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Sample records for epithelial tumors outcome

  1. Isolation by Size of Epithelial Tumor Cells

    PubMed Central

    Vona, Giovanna; Sabile, Abdelmajid; Louha, Malek; Sitruk, Veronique; Romana, Serge; Schütze, Karin; Capron, Frédérique; Franco, Dominique; Pazzagli, Mario; Vekemans, Michel; Lacour, Bernard; Bréchot, Christian; Paterlini-Bréchot, Patrizia

    2000-01-01

    We have developed a new assay, ISET (isolation by size of epithelial tumor cells), which allows the counting and the immunomorphological and molecular characterization of circulating tumor cells in patients with carcinoma, using peripheral blood sample volumes as small as 1 ml. Using this assay, epithelial tumor cells can be isolated individually by filtration because of their larger size when compared to peripheral blood leukocytes. ISET parameters were defined using peripheral blood spiked with tumor cell lines (HepG2, Hep3B, MCF-7, HeLa, and LNCaP). ISET can detect a single, micropipetted tumor cell, added to 1 ml of blood. We also demonstrate that fluorescence in situ hybridization can be used to perform chromosomal analyses on tumor cells collected using ISET. Polymerase chain reaction-based genetic analyses can be applied to ISET-isolated cells, and, as an example, we demonstrate homozygous p53 deletion in single Hep3B cells after filtration and laser microdissection. Finally, we provide evidence for the in vivo feasibility of ISET in patients with hepatocellular carcinoma undergoing tumor resection. ISET, but not reverse transcriptase-polymerase chain reaction, allowed analysis of cell morphology, counting of tumor cells, and demonstration of tumor microemboli spread into peripheral blood during surgery. Overall, ISET constitutes a novel approach that should open new perpectives in molecular medicine. PMID:10623654

  2. Normal morphogenesis of epithelial tissues and progression of epithelial tumors

    PubMed Central

    Wang, Chun-Chao; Jamal, Leen; Janes, Kevin A.

    2011-01-01

    Epithelial cells organize into various tissue architectures that largely maintain their structure throughout the life of an organism. For decades, the morphogenesis of epithelial tissues has fascinated scientists at the interface of cell, developmental, and molecular biology. Systems biology offers ways to combine knowledge from these disciplines by building integrative models that are quantitative and predictive. Can such models be useful for gaining a deeper understanding of epithelial morphogenesis? Here, we take inventory of some recurring themes in epithelial morphogenesis that systems approaches could strive to capture. Predictive understanding of morphogenesis at the systems level would prove especially valuable for diseases such as cancer, where epithelial tissue architecture is profoundly disrupted. PMID:21898857

  3. Normal morphogenesis of epithelial tissues and progression of epithelial tumors.

    PubMed

    Wang, Chun-Chao; Jamal, Leen; Janes, Kevin A

    2012-01-01

    Epithelial cells organize into various tissue architectures that largely maintain their structure throughout the life of an organism. For decades, the morphogenesis of epithelial tissues has fascinated scientists at the interface of cell, developmental, and molecular biology. Systems biology offers ways to combine knowledge from these disciplines by building integrative models that are quantitative and predictive. Can such models be useful for gaining a deeper understanding of epithelial morphogenesis? Here, we take inventory of some recurring themes in epithelial morphogenesis that systems approaches could strive to capture. Predictive understanding of morphogenesis at the systems level would prove especially valuable for diseases such as cancer, where epithelial tissue architecture is profoundly disrupted.

  4. Epithelial derived CTGF promotes breast tumor progression via inducing EMT and collagen I fibers deposition

    PubMed Central

    Zhao, Zhen; Sheng, Jianting; Wang, Jiang; Liu, Jiyong; Cui, Kemi; Chang, Jenny; Zhao, Hong; Wong, Stephen

    2015-01-01

    Interactions among tumor cells, stromal cells, and extracellular matrix compositions are mediated through cytokines during tumor progression. Our analysis of 132 known cytokines and growth factors in published clinical breast cohorts and our 84 patient-derived xenograft models revealed that the elevated connective tissue growth factor (CTGF) in tumor epithelial cells significantly correlated with poor clinical prognosis and outcomes. CTGF was able to induce tumor cell epithelial-mesenchymal transition (EMT), and promote stroma deposition of collagen I fibers to stimulate tumor growth and metastasis. This process was mediated through CTGF-tumor necrosis factor receptor I (TNFR1)-IκB autocrine signaling. Drug treatments targeting CTGF, TNFR1, and IκB signaling each prohibited the EMT and tumor progression. PMID:26318291

  5. Epithelial-mesenchymal, mesenchymal-epithelial, and endothelial-mesenchymal transitions in malignant tumors: An update

    PubMed Central

    Gurzu, Simona; Turdean, Sabin; Kovecsi, Attila; Contac, Anca Otilia; Jung, Ioan

    2015-01-01

    Epithelial-to-mesenchymal transition (EMT) represents conversion of an epithelial cell in an elongated cell with mesenchymal phenotype, which can occur in physiologic and pathologic processes such as embryogenesis (type 1 EMT), wound healing and/or fibrosis (type 2 EMT) and malignant tumors (type 3 EMT). The proliferation rate, metastasizing and recurrence capacity, as also the individualized response at chemotherapics, in both epithelial and mesenchymal malignant tumors is known to be influenced by reversible switch between EMT and mesenchymal-to-epithelial transition (MET). Although much research work has already been done in these fields, the specific molecular pathways of EMT, relating to the tumor type and tumor localization, are yet to be elucidated. In this paper, based on the literature and personal experience of the authors, an update in the field of EMT vs MET in epithelial and mesenchymal tumors is presented. The authors tried to present the latest data about the particularities of these processes, and also of the so-called endothelial-to-mesenchymal transition, based on tumor location. The EMT-angiogenesis link is discussed as a possible valuable parameter for clinical follow-up and targeted therapeutic oncologic management. The paper begins with presentation of the basic aspects of EMT, its classification and assessment possibilities, and concludes with prognostic and therapeutic perspectives. The particularities of EMT and MET in gastric and colorectal carcinomas, pancreatic cancer, hepatocellular and cholangiocarcinomas, and lung, breast and prostate cancers, respectively in sarcomas and gastrointestinal stromal tumors are presented in detail. PMID:25984514

  6. Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells

    PubMed Central

    Celià-Terrassa, Toni; Meca-Cortés, Óscar; Mateo, Francesca; Martínez de Paz, Alexia; Rubio, Nuria; Arnal-Estapé, Anna; Ell, Brian J.; Bermudo, Raquel; Díaz, Alba; Guerra-Rebollo, Marta; Lozano, Juan José; Estarás, Conchi; Ulloa, Catalina; ρlvarez-Simón, Daniel; Milà, Jordi; Vilella, Ramón; Paciucci, Rosanna; Martínez-Balbás, Marian; García de Herreros, Antonio; Gomis, Roger R.; Kang, Yibin; Blanco, Jerónimo; Fernández, Pedro L.; Thomson, Timothy M.

    2012-01-01

    Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial-mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs. PMID:22505459

  7. [A case of the calcifying epithelial odontogenic tumor (Pindborg's tumor). Reported and literature review].

    PubMed

    Peña-Torres, Leandro Miguel; Monterrubio-Guerrero, Alejandro; Díaz de León-Sandoval, Laura Alejandra

    2010-01-01

    The calcifying epithelial odontogenic tumor known as Pindborg's tumor, is a rare odontogenic neoplasm of the jaws. One of their characteristics is the cortical expansion and the relationship with a non erupted tooth. Since the original description in 1955, only 200 cases approximately have been described in the world literature. This article reviews the literature and describes a case of patient who presented calcifying epithelial odontogenic tumor in the jaw undergoing surgical excision treatment with an evolution without complications.

