, Tianxin; Qiu, Jia-Xuan; Zhou, Shu-Feng

2015-01-01

Natural and synthetic triterpenoids have been shown to kill cancer cells via multiple mechanisms. The therapeutic effect and underlying mechanism of the synthetic triterpenoid bardoxolone methyl (C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; CDDO-Me) on esophageal cancer are unclear. Herein, we aimed to investigate the anticancer effects and underlying mechanisms of CDDO-Me in human esophageal squamous cell carcinoma (ESCC) cells. Our study showed that CDDO-Me suppressed the proliferation and arrested cells in G2/M phase, and induced apoptosis in human ESCC Ec109 and KYSE70 cells. The G2/M arrest was accompanied with upregulated p21Waf1/Cip1 and p53 expression. CDDO-Me significantly decreased B-cell lymphoma-extra large (Bcl-xl), B-cell lymphoma 2 (Bcl-2), cleaved caspase-9, and cleaved poly ADP ribose polymerase (PARP) levels but increased the expression level of Bcl-2-associated X (Bax). Furthermore, CDDO-Me induced autophagy in both Ec109 and KYSE70 cells via suppression of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway. There were interactions between the autophagic and apoptotic pathways in Ec109 and KYSE70 cells subject to CDDO-Me treatment. CDDO-Me also scavenged reactive oxygen species through activation of the nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) pathway in Ec109 and KYSE70 cells. CDDO-Me inhibited cell invasion, epithelial-mesenchymal transition, and stemness in Ec109 and KYSE70 cells. CDDO-Me significantly downregulated E-cadherin but upregulated Snail, Slug, and zinc finger E-box-binding homeobox 1 (TCF-8/ZEB1) in Ec109 and KYSE70 cells. CDDO-Me significantly decreased the expression of octamer-4, sex determining region Y-box 2 (Sox-2), Nanog, and B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1), all markers of cancer cell stemness, in Ec109 and KYSE70 cells. Taken together, these results indicate that CDDO-Me is a promising anticancer agent against ESCC. Further studies are warranted to explore the molecular targets, efficacy and safety of CDDO-Me in the treatment of ESCC.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Toki, Hideaki; Minowa, Osamu; Inoue, Maki

Dominant mutations in the Serca2 gene, which encodes sarco(endo)plasmic reticulum calcium-ATPase, predispose mice to gastrointestinal epithelial carcinoma [1–4] and humans to Darier disease (DD) [14–17]. In this study, we generated mice harboring N-ethyl-N-nitrosourea (ENU)-induced allelic mutations in Serca2: three missense mutations and one nonsense mutation. Mice harboring these Serca2 mutations developed tumors that were categorized as either early onset squamous cell tumors (SCT), with development similar to null-type knockout mice [2,4] (aggressive form; M682, M814), or late onset tumors (mild form; M1049, M1162). Molecular analysis showed no aberration in Serca2 mRNA or protein expression levels in normal esophageal cells ofmore » any of the four mutant heterozygotes. There was no loss of heterozygosity at the Serca2 locus in the squamous cell carcinomas in any of the four lines. The effect of each mutation on Ca{sup 2+}-ATPase activity was predicted using atomic-structure models and accumulated mutated protein studies, suggesting that putative complete loss of Serca2 enzymatic activity may lead to early tumor onset, whereas mutations in which Serca2 retains residual enzymatic activity result in late onset. We propose that impaired Serca2 gene product activity has a long-term effect on squamous cell carcinogenesis from onset to the final carcinoma stage through an as-yet unrecognized but common regulatory pathway. -- Highlights: •Novel mutations in murine Serca2 caused early onset or late onset of tumorigenesis. •They also caused higher or lower incidence of Darier Disease phenotype. •3D structure model suggested the former mutations led to severer defect on ATPase. •Driver gene mutations via long-range effect on Ca2+ distributions are suggested.« less

Atypical squamous cells in the urine revealing endometrioid adenocarcinoma of the endometrium with squamous cell differentiation: a case report.

PubMed

Wang, Yinong; Otis, Christopher N; Florence, Roxanne R

2015-01-01

Urine cytology is mainly used to detect urothelial carcinoma (UC), especially for high-grade lesions including urothelial carcinoma in situ. Benign squamous cells are often seen in the urine specimens of women, they are either exfoliated from the trigone area of the bladder, the urethra, or the cervicovaginal region. However, abnormal squamous cells in the urine raise concerns of abnormalities of the urinary tract and cervicovaginal area which range from squamous metaplasia of the urothelium, a cervicovaginal squamous intraepithelial lesion, condyloma acuminatum of the bladder, UC with squamous differentiation, and squamous cell carcinoma. We present here a unique case of atypical squamous cells (ASCs) in the urine subsequently leading to the diagnosis of endometrioid adenocarcinoma of the endometrium with squamous differentiation. The presence of ASCs in voided urine is a rare finding that may indicate an underlying malignancy. Careful evaluation of squamous cells in the urine is an important part of our daily cytopathology practice. © 2014 Wiley Periodicals, Inc.

Erlotinib and Cetuximab With or Without Bevacizumab in Treating Patients With Metastatic or Unresectable Kidney, Colorectal, Head and Neck, Pancreatic, or Non-Small Cell Lung Cancer

ClinicalTrials.gov

2014-06-10

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Colon Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Basal Cell Carcinoma of the Lip; Stage III Colon Cancer; Stage III Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage III Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage III Lymphoepithelioma of the Nasopharynx; Stage III Lymphoepithelioma of the Oropharynx; Stage III Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Pancreatic Cancer; Stage III Rectal Cancer; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IIIB Non-small Cell Lung Cancer; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Colon Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Non-small Cell Lung Cancer; Stage IV Pancreatic Cancer; Stage IV Rectal Cancer; Stage IV Renal Cell Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Untreated Metastatic Squamous Neck Cancer With Occult Primary

Keratin 17 in premalignant and malignant squamous lesions of the cervix: proteomic discovery and immunohistochemical validation as a diagnostic and prognostic biomarker

PubMed Central

Escobar-Hoyos, Luisa F; Yang, Jie; Zhu, Jiawen; Cavallo, Julie-Ann; Zhai, Haiyan; Burke, Stephanie; Koller, Antonius; Chen, Emily I; Shroyer, Kenneth R

2014-01-01

Most previously described immunohistochemical markers of cervical high-grade squamous intraepithelial lesion (HSIL) and squamous cell carcinoma may help to improve diagnostic accuracy but have a minimal prognostic value. The goals of the current study were to identify and validate novel candidate biomarkers that could potentially improve diagnostic and prognostic accuracy for cervical HSIL and squamous cell carcinoma. Microdissected tissue sections from formalin-fixed paraffin-embedded normal ectocervical squamous mucosa, low-grade squamous intraepithelial lesion (LSIL), HSIL and squamous cell carcinoma sections were analyzed by mass spectrometry-based shotgun proteomics for biomarker discovery. The diagnostic specificity of candidate biomarkers was subsequently evaluated by immunohistochemical analysis of tissue microarrays. Among 1750 proteins identified by proteomic analyses, keratin 4 (KRT4) and keratin 17 (KRT17) showed reciprocal patterns of expression in the spectrum of cases ranging from normal ectocervical squamous mucosa to squamous cell carcinoma. Immunohistochemical studies confirmed that KRT4 expression was significantly decreased in squamous cell carcinoma compared with the other diagnostic categories. By contrast, KRT17 expression was significantly increased in HSIL and squamous cell carcinoma compared with normal ectocervical squamous mucosa and LSIL. KRT17 was also highly expressed in immature squamous metaplasia and in endocervical reserve cells but was generally not detected in mature squamous metaplasia. Furthermore, high levels of KRT17 expression were significantly associated with poor survival of squamous cell carcinoma patients (Hazard ratio = 14.76, P = 0.01). In summary, both KRT4 and KRT17 expressions are related to the histopathology of the cervical squamous mucosa; KRT17 is highly overexpressed in immature squamous metaplasia, in HSIL, and in squamous cell carcinoma and the level of KRT17 in squamous cell carcinoma may help to identify patients who are at greatest risk for cervical cancer mortality. PMID:24051697

Derlin-1 is a target to improve radiotherapy effect of esophageal squamous cell carcinoma

PubMed Central

Zhao, Yue; Liu, Yang; Li, Qingchang; Qiu, Xueshan; Wang, Enhua

2017-01-01

Radiotherapy is widely used for treatment of esophageal squamous cell carcinoma (ESCC). This study aimed to explore the role of Derlin-1 on the sensitivity of ESCC to radiotherapy and its underlying mechanism. We examined the clinical significance of Derlin-1 in 125 ESCC tissues. We found that Derlin-1 protein was higher in ESCC tissues than that in normal esophageal epithelial tissues. Derlin-1 overexpression was correlated with chemoradiotherapy resistance in ESCC patients and served an independent predictor for short overall survival. siRNA knockdown and plasmid transfection were carried out in ESCC cell lines. Derlin-1 depletion inhibited cell growth while its overexpression facilitated cell growth. Derlin-1 overexpression in Eca-109 cells dramatically enhanced its resistance to radiotherapy with decreased apoptosis rate. On the contrary, Derlin-1 depletion in TE-1 cell line showed the opposite effects. In addition, radioresistance conferred by Derlin-1 was attributed to its role of activating AKT/Bcl-2 signaling pathway and reducing caspase3 cleavage. Blockage of AKT signaling attenuated the role of Derlin-1 on radioresistance. Furthermore, Derlin-1 could interact with PI3K p110α in ESCC cell lines. Taken together, Our data demonstrate that Derlin-1 overexpression predicts poor prognosis and protects ESCC from irradiation induced apoptosis through PI3K/AKT/Bcl-2 signaling pathway. Derlin-1 may serve as a novel predictor for radiosentivity and a molecular target for ESCC. PMID:28903408

Bison and bovine rectoanal junctions exhibit similar cellular architecture and Escherichia coli O157 adherence patterns

PubMed Central

2013-01-01

Background Escherichia coli O157 (E. coli O157) has been isolated from bison retail meat, a fact that is important given that bison meat has been implicated in an E. coli O157-multistate outbreak. In addition, E. coli O157 has also been isolated from bison feces at slaughter and on farms. Cattle are well documented as E. coli O157 reservoirs, and the primary site of E. coli O157 persistence in such reservoirs is the rectoanal junction (RAJ), located at the distal end of the bovine gastrointestinal tract. Since bison and cattle share many genetic similarities manifested as common lineage, susceptibility to infection and the nature of immune responses to infectious agents, we decided to evaluate whether the RAJ of these animals were comparable both in terms of cellular architecture and as sites for adherence of E. coli O157. Specifically, we compared the histo-morphologies of the RAJ and evaluated the E. coli O157 adherence characteristics to the RAJ squamous epithelial (RSE) cells, from these two species. Results We found that the RAJ of both bison and cattle demonstrated similar distribution of epithelial cell markers villin, vimentin, cytokeratin, E-cadherin and N-cadherin. Interestingly, N-cadherin predominated in the stratified squamous epithelium reflecting its proliferative nature. E. coli O157 strains 86–24 SmR and EDL 933 adhered to RSE cells from both animals with similar diffuse and aggregative patterns, respectively. Conclusion Our observations further support the fact that bison are likely ‘wildlife’ reservoirs for E. coli O157, harboring these bacteria in their gastrointestinal tract. Our results also extend the utility of the RSE-cell assay, previously developed to elucidate E. coli O157-cattle RAJ interactions, to studies in bison, which are warranted to determine whether these observations in vitro correlate with those occurring in vivo at the RAJ within the bison gastrointestinal tract. PMID:24373611

Bison and bovine rectoanal junctions exhibit similar cellular architecture and Escherichia coli O157 adherence patterns.

PubMed

Kudva, Indira T; Stasko, Judith A

2013-12-28

Escherichia coli O157 (E. coli O157) has been isolated from bison retail meat, a fact that is important given that bison meat has been implicated in an E. coli O157-multistate outbreak. In addition, E. coli O157 has also been isolated from bison feces at slaughter and on farms. Cattle are well documented as E. coli O157 reservoirs, and the primary site of E. coli O157 persistence in such reservoirs is the rectoanal junction (RAJ), located at the distal end of the bovine gastrointestinal tract. Since bison and cattle share many genetic similarities manifested as common lineage, susceptibility to infection and the nature of immune responses to infectious agents, we decided to evaluate whether the RAJ of these animals were comparable both in terms of cellular architecture and as sites for adherence of E. coli O157. Specifically, we compared the histo-morphologies of the RAJ and evaluated the E. coli O157 adherence characteristics to the RAJ squamous epithelial (RSE) cells, from these two species. We found that the RAJ of both bison and cattle demonstrated similar distribution of epithelial cell markers villin, vimentin, cytokeratin, E-cadherin and N-cadherin. Interestingly, N-cadherin predominated in the stratified squamous epithelium reflecting its proliferative nature. E. coli O157 strains 86-24 SmR and EDL 933 adhered to RSE cells from both animals with similar diffuse and aggregative patterns, respectively. Our observations further support the fact that bison are likely 'wildlife' reservoirs for E. coli O157, harboring these bacteria in their gastrointestinal tract. Our results also extend the utility of the RSE-cell assay, previously developed to elucidate E. coli O157-cattle RAJ interactions, to studies in bison, which are warranted to determine whether these observations in vitro correlate with those occurring in vivo at the RAJ within the bison gastrointestinal tract.

Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett’s oesophagus

PubMed Central

Leedham, S J; Preston, S L; McDonald, S A C; Elia, G; Bhandari, P; Poller, D; Harrison, R; Novelli, M R; Jankowski, J A; Wright, N A

2008-01-01

Objectives: Current models of clonal expansion in human Barrett’s oesophagus are based upon heterogenous, flow-purified biopsy analysis taken at multiple segment levels. Detection of identical mutation fingerprints from these biopsy samples led to the proposal that a mutated clone with a selective advantage can clonally expand to fill an entire Barrett’s segment at the expense of competing clones (selective sweep to fixation model). We aimed to assess clonality at a much higher resolution by microdissecting and genetically analysing individual crypts. The histogenesis of Barrett’s metaplasia and neo-squamous islands has never been demonstrated. We investigated the oesophageal gland squamous ducts as the source of both epithelial sub-types. Methods: Individual crypts across Barrett’s biopsy and oesophagectomy blocks were dissected. Determination of tumour suppressor gene loss of heterozygosity patterns, p16 and p53 point mutations were carried out on a crypt-by-crypt basis. Cases of contiguous neo-squamous islands and columnar metaplasia with oesophageal squamous ducts were identified. Tissues were isolated by laser capture microdissection and genetically analysed. Results: Individual crypt dissection revealed mutation patterns that were masked in whole biopsy analysis. Dissection across oesophagectomy specimens demonstrated marked clonal heterogeneity, with multiple independent clones present. We identified a p16 point mutation arising in the squamous epithelium of the oesophageal gland duct, which was also present in a contiguous metaplastic crypt, whereas neo-squamous islands arising from squamous ducts were wild-type with respect to surrounding Barrett’s dysplasia. Conclusions: By studying clonality at the crypt level we demonstrate that Barrett’s heterogeneity arises from multiple independent clones, in contrast to the selective sweep to fixation model of clonal expansion previously described. We suggest that the squamous gland ducts situated throughout the oesophagus are the source of a progenitor cell that may be susceptible to gene mutation resulting in conversion to Barrett’s metaplastic epithelium. Additionally, these data suggest that wild-type ducts may be the source of neo-squamous islands. PMID:18305067

Oncogenic HRAS activates epithelial-mesenchyme transition and confers stemness to p53-deficient urothelial cells to drive muscle invasion of basal subtype carcinomas

PubMed Central

He, Feng; Melamed, Jonathan; Tang, Moon-shong; Huang, Chuanshu; Wu, Xue-Ru

2015-01-01

Muscle-invasive urothelial carcinomas of the bladder (MIUCB) exhibit frequent receptor tyrosine kinase alterations but the precise nature of their contributions to tumor pathophysiology is unclear. Using mutant HRAS (HRAS*) as an oncogenic prototype, we obtained evidence in transgenic mice that RTK/RAS pathway activation in urothelial cells causes hyperplasia that neither progresses to frank carcinoma nor regresses to normal urothelium through a period of one year. This persistent hyperplastic state appeared to result from an equilibrium between pro-mitogenic factors and compensatory tumor barriers in the p19-MDM2-p53-p21 axis and a prolonged G2 arrest. Conditional inactivation of p53 in urothelial cells of transgenic mice expressing HRAS* resulted in carcinoma-in-situ and basal-subtype MIUCB with focal squamous differentiation resembling the human counterpart. The transcriptome of microdissected MIUCB was enriched in genes that drive epithelial-mesenchyme transition, the upregulation of which is associated with urothelial cells expressing multiple progenitor/stem cell markers. Taken together, our results provide evidence for RTK/RAS pathway activation and p53 deficiency as a combinatorial theranostic biomarker which may inform the progression and treatment of urothelial carcinoma. PMID:25795707

Differential cytotoxicity of long-chain bases for human oral gingival epithelial keratinocytes, oral fibroblasts, and dendritic cells

PubMed Central

Mehalick, Leslie A.; Poulsen, Christopher; Fischer, Carol L.; Lanzel, Emily A.; Bates, Amber M.; Walters, Katherine S.; Cavanaugh, Joseph E.; Guthmiller, Janet M.; Johnson, Georgia K.; Wertz, Philip W.; Brogden, Kim A.

2015-01-01

Long-chain bases, found in the oral cavity, have potent antimicrobial activity against oral pathogens. In an article associated with this dataset, Poulson and colleagues determined the cytotoxicities of long-chain bases (sphingosine, dihydrosphingosine, and phytosphingosine) for human oral gingival epithelial (GE) keratinocytes, oral gingival fibroblasts (GF), dendritic cells (DC), and squamous cell carcinoma (SCC) cell lines [1]. Poulson and colleagues found that GE keratinocytes were more resistant to long-chain bases as compared to GF, DC, and SCC cell lines [1]. In this study, we assess the susceptibility of DC to lower concentrations of long chain bases. 0.2–10.0 µM long-chain bases and GML were not cytotoxic to DC; 40.0–80.0 µM long-chain bases, but not GML, were cytotoxic for DC; and 80.0 µM long-chain bases were cytotoxic to DC and induced cellular damage and death in less than 20 mins. Overall, the LD50 of long-chain bases for GE keratinocytes, GF, and DC were considerably higher than their minimal inhibitory concentrations for oral pathogens, a finding important to pursuing their future potential in treating periodontal and oral infections. PMID:26550599

Expression of matrix metalloproteinase-13 and Ki-67 in nonmelanoma skin cancer in xeroderma pigmentosum and non-xeroderma pigmentosum.

PubMed

El-Hawary, Amira K; Yassin, Eman; Khater, Ashraf; Abdelgaber, Soheir

2013-02-01

Xeroderma pigmentosum (XP) is a heterogenous group of genetic diseases in which basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer (NMSC) followed by squamous cell carcinoma (SCC). The aim of this study was to investigate the expression of matrix metalloproteinase (MMP)-13 and Ki-67 in SCC and BCC from patients with and without XP to elucidate their roles in the pathogenesis of these highly aggressive tumors in patients with XP. Immunolabeling using MMP-13 and Ki-67 antibodies was performed on tissue sections derived from skin biopsies of SCC and BCC of 15 patients with XP and 40 non-XP patients. There was no significant difference between XP and non-XP patients as regards MMP-13 expression by epithelial and stromal cells of SCC or BCC. Ki-67 expression in SCC and BCC of patients with XP was significantly higher than in non-XP patients. We concluded that the higher expression of Ki-67 in NMSC of patients with XP than of non-XP patients may reflect the growth and invasive capacity of these tumors in patients with XP. MMP-13 is expressed by tumor epithelial cells, stromal and inflammatory cells of NMSC of both XP and non-XP patients.

A Phase I Study of LJM716 in Squamous Cell Carcinoma of Head and Neck, or HER2+ Breast Cancer or Gastric Cancer

ClinicalTrials.gov

2014-04-21

HER2 + Breast Cancer, HER2 + Gastric Cancer, Squamous Cell Carcinoma of Head and Neck, Esophageal Squamous Cell Carcinoma; HER2 + Breast Cancer; HER2 + Gastric Cancer; Squamous Cell Carcinoma of Head and Neck; Esophageal Squamous Cell Carcinoma

KERATOACANTHOMA OF THE INFERIOR LIP: REVIEW AND REPORT OF CASE WITH SPONTANEOUS REGRESSION

PubMed Central

Ramos, Lara Maria A.; Cardoso, Sérgio V.; Loyola, Adriano M.; Rocha, Marcus A.; Durighetto, Antônio Francisco

2009-01-01

Keratoacanthoma (KA) is a self-limited benign epithelial proliferative lesion that eventually presents with very similar clinical features to squamous cell carcinoma. Many KA appear in the vermilion border of the lips and therefore dental professionals must be familiar of the disease. This article reports the case of a 40-year-old female patient presenting with an exophytic ulcerative tumor in her lower lip that resolved after incisional biopsy. Photographic documentation of the case is presented and topics that are relevant to the clinical management of the disease are addressed. PMID:19466263

Odontogenic Cysts and Neoplasms.

PubMed

Bilodeau, Elizabeth Ann; Collins, Bobby M

2017-03-01

This article reviews a myriad of common and uncommon odontogenic cysts and tumors. The clinical presentation, gross and microscopic features, differential diagnosis, prognosis, and diagnostic pitfalls are addressed for inflammatory cysts (periapical cyst, mandibular infected buccal cyst/paradental cyst), developmental cysts (dentigerous, lateral periodontal, glandular odontogenic, orthokeratinized odontogenic cyst), benign tumors (keratocystic odontogenic tumor, ameloblastoma, adenomatoid odontogenic tumor, calcifying epithelial odontogenic tumor, ameloblastic fibroma and fibroodontoma, odontoma, squamous odontogenic tumor, calcifying cystic odontogenic tumor, primordial odontogenic tumor, central odontogenic fibroma, and odontogenic myxomas), and malignant tumors (clear cell odontogenic carcinoma, ameloblastic carcinoma, ameloblastic fibrosarcoma). Copyright © 2016 Elsevier Inc. All rights reserved.

Transoral Robotic Surgery in Treating Patients With Benign or Malignant Tumors of the Head and Neck

ClinicalTrials.gov

2018-06-26

Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage 0 Hypopharyngeal Cancer; Stage 0 Laryngeal Cancer; Stage 0 Lip and Oral Cavity Cancer; Stage I Adenoid Cystic Carcinoma of the Oral Cavity; Stage I Mucoepidermoid Carcinoma of the Oral Cavity; Stage I Squamous Cell Carcinoma of the Hypopharynx; Stage I Squamous Cell Carcinoma of the Larynx; Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage I Verrucous Carcinoma of the Larynx; Stage I Verrucous Carcinoma of the Oral Cavity; Stage II Adenoid Cystic Carcinoma of the Oral Cavity; Stage II Mucoepidermoid Carcinoma of the Oral Cavity; Stage II Squamous Cell Carcinoma of the Hypopharynx; Stage II Squamous Cell Carcinoma of the Larynx; Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage II Verrucous Carcinoma of the Larynx; Stage II Verrucous Carcinoma of the Oral Cavity; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IVA Adenoid Cystic Carcinoma of the Oral Cavity; Stage IVA Mucoepidermoid Carcinoma of the Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Adenoid Cystic Carcinoma of the Oral Cavity; Stage IVB Mucoepidermoid Carcinoma of the Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Adenoid Cystic Carcinoma of the Oral Cavity; Stage IVC Mucoepidermoid Carcinoma of the Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer

Evaluation of Barrett esophagus by multiphoton microscopy.