  8. Mitochondrial DNA Mutations in Epithelial Ovarian Tumor Progression

    DTIC Science & Technology

    2007-12-01

    histological subtype of ovarian cancer and is the most lethal gynecologic malignancy. The relationship between stage at presentation and survival in serous ...among and within stages of epithelial ovarian cancer , focusing on serous , mucinous and endometrioid subtypes (1-18 Months). a. Collections and...not serous or mucinous epithelial ovarian tumors. Cancer Res 58: 2095-2097, 1998. 7. Aikhionbare FO et al:.: Is cumulative frequency of mitochondrial

  9. Epithelial membrane protein 1 expression in ovarian serous tumors.

    PubMed

    Demirag, Guzin Gonullu; Kefeli, Mehmet; Kemal, Yasemin; Yucel, Idris

    2016-03-01

    The present study aimed to analyze the clinical significance of epithelial membrane protein 1 (EMP1) expression in ovarian serous tumors. A total of 84 cases of ovarian serous tumor (50 patients with malignant ovarian serous tumors and 34 patients with borderline and benign serous tumors) were retrospectively analyzed. Differences in the expression levels of EMP1 between the malignant and non-malignant tumor groups were evaluated by immunohistochemical staining. In addition, the association between EMP1 expression and prognostic factors in malignant ovarian serous tumors was investigated. The expression levels of EMP1 were significantly reduced in all the 50 malignant ovarian serous tumors, compared with the 34 non-malignant ovarian serous tumors (P<0.000). Reduced expression of EMP1 was correlated with high grade (P=0.009) and stage (P<0.000) of malignant tumors. EMP1 expression was not observed to be correlated with any other investigated parameters, including surgery, type of operation and chemotherapy response (P>0.005). These results indicated that EMP1 may have a significant role as a negative regulator in ovarian serous tumors, and reduced EMP1 expression in serous tumors may be associated with increased disease severity.

  10. Heterogeneous proliferative potential of occult metastatic cells in bone marrow of patients with solid epithelial tumors

    PubMed Central

    Solakoglu, Oender; Maierhofer, Christine; Lahr, Georgia; Breit, Elisabeth; Scheunemann, Peter; Heumos, Isabella; Pichlmeier, Uwe; Schlimok, Günter; Oberneder, Ralph; Köllermann, Manfred W.; Köllermann, Jens; Speicher, Michael R.; Pantel, Klaus

    2002-01-01

    Bone marrow is a major homing site for circulating epithelial tumor cells. The present study was aimed to assess the proliferative capacity of occult metastatic cells in bone marrow of patients with operable solid tumors especially with regard to their clinical outcome. We obtained bone marrow aspirates from 153 patients with carcinomas of the prostate (n = 46), breast (n = 45), colon (n = 33), and kidney (n = 29). Most of the patients (87%) had primary disease with no clinical signs of overt metastases [tumor-node-metastasis (TNM)-stage UICC (Union Internationale Contre le Cancer) I-III]. After bone marrow was cultured for 21–102 days under special cell culture conditions, viable epithelial cells were detected by cytokeratin staining in 124 patients (81%). The cultured epithelial cells harbored Ki-ras2 mutations and numerical chromosomal aberrations. The highest median number of expanded tumor cells was observed in prostate cancer (2,619 per flask). There was a significant positive correlation between the number of expanded tumor cells and the UICC-stage of the patients (P = 0.03) or the presence of overt metastases (P = 0.04). Moreover, a strong expansion of tumor cells was correlated to an increased rate of cancer-related deaths (P = 0.007) and a reduced survival of the patients (P = 0.006). In conclusion, the majority of cancer patients have viable tumor cells in their bone marrow at primary tumor diagnosis, and the proliferative potential of these cells determines the clinical outcome. PMID:11854519

  11. Neuroendocrine marker expression in thyroid epithelial tumors.

    PubMed

    Satoh, F; Umemura, S; Yasuda, M; Osamura, R Y

    2001-01-01

    Tissue sections from 50 cases with thyroid tumors, composed of 11 follicular adenomas, 10 follicular carcinomas, 14 papillary carcinomas, 10 anaplastic carcinomas, and 5 medullary carcinomas, were immunohistochemically analyzed for representative neuroendocrine markers. Immunoexpression ratios of these neuroendocrine markers were as follows: Follicular adenomas, neuron-specific enolase (NSE)63.6%, synaptophysin (SynP) 45.5%, Leu7 27.3%, NCAM 45.5%, chromogranin A (CgA) 0%, SNAP25 0%; follicular carcinomas, NSE 90.0%, SynP 80.0%, Leu7 80.0%, NCAM 0%, CgA 0%, SNAP25 0%; papillary carcinomas, NSE 85.7%, SynP 78.6%, Leu7 100%, NCAM 7.0%, CgA 0%, SNAP25.0%; anaplastic carcinomas, NSE 10.0%, SynP 0%, Leu7 0%, NCAM 0%, CgA 0%, SNAP25 0%; medullary carcinomas, NSE 100%, SynP100%, Leu7 80.0%, NCAM 40.0%, CgA 100%, SNAP25 100%. The two follicular carcinomas, which were morphologically characterized by "insular" (or "alveolar") arrangements, showed distinct immunoexpression of NSE and SynP at the same time. By in situ hybridization (ISH), expression of mRNA for NSE was confirmed in cases with marked immunoexpression of NSE. Although no endocrine granules were found, our results suggested that a specific type of follicular carcinoma, i.e., insular variant, may be immaturely neuroendocrine-differentiated.

  12. Mixed epithelial and stromal tumor of the kidney.

    PubMed

    Adsay, N V; Eble, J N; Srigley, J R; Jones, E C; Grignon, D J

    2000-07-01

    We describe the clinicopathologic features of 12 patients with a distinctive tumor of the kidney characterized by a mixture of epithelial and stromal elements that form solid and cystic growth patterns. Similar tumors were reported previously in the literature under various names, including adult mesoblastic nephroma. All but one of the patients were women. The only man had a long history of treatment with lupron and diethylstilbesterol. Seven of the women had histories of long-term oral estrogen use of whom six had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy several years prior, and the seventh patient had been using oral contraceptives for many years. Another woman had this operation but did not receive any hormone therapy. Ages ranged from 31 to 71 years (mean, 56 yrs). Six patients presented with symptoms, including pain and infections attributable to mass effect, and in six the tumor was detected incidentally. Grossly, the tumors were well-circumscribed (mean size, 6 cm; range, 3-12 cm) and consisted of solid and cystic components, most often in equal proportions but in variable distribution. Microscopically, the spindle cell component ranged in appearance from scar-like fibrous tissue to leiomyoma-like interlacing fascicles; usually there was a mixture of both. More cellular foci reminiscent of ovarian stroma or solitary fibrous tumor were also present. No blastema was present. Epithelial elements (composed of clusters of tubules with variable lining) were scattered amidst the spindle cells, and focally transformed into large cysts lined by cells with abundant pink cytoplasm and a hobnail appearance. Immature epithelial elements typical of Wilms' tumor were not present. Muscle markers (desmin and smooth muscle actin) were positive diffusely and strongly in the spindle cells of all tumors, whereas HMB-45 and CD34 were absent. Estrogen receptors were detected in the nuclei of spindle cells in seven tumors and progesterone

  13. Calcifying epithelial odontogenic tumor: a clinico-radio-pathological dilemma.

    PubMed

    Hada, M S; Sable, M; Kane, S V; Pai, Prathamesh S; Juvekar, S L

    2014-01-01

    The calcifying epithelial odontogenic tumor (CEOT) is a rare benign neoplasm of mandible in adults. The presentation of this entity is varied and often confused with a variety of mucosal and jaw lesions and clinical, radiological, and pathological feature of CEOT often-mimic malignancy. The objective of this report is to highlight the clinical features and radiological findings which should arouse suspicion of a benign lesion and importance of providing adequate clinical information to the pathologist to attain accurate diagnosis.We discussed two cases with tumors located in the maxilla. Both presented as expansile lesions with one biopsy proven squamous cell carcinoma. Both were pursued with clinico-radiological suspicion of benign lesions and confirmed with pathological correlation of histology and immunohistochemistry as CEOT. Therefore a High index of suspicion and clinico-radiological information are the key feature for diagnosis of this rare tumor.