PubMed

Chen, Jianxin; Wong, Serena; Nathanson, Michael H; Jain, Dhanpat

2014-02-01

Multiphoton microscopy (MPM) based on 2-photon excitation fluorescence and second-harmonic generation allows simultaneous visualization of cellular details and extracellular matrix components of fresh, unfixed, and unstained tissue. Portable multiphoton microscopes, which could be placed in endoscopy suites, and multiphoton endomicroscopes are in development, but their clinical utility is unknown. To examine fresh, unfixed endoscopic biopsies obtained from the distal esophagus and gastroesophageal junction to (1) define the MPM characteristics of normal esophageal squamous mucosa and gastric columnar mucosa, and (2) evaluate whether diagnosis of intestinal metaplasia/Barrett esophagus (BE) could be made reliably with MPM. The study examined 35 untreated, fresh biopsy specimens from 25 patients who underwent routine upper endoscopy. A Zeiss LSM 710 Duo microscope (Carl Zeiss, Thornwood, New York) coupled to a Spectra-Physics (Mountain View, California) Tsunami Ti:sapphire laser was used to obtain a MPM image within 4 hours of fresh specimen collection. After obtaining MPM images, the biopsy specimens were placed in 10% buffered formalin and submitted for routine histopathologic examination. Then, the MPM images were compared with the findings in the hematoxylin-eosin-stained, formalin-fixed, paraffin-embedded sections. The MPM characteristics of the squamous, gastric-type columnar and intestinal-type columnar epithelium were analyzed. In biopsies with discrepancy between MPM imaging and hematoxylin-eosin-stained sections, the entire tissue block was serially sectioned and reevaluated. A diagnosis of BE was made when endoscopic and histologic criteria were satisfied. Based on effective 2-photon excitation fluorescence of cellular reduced pyridine nucleotides and flavin adenine dinucleotide and lack of 2-photon excitation fluorescence of mucin and cellular nuclei, MPM could readily identify and distinguish among squamous epithelial cells, goblet cells, gastric foveolar-type mucous cells, and parietal cells in the area of gastroesophageal junction. Based on the cell types identified, the mucosa was defined as squamous, columnar gastric type (cardia/fundic-type), and metaplastic columnar intestinal-type/BE. Various types of mucosa seen in the study of 35 biopsies included normal squamous mucosa only (n = 14; 40%), gastric cardia-type mucosa only (n = 2; 6%), gastric fundic mucosa (n = 6; 17%), and both squamous and gastric mucosa (n = 13; 37%). Intestinal metaplasia was identified by the presence of goblet cells in 10 of 25 cases (40%) leading to a diagnosis of BE on MPM imaging and only in 7 cases (28%) by histopathology. In 3 of 35 biopsies (9%), clear-cut goblet cells were seen by MPM imaging but not by histopathology, even after the entire tissue block was sectioned. Based on effective 2-photon excitation fluorescence of elastin and second-harmonic generation of collagen, connective tissue in the lamina propria and the basement membrane was also visualized with MPM. Multiphoton microscopy has the ability to accurately distinguish squamous epithelium and different cellular elements of the columnar mucosa obtained from biopsies around the gastroesophageal junction, including goblet cells that are important for the diagnosis of BE. Thus, use of MPM in the endoscopy suite might provide immediate microscopic images during endoscopy, improving screening and surveillance of patients with BE.

Impact of gastro-oesophageal reflux on microRNA expression, location and function

PubMed Central

2013-01-01

Background Ulceration of the oesophageal squamous mucosa (ulcerative oesophagitis) is a pathological manifestation of gastro-oesophageal reflux disease, and is a major risk factor for the development of Barrett’s oesophagus. Barrett’s oesophagus is characterised by replacement of reflux-damaged oesophageal squamous epithelium with a columnar intestinal-like epithelium. We previously reported discovery of microRNAs that are differentially expressed between oesophageal squamous mucosa and Barrett’s oesophagus mucosa. Now, to better understand early steps in the initiation of Barrett’s oesophagus, we assessed the expression, location and function of these microRNAs in oesophageal squamous mucosa from individuals with ulcerative oesophagitis. Methods Quantitative real-time PCR was used to compare miR-21, 143, 145, 194, 203, 205 and 215 expression levels in oesophageal mucosa from individuals without pathological gastro-oesophageal reflux to individuals with ulcerative oesophagitis. Correlations between microRNA expression and messenger RNA differentiation markers BMP-4, CK8 and CK14 were analyzed. The cellular localisation of microRNAs within the oesophageal mucosa was determined using in-situ hybridisation. microRNA involvement in proliferation and apoptosis was assessed following transfection of a human squamous oesophageal mucosal cell line (Het-1A). Results miR-143, miR-145 and miR-205 levels were significantly higher in gastro-oesophageal reflux compared with controls. Elevated miR-143 expression correlated with BMP-4 and CK8 expression, and elevated miR-205 expression correlated negatively with CK14 expression. Endogenous miR-143, miR-145 and miR-205 expression was localised to the basal layer of the oesophageal epithelium. Transfection of miR-143, 145 and 205 mimics into Het-1A cells resulted in increased apoptosis and decreased proliferation. Conclusions Elevated miR-143, miR-145 and miR-205 expression was observed in oesophageal squamous mucosa of individuals with ulcerative oesophagitis. These miRNAs localised to the basal layer of the oesophageal epithelium. They reduced proliferation and increased apoptosis, and may play roles in regulating epithelial restoration in response to injury caused by gastro-oesophageal reflux. PMID:23297865

Impact of gastro-oesophageal reflux on microRNA expression, location and function.

PubMed

Smith, Cameron M; Michael, Michael Z; Watson, David I; Tan, Grace; Astill, David St J; Hummel, Richard; Hussey, Damian J

2013-01-08

Ulceration of the oesophageal squamous mucosa (ulcerative oesophagitis) is a pathological manifestation of gastro-oesophageal reflux disease, and is a major risk factor for the development of Barrett's oesophagus. Barrett's oesophagus is characterised by replacement of reflux-damaged oesophageal squamous epithelium with a columnar intestinal-like epithelium. We previously reported discovery of microRNAs that are differentially expressed between oesophageal squamous mucosa and Barrett's oesophagus mucosa. Now, to better understand early steps in the initiation of Barrett's oesophagus, we assessed the expression, location and function of these microRNAs in oesophageal squamous mucosa from individuals with ulcerative oesophagitis. Quantitative real-time PCR was used to compare miR-21, 143, 145, 194, 203, 205 and 215 expression levels in oesophageal mucosa from individuals without pathological gastro-oesophageal reflux to individuals with ulcerative oesophagitis. Correlations between microRNA expression and messenger RNA differentiation markers BMP-4, CK8 and CK14 were analyzed. The cellular localisation of microRNAs within the oesophageal mucosa was determined using in-situ hybridisation. microRNA involvement in proliferation and apoptosis was assessed following transfection of a human squamous oesophageal mucosal cell line (Het-1A). miR-143, miR-145 and miR-205 levels were significantly higher in gastro-oesophageal reflux compared with controls. Elevated miR-143 expression correlated with BMP-4 and CK8 expression, and elevated miR-205 expression correlated negatively with CK14 expression. Endogenous miR-143, miR-145 and miR-205 expression was localised to the basal layer of the oesophageal epithelium. Transfection of miR-143, 145 and 205 mimics into Het-1A cells resulted in increased apoptosis and decreased proliferation. Elevated miR-143, miR-145 and miR-205 expression was observed in oesophageal squamous mucosa of individuals with ulcerative oesophagitis. These miRNAs localised to the basal layer of the oesophageal epithelium. They reduced proliferation and increased apoptosis, and may play roles in regulating epithelial restoration in response to injury caused by gastro-oesophageal reflux.

The Harderian gland, its secretory duct and porphyrin content in the woodmouse (Apodemus sylvaticus).

PubMed Central

Johnston, H S; McGadey, J; Payne, A P; Thompson, G G; Moore, M R

1987-01-01

The Harderian gland of the woodmouse (Apodemus sylvaticus) consists of tubules lined by a single layer of epithelial cells with a surrounding layer of myoepithelial cells. The epithelium contains two cell types, one with numerous small, clear, lipid vacuoles (Type I), the other with large electron-dense ones (Type II). Each type is further subdivided into cells where the smooth endoplasmic reticulum exhibits pronounced vacuolation (Ia and IIa). The lipid vacuoles frequently coalesce and are released by exocytosis. They possess a multilamellar cap; similar multilamellar whorls (without a vacuole) are also seen. Polytubular complexes are a feature of Type II cells; tubules are in continuity with the smooth endoplasmic reticulum. Peroxisomes are also present. Fenestrated capillaries occur frequently in the interstitium, and (where no myoepithelial cell intervenes) the basal surface of the gland epithelial cell is covered with microvilli. There is no morphologically distinct duct system within the gland. The extraglandular duct is lined by columnar epithelium except at the opening on to the nictitating membrane where there is stratified squamous epithelium, with melanocytes and nests of mucus-secreting cells. The porphyrin content of the gland is low and solid intraluminal deposits are not seen. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 Fig. 14 Fig. 15 Fig. 16 PMID:3429316

Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain.

PubMed

Pichery, Mélanie; Mirey, Emilie; Mercier, Pascale; Lefrancais, Emma; Dujardin, Arnaud; Ortega, Nathalie; Girard, Jean-Philippe

2012-04-01

IL-33 (previously known as NF from high endothelial venules) is an IL-1 family cytokine that signals through the ST2 receptor and drives cytokine production in mast cells, basophils, eosinophils, invariant NKT and NK cells, Th2 lymphocytes, and type 2 innate immune cells (natural helper cells, nuocytes, and innate helper 2 cells). Little is known about endogenous IL-33; for instance, the cellular sources of IL-33 in mouse tissues have not yet been defined. In this study, we generated an Il-33-LacZ gene trap reporter strain (Il-33(Gt/Gt)) and used this novel tool to analyze expression of endogenous IL-33 in vivo. We found that the Il-33 promoter exhibits constitutive activity in mouse lymphoid organs, epithelial barrier tissues, brain, and embryos. Immunostaining with anti-IL-33 Abs, using Il-33(Gt/Gt) (Il-33-deficient) mice as control, revealed that endogenous IL-33 protein is highly expressed in mouse epithelial barrier tissues, including stratified squamous epithelia from vagina and skin, as well as cuboidal epithelium from lung, stomach, and salivary gland. Constitutive expression of IL-33 was not detected in blood vessels, revealing the existence of species-specific differences between humans and mice. Importantly, IL-33 protein was always localized in the nucleus of producing cells with no evidence for cytoplasmic localization. Finally, strong expression of the Il-33-LacZ reporter was also observed in inflamed tissues, in the liver during LPS-induced endotoxin shock, and in the lung alveoli during papain-induced allergic airway inflammation. Together, our findings support the possibility that IL-33 may function as a nuclear alarmin to alert the innate immune system after injury or infection in epithelial barrier tissues.

WNT4 is a key regulator of normal postnatal uterine development and progesterone signaling during embryo implantation and decidualization in the mouse

PubMed Central

Franco, Heather L.; Dai, Daisy; Lee, Kevin Y.; Rubel, Cory A.; Roop, Dennis; Boerboom, Derek; Jeong, Jae-Wook; Lydon, John P.; Bagchi, Indrani C.; Bagchi, Milan K.; DeMayo, Francesco J.

2011-01-01

WNT4, a member of the Wnt family of ligands, is critical for the development of the female reproductive tract. Analysis of Wnt4 expression in the adult uterus during pregnancy indicates that it may play a role in the regulation of endometrial stromal cell proliferation, survival, and differentiation, which is required to support the developing embryo. To investigate the role of Wnt4 in adult uterine physiology, conditional ablation of Wnt4 using the PRcre mouse model was accomplished. Ablation of Wnt4 rendered female mice subfertile due to a defect in embryo implantation and subsequent defects in endometrial stromal cell survival, differentiation, and responsiveness to progesterone signaling. In addition to altered stromal cell function, the uteri of PRcre/+Wnt4f/f (Wnt4d/d) mice displayed altered epithelial differentiation characterized by a reduction in the number of uterine glands and the emergence of a p63-positive basal cell layer beneath the columnar luminal epithelial cells. The altered epithelial cell phenotype was further escalated by chronic estrogen treatment, which caused squamous cell metaplasia of the uterine epithelium in the Wnt4d/d mice. Thus, WNT4 is a critical regulator not only of proper postnatal uterine development, but also embryo implantation and decidualization.—Franco, H. L., Dai, D., Lee, K. Y., Rubel, C. S., Roop, D., Boerboom, D., Jeong, J.-W., Lydon, J.-P., Bagchi, I. C., Bagchi, M. K., DeMayo, F. J. WNT4 is a key regulator of normal postnatal uterine development and progesterone signaling during embryo implantation and decidualization in the mouse. PMID:21163860

p16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma.

PubMed

Alexander, Riley E; Hu, Yingchuan; Kum, Jennifer B; Montironi, Rodolfo; Lopez-Beltran, Antonio; Maclennan, Gregory T; Idrees, Muhammad T; Emerson, Robert E; Ulbright, Thomas M; Grignon, David G; Eble, John N; Cheng, Liang

2012-11-01

Squamous cell carcinoma of the urinary bladder is unusual and of unknown etiology. There is a well-established association between human papillomavirus (HPV) infection and the development of cervical and head/neck squamous cell carcinomas. However, the role of HPV in the pathogenesis of squamous cell carcinoma of the urinary bladder is uncertain. The purposes of this study were to investigate the possible role of HPV in the development of squamous cell carcinoma of the urinary bladder and to determine if p16 expression could serve as a surrogate marker for HPV in this malignancy. In all, 42 cases of squamous cell carcinoma of the urinary bladder and 27 cases of urothelial carcinoma with squamous differentiation were investigated. HPV infection was analyzed by both in situ hybridization at the DNA level and immunohistochemistry at the protein level. p16 protein expression was analyzed by immunohistochemistry. HPV DNA and protein were not detected in 42 cases of squamous cell carcinoma (0%, 0/42) or 27 cases of urothelial carcinoma with squamous differentiation (0%, 0/15). p16 expression was detected in 13 cases (31%, 13/42) of squamous cell carcinoma and 9 cases (33%, 9/27) of urothelial carcinoma with squamous differentiation. There was no correlation between p16 expression and the presence of HPV infection in squamous cell carcinoma of the bladder or urothelial carcinoma with squamous differentiation. Our data suggest that HPV does not play a role in the development of squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation. p16 expression should not be used as a surrogate marker for evidence of HVP infection in either squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation as neither HVP DNA nor protein is detectable in these neoplasms.

Prevalence of cervical neoplastic lesions and Human Papilloma Virus infection in Egypt: National Cervical Cancer Screening Project

PubMed Central

Abd El All, Howayda S; Refaat, Amany; Dandash, Khadiga

2007-01-01

Background Data from Egyptian studies provide widely varying estimates on the prevalence of pre-malignant and malignant cervical abnormalities and human papilloma virus (HPVs) infection. To define the prevalence and risk factors of pre-invasive and invasive cervical cancer (cacx), a community based full-scale cross sectional, household survey including 5453 women aged between 35 and 60 years was conducted. Methods The study period was between February 2000 and December 2002. Initially, conventional Papanicolaou (Pap) smears were evaluated using the Bethesda system (TBS), followed by colposcopic guided biopsy (CGB) for all epithelial abnormalities (EA). In a third step, HPV was tested on all EA by in-situ hybridization (ISH) using first the broad spectrum HPV probe recognizing HPVs 6, 11, 16, 18, 30, 31, 35, 45, 51 and 52 followed by subtyping with probes 6/11, 16/18 and 31/33. Lastly, unequivocal cases were immunostained for herpes simplex type-2 (HSV-2), cytomegalovirus (CMV), and human immunodeficiency virus (HIV). Results EA representing 7.8% (424/5453), were categorized into atypical squamous cell of undetermined significance (ASCUS) (34.4%), atypical glandular cell of undetermined significance (AGCUS) (15.3%), combined ASCUS and AGCUS (3.1%), low grade squamous intraepithelial lesions (SIL) (41.0%), high grade SIL (5.2%) and invasive lesions (1%). CGB of EA (n = 281) showed non neoplastic lesions (12.8%), atypical squamous metaplasia (ASM) (19.2%), cervical intraepithelial neoplasia I (CIN) (44.4%), CIN II (4.4%), CINIII (2.8%), endocervical lesions (5.2%), combined squamous and endocervical lesions (10.0%), invasive squamous cell carcinoma (SCC) (0.02%) and extranodal marginal zone B cell lymphoma (MZBCL) (0.02%). The overall predictive value of cytology was 87% while the predictive value for high grade lesions was 80%. On histological basis, HPVs were present in 94.3% of squamous lesions while it was difficult to be identified in endocervical ones. ISH revealed positivity for pan HPV in 65.9% of the studied biopsies (n = 217), with incorporation of the viral genome HPV 6/11, 16/18 and 31/33 in 11.1%, 33.3% and 17.1% respectively. Multiple HPVs infections were identified in 0.02%. Conclusion Pre-invasive high grade lesions and invasive cervical carcinoma represent 0.5% and 0.04% respectively in Egyptian women. HPV mostly 16/18 as a risk factor (p < 0.001), was frequently associated with mixed infections (p < 0.001) and bilharzial infestation (p < 0.001). PMID:17610742

Hypermethylated ZNF582 and PAX1 genes in mouth rinse samples as biomarkers for oral dysplasia and oral cancer detection.

PubMed

Cheng, Shih-Jung; Chang, Chi-Feng; Ko, Hui-Hsin; Lee, Jang-Jaer; Chen, Hsin-Ming; Wang, Huei-Jen; Lin, Hsiao-Shan; Chiang, Chun-Pin

2018-02-01

Effective biomarkers for oral cancer screening are important for early diagnosis and treatment of oral cancer. Oral epithelial cell samples collected by mouth rinse were obtained from 65 normal control subjects, 108 patients with oral potentially malignant disorders, and 94 patients with oral squamous cell carcinoma (OSCC). Methylation levels of zinc-finger protein 582 (ZNF582) and paired-box 1 (PAX1) genes were quantified by real-time methylation-specific polymerase chain reaction after bisulfite conversion. An abrupt increase in methylated ZNF582 (ZNF582 m ) and PAX1 (PAX1 m ) levels and positive rates from mild dysplasia to moderate/severe dysplasia, indicating that both ZNF582 m and PAX1 m are effective biomarkers for differentiating moderate dysplasia or worse (MODY+) oral lesions. When ZNF582 m /PAX1 m tests were used for identifying MODY+ oral lesions, the sensitivity, specificity, and odds ratio (OR) were 0.65/0.64, 0.75/0.82, and 5.6/8.0, respectively. Hypermethylated ZNF582 and PAX1 genes in oral epithelial cells collected by mouth rinse are effective biomarkers for the detection of oral dysplasia and oral cancer. © 2017 Wiley Periodicals, Inc.

Esophagoscopy in Evaluating Treatment in Patients With Stage I-IV Head and Neck Cancer Who Are Undergoing Radiation Therapy and/or Chemotherapy

ClinicalTrials.gov

2017-05-25

Stage I Adenoid Cystic Carcinoma of the Oral Cavity; Stage I Mucoepidermoid Carcinoma of the Oral Cavity; Stage I Squamous Cell Carcinoma of the Hypopharynx; Stage I Squamous Cell Carcinoma of the Larynx; Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage I Verrucous Carcinoma of the Larynx; Stage I Verrucous Carcinoma of the Oral Cavity; Stage II Adenoid Cystic Carcinoma of the Oral Cavity; Stage II Mucoepidermoid Carcinoma of the Oral Cavity; Stage II Squamous Cell Carcinoma of the Hypopharynx; Stage II Squamous Cell Carcinoma of the Larynx; Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage II Verrucous Carcinoma of the Larynx; Stage II Verrucous Carcinoma of the Oral Cavity; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity

Implication of Highly Cytotoxic Natural Killer Cells for Esophageal Squamous Cell Carcinoma Treatment.

PubMed

Lim, Kee Siang; Mimura, Kosaku; Kua, Ley-Fang; Shiraishi, Kensuke; Kono, Koji

2018-04-20

Esophageal squamous cell carcinoma (ESCC) is an aggressive upper gastrointestinal cancer and effective treatments are limited. Previous studies reported that natural killer (NK) cells expanded by coculturing with K562-mb15-41BBL feeder cells, a genetically modified K562 leukemia cell line that expresses membrane-bound interleukin (IL)-15 and 41BBL ligand, were highly proliferative and highly cytotoxic. Here, we investigated the potential of expanded NK cells for ESCC treatment. We analyzed both genetic and surface expression levels of NKG2D ligands (NKG2DLs) in ESCC using publicly available microarray data sets and ESCC cell lines. The cytotoxicity of resting and of IL-2-activated NK cells against ESCC cell lines was compared with that of expanded NK cells. We then also investigated the effect of epithelial mesenchymal transition (EMT) inducers, GSK3β inhibitor and epidermal growth factor, on NKG2DLs expressions. As a result, MICA and MICB were significantly overexpressed in ESCC compared with adjacent normal tissues and surface NKG2DLs were expressed in ESCC cell lines. Expanded NK cells were much potent than IL-2-activated and resting NK cells against ESCC cell lines. Blocking of NKG2D with anti-NKG2D monoclonal antibody dampened expanded NK cell cytotoxicity, suggesting that the NKG2DLs-NKG2D interaction is crucial for NK cells to eliminate ESCC cells. EMT inducers concurrently induced EMT and NKG2DLs expression in ESCC cell lines rendering transitioned cells more sensitive to expanded NK cells. In conclusion, expanded NK cells were highly cytotoxic against NKG2DLs-expressing ESCC cells, particularly the EMT phenotype. These results provide a strong rationale for clinical use of these NK cells in ESCC patients.

Gefitinib in Treating Patients With Metastatic or Unresectable Head and Neck Cancer or Non-Small Cell Lung Cancer

ClinicalTrials.gov

2013-01-11

Anaplastic Thyroid Cancer; Insular Thyroid Cancer; Metastatic Parathyroid Cancer; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Parathyroid Cancer; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Thyroid Cancer; Recurrent Verrucous Carcinoma of the Larynx; Stage III Follicular Thyroid Cancer; Stage III Papillary Thyroid Cancer; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Larynx; Stage IIIB Non-small Cell Lung Cancer; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Non-small Cell Lung Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Adenoid Cystic Carcinoma of the Oral Cavity; Stage IVA Basal Cell Carcinoma of the Lip; Stage IVA Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Follicular Thyroid Cancer; Stage IVA Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IVA Lymphoepithelioma of the Oropharynx; Stage IVA Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IVA Mucoepidermoid Carcinoma of the Oral Cavity; Stage IVA Papillary Thyroid Cancer; Stage IVA Salivary Gland Cancer; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Adenoid Cystic Carcinoma of the Oral Cavity; Stage IVB Basal Cell Carcinoma of the Lip; Stage IVB Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Follicular Thyroid Cancer; Stage IVB Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IVB Lymphoepithelioma of the Oropharynx; Stage IVB Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IVB Mucoepidermoid Carcinoma of the Oral Cavity; Stage IVB Papillary Thyroid Cancer; Stage IVB Salivary Gland Cancer; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Adenoid Cystic Carcinoma of the Oral Cavity; Stage IVC Basal Cell Carcinoma of the Lip; Stage IVC Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Follicular Thyroid Cancer; Stage IVC Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IVC Lymphoepithelioma of the Oropharynx; Stage IVC Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IVC Mucoepidermoid Carcinoma of the Oral Cavity; Stage IVC Papillary Thyroid Cancer; Stage IVC Salivary Gland Cancer; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Thryoid Gland Nonmedullary Carcinoma; Thyroid Gland Medullary Carcinoma; Tongue Cancer; Untreated Metastatic Squamous Neck Cancer With Occult Primary

Increased expression of the retinoic acid-metabolizing enzyme CYP26A1 during the progression of cervical squamous neoplasia and head and neck cancer.

PubMed

Osanai, Makoto; Lee, Gang-Hong

2014-10-07

Retinoic acid (RA) is a critical regulator of cell differentiation, proliferation, and apoptosis in various cell types. Recently, the RA-metabolizing enzyme CYP26A1 (cytochrome P450, family 26, subfamily A, polypeptide 1) has been shown to have an oncogenic function in breast carcinogenesis. However, the relevance of elevated CYP26A1 expression in human cancers remains to be clarified. We immunohistochemically examined the expression of CYP26A1 in cervical squamous cell carcinoma (SCC) and its precursors, including low- and high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively), as well as head and neck cancer (HNC). The association between CYP26A1 expression and a number of clinicopathological parameters was also evaluated. CYP26A1 was not expressed in normal cervical epithelium. CYP26A1 expression was present in LSIL but limited to basal and parabasal cells. HSIL cases exhibited strong nuclear expression of CYP26A1 and mixed cytoplasmic expression patterns with widely distributed expression toward the epithelial surface. Importantly, strong cytoplasmic staining of CYP26A1 was observed in 19 of 50 (38%) patients with cervical SCC. Elevated expression of CYP26A1 was significantly associated with younger age (<50 years) and lymph node involvement (pN). Similarly, CYP26A1 was not expressed in non-neoplastic tissues of the head and neck, but strong cytoplasmic staining of CYP26A1 was observed in 52 of 128 (41%) HNC cases. Such strong CYP26A1 expression was significantly associated with the primary tumor stage of carcinomas (pT) and the pathological tumor-node-metastasis (pTNM) stage in HNC. Our results indicated an elevated CYP26A1 expression in malignant and precancerous dysplastic lesions of the human cervix, which also increased with the progression of cervical squamous neoplasia. In addition, this report is the first to demonstrate the increased expression of CYP26A1 in HNC and its significant correlation with primary tumor growth. These data suggested that CYP26A1 overexpression might contribute to the development and progression of cervical malignancies and squamous neoplasia of the head and neck.