  14. Epithelial borderline ovarian tumor: Diagnosis and treatment strategy.

    PubMed

    Ushijima, Kimio; Kawano, Kouichiro; Tsuda, Naotake; Nishio, Shin; Terada, Atsumu; Kato, Hiroyuki; Tasaki, Kazuto; Matsukuma, Ken

    2015-05-01

    Epithelial borderline ovarian tumors (BOT) are distinctive from benign tumors and carcinoma. They occur in younger women more often than carcinoma, and there is some difficulty making correct diagnosis of BOT. Two subtypes of BOT, serous and mucinous borderline tumor have different characteristics and very different clinical behavior. Serous borderline tumor (SBT) with micropapillary pattern shows more incidence of extra ovarian disease and often coexists with invasive implant. SBT with micropapillary pattern in advanced stage has showed a worse prognosis than typical SBT. Huge mucinous borderline tumors have histologic heterogeneity, and the accuracy of frozen section diagnosis is relatively low. Extensive sampling is required to reach a correct pathological diagnosis. Mucinous adenoma (intestinal type) also runs the risk of recurrence after cystectomy, or intraoperative rupture of cyst. Laparoscopic procedure for BOT has not increased the risk of recurrence. Fertility preserving procedures are generally accepted, except in advanced stage SBT with invasive implants. Only cystectomy shows a significant risk of recurrence. Re-staging surgery and full staging surgery is not necessary for all BOT. We should not attempt to treat them uniformly, by the single diagnosis of "borderline tumor". It depends on histologic type. Close communication with the pathologist is necessary to gain more detail and ask more pathological samples in order to make the optimal treatment strategy for each individual patients.

  15. Epithelial mesenchymal transition and tumor budding in aggressive colorectal cancer: tumor budding as oncotarget.

    PubMed

    Zlobec, Inti; Lugli, Alessandro

    2010-11-01

    Epithelial mesenchymal transition (EMT) is proposed as a critical mechanism for the acquisition of malignant phenotypes by epithelial cells. In colorectal cancer, tumor cells having undergone EMT are histologically represented by the presence of tumor buds defined as single cells or small clusters of de-differentiated tumor cells at the invasive front. Tumor budding is not a static, histological feature rather it represents a snap-shot of a dynamic process undertaken by an aggressive tumor with the potential to disseminate and metastasize. Strong, consistent evidence shows that tumor budding is a predictor of lymph node metastasis, distant metastatic disease, local recurrence, worse overall and disease-free survival time and an independent prognostic factor. Moreover, the International Union against Cancer (UICC) recognizes tumor budding as a highly relevant, additional prognostic parameter. The aim of this review is to summarize the evidence supporting the implementation of tumor budding into diagnostic pathology and patient management and additionally to illustrate its worthiness as a potential therapeutic target.

  16. Epithelial mesenchymal transition and tumor budding in aggressive colorectal cancer: Tumor budding as oncotarget

    PubMed Central

    Zlobec, Inti; Lugli, Alessandro

    2010-01-01

    Epithelial mesenchymal transition (EMT) is proposed as a critical mechanism for the acquisition of malignant phenotypes by epithelial cells. In colorectal cancer, tumor cells having undergone EMT are histologically represented by the presence of tumor buds defined as single cells or small clusters of de-differentiated tumor cells at the invasive front. Tumor budding is not a static, histological feature rather it represents a snap-shot of a dynamic process undertaken by an aggressive tumor with the potential to disseminate and metastasize. Strong, consistent evidence shows that tumor budding is a predictor of lymph node metastasis, distant metastatic disease, local recurrence, worse overall and disease-free survival time and an independent prognostic factor. Moreover, the International Union against Cancer (UICC) recognizes tumor budding as a highly relevant, additional prognostic parameter. The aim of this review is to summarize the evidence supporting the implementation of tumor budding into diagnostic pathology and patient management and additionally to illustrate its worthiness as a potential therapeutic target. PMID:21317460

  17. Assessing Metabolic Stress and Autophagy Status in Epithelial Tumors

    PubMed Central

    Mathew, Robin; Karantza-Wadsworth, Vassiliki; White, Eileen

    2010-01-01

    Autophagy is a survival mechanism activated in response to metabolic stress. In normal tissues autophagy plays a major role in energy homeostasis through catabolic self-digestion of damaged proteins and organelles. Contrary to its survival function, autophagy defects are implicated in tumorigenesis suggesting that autophagy is a tumor suppression mechanism. Although the exact mechanism of this tumor suppressor function is not known, it likely involves mitigation of cellular damage leading to chromosomal instability. The complex role of functional autophagy in tumors calls for model systems that allow the assessment of autophagy status, stress management and the impact on oncogenesis both in vitro as well as in vivo. We developed model systems that involve generation of genetically defined, isogenic and immortal epithelial cells from different tissue types that are applicable to both wild-type and mutant mice. This permits the study of tissue- as well as gene-specific tumor promoting functions. We successfully employed this strategy to generate isogenic, immortal epithelial cell lines from wild-type and mutant mice deficient in essential autophagy genes such as beclin 1 (beclin 1+/-) and atg5 (atg 5-/-). As these cell lines are amenable to further genetic manipulation, they allowed us to generate cell lines with apoptosis defects and stable expression of the autophagy marker EGFP-LC3 that facilitate in vitro and in vivo assessment of stress-mediated autophagy induction. We applied this model system to directly monitor autophagy in cells and 3D-morphogenesis in vitro as well as in tumor allografts in vivo. Using this model system we demonstrated that autophagy is a survival response in solid tumors that co-localizes with hypoxic regions, allowing tolerance to metabolic stress. Furthermore, our studies have established that autophagy also protects tumor cells from genome damage and limits cell death and inflammation as possible means to tumor suppression. Additionally

  18. Surgical staging of early invasive epithelial ovarian tumors.

    PubMed

    Leblanc, E; Querleu, D; Narducci, F; Chauvet, M P; Chevalier, A; Lesoin, A; Vennin, P; Taieb, S

    2000-01-01

    Early stage epithelial ovarian carcinoma is defined pathologically as a tumor strictly limited to one or both ovaries without any extra-ovarian disease (i.e., Stage IA or B of the International Federation of Gynecology and Obstetrics (FIGO) classification). This diagnosis can be obtained only after an exhaustive surgical staging procedure, performed as soon as the diagnosis of epithelial invasive ovarian carcinoma is established. This staging surgery currently encompasses a peritoneal cytology, the thorough inspection of all the visceral and parietal peritoneal surfaces with biopsy of any abnormality, total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH + BSO), random peritoneal biopsies, omentectomy, appendectomy and bilateral pelvic and para-aortic lymphadenectomies, up to the left renal vein. The results of this staging procedure and its indications are discussed. In all of the cases, the radical removal of the pathologic adnexa is indicated, along with the complete peritoneal and retroperitoneal staging. While fertility-sparing surgery (avoiding hysterectomy and contralateral adnexectomy, if possible) seems to be safe for young women, a TAH + BSO is the rule for the others. Adjuvant chemotherapy can be omitted in well-differentiated tumors with a negative staging operation, but currently it remains indicated in all other cases. Indeed, the ultimate goal in early stage ovarian carcinoma is to not impair by inadequate management the high chance of a cure. Copyright 2000 Wiley-Liss, Inc.