Anti-tumor Effects of Plasma Activated Media and Correlation with Hydrogen Peroxide Concentration

NASA Astrophysics Data System (ADS)

Laroussi, Mounir; Mohades, Soheila; Barekzi, Nazir; Maruthamuthu, Venkat; Razavi, Hamid

2016-09-01

Plasma activated media (PAM) can induce death in cancer cells. In our research, PAM is produced by exposing liquid culture medium to a helium plasma pencil. Reactive oxygen and nitrogen species in the aqueous state are known factors in anti-tumor effects of PAM. The duration of plasma exposure determines the concentrations of reactive species produced in PAM. Stability of the plasma generated reactive species and their lifetime depend on parameters such as the chemical composition of the medium. Here, a complete cell culture medium was employed to make PAM. Later, PAM was used to treat SCaBER cancer cells either as an immediate PAM (right after exposure) or as an aged-PAM (after storage). SCaBER (ATCC®HTB-3™) is an epithelial cell line from a human bladder with the squamous carcinoma disease. A normal epithelial cell line from a kidney tissue of a dog - MDCK (ATCC®CCL-34™) - was used to analyze the selective effect of PAM. Correspondingly, we measured the concentration of hydrogen peroxide- as a stable species with biological impact on cell viability- in both immediate PAM and aged-PAM. In addition, we report on the effect of serum supplemented in PAM on the H2O2 concentration measured by Amplex red assay kit. Finally, we evaluate the effects of PAM on growth and morphological changes in MDCK cells using fluorescence microscopy.

Bevacizumab in Reducing CNS Side Effects in Patients Who Have Undergone Radiation Therapy to the Brain for Primary Brain Tumor, Meningioma, or Head and Neck Cancer

ClinicalTrials.gov

2014-04-21

Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Central Nervous System Germ Cell Tumor; Adult Choroid Plexus Tumor; Adult Diffuse Astrocytoma; Adult Ependymoma; Adult Grade II Meningioma; Adult Grade III Meningioma; Adult Malignant Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineocytoma; Malignant Neoplasm; Meningeal Melanocytoma; Radiation Toxicity; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Brain Tumor; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage I Adenoid Cystic Carcinoma of the Oral Cavity; Stage I Basal Cell Carcinoma of the Lip; Stage I Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage I Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage I Lymphoepithelioma of the Nasopharynx; Stage I Lymphoepithelioma of the Oropharynx; Stage I Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage I Mucoepidermoid Carcinoma of the Oral Cavity; Stage I Salivary Gland Cancer; Stage I Squamous Cell Carcinoma of the Hypopharynx; Stage I Squamous Cell Carcinoma of the Larynx; Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage I Squamous Cell Carcinoma of the Nasopharynx; Stage I Squamous Cell Carcinoma of the Oropharynx; Stage I Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage I Verrucous Carcinoma of the Larynx; Stage I Verrucous Carcinoma of the Oral Cavity; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Basal Cell Carcinoma of the Lip; Stage III Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage III Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage III Lymphoepithelioma of the Nasopharynx; Stage III Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity

Reduced-Dose Intensity-Modulated Radiation Therapy With or Without Cisplatin in Treating Patients With Advanced Oropharyngeal Cancer

ClinicalTrials.gov

2018-01-08

Stage III Oropharyngeal Squamous Cell Carcinoma; Stage IVA Oropharyngeal Squamous Cell Carcinoma; Stage IVB Oropharyngeal Squamous Cell Carcinoma; Stage IVC Oropharyngeal Squamous Cell Carcinoma; Tongue Carcinoma

A Study of LGK974 in Patients With Malignancies Dependent on Wnt Ligands

ClinicalTrials.gov

2018-05-16

Pancreatic Cancer; BRAF Mutant Colorectal Cancer; Melanoma; Triple Negative Breast Cancer; Head and Neck Squamous Cell Cancer; Cervical Squamous Cell Cancer; Esophageal Squamous Cell Cancer; Lung Squamous Cell Cancer

A unique cell-surface protein phenotype distinguishes human small-cell from non-small-cell lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baylin, S.B.; Gazdar, A.F.; Minna, J.D.

1982-08-01

Radioiodination (/sup 125/I) and two-dimensional polyacrylamide gel electrophoresis was used to determine that small-(oat) cell lung carcinoma (SCC)-a tumor with neuroedocrine features-possesses a surface protein pattern distinct from the other types of lung cancer cells (squamous, adeno-, and large-cell undifferentiated carcinoma). Twelve distinguishing proteins, 40 to 70 kilodaltons (kDal), characterized four separate lines of SCC; three of these, designated E (60 kDal; pI = 7.3), S (30 kDal; pI = 6.0), and U 57 kDal; pI = 5.6), may be unique SCC gene products and were identified only in (/sup 35/S)methionine labeling of SCC and not in non-SCC or humanmore » fibroblasts. Two lines of adeno-, one of squamous, and one of undifferentiated large-cell lung carcinoma exhibited similar surface protein patterns to one another. Nine distinguishing proteins (40 to 100 kDal) and at least five large proteins (>100 kDal) were unique to these lines. The surface protein phenotypes for SCC and non-SCC were distinct from those for human lymphoblastoid cells and fibroblasts. However, the neuroendocrine features of SCC were further substantiated because 6 of the 12 distinguishing SCC surface proteins, including E and U, were identified on human neuroblastoma cells. The proteins identified should (i) help define differentiation steps for normal and neoplastic bronchial epithelial cells, (ii) prove useful in better classifying lung cancers, and (iii) be instrumental in tracing formation of neuroendocrine cells.« less

DOK, a cell line established from human dysplastic oral mucosa, shows a partially transformed non-malignant phenotype.

PubMed

Chang, S E; Foster, S; Betts, D; Marnock, W E

1992-12-02

There are many reports of cell lines being established from human oral squamous-cell carcinomas but apparently none of cell lines from dysplastic or "pre-malignant" oral mucosa. We describe here the isolation and characterization of a cell line, DOK (dysplastic oral keratinocyte), from a piece of dorsal tongue showing epithelial dysplasia. The tissue was obtained from a 57-year-old man who was a heavy smoker prior to the appearance of a white patch on his tongue. Eleven years later a squamous-cell carcinoma developed at the site and was excised. Subsequently the remaining dysplasia was removed, and it was from a piece of this that the primary cell cultures which eventually gave rise to DOK were initiated. The DOK line has been single-cell cloned and is apparently immortal. It grows in the absence of 3T3 feeder cells, is anchorage-dependent for growth and is non-tumorigenic in nude mice. The keratin profile of the cells shows a striking similarity to that of the original tongue dysplasia. The karyotype of DOK is aneuploid and complex. By PCR and oligonucleotide hybridization on dot blots, codons 12, 13 and 61 of Ha-ras, Ki-ras and N-ras in DNA extracted from DOK cells were shown to be normal. Immunohistochemistry showed no abnormal, i.e., elevated expression of the onco-suppressor protein p53. Because of its origin and partially transformed phenotype, DOK presents an opportunity to study whether specific carcinogens associated with tobacco and areca nut can cause malignant transformation of oral keratinocytes in vitro.

Identification and validation of FGFR2 peptide for detection of early Barrett's neoplasia

PubMed Central

Zhou, Juan; He, Lei; Pang, Zhijun; Appelman, Henry D.; Kuick, Rork; Beer, David G.; Li, Meng; Wang, Thomas D.

2017-01-01

The incidence of esophageal adenocarcinoma (EAC) is rising rapidly, and early detection within the precursor state of Barrett's esophagus (BE) is challenged by flat premalignant lesions that are difficult detect with conventional endoscopic surveillance. Overexpression of cell surface fibroblast growth factor receptor 2 (FGFR2) is an early event in progression of BE to EAC, and is a promising imaging target. We used phage display to identify the peptide SRRPASFRTARE that binds specifically to the extracellular domain of FGFR2. We labeled this peptide with a near-infrared fluorophore Cy5.5, and validated the specific binding to FGFR2 overexpressed in cells in vitro. We found high affinity kd = 68 nM and rapid binding k = 0.16 min−1 (6.2 min). In human esophageal specimens, we found significantly greater peptide binding to high-grade dysplasia (HGD) versus either BE or normal squamous epithelium, and good correlation with anti-FGFR2 antibody. We also observed significantly greater peptide binding to excised specimens of esophageal squamous cell carcinoma and gastric cancer compared to normal mucosa. These results demonstrate potential for this FGFR2 peptide to be used as a clinical imaging agent to guide tissue biopsy and improve methods for early detection of EAC and potentially other epithelial-derived cancers. PMID:29152066

Photodynamic Therapy Using Temoporfin Before Surgery in Treating Patients With Recurrent Oral Cavity or Oropharyngeal Cancer

ClinicalTrials.gov

2014-09-02

Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage I Squamous Cell Carcinoma of the Oropharynx; Stage I Verrucous Carcinoma of the Oral Cavity; Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage II Squamous Cell Carcinoma of the Oropharynx; Stage II Verrucous Carcinoma of the Oral Cavity; Tongue Cancer

Immunohistochemical expression of basement membrane proteins of verrucous carcinoma of the oral mucosa.

PubMed

Arduino, Paolo G; Carrozzo, Marco; Pagano, Marco; Broccoletti, Roberto; Scully, Crispian; Gandolfo, Sergio

2010-06-01

Squamous cell carcinoma (SCC) of the oral cavity is an extremely invasive tumour of stratified squamous epithelium that spreads throughout degradation of the basement membrane (BM) and extra-cellular matrix. Oral verrucous carcinoma (VC) is a rare low-grade variant of oral SCC that penetrates into the subepithelial connective tissue. It also has a different clinical behaviour from classical oral SCC. We investigated the immunohistochemical expression of laminin, laminin-5, collagen IV and fibronectin in VC, severe epithelial dysplasia (SED) and SCC in order to analyse if the pattern of these molecules expression contributes to the differences in the biological behaviour of these diseases. The staining pattern of laminin was less intensive in SCC compared with SED and VC, and collagen IV expression was increased in VC compared with SED. Discontinuities of laminin, collagen IV and fibronectin were more evident in SED than in VC. This study indicates that VC has a biological behaviour different from SED or SCC, observable by immunohistochemistry in the BM zone.

Frequent β-catenin gene mutations in atypical polypoid adenomyoma of the uterus.

PubMed

Takahashi, Hiroyuki; Yoshida, Tsutomu; Matsumoto, Toshihide; Kameda, Yoichi; Takano, Yasuo; Tazo, Yuki; Inoue, Hisako; Saegusa, Makoto

2014-01-01

Atypical polypoid adenomyoma (APA) is an uncommon polypoid lesion of the uterus. To clarify the mechanism of its histogenesis, we examined the functional role of β-catenin, with reference to expression of p21(waf1), cyclin D1, cyclin E, CD10, and α-smooth muscle actin (SMA), as well as cell proliferation, in 7 lesions. In the epithelial components, expression of nuclear β-catenin, p21(waf1), and cyclin D1 was increased in a stepwise fashion from normal tissue through complex atypical hyperplasia and adenomyoma to APA lesions, particularly in squamous morular areas, whereas cell proliferation, as well as cyclin E expression, was significantly decreased in the latter. Similar findings were evident in the stromal lesions, with the exception of a case of nuclear β-catenin. In addition, coexpression of CD10 and α-SMA markers was observed in the stromal components in 3 APA cases, in line with the results of normal secretory endometrial and adenomyoma samples, suggesting that cells progress to myofibromatous cells in response to differentiation-promoting events. Finally, β-catenin gene (CTNNB1) mutations were detected in all APA cases, the single nucleotide substitutions being in the epithelial but not the stromal components. These findings suggest that activation of β-catenin signaling, probably secondary to the gene abnormalities, plays an important role in the formation of the complex epithelial architecture in APAs, leading to inhibition of cell proliferation through overexpression of p21(waf1). In contrast, changes in the stromal cell phenotype may occur through a shift from CD10 to α-SMA immunopositivity, independent of CTNNB1 status. © 2013.

Occludin Is Involved in Adhesion, Apoptosis, Differentiation and Ca2+-Homeostasis of Human Keratinocytes: Implications for Tumorigenesis

PubMed Central

Ohnemus, Ulrich; Kirschner, Nina; Vidal-y-Sy, Sabine; von den Driesch, Peter; Börnchen, Christian; Eberle, Jürgen; Mildner, Michael; Vettorazzi, Eik; Rosenthal, Rita; Moll, Ingrid; Brandner, Johanna M.

2013-01-01

Tight junction (TJ) proteins are involved in a number of cellular functions, including paracellular barrier formation, cell polarization, differentiation, and proliferation. Altered expression of TJ proteins was reported in various epithelial tumors. Here, we used tissue samples of human cutaneous squamous cell carcinoma (SCC), its precursor tumors, as well as sun-exposed and non-sun-exposed skin as a model system to investigate TJ protein alteration at various stages of tumorigenesis. We identified that a broader localization of zonula occludens protein (ZO)-1 and claudin-4 (Cldn-4) as well as downregulation of Cldn-1 in deeper epidermal layers is a frequent event in all the tumor entities as well as in sun-exposed skin, suggesting that these changes result from chronic UV irradiation. In contrast, SCC could be distinguished from the precursor tumors and sun-exposed skin by a frequent complete loss of occludin (Ocln). To elucidate the impact of down-regulation of Ocln, we performed Ocln siRNA experiments in human keratinocytes and uncovered that Ocln downregulation results in decreased epithelial cell-cell adhesion and reduced susceptibility to apoptosis induction by UVB or TNF-related apoptosis-inducing ligand (TRAIL), cellular characteristics for tumorigenesis. Furthermore, an influence on epidermal differentiation was observed, while there was no change of E-cadherin and vimentin, markers for epithelial-mesenchymal transition. Ocln knock-down altered Ca2+-homeostasis which may contribute to alterations of cell-cell adhesion and differentiation. As downregulation of Ocln is also seen in SCC derived from other tissues, as well as in other carcinomas, we suggest this as a common principle in tumor pathogenesis, which may be used as a target for therapeutic intervention. PMID:23390516

A black raspberry extract inhibits proliferation and regulates apoptosis in cervical cancer cells

PubMed Central

Zhang, Zhaoxia; Knobloch, Thomas J.; Seamon, Leigh G.; Stoner, Gary D.; Cohn, David E.; Paskett, Electra D.; Fowler, Jeffrey M.; Weghorst, Christopher M.

2014-01-01

Objective Cervical cancer is the second most common female cancer worldwide, and it remains a challenge to manage preinvasive and invasive lesions. Food-based cancer prevention entities, such as black raspberries and their derivatives, have demonstrated a marked ability to inhibit preclinical models of epithelial cancer cell growth and tumor formation. Here, we extend the role of black raspberry-mediated chemoprevention to that of cervical carcinogenesis. Methods Three human cervical cancer cell lines, HeLa (HPV16−/HPV18+, adenocarcinoma), SiHa (HPV16+/HPV18−, squamous cell carcinoma) and C-33A (HPV16−/HPV18−, squamous cell carcinoma), were treated with a lyophilized black raspberry ethanol extract (RO-ET) at 25, 50, 100 or 200 μg/ml for 1, 3 and 5 days, respectively. Cell proliferation was measured by WST1 (tetrazolium salt cleavage) assays. Flow cytometry (propidium iodide and Annexin V staining) and fluorescence microscopy analysis were used to measure apoptotic cell changes. Results We found that non-toxic levels of RO-ET significantly inhibited the growth of human cervical cancer cells, in a dose-dependent and time-dependent manner to a maximum of 54%, 52% and 67%, respectively (p<0.05). Furthermore, cell growth inhibition was persistent following short-term withdrawal of RO-ET from the culture medium. Flow cytometry and fluorescence microscopy demonstrated RO-ET-induced apoptosis in all cell lines. Conclusion Black raspberries and their bioactive components represent promising candidates for future phytochemical-based mechanistic pathway-targeted cancer prevention strategies. PMID:21831414

CEACAM1 in Cervical Cancer and Precursor Lesions: Association With Human Papillomavirus Infection

PubMed Central

Albarran-Somoza, Benibelks; Franco-Topete, Ramon; Delgado-Rizo, Vidal; Cerda-Camacho, Felipe; Acosta-Jimenez, Lourdes; Lopez-Botet, Miguel; Daneri-Navarro, Adrian

2006-01-01

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is an adhesion molecule expressed in a wide variety of tissues including epithelial cells, leukocytes, and tumors that may establish both homotypic and heterotypic interactions. The aim of this work was to study the protein expression pattern of CEACAM1 in cervical cancer and precursor lesions in the context of human papillomavirus (HPV) infection. We used immunohistochemistry to analyze CEACAM1 expression in formalin-fixed, paraffin-embedded cervical tissues from 15 healthy women, 15 patients with low-grade squamous intraepithelial lesions (SIL), 15 patients with high-grade SIL, and 15 patients with squamous carcinomas. HPV types were identified by PCR. CEACAM1 was either undetectable (13/15) or low (2/15) in normal cervical tissues. By contrast, CEACAM1 expression was increased in high-grade SIL (10 samples staining intermediate/high and 4 samples staining low) as compared with low-grade SIL with undetectable (n=3) or low (n= 12) expression. CEACAM1 expression was undetectable or low in cervical carcinoma. Our results suggest that CEACAM1 may be an interesting progression marker in SIL and cervical cancer, in particular due to reported immunoregulatory properties. PMID:16924126

Human esophageal myofibroblasts secrete proinflammatory cytokines in response to acid and Toll-like receptor 4 ligands

PubMed Central

Gargus, Matthew; Niu, Chao; Vallone, John G.; Binkley, Jana; Rubin, Deborah C.

2015-01-01

The pathophysiology of esophageal injury, repair, and inflammation in gastroesophageal reflux-disease (GERD) is complex. Whereas most studies have focused on the epithelial response to GERD injury, we are interested in the stromal response. We hypothesized that subepithelial esophageal myofibroblasts in GERD secrete proinflammatory cytokines in response to injurious agents encountered via epithelial barrier breaches or through dilated epithelial intercellular spaces. We determined the percentage of myofibroblasts [α-smooth muscle actin (α-SMA)+vimentin+CD31−] in the subepithelial GERD and normal esophageal stroma by immunomorphologic analysis. We performed α-SMA coimmunostaining with IL-6 and p65. We established and characterized primary cultures of α-SMA+vimentin+CD31−CD45− human esophageal myofibroblasts (HuEso MFs). We modeled GERD by treatment with pH 4.5-acidified media and Toll-like receptor 4 (TLR4) ligands, LPS and high-mobility group box 1 protein (HMGB1), and determined myofibroblast cytokine secretion in response to GERD injury. We demonstrate that spindle-shaped cell myofibroblasts are located near the basement membrane of stratified squamous epithelium in normal esophagus. We identify an increase in subepithelial myofibroblasts and activation of proinflammatory pathways in patients with GERD. Primary cultures of stromal cells obtained from normal esophagus retain myofibroblast morphology and express the acid receptor transient receptor potential channel vanilloid subfamily 1 (TRPV1) and TLR4. HuEso MFs stimulated with acid and TLR4 agonists LPS and HMGB1 increase IL-6 and IL-8 secretion via TRPV1 and NF-κB activation. Our work implicates a role for human subepithelial stromal cells in the pathogenesis of GERD-related esophageal injury. Findings of this study can be extended to the investigation of epithelial-stromal interactions in inflammatory esophageal mucosal disorders. PMID:25882613

A global analysis of the complex landscape of isoforms and regulatory networks of p63 in human cells and tissues.

PubMed

Sethi, Isha; Romano, Rose-Anne; Gluck, Christian; Smalley, Kirsten; Vojtesek, Borivoj; Buck, Michael J; Sinha, Satrajit

2015-08-07

The transcription factor p63 belongs to the p53/p63/p73 family and plays key functional roles during normal epithelial development and differentiation and in pathological states such as squamous cell carcinomas. The human TP63 gene, located on chromosome 3q28 is driven by two promoters that generate the full-length transactivating (TA) and N-terminal truncated (ΔN) isoforms. Furthermore alternative splicing at the C-terminus gives rise to additional α, β, γ and likely several other minor variants. Teasing out the expression and biological function of each p63 variant has been both the focus of, and a cause for contention in the p63 field. Here we have taken advantage of a burgeoning RNA-Seq based genomic data-sets to examine the global expression profiles of p63 isoforms across commonly utilized human cell-lines and major tissues and organs. Consistent with earlier studies, we find ΔNp63 transcripts, primarily that of the ΔNp63α isoforms, to be expressed in most cells of epithelial origin such as those of skin and oral tissues, mammary glands and squamous cell carcinomas. In contrast, TAp63 is not expressed in the majority of normal cell-types and tissues; rather it is selectively expressed at moderate to high levels in a subset of Burkitt's and diffuse large B-cell lymphoma cell lines. We verify this differential expression pattern of p63 isoforms by Western blot analysis, using newly developed ΔN and TA specific antibodies. Furthermore using unsupervised clustering of human cell lines, tissues and organs, we show that ΔNp63 and TAp63 driven transcriptional networks involve very distinct sets of molecular players, which may underlie their different biological functions. In this study we report comprehensive and global expression profiles of p63 isoforms and their relationship to p53/p73 and other potential transcriptional co-regulators. We curate publicly available data generated in part by consortiums such as ENCODE, FANTOM and Human Protein Atlas to delineate the vastly different transcriptomic landscapes of ΔNp63 and TAp63. Our studies help not only in dispelling prevailing myths and controversies on p63 expression in commonly used human cell lines but also augur new isoform- and cell type-specific activities of p63.

Cell-type-specific roles for COX-2 in UVB-induced skin cancer

PubMed Central

Herschman, Harvey

2014-01-01

In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2 flox/flox mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2 flox/flox;K14Cre + mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2 flox/flox;K14Cre + papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2 flox/flox; LysMCre + myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer. PMID:24469308

Cell-type-specific roles for COX-2 in UVB-induced skin cancer.

PubMed

Jiao, Jing; Mikulec, Carol; Ishikawa, Tomo-o; Magyar, Clara; Dumlao, Darren S; Dennis, Edward A; Fischer, Susan M; Herschman, Harvey

2014-06-01

In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2(flox/flox) mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2(flox/flox);K14Cre(+) mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2(flox/flox);K14Cre(+) papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2(flox/flox); LysMCre(+) myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

How Are Squamous and Basal Cell Skin Cancers Diagnosed?

MedlinePlus

... and Staging Tests for Basal and Squamous Cell Skin Cancers Most skin cancers are brought to a doctor’s ... Skin Cancers? More In Basal and Squamous Cell Skin Cancer About Basal and Squamous Cell Skin Cancer Causes, ...