  19. Cutis rhomboidalis protects skin from malignant epithelial tumors.

    PubMed

    Bonkevitch, F; Souza, P R M

    2014-06-01

    Cutis rhomboidalis nuchae is a skin alteration which comes from chronic sun exposure and it integrates the solar elastosis group, acquiring a coriaceous aspect, with a yellowish and grooved surface. There is the occurrence of elastic and collagen fibers degeneration found in the dermis caused by ultraviolet radiation [1]. Another group of skin diseases which has solar exposure as a determining factor is the group of actinic keratoses, the non-melanoma malignant epithelial tumors {basal cell carcinoma (CBC) and squamous cell carcinoma (CEC)} [2]. However, the occurrence of actinic keratoses, CBCs or CECs on the area of cutis rhomboidalis is infrequent in dermatology clinical practice. The authors do not know why people with neoplasias and pre neoplastic lesions in some areas with chronic photo damage amendments (face and upper limbs), do not present the same pre and neoplastic lesions in areas with similar appearance of chronic sun damage (nape). The authors seek to understand why the nape is protected for pre and neoplastic lesions. We suggest that cutis rhomboidalis protects skin from malignant epithelial tumors in nuchae.

  20. Clinicopathological characteristics of duodenal epithelial neoplasms: Focus on tumors with a gastric mucin phenotype (pyloric gland-type tumors)

    PubMed Central

    Mitsuishi, Takehiro; Hamatani, Shigeharu; Hirooka, Shinichi; Fukasawa, Nei; Aizawa, Daisuke; Hara, Yuko; Dobashi, Akira; Goda, Kenichi; Fukuda, Takahiro; Saruta, Masayuki; Urashima, Mitsuyoshi; Ikegami, Masahiro

    2017-01-01

    Objective Epithelial tumors less commonly occur in the duodenum than in the stomach or large intestine. The clinicopathological characteristics of duodenal epithelial tumors remain a matter of debate. We therefore studied resected specimens to investigate the clinicopathological characteristics of duodenal epithelial tumors. Materials and methods Among duodenal epithelial tumors resected endoscopically or surgically in our hospital, we studied the clinicopathological characteristics of 110 adenomas or intramucosal carcinomas. The grade of atypia of all tumors was classified into 3 groups according to the World Health Organization (WHO) 2010 classification. The tumors were immunohistochemically evaluated to determine the frequency of differentiation toward fundic glands. Results As for patient characteristics, there were 76 men (75.2%) and 25 women (24.8%), with a median age of 65 years (range, 34 to 84). The tumors most commonly arose in the first to second part of the duodenum. Many lesions were flat, and the median tumor diameter was 8.0 mm. The lesions were classified into 2 types according to mucin phenotype: intestinal-type tumors (98 lesions, 89.1%) and gastric-type tumors (12 lesions, 10.9%). Intestinal-type tumors were subdivided into 2 groups: tubular-type tumors (91 lesions, 82.7%) and tubulovillous-type tumors (7 lesions, 6.4%). Gastric-type tumors were classified into 2 types: foveolar type (3 lesions, 2.7%) and pyloric gland-type (PG) tumors (9 lesions, 8.2%). The grade of atypia was significantly higher in gastric-type tumors (p<0.01). PG tumors were gastric-type tumors characterized by pyloric glands and findings suggesting differentiation toward fundic glands. Conclusions About 10% of the duodenal tumors had a gastric-type mucin phenotype. Gastric-type tumors showed high-grade atypia. In particular, PG tumors showed similarities to PG tumors of the stomach, such as differentiation toward fundic glands. PMID:28376132

  1. Epithelial Tumors Originate in Tumor Hotspots, a Tissue-Intrinsic Microenvironment

    PubMed Central

    Tamori, Yoichiro; Suzuki, Emiko; Deng, Wu-Min

    2016-01-01

    Malignant tumors are caused by uncontrolled proliferation of transformed mutant cells that have lost the ability to maintain tissue integrity. Although a number of causative genetic backgrounds for tumor development have been discovered, the initial steps mutant cells take to escape tissue integrity and trigger tumorigenesis remain elusive. Here, we show through analysis of conserved neoplastic tumor-suppressor genes (nTSGs) in Drosophila wing imaginal disc epithelia that tumor initiation depends on tissue-intrinsic local cytoarchitectures, causing tumors to consistently originate in a specific region of the tissue. In this “tumor hotspot” where cells constitute a network of robust structures on their basal side, nTSG-deficient cells delaminate from the apical side of the epithelium and begin tumorigenic overgrowth by exploiting endogenous Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling activity. Conversely, in other regions, the “tumor coldspot” nTSG-deficient cells are extruded toward the basal side and undergo apoptosis. When the direction of delamination is reversed through suppression of RhoGEF2, an activator of the Rho family small GTPases, and JAK/STAT is activated ectopically in these coldspot nTSG-deficient cells, tumorigenesis is induced. These data indicate that two independent processes, apical delamination and JAK/STAT activation, are concurrently required for the initiation of nTSG-deficient-induced tumorigenesis. Given the conservation of the epithelial cytoarchitecture, tumorigenesis may be generally initiated from tumor hotspots by a similar mechanism. PMID:27584724

  2. Distinctive properties of an anaplastic Wilms' tumor and its associated epithelial cell line.

    PubMed Central

    Hazen-Martin, D. J.; Re, G. G.; Garvin, A. J.; Sens, D. A.

    1994-01-01

    Clinically the anaplastic variant of Wilms' tumor differs from the classical Wilms' tumor by its poor prognosis. To begin to understand and characterize the distinctive biology of this rare form of Wilms' tumor, a study of the histology, ultrastructure, and mRNA expression was performed on the anaplastic tumor and its associated cell line. The anaplastic tumor generated mouse heterotransplants that were readily used to establish epithelial cell cultures. The epithelial cultures, in turn, produced tumors when reinjected into nude mice. Microscopic evaluation revealed that the anaplastic epithelial cells were less differentiated than their epithelial counterpart in classical Wilms' tumors. In general the molecular profile of the anaplastic tumor was more consistent with that of an epithelial-rich classic Wilms' tumor than with the classic triphasic Wilms' tumor. Unlike the classic triphasic Wilms' tumor that contains blastema, stroma, and epithelial tubules, the anaplastic tumor expressed only marginal levels of insulin-like growth factor 2 (IGF-2) mRNA and imperceptible levels of the Wilms' tumor gene (WT-1), Pax-2, and Pax-8 mRNA. In common with the classic Wilms' tumor, the anaplastic variant retained the expression of the N-myc gene while failing to express C-myc. A comparison of cultures derived from an epithelial-rich, classic Wilms' tumor and the anaplastic Wilm's tumor indicated that both lacked IGF-2 and WT-1 mRNA expression. However, the well-differentiated epithelial cell culture derived from the classic Wilms' tumor expressed C-myc, Pax-8, and Pax-2 mRNA, none of which were expressed by the anaplastic epithelial cells. Furthermore, the well-differentiated epithelial cell component failed to express N-myc, which was expressed by both the primary triphasic Wilms' tumor and the anaplastic tumor. Overall, the findings indicate that patterns of gene expression within a single component do not correlate with the aggressive clinical behavior of the anaplastic

  3. Estrogen-related receptor gamma promotes mesenchymal-to-epithelial transition and suppresses breast tumor growth.

    PubMed

    Tiraby, Claire; Hazen, Bethany C; Gantner, Marin L; Kralli, Anastasia

    2011-04-01

    Estrogen-related receptors (ERR), ERR alpha (ERRα) and ERR gamma (ERRγ), are orphan nuclear receptors implicated in breast cancer that function similarly in the regulation of oxidative metabolism genes. Paradoxically, in clinical studies, high levels of ERRα are associated with poor outcomes whereas high levels of ERRγ are associated with a favorable course. Recent studies suggest that ERRα may indeed promote breast tumor growth. The roles of ERRγ in breast cancer progression and how ERRα and ERRγ may differentially affect cancer growth are unclear. In mammary carcinoma cells that do not express endogenous ERRγ, we found that ectopic expression of ERRγ enhanced oxidative metabolism in vitro and inhibited the growth of tumor xenografts in vivo. In contrast, ectopic expression of the ERRα coactivator PGC-1α enhanced oxidative metabolism but did not affect tumor growth. Notably, ERRγ activated expression of a genetic program characteristic of mesenchymal-to-epithelial transition (MET). This program was apparent by changes in cellular morphology, upregulation of epithelial cell markers, downregulation of mesenchymal markers, and decreased cellular invasiveness. We determined that this program was also associated with upregulation of E-cadherin, which is activated directly by ERRγ. In contrast, PGC-1α activated only a subset of genes characteristic of the MET program and, unlike ERRγ, did not upregulate E-cadherin. In conclusion, these results show that ERRγ induces E-cadherin, promotes MET, and suppresses breast cancer growth. Our findings suggest that ERRγ agonists may have applications in the treatment of breast cancer.