Immunotherapy With MK-3475 in Surgically Resectable Head and Neck Squamous Cell Carcinoma

ClinicalTrials.gov

2018-02-08

Cancer of Head and Neck; Head and Neck Cancer; Neoplasms, Head and Neck; Carcinoma, Squamous Cell of Head and Neck; Squamous Cell Carcinoma of the Head and Neck; Squamous Cell Carcinoma, Head and Neck

Langerhans Cells and Their Role in Oral Mucosal Diseases

PubMed Central

Upadhyay, Juhi; Upadhyay, Ram B; Agrawal, Pankaj; Jaitley, Shweta; Shekhar, Rhitu

2013-01-01

Dendritic cells are arguably the most potent antigen-presenting cells and may be the only cells capable of initiating the adaptive immune response. The epithelial residents of dendritic cells are Langerhans cells, which serve as the “sentinels” of the mucosa, altering the immune system not only to pathogen entry but also of tolerance to self antigen and commensal microbes. Oral mucosal Langerhans cells are capable of engaging and internalizing a wide variety of pathogens and have been found responsive to nickel in patients with nickel allergies, oral Candida species, oral lichen planus, lichenoid drug eruptions, graft versus host diseases, periodontal diseases median rhomboid glossitis, human immunodeficiency virus infection, hairy leukoplakia of the tongue, and oral squamous cell carcinoma. Review focuses on the role of antigen-presenting cells in particular Langerhans cells to better understand the mechanisms underlying immune responses. In this review, comprehensive detail about mucosal diseases has been compiled using the PubMed database and through textbooks. PMID:24251267

Prevention of esophageal strictures after endoscopic submucosal dissection

PubMed Central

Kobayashi, Shinichiro; Kanai, Nobuo; Ohki, Takeshi; Takagi, Ryo; Yamaguchi, Naoyuki; Isomoto, Hajime; Kasai, Yoshiyuki; Hosoi, Takahiro; Nakao, Kazuhiko; Eguchi, Susumu; Yamamoto, Masakazu; Yamato, Masayuki; Okano, Teruo

2014-01-01

Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have recently been accepted as less invasive methods for treating patients with early esophageal cancers such as squamous cell carcinoma and dysplasia of Barrett’s esophagus. However, the large defects in the esophageal mucosa often cause severe esophageal strictures, which dramatically reduce the patient’s quality of life. Although preventive endoscopic balloon dilatation can reduce dysphagia and the frequency of dilatation, other approaches are necessary to prevent esophageal strictures after ESD. This review describes several strategies for preventing esophageal strictures after ESD, with a particular focus on anti-inflammatory and tissue engineering approaches. The local injection of triamcinolone acetonide and other systemic steroid therapies are frequently used to prevent esophageal strictures after ESD. Tissue engineering approaches for preventing esophageal strictures have recently been applied in basic research studies. Scaffolds with temporary stents have been applied in five cases, and this technique has been shown to be safe and is anticipated to prevent esophageal strictures. Fabricated autologous oral mucosal epithelial cell sheets to cover the defective mucosa similarly to how commercially available skin products fabricated from epidermal cells are used for skin defects or in cases of intractable ulcers. Fabricated autologous oral-mucosal-epithelial cell sheets have already been shown to be safe. PMID:25386058

Determination of the cellular retinoic-acid-binding protein in dysplastic epithelia of the cervix uteri, differentiated into apo and holo forms.

PubMed

Volz-Köster, S; Volz, J; Kiefer, A; Biesalski, H K

2000-01-01

The appearance of the cervical mucosa is regulated by different factors including retinoic acid. Hormone-dependent alteration of the cervix uteri mucosa is accompanied by a decrease or increase of cytoplasmatic retinoic-acid-binding protein (CRABP). To elucidate whether this hormone-dependent alteration of CRABP is preserved in the case of neoplasms of the cervix uteri, we measured the level of total and apo-CRABP in normal and neoplastically transformed cervical cells. In a prospective pilot study, standardised biopsies of normal epithelium and cervical intra-epithelial neoplasm grade 3 (CIN III) were taken from 24 patients. A newly developed method was used to determine the intra-epithelial level of apo- and total CRABP. The concentration of total CRABP in normal squamous epithelium compared with that in intra-epithelial neoplasm grade 3 is very significantly lower in the CIN III areas (normal: 3.66 +/- 1.46 pmol/ mg wet weight +/- SD; CIN III 1.43 +/- 0.59 pmol/mg P < 0.01). In addition CRABP in the apo form is lower in normal than in neoplastic epithelium (Wilcoxon test for paired non-parametric values: P < 0.05; mean for all patients: normal: 1.65 + 0.82 pmol/mg; CIN III: 1.14 +/- 0.23 pmol/mg). From our results we conclude that, in neoplastically transformed cells, the hormone-dependent CRABP cycle is interrupted. Whether this has consequences for the further development of the neoplastic cells has to be elucidated.

Tissue-engineered skin preserving the potential of epithelial cells to differentiate into hair after grafting.

PubMed

Larouche, Danielle; Cuffley, Kristine; Paquet, Claudie; Germain, Lucie

2011-03-01

The aim of this study was to evaluate whether tissue-engineered skin produced in vitro was able to sustain growth of hair follicles in vitro and after grafting. Different tissues were designed. Dissociated newborn mouse keratinocytes or newborn mouse hair buds (HBs) were added onto dermal constructs consisting of a tissue-engineered cell-derived matrix elaborated from either newborn mouse or adult human fibroblasts cultured with ascorbic acid. After 7-21 days of maturation at the air-liquid interface, no hair was noticed in vitro. Epidermal differentiation was observed in all tissue-engineered skin. However, human fibroblast-derived tissue-engineered dermis (hD) promoted a thicker epidermis than mouse fibroblast-derived tissue-engineered dermis (mD). In association with mD, HBs developed epithelial cyst-like inclusions presenting outer root sheath-like attributes. In contrast, epidermoid cyst-like inclusions lined by a stratified squamous epithelium were present in tissues composed of HBs and hD. After grafting, pilo-sebaceous units formed and hair grew in skin elaborated from HBs cultured 10-26 days submerged in culture medium in association with mD. However, the number of normal hair follicles decreased with longer culture time. This hair-forming capacity after grafting was not observed in tissues composed of hD overlaid with HBs. These results demonstrate that epithelial stem cells can be kept in vitro in a permissive tissue-engineered dermal environment without losing their potential to induce hair growth after grafting.

Identification of Prognostic Biomarkers for Progression of Invasive Squamous Cell Carcinoma

ClinicalTrials.gov

2017-10-09

Carcinoma, Squamous Cell; Carcinoma, Squamous; Squamous Cell Carcinoma; Lung Neoplasms; Cancer of Lung; Cancer of the Lung; Lung Cancer; Neoplasms, Lung; Neoplasms, Pulmonary; Pulmonary Cancer; Pulmonary Neoplasms

A case of usual (basaloid)-type vulvar intraepithelial neoplasia that failed to respond to imiquimod cream: clinical implications.

PubMed

Shiozaki, Takaya; Tabata, Tsutomu; Toriyabe, Kuniaki; Motohashi, Takashi; Kondo, Eiji; Tanida, Kouji; Okugawa, Toshiharu; Sagawa, Norimasa

2011-10-01

The authors report a case of usual-type (basaloid-type) vulvar intraepithelial neoplasia (VIN) 3 that failed to respond to imiquimod cream. A 51-year-old Japanese woman visited her local gynecologist complaining of vulvar itching. Atypical cells were noted in cytology smears, but nine vulvar biopsy specimens showed benign proliferation of epithelial tissue. The patient was placed under careful observation for 8 months, when the vulvar smears once again showed atypical cells and biopsy specimens revealed VIN3. The patient was then referred to our hospital where she was given a diagnosis of VIN 3, basaloid type of usual type. The biopsy specimens were positive for p16 and the lesions were confirmed to be human papilloma virus (HPV)-related. We recommended simple vulvectomy but the patient requested conservative treatment with imiquimod cream. With her written informed consent, we prescribed imiquimod cream to be self-administered 3 times a week. Colposcopy and pap smear test were performed every 2 weeks. Four weeks after the start of treatment, a fingertip-sized papule was detected at the patient's vaginal introitus. By 6 weeks, the lesion had enlarged, and biopsy specimens revealed invasive squamous cell carcinoma. At 7 weeks, we performed simple vulvectomy. The surgical specimen showed stage pT1b keratinizing-type squamous cell carcinoma. HPV-16 DNA was detected in the specimen.

Phase Ib Study of BKM120 With Cisplatin and XRT in High Risk Locally Advanced Squamous Cell Cancer of Head and Neck

ClinicalTrials.gov

2017-05-19

Carcinoma, Squamous Cell of Head and Neck; HPV Positive Oropharyngeal Squamous Cell Carcinoma; Hypopharyngeal Cancer; Early Invasive Cervical Squamous Cell Carcinoma; Carcinoma of Larynx; Cancer of Nasopharynx

Patient Preferences in Making Treatment Decisions in Patients With Stage I-IVA Oropharyngeal Cancer

ClinicalTrials.gov

2015-09-01

Stage I Squamous Cell Carcinoma of the Oropharynx; Stage II Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Tongue Cancer

Comparison of Adaptive Dose Painting by Numbers With Standard Radiotherapy for Head and Neck Cancer.

ClinicalTrials.gov

2018-05-17

Primary Non-operated Squamous Cell Carcinoma of Oral Cavity; Primary Non-operated Squamous Cell Carcinoma of Oropharynx; Primary Non-operated Squamous Cell Carcinoma of Hypopharynx; Primary Non-operated Squamous Cell Carcinoma of Larynx

In epithelial cancers, aberrant COL17A1 promoter methylation predicts its misexpression and increased invasion.

PubMed

Thangavelu, Pulari U; Krenács, Tibor; Dray, Eloise; Duijf, Pascal H G

2016-01-01

Metastasis is a leading cause of death among cancer patients. In the tumor microenvironment, altered levels of extracellular matrix proteins, such as collagens, can facilitate the first steps of cancer cell metastasis, including invasion into surrounding tissue and intravasation into the blood stream. However, the degree of misexpression of collagen genes in tumors remains understudied, even though this knowledge could greatly facilitate the development of cancer treatment options aimed at preventing metastasis. We systematically evaluate the expression of all 44 collagen genes in breast cancer and assess whether their misexpression provides clinical prognostic significance. We use immunohistochemistry on 150 ductal breast cancers and 361 cervical cancers and study DNA methylation in various epithelial cancers. In breast cancer, various tests show that COL4A1 and COL4A2 overexpression and COL17A1 ( BP180 , BPAG2 ) underexpression provide independent prognostic strength (HR = 1.25, 95% CI = 1.17-1.34, p  = 3.03 × 10 -10 ; HR = 1.18, 95% CI = 1.11-1.25, p  = 8.11 × 10 -10 ; HR = 0.86, 95% CI = 0.81-0.92, p  = 4.57 × 10 -6 ; respectively). Immunohistochemistry on ductal breast cancers confirmed that the COL17A1 protein product, collagen XVII, is underexpressed. This strongly correlates with advanced stage, increased invasion, and postmenopausal status. In contrast, immunohistochemistry on cervical tumors showed that collagen XVII is overexpressed in cervical cancer and this is associated with increased local dissemination. Interestingly, consistent with the opposed direction of misexpression in these cancers, the COL17A1 promoter is hypermethylated in breast cancer and hypomethylated in cervical cancer. We also find that the COL17A1 promoter is hypomethylated in head and neck squamous cell carcinoma, lung squamous cell carcinoma, and lung adenocarcinoma, in all of which collagen XVII overexpression has previously been shown. Paradoxically, collagen XVII is underexpressed in breast cancer and overexpressed in cervical and other epithelial cancers. However, the COL17A1 promoter methylation status accurately predicts both the direction of misexpression and the increased invasive nature for five out of five epithelial cancers. This implies that aberrant epigenetic control is a key driver of COL17A1 gene misexpression and tumor cell invasion. These findings have significant clinical implications, suggesting that the COL17A1 promoter methylation status can be used to predict patient outcome. Moreover, epigenetic targeting of COL17A1 could represent a novel strategy to prevent metastasis in patients.

[The structure of the gastric mucosa of the llamas (Lama guanocoe and Lama lamae). I. Forestomach].

PubMed

Luciano, L; Voss-Wermbter, G; Behnke, M; von Engelhardt, W; Reale, E

1979-01-01

The mucous membrane of the first and second compartments (ventral regions) as well as of the third compartment of Lama guanacoe and Lama lamae stomach shows tubular glands opening into pits. Below the surface epithelium blood capillaries of the fenestrated type form a regular network, each mesh of which surrounds a gastric pit. From a morphological point of view (thin section and freeze-fracture replicas) the columnar cells of the surface epithelium and those of the pits closest to the capillaries are largely similar to the epithelial cells of the rabbit gallbladder. This similarity suggests that at the level of the columnar cells sodium-dependent water reabsorption occurs. This reabsorption has already been demonstrated in the abovementioned compartments by physiological methods. The surface and foveolae epithelial cells as well as some cells of the tubular glands have a secretory function. Their secretory granules contain mucosubstances, as indicated by light-(PAS- and Alcian blue reactions) and electron microscopic (PA-TCH-Ag-reaction) histochemistry. The secretory granules originate from the Golgi complex which shows a positive histochemical reaction in its innermost sacculi at the electron microscope level. Endocrine cells (s. second part of this investigation) are rare. The mucosal membrane of each muscular lip separating the glandular sacs in the first compartment shows a stratified, not keratinized, squamous epithelium.

Chemotherapy-Induced Long Non-coding RNA 1 Promotes Metastasis and Chemo-Resistance of TSCC via the Wnt/β-Catenin Signaling Pathway.