  4. Current Concepts and Occurrence of Epithelial Odontogenic Tumors: I. Ameloblastoma and Adenomatoid Odontogenic Tumor

    PubMed Central

    Kim, Yeon Sook

    2013-01-01

    Ameloblastomas and adenomatoid odontogenic tumors (AOTs) are common epithelial tumors of odontogenic origin. Ameloblastomas are clinico-pathologically classified into solid/multicystic, unicystic, desmoplastic, and peripheral types, and also divided into follicular, plexiform, acanthomatous, granular types, etc., based on their histological features. Craniopharyngiomas, derived from the remnants of Rathke's pouch or a misplaced enamel organ, are also comparable to the odontogenic tumors. The malignant transformation of ameloblastomas results in the formation of ameloblastic carcinomas and malignant ameloblastomas depending on cytological dysplasia and metastasis, respectively. AOTs are classified into follicular, extrafollicular, and peripheral types. Ameloblastomas are common, have an aggressive behavior and recurrent course, and are rarely metastatic, while AOTs are hamartomatous benign lesions derived from the complex system of the dental lamina or its remnants. With advances in the elucidation of molecular signaling mechanisms in cells, the cytodifferentiation of epithelial tumor cells in ameloblastomas and AOTs can be identified using different biomarkers. Therefore, it is suggested that comprehensive pathological observation including molecular genetic information can provide a more reliable differential diagnosis for the propagation and prognosis of ameloblastomas and AOTs. This study aimed to review the current concepts of ameloblastomas and AOTs and to discuss their clinico-pathological features relevant to tumorigenesis and prognosis. PMID:23837011

  5. Survival outcomes of recurrent epithelial ovarian cancer: experience from a Thailand northern tertiary care center.

    PubMed

    Jansaka, Natpat; Suprasert, Prapaporn

    2014-01-01

    To assess survival outcomes in a retrospective study, recurrent epithelial ovarian cancer patients were divided into three groups according to the platinum free interval as follows: platinum refractory that included the patients with tumor progression during treatment; platinum resistant and platinum sensitive that included the patients with tumor progression less than or more than six months, respectively. Clinical data for tumor progression in epithelial ovarian cancer patients treated at Chiang Mai University Hospital between January, 2006 and December, 2010 were reviewed. Thirty-nine patients were in the platinum refractory group while 27 were in the platinum resistant group and 75 in the platinum sensitive group. The mean age, the parity, the administration of neoadjuvant chemotherapy and the serous type did not significantly different across groups while the mean total number of chemotherapy regimens, the early stage patients, the patients with complete surgery and the surviving patients were significant more frequent in the platinum sensitive group. Regarding subsequent treatment after tumor recurrence, 87.2% underwent chemotherapy. With the median follow up time at 29 months, the median overall survival rates were 20 months, 14 months and 42 months in platinum refractory, platinum resistant and platinum sensitive groups, respectively (p<0.001). In addition, when the platinum sensitive patients developed the next episode of tumor progression, the median progression free interval time was only three to four months. In conclusion, the outcomes for platinum refractory the and platinum resistant groups was poorer than the platinum sensitive group. However, subsequent progression in the platinum sensitive group was also associated with a poor outcome.

  6. Epithelialization of mouse ovarian tumor cells originating in the fallopian tube stroma

    PubMed Central

    Hua, Yuanyuan; Choi, Pui-Wah; Trachtenberg, Alexander J.; Ng, Allen C.; Kuo, Winston P.; Ng, Shu-Kay; Dinulescu, Daniela M.; Matzuk, Martin M.; Berkowitz, Ross S.; Ng, Shu-Wing

    2016-01-01

    Epithelial ovarian carcinoma accounts for 90% of all ovarian cancer and is the most deadly gynecologic malignancy. Recent studies have suggested that fallopian tube fimbriae can be the origin of cells for high-grade serous subtype of epithelial ovarian carcinoma (HGSOC). A mouse HGSOC model with conditional Dicer-Pten double knockout (Dicer-Pten DKO) developed primary tumors, intriguingly, from the fallopian tube stroma. We examined the growth and epithelial phenotypes of the Dicer-Pten DKO mouse tumor cells contributable by each gene knockout. Unlike human ovarian epithelial cancer cells that expressed full-length E-cadherin, the Dicer-Pten DKO stromal tumor cells expressed cleaved E-cadherin fragments and metalloproteinase 2, a mixture of epithelial and mesenchymal markers. Although the Dicer-Pten DKO tumor cells lost the expression of mature microRNAs as expected, they showed high levels of tRNA fragment expression and enhanced AKT activation due to the loss of PTEN function. Introduction of a Dicer1-expressing construct into the DKO mouse tumor cells significantly reduced DNA synthesis and the cell growth rate, with concurrent diminished adhesion and ZO1 epithelial staining. Hence, it is likely that the loss of Dicer promoted mesenchymal-epithelial transition in fallopian tube stromal cells, and in conjunction with Pten loss, further promoted cell proliferation and epithelial-like tumorigenesis. PMID:27602775

  7. Morphology and growth characteristics of epithelial cells from classic Wilms' tumors.

    PubMed Central

    Hazen-Martin, D. J.; Garvin, A. J.; Gansler, T.; Tarnowski, B. I.; Sens, D. A.

    1993-01-01

    The ability to establish cell cultures representing the epithelial component of Wilms' tumor was determined for 18 cases of classic Wilms' tumors. From these 18 cases only two resulted in the culture of epithelial cells. Although the tumors from both cases were composed of a prominent epithelial component, other classic tumors not producing epithelial cell cultures also possessed appreciable epithelial components. Likewise, heterotransplants of these two primary tumors failed to give rise to epithelial cell cultures, although cultures of the blastemal element were produced. This suggests that Wilms' tumors may be prone to differentiate in different directions at varying times during tumor growth, possibly dependent on local tumor environment. Epithelial cells from these two classic cases were grown in culture in basal medium composed of a 1:1 mixture of Dulbecco's modified Eagle's medium and Ham's F-12 medium, supplemented with selenium, insulin, transferrin, hydrocortisone, tri-iodothyronine, and epidermal growth factor, on a collagen type I matrix with absorbed fetal calf serum proteins. One of the two cases also required the addition of bovine pituitary extract, ethanolamine, prostaglandin E1, and putrescine for optimum growth. Morphological analysis disclosed that the cultured cells were very similar to normal renal tubular cells in culture, except that the cells displayed little evidence for differentiated active ion transport and tended to grow in a multilayered arrangement. The culture of the epithelial cells from classic Wilms' tumors provides a model system for the study of tumor differentiation and progression. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 PMID:8384407

  8. Leading malignant cells initiate collective epithelial cell invasion in a three-dimensional heterotypic tumor spheroid model.

    PubMed

    Carey, Shawn P; Starchenko, Alina; McGregor, Alexandra L; Reinhart-King, Cynthia A

    2013-06-01

    Solid tumors consist of genetically and phenotypically diverse subpopulations of cancer cells with unique capacities for growth, differentiation, and invasion. While the molecular and microenvironmental bases for heterogeneity are increasingly appreciated, the outcomes of such intratumor heterogeneity, particularly in the context of tumor invasion and metastasis, remain poorly understood. To study heterotypic cell-cell interactions and elucidate the biological consequences of intratumor heterogeneity, we developed a tissue-engineered multicellular spheroid (MCS) co-culture model that recapitulates the cellular diversity and fully three-dimensional cell-cell and cell-matrix interactions that characterize human carcinomas. We found that "invasion-competent" malignant cells induced the collective invasion of otherwise "invasion-incompetent" epithelial cells, and that these two cell types consistently exhibited distinct leader and follower roles during invasion. Analysis of extracellular matrix (ECM) microarchitecture revealed that malignant cell invasion was accompanied by extensive ECM remodeling including matrix alignment and proteolytic track-making. Inhibition of cell contractility- and proteolysis-mediated matrix reorganization prevented leader-follower behavior and malignant cell-induced epithelial cell invasion. These results indicate that heterogeneous subpopulations within a tumor may possess specialized roles during tumor progression and suggest that complex interactions among the various subpopulations of cancer cells within a tumor may regulate critical aspects of tumor biology and affect clinical outcome.

  9. Epithelial-mesenchymal transitions during cell culture of primary thyroid tumors?

    PubMed

    Herrmann, M E; Trevor, K T

    1993-04-01

    Fibroblast contamination of epithelial tumor cell cultures is of great concern when examining tumor cells in vitro for specific biochemical and cytogenetic changes. The observations of normal karyotypes in thyroid tumor cell cultures have raised the concern of whether residual tissue fibroblasts might obscure the cytogenetic analysis of transformed epithelial cells. We have characterized early passaged thyroid tumor cells to examine the proportions of epithelial and fibroblastic cell types. Cells were analyzed by immunocytology using antibodies recognizing the thyroid prohormone thyroglobulin, epithelial cytokeratins, and vimentin, a mesenchyme marker. Tumors consisted of one follicular adenoma and five papillary carcinomas. When examined by day 15 in culture, all cells contained filaments composed of vimentin, which most likely represents an adaptation to culture conditions. Double immunofluorescence staining for thyroglobulin and cytokeratin revealed the presence of not only epithelial but also spindle-like fibroblastoid cells possessing thyroid epithelial cell markers. The results suggest that in thyroid tumor cultures there is a unique cell type intermediate between epithelial and mesenchyme phenotypes that must be considered when performing cytogenetic analysis.

  10. Surgical Approaches for Stage IVA Thymic Epithelial Tumors

    PubMed Central

    Shapiro, Mark; Korst, Robert J.

    2014-01-01

    Thymic epithelial tumors (TET) are rare mediastinal neoplasms that can metastasize to the pleural space (stage IVA). Complete surgical resection remains the backbone of therapy for patients with early stage TET, however, the role of surgery in the management of patients with stage IVA disease is not fully defined. Published reports in this regard are mainly small, retrospective, and uncontrolled, with unclear inclusion criteria. Surgical options to manage pleural disease include metastasectomy, extrapleural pneumonectomy, and metastasectomy/pleurectomy combined with heated intrapleural chemotherapy. The choice of the most appropriate surgical strategy needs to be individualized according to the quantity and location of disease, the patient’s overall condition, as well as operator and institutional expertise. In the majority of cases, metastasectomy of pleural implants will be sufficient to achieve a complete resection. The available literature suggests that in selected patients with stage IVA TET, delivery of neoadjuvant chemotherapy followed by complete resection is a viable treatment option that can be associated with long-term survival. PMID:24459636

  11. Surgical Approaches for Stage IVA Thymic Epithelial Tumors.

    PubMed

    Shapiro, Mark; Korst, Robert J

    2014-01-14

    Thymic epithelial tumors (TET) are rare mediastinal neoplasms that can metastasize to the pleural space (stage IVA). Complete surgical resection remains the backbone of therapy for patients with early stage TET, however, the role of surgery in the management of patients with stage IVA disease is not fully defined. Published reports in this regard are mainly small, retrospective, and uncontrolled, with unclear inclusion criteria. Surgical options to manage pleural disease include metastasectomy, extrapleural pneumonectomy, and metastasectomy/pleurectomy combined with heated intrapleural chemotherapy. The choice of the most appropriate surgical strategy needs to be individualized according to the quantity and location of disease, the patient's overall condition, as well as operator and institutional expertise. In the majority of cases, metastasectomy of pleural implants will be sufficient to achieve a complete resection. The available literature suggests that in selected patients with stage IVA TET, delivery of neoadjuvant chemotherapy followed by complete resection is a viable treatment option that can be associated with long-term survival.

  12. Snail1-Dependent Activation of Cancer-Associated Fibroblast Controls Epithelial Tumor Cell Invasion and Metastasis.

    PubMed

    Alba-Castellón, Lorena; Olivera-Salguero, Rubén; Mestre-Farrera, Aida; Peña, Raúl; Herrera, Mercedes; Bonilla, Félix; Casal, J Ignacio; Baulida, Josep; Peña, Cristina; García de Herreros, Antonio

    2016-11-01

    Snail1 transcriptional factor is essential for triggering epithelial-to-mesenchymal transition (EMT) and inducing tumor cell invasion. We report here an EMT-independent action of Snail1 on tumor invasion, as it is required for the activation of cancer-associated fibroblasts (CAF). Snail1 expression in fibroblasts requires signals derived from tumor cells, such as TGFβ; reciprocally, in fibroblasts, Snail1 organizes a complex program that stimulates invasion of epithelial cells independent of the expression of Snail1 in these cells. Epithelial cell invasion is stimulated by the secretion by fibroblast of diffusible signaling molecules, such as prostaglandin E2 The capability of human or murine CAFs to promote tumor invasion is dependent on Snail1 expression. Inducible Snail1 depletion in mice decreases the invasion of breast tumors; moreover, epithelial tumor cells coxenografted with Snail1-depleted fibroblasts originated tumors with lower invasion than those transplanted with control fibroblasts. Therefore, these results demonstrate that the role of Snail1 in tumor invasion is not limited to EMT, but it is also dependent on its activity in stromal fibroblasts, where it orchestrates the cross-talk with epithelial tumor cells. Cancer Res; 76(21); 6205-17. ©2016 AACR. ©2016 American Association for Cancer Research.

  13. Epithelial Hypoxia-Inducible Factor 2α Facilitates the Progression of Colon Tumors through Recruiting Neutrophils

    PubMed Central

    Triner, Daniel; Xue, Xiang; Schwartz, Andrew J.; Jung, Inkyung; Colacino, Justin A.