PubMed

Lin, Zhaoyu; Sun, Lijuan; Xie, Shule; Zhang, Shanyi; Fan, Song; Li, Qunxing; Chen, Weixiong; Pan, Guokai; Wang, Weiwei; Weng, Bin; Zhang, Zhang; Liu, Bodu; Li, Jinsong

2018-06-06

Increasing evidence has shown that chemo-resistance is related to the process of epithelial-mesenchymal transition (EMT) and increased invasiveness by tongue squamous cell carcinoma (TSCC) cells. Long non-coding RNAs (lncRNAs) play pivotal roles in tumor metastasis and progression. However, the roles and mechanisms of lncRNAs in cisplatin-resistance-induced EMT and metastasis are not well understood. In this study, a chemotherapy-induced lncRNA 1 (CILA1) was discovered by using microarrays and was functionally identified as a regulator of chemo-sensitivity in TSCC cells. Upregulation of CILA1 promotes EMT, invasiveness, and chemo-resistance in TSCC cells, whereas the inhibition of CILA1 expression induces mesenchymal-epithelial transition (MET) and chemo-sensitivity, and inhibits the invasiveness of cisplatin-resistant cells both in vitro and in vivo. We also found that CILA1 exerts its functions via the activation of the Wnt/β-catenin signaling pathway. High CILA1 expression levels and low levels of phosphorylated β-catenin were closely associated with cisplatin resistance and advanced disease stage, and were predictors of poor prognosis in TSCC patients. These findings provided a new biomarker for the chemo-sensitivity of TSCC tumors and a therapeutic target for TSCC treatment. Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Targeting cancer stem cell plasticity through modulation of epidermal growth factor and insulin-like growth factor receptor signaling in head and neck squamous cell cancer.

PubMed

Leong, Hui Sun; Chong, Fui Teen; Sew, Pui Hoon; Lau, Dawn P; Wong, Bernice H; Teh, Bin-Tean; Tan, Daniel S W; Iyer, N Gopalakrishna

2014-09-01

Emerging data suggest that cancer stem cells (CSCs) exist in equilibrium with differentiated cells and that stochastic transitions between these states can account for tumor heterogeneity and drug resistance. The aim of this study was to establish an in vitro system that recapitulates stem cell plasticity in head and neck squamous cell cancers (HNSCCs) and identify the factors that play a role in the maintenance and repopulation of CSCs. Tumor spheres were established using patient-derived cell lines via anchorage-independent cell culture techniques. These tumor spheres were found to have higher aldehyde dehydrogenase (ALD) cell fractions and increased expression of Kruppel-like factor 4, SRY (sex determining region Y)-box 2, and Nanog and were resistant to γ-radiation, 5-fluorouracil, cisplatin, and etoposide treatment compared with monolayer culture cells. Monolayer cultures were subject to single cell cloning to generate clones with high and low ALD fractions. ALDHigh clones showed higher expression of stem cell and epithelial-mesenchymal transition markers compared with ALDLow clones. ALD fractions, representing stem cell fractions, fluctuated with serial passaging, equilibrating at a level specific to each cell line, and could be augmented by the addition of epidermal growth factor (EGF) and/or insulin. ALDHigh clones showed increased EGF receptor (EGFR) and insulin-like growth factor-1 receptor (IGF-1R) phosphorylation, with increased activation of downstream pathways compared with ALDLow clones. Importantly, blocking these pathways using specific inhibitors against EGFR and IGF-1R reduced stem cell fractions drastically. Taken together, these results show that HNSCC CSCs exhibit plasticity, with the maintenance of the stem cell fraction dependent on the EGFR and IGF-1R pathways and potentially amenable to targeted therapeutics. ©AlphaMed Press.

Artificial Polymeric Scaffolds as Extracellular Matrix Substitutes for Autologous Conjunctival Goblet Cell Expansion

PubMed Central

He, Min; Storr-Paulsen, Thomas; Wang, Annie L.; Ghezzi, Chiara E.; Wang, Siran; Fullana, Matthew; Karamichos, Dimitrios; Utheim, Tor P.; Islam, Rakibul; Griffith, May; Islam, M. Mirazul; Hodges, Robin R.; Wnek, Gary E.; Kaplan, David L.; Dartt, Darlene A.

2016-01-01

Purpose We fabricated and investigated polymeric scaffolds that can substitute for the conjunctival extracellular matrix to provide a substrate for autologous expansion of human conjunctival goblet cells in culture. Methods We fabricated two hydrogels and two silk films: (1) recombinant human collagen (RHC) hydrogel, (2) recombinant human collagen 2-methacryloylxyethyl phosphorylcholine (RHC-MPC) hydrogel, (3) arginine-glycine-aspartic acid (RGD) modified silk, and (4) poly-D-lysine (PDL) coated silk, and four electrospun scaffolds: (1) collagen, (2) poly(acrylic acid) (PAA), (3) poly(caprolactone) (PCL), and (4) poly(vinyl alcohol) (PVA). Coverslips and polyethylene terephthalate (PET) were used for comparison. Human conjunctival explants were cultured on scaffolds for 9 to 15 days. Cell viability, outgrowth area, and the percentage of cells expressing markers for stratified squamous epithelial cells (cytokeratin 4) and goblet cells (cytokeratin 7) were determined. Results Most of cells grown on all scaffolds were viable except for PCL in which only 3.6 ± 2.2% of the cells were viable. No cells attached to PVA scaffold. The outgrowth was greatest on PDL-silk and PET. Outgrowth was smallest on PCL. All cells were CK7-positive on RHC-MPC while 84.7 ± 6.9% of cells expressed CK7 on PDL-silk. For PCL, 87.10 ± 3.17% of cells were CK7-positive compared to PET where 67.10 ± 12.08% of cells were CK7-positive cells. Conclusions Biopolymer substrates in the form of hydrogels and silk films provided for better adherence, proliferation, and differentiation than the electrospun scaffolds and could be used for conjunctival goblet cell expansion for eventual transplantation once undifferentiated and stratified squamous cells are included. Useful polymer scaffold design characteristics have emerged from this study. PMID:27832279

Artificial Polymeric Scaffolds as Extracellular Matrix Substitutes for Autologous Conjunctival Goblet Cell Expansion.

PubMed

He, Min; Storr-Paulsen, Thomas; Wang, Annie L; Ghezzi, Chiara E; Wang, Siran; Fullana, Matthew; Karamichos, Dimitrios; Utheim, Tor P; Islam, Rakibul; Griffith, May; Islam, M Mirazul; Hodges, Robin R; Wnek, Gary E; Kaplan, David L; Dartt, Darlene A

2016-11-01

We fabricated and investigated polymeric scaffolds that can substitute for the conjunctival extracellular matrix to provide a substrate for autologous expansion of human conjunctival goblet cells in culture. We fabricated two hydrogels and two silk films: (1) recombinant human collagen (RHC) hydrogel, (2) recombinant human collagen 2-methacryloylxyethyl phosphorylcholine (RHC-MPC) hydrogel, (3) arginine-glycine-aspartic acid (RGD) modified silk, and (4) poly-D-lysine (PDL) coated silk, and four electrospun scaffolds: (1) collagen, (2) poly(acrylic acid) (PAA), (3) poly(caprolactone) (PCL), and (4) poly(vinyl alcohol) (PVA). Coverslips and polyethylene terephthalate (PET) were used for comparison. Human conjunctival explants were cultured on scaffolds for 9 to 15 days. Cell viability, outgrowth area, and the percentage of cells expressing markers for stratified squamous epithelial cells (cytokeratin 4) and goblet cells (cytokeratin 7) were determined. Most of cells grown on all scaffolds were viable except for PCL in which only 3.6 ± 2.2% of the cells were viable. No cells attached to PVA scaffold. The outgrowth was greatest on PDL-silk and PET. Outgrowth was smallest on PCL. All cells were CK7-positive on RHC-MPC while 84.7 ± 6.9% of cells expressed CK7 on PDL-silk. For PCL, 87.10 ± 3.17% of cells were CK7-positive compared to PET where 67.10 ± 12.08% of cells were CK7-positive cells. Biopolymer substrates in the form of hydrogels and silk films provided for better adherence, proliferation, and differentiation than the electrospun scaffolds and could be used for conjunctival goblet cell expansion for eventual transplantation once undifferentiated and stratified squamous cells are included. Useful polymer scaffold design characteristics have emerged from this study.

Overexpression of angiopoietin 2 promotes the formation of oral squamous cell carcinoma by increasing epithelial-mesenchymal transition-induced angiogenesis.

PubMed

Li, C; Li, Q; Cai, Y; He, Y; Lan, X; Wang, W; Liu, J; Wang, S; Zhu, G; Fan, J; Zhou, Y; Sun, R

2016-09-01

Oral squamous cell carcinoma (OSCC) is the most common cancer of the head and neck and is associated with a high rate of lymph node metastasis. The initial step in the metastasis and transition of tumors is epithelial-mesenchymal transition (EMT)-induced angiogenesis, which can be mediated by angiopoietin 2 (ANG2), a key regulatory factor in angiogenesis. In the present study, immunohistochemistry and real-time quantitative reverse transcriptase (qRT-PCR) were used to measure the expression of ANG2 in OSCC tissues. Plasmids encoding ANG2 mRNA were used for increased ANG2 expression in the OSCC cell line TCA8113. The short interfering RNA (siRNA)-targeting ANG2 mRNA sequences were used to inhibit ANG2 expression in TCA8113 cells. Subsequently, transwell assays were performed to examine the effects of ANG2 on TCA8113 cell migration and invasion. Furthermore, in vivo assays were performed to assess the effect of ANG2 on tumor growth. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays and immunohistochemistry were used to examine cell apoptosis and angiogenesis in tumor tissues, respectively. Finally, western blot analysis was performed to evaluate tumor formation-related proteins in OSCC tissues. We found that protein expression of ANG2 was remarkably upregulated in OSCC tissues. Overexpression of ANG2 increased the migration and invasion of TCA8113 cells by regulating EMT. Further investigations showed that overexpression of ANG2 increased tumor growth in nude mice, and angiogenesis of OSCC tissues increased in the presence of ANG2 overexpression. Overexpression of ANG2 also reduced cell apoptosis in tumor tissue cells. Finally, we found that overexpression of ANG2 resulted in changes in the expression of tumor formation-related proteins including vimentin, E-cadherin, Bim, PUMA, Bcl-2, Bax, Cyclin D1, PCNA and CD31. Our findings show that ANG2 has an important role in the migration and invasion of OSCC. More importantly, further investigations suggested that overexpression of ANG2 might increase OSCC metastasis by promoting angiogenesis in nude mice. This stimulatory effect could be achieved by inducing abnormal EMT and by reducing apoptosis and increasing proliferation of cells.

Original Research: miR-194 inhibits proliferation and invasion and promotes apoptosis by targeting KDM5B in esophageal squamous cell carcinoma cells.

PubMed

Cui, Guanghui; Liu, Donglei; Li, Weihao; Li, Yuhang; Liang, Youguang; Shi, Wensong; Zhao, Song

2017-01-01

Increasing evidence suggests that miR-194 is down-regulated in esophageal squamous cell carcinoma tumor tissue. However, the role and underlying mechanism of miR-194 in esophageal squamous cell carcinoma have not been well defined. We used DIANA, TargetScan and miRanda to perform target prediction analysis and found KDM5B is a potential target of miR-194. Based on these findings, we speculated that miR-194 might play a role in esophageal squamous cell carcinoma development and progression by regulation the expression of KDM5B. We detected the expression of miR-194 and KDM5B by quantitative real-time reverse transcription PCR (qRT-PCR) and Western blot assays, respectively, and found down-regulation of miR-194 and up-regulation of KDM5B existed in esophageal squamous cell carcinoma cell lines. By detecting proliferation, invasion and apoptosis of TE6 and TE14 cells transfected with miR-194 mimics or mimic control, miR-194 was found to inhibit proliferation and invasion and promote apoptosis of esophageal squamous cell carcinoma cells. miR-194 was further verified to regulate proliferation, apoptosis and invasion of esophageal squamous cell carcinoma cells by directly targeting KDM5B. Furthermore, animal studies were performed and showed that overexpression of miR-194 inhibited the growth of esophageal squamous cell carcinoma tumors in vivo. These results confirmed our speculation that miR-194 targets KDM5B to inhibit esophageal squamous cell carcinoma development and progression. These findings offer new clues for esophageal squamous cell carcinoma development and progression and novel potential therapeutic targets for esophageal squamous cell carcinoma. © 2016 by the Society for Experimental Biology and Medicine.