    2016-01-01

    ABSTRACT Inflammation is a significant risk factor for colon cancer. Recent work has demonstrated essential roles for several infiltrating immune populations in the metaplastic progression following inflammation. Hypoxia and stabilization of hypoxia-inducible factors (HIFs) are hallmark features of inflammation and solid tumors. Previously, we demonstrated an important role for tumor epithelial HIF-2α in colon tumors; however, the function of epithelial HIF-2α as a critical link in the progression of inflammation to cancer has not been elucidated. In colitis-associated colon cancer models, epithelial HIF-2α was essential in tumor growth. Concurrently, epithelial disruption of HIF-2α significantly decreased neutrophils in the colon tumor microenvironment. Intestinal epithelial HIF-2α-overexpressing mice demonstrated that neutrophil recruitment was a direct response to increased epithelial HIF-2α signaling. High-throughput RNA sequencing (RNA-seq) analysis of HIF-2α-overexpressing mice in conjunction with data mining from the Cancer Genome Atlas showed that the neutrophil chemokine CXCL1 gene was highly upregulated in colon tumor epithelium in a HIF-2α-dependent manner. Using selective peptide inhibitors of the CXCL1-CXCR2 signaling axis identified HIF-2α-dependent neutrophil recruitment as an essential mechanism to increase colon carcinogenesis. These studies demonstrate that HIF-2α is a novel regulator of neutrophil recruitment to colon tumors and that it is essential in shaping the protumorigenic inflammatory microenvironment in colon cancer. PMID:27956697

  14. Graded activation of the MEK1/MT1-MMP axis determines renal epithelial cell tumor phenotype.

    PubMed

    Mahimkar, Rajeev; Alfonso-Jaume, Maria Alejandra; Cape, Leslie M; Dahiya, Rajvir; Lovett, David H

    2011-12-01

    Activation of Raf/Ras/mitogen-activated protein kinase (MEK)/mitogen-activated protein kinase signaling and elevated expression of membrane type-1 matrix metalloproteinase (MT1-MMP) are associated with von Hippel-Lindau gene alterations in renal cell carcinoma. We postulated that the degree of MEK activation was related to graded expression of MT1-MMP and the resultant phenotype of renal epithelial tumors. Madin Darby canine kidney epithelial cells transfected with a MEK1 expression plasmid yielded populations with morphologic phenotypes ranging from epithelial, mixed epithelial/mesenchymal to mesenchymal. Clones were analyzed for MEK1 activity, MT1-MMP expression and extent of epithelial-mesenchymal transition. Phenotypes of the MDCK-MEK1 clones were evaluated in vivo with nu/nu mice. Tissue microarray of renal cell cancers was quantitatively assessed for expression of phosphorylated MEK1 and MT1-MMP proteins and correlations drawn to Fuhrman nuclear grade. Graded increases in the MEK signaling module were associated with graded induction of epithelial-mesenchymal transition of the MDCK cells and induction of MT1-MMP transcription and synthesis. Inhibition of MEK1 and MT1-MMP activity reversed the epithelial-mesenchymal transition. Tumors generated by epithelial, mixed epithelial/mesenchymal and mesenchymal MDCK clones demonstrated a gradient of phenotypes extending from well-differentiated, fully encapsulated non-invasive tumors to tumors with an anaplastic morphology, high Fuhrman nuclear score, neoangiogenesis and invasion. Tumor microarray demonstrated a statistically significant association between the extent of phosphorylated MEK1, MT1-MMP expression and nuclear grade. We conclude that graded increases in the MEK1 signaling module are correlated with M1-MMP expression, renal epithelial cell tumor phenotype, invasive activity and nuclear grade. Phosphorylated MEK1 and MT1-MMP may represent novel, and mechanistic, biomarkers for the assessment of renal cell

  15. Primary Hepatic Carcinoid Tumor with Poor Outcome.

    PubMed

    Parkash, Om; Ayub, Adil; Naeem, Buria; Najam, Sehrish; Ahmed, Zubair; Jafri, Wasim; Hamid, Saeed

    2016-03-01

    Primary Hepatic Carcinoid Tumor (PHCT) represents an extremely rare clinical entity with only a few cases reported to date. These tumors are rarely associated with metastasis and surgical resection is usually curative. Herein, we report two cases of PHCT associated with poor outcomes due to late diagnosis. Both cases presented late with non-specific symptoms. One patient presented after a 2-week history of symptoms and the second case had a longstanding two years symptomatic interval during which he remained undiagnosed and not properly worked up. Both these cases were diagnosed with hepatic carcinoid tumor, which originates from neuroendocrine cells. Case 1 opted for palliative care and expired in one month’s time. Surgical resection was advised to the second case, but he left against medical advice.

  16. Transforming growth factor beta 2 in epithelial differentiation of developing teeth and odontogenic tumors.

    PubMed Central

    Heikinheimo, K; Happonen, R P; Miettinen, P J; Ritvos, O

    1993-01-01

    Dysregulation of TGF beta 2, a modulator of cell growth and differentiation, can result in uncontrolled growth and tumor formation. Our comparative studies on the expression of TGF beta 2 mRNA and protein indicate that TGF beta 2 may primarily be a regulator of epithelial differentiation during tooth development (between 13 and 20 gestational wk) and tumorigenesis of odontogenic neoplasms. A paracrine mode of action for TGF beta 2 in early human tooth germ (cap/early bell stage) is suggested by location of mRNA in the mesenchyme surrounding the tooth germ, whereas protein is found in the epithelial dental lamina and enamel organ. During the late bell stage, TGF beta 2 gene expression shifted from the mesenchyme to the odontogenic epithelium and was colocalized with protein, suggesting an autocrine role for the terminal differentiation of ameloblasts. In odontogenic tumors of epithelial origin (ameloblastomas) and epithelial-ectomesencymal origin (ameloblastic fibromas), TGF beta 2 mRNA was mostly located in the mesenchymal tumor component and protein in the epithelial tumor component. Odontogenic ectomesenchymal tumors (myxomas) were not associated with TGF beta 2 mRNA and protein expression. The results imply that TGF beta 2 may play an important role in epithelial-mesenchymal interactions in human tooth morphogenesis and development of odontogenic tumors. Images PMID:8450031

  17. Isolation of circulating epithelial and tumor progenitor cells with an invasive phenotype from breast cancer patients

    PubMed Central

    Lu, Janice; Fan, Tina; Zhao, Qiang; Zeng, Wei; Zaslavsky, Eva; Chen, John J.; Frohman, Michael A.; Golightly, Marc G.; Madajewicz, Stefan; Chen, Wen-Tien

    2009-01-01

    Recent research advances show that tumor cell intravasation (entry into the circulation) and metastasis occur very early in breast cancer progression. Clinical studies also illustrate the potential importance of detection of circulating tumor cells (CTCs) in outcomes of patients with metastatic breast cancer. Whether these cells exhibit the invasiveness and express tumor stem or progenitor markers, hallmark of the metastatic phenotype, is less well characterized. To detect CTCs with the invasive phenotype and to explore their molecular features, we applied a functional cell separation method, called collagen adhesion matrix (CAM) assay, as enrichment and identification steps. The CAM-coated device successfully recovered tumor cells spiked in one mL of blood with a 54%±9% (n=18) recovery rate and 0.5-35% purity, and detected invasive tumor cells in 10/10 blood samples (100% yield) from patients with metastatic breast cancer with a range of 18 to 256 CTCs/mL and average of 126±25 (mean±SD) CTCs/mL. CTCs were detected in blood samples of 28/54 (52%) stage I-III breast cancer patients with a mean count of 61 CTCs/mL. Furthermore, the relative frequency of these cells correlated to the staging, lymph node-status and survival of patients with early stage breast cancer. CAM-captured cells were capable of propagation in culture. Gene expression and multiplex flow cytometric analyses on CAM-captured cells demonstrated the existence of distinct populations of CTCs including these of epithelial lineage and stem or progenitor cells. Thus, CAM-initiated CTC detection provides advantages for examining invasiveness and tumor progenitor phenotypes. PMID:19662651

  18. Neurological outcome of childhood brain tumor survivors.

    PubMed

    Pietilä, Sari; Korpela, Raija; Lenko, Hanna L; Haapasalo, Hannu; Alalantela, Riitta; Nieminen, Pirkko; Koivisto, Anna-Maija; Mäkipernaa, Anne

    2012-05-01

    We assessed neurological and neurocognitive outcome in childhood brain tumor survivors. Altogether, 75 out of 80 brain tumor survivors diagnosed below 17 years between 1983 and 1997; and treated in Tampere University Hospital, Finland, were invited to participate in this population-based cross-sectional study. Fifty-two (69%) participated [mean age 14.2 (3.8-28.7) years, mean follow-up 7.5 (1.5-15.1) years]. Neurological status was abnormal in 69% cases. All were ambulatory, but only 50% showed normal motor function. Twenty-nine percent showed clumsiness/mild asymmetry and 21% hemiparesis. One suffered from intractable epilepsy. According to structured interview, 87% coped normally in daily living. Median full-scale IQ was 85 (39-110) in 21 6-16 year olds (70%); in 29% IQ was <70. Thirty of the 44 school-aged subjects attended school with normal syllabus and 32% needed special education. Six of the 16 patients over 18 years of age were working. Regarding quality of life, 38% were active without disability, 33% active with mild disability, 21% were partially disabled, but capable of self-care, and 8% had severe disability, being incapable of self-care. Supratentorial/hemispheric tumor location, tumor reoperations, shunt revisions and chemotherapy were associated with neurological, cognitive and social disabilities. In conclusion, of the 52 survivors, neurological status was abnormal in 69%; 71% lived an active life with minor disabilities, 29% had major neurological, cognitive and social disabilities, and 8% of them were incapable of self-care. Predictors of these disabilities included supratentorial/hemispheric tumor location, tumor reoperations, shunt revisions and chemotherapy. Survivors need life-long, tailor-made multiprofessional support and follow-up.

  19. The tumor microenvironment: An irreplaceable element of tumor budding and epithelial-mesenchymal transition-mediated cancer metastasis.

    PubMed

    Li, Hui; Xu, Fangying; Li, Si; Zhong, Anjing; Meng, Xianwen; Lai, Maode

    2016-07-03

    Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo-resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy.

  20. The tumor microenvironment: An irreplaceable element of tumor budding and epithelial-mesenchymal transition-mediated cancer metastasis

    PubMed Central

    Li, Hui; Xu, Fangying; Li, Si; Zhong, Anjing; Meng, Xianwen; Lai, Maode

    2016-01-01

    ABSTRACT Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo-resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy. PMID:26743180

  1. Expression of AQP6 and AQP8 in epithelial ovarian tumor.

    PubMed

    Ma, Jiong; Zhou, Chunxia; Yang, Jianhua; Ding, Xiaoyan; Zhu, Yunshan; Chen, Xuejun

    2016-04-01

    Aquaporins (AQPs), the rapid transition pores for water molecules, play an important role in maintenance of intracellular water balance. Studies showed that AQPs were also involved in occurrence, development, invasion and metastasis of tumors. In this study, we aimed to explore the distribution and expression differences of aquaporin 6 (AQP6) and aquaporin 8 (AQP8) in epithelial ovarian tumors. The expression of AQP6 and AQP8 in 47 cases of epithelial ovarian tumors were measured by immunochemical technique and Western blotting. AQP6 was strongly expressed in benign ovarian tumors, but weak signal was shown in malignant tumors. The difference was not statistically significant (P > 0.05). Compared with serous adenoma and normal tissues, AQP6 expression in serous carcinoma was obviously decreased (P < 0.05). AQP8 expressions were both identified in benign and malignant tumors, but there was no significantly statistical difference (P > 0.05). For patients with large volume of malignant ascites (>1000 ml), AQP8 expression was increased (P < 0.05). AQP8 expression in malignant tumors was not related to different clinical stages, presence of lymphatic metastasis, and differentiation degrees (P > 0.05). These data showed that AQP6 and AQP8 had different expression degrees in epithelial ovarian tissues, which suggests that AQP6 and AQP8 may play certain roles in epithelial ovarian tumors.

  2. Multifocal epithelial tumors and field cancerization: stroma as a primary determinant

    PubMed Central

    Dotto, G. Paolo

    2014-01-01

    It is increasingly evident that cancer results from altered organ homeostasis rather than from deregulated control of single cells or groups of cells. This applies especially to epithelial cancer, the most common form of human solid tumors and a major cause of cancer lethality. In the vast majority of cases, in situ epithelial cancer lesions do not progress into malignancy, even if they harbor many of the genetic changes found in invasive and metastatic tumors. While changes in tumor stroma are frequently viewed as secondary to changes in the epithelium, recent evidence indicates that they can play a primary role in both cancer progression and initiation. These processes may explain the phenomenon of field cancerization, i.e., the occurrence of multifocal and recurrent epithelial tumors that are preceded by and associated with widespread changes of surrounding tissue or organ “fields.” PMID:24691479

  3. A mixed epithelial and stromal tumor of the kidney in a ringtail lemur (Lemur catta).

    PubMed

    Muller, S; Oevermann, A; Wenker, C; Altermatt, H J; Robert, N

    2007-03-01

    Primary renal tumors are rare neoplasms in nonhuman primates. This report describes a mixed epithelial and stromal tumor of the kidney (MESTK) in a 14.5-year-old female ringtail lemur. The well-demarcated, solid, and cystic mass was located in the pelvis of the left kidney and consisted histologically of both epithelial and mesenchymal components. The mesenchymal cells were arranged in fascicles around cysts lined by a well-differentiated epithelium. Neither the mesenchymal nor the epithelial parts showed significant nuclear atypia or mitotic figures. To our knowledge, only 1 similar case, classified as adenoleiomyofibromatous hamartoma, has been reported in a ringtail lemur. In humans this tumor affects predominantly perimenopausal women and can express estrogen and progesterone receptors. However, neither estrogen nor progesterone receptors could be identified by immunohistochemistry in the tumor of the present ringtail lemur. Therefore, a hormonal mechanism could not be demonstrated in this case.

  4. Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells.

    PubMed

    Kopp, Florian; Hermawan, Adam; Oak, Prajakta Shirish; Ulaganathan, Vijay Kumar; Herrmann, Annika; Elnikhely, Nefertiti; Thakur, Chitra; Xiao, Zhiguang; Knyazev, Pjotr; Ataseven, Beyhan; Savai, Rajkumar; Wagner, Ernst; Roidl, Andreas

    2014-12-01

    Acquiring therapy resistance is one of the major obstacles in the treatment of patients with cancer. The discovery of the cancer stem cell (CSC)-specific drug salinomycin raised hope for improved treatment options by targeting therapy-refractory CSCs and mesenchymal cancer cells. However, the occurrence of an acquired salinomycin resistance in tumor cells remains elusive. To study the formation of salinomycin resistance, mesenchymal breast cancer cells were sequentially treated with salinomycin in an in vitro cell culture assay, and the resulting differences in gene expression and salinomycin susceptibility were analyzed. We demonstrated that long-term salinomycin treatment of mesenchymal cancer cells resulted in salinomycin-resistant cells with elevated levels of epithelial markers, such as E-cadherin and miR-200c, a decreased migratory capability, and a higher susceptibility to the classic chemotherapeutic drug doxorubicin. The formation of salinomycin resistance through the acquisition of epithelial traits was further validated by inducing mesenchymal-epithelial transition through an overexpression of miR-200c. The transition from a mesenchymal to a more epithelial-like phenotype of salinomycin-treated tumor cells was moreover confirmed in vivo, using syngeneic and, for the first time, transgenic mouse tumor models. These results suggest that the acquisition of salinomycin resistance through the clonal selection of epithelial-like cancer cells could become exploited for improved cancer therapies by antagonizing the tumor-progressive effects of epithelial-mesenchymal transition.

  5. Graded activation of the MEK1/MT1-MMP axis determines renal epithelial cell tumor phenotype

    PubMed Central

    Mahimkar, Rajeev; Alfonso-Jaume, Maria Alejandra; Cape, Leslie M.; Dahiya, Rajvir; Lovett, David H.

    2011-01-01

    Activation of Raf/Ras/mitogen-activated protein kinase (MEK)/mitogen-activated protein kinase signaling and elevated expression of membrane type-1 matrix metalloproteinase (MT1-MMP) are associated with von Hippel–Lindau gene alterations in renal cell carcinoma. We postulated that the degree of MEK activation was related to graded expression of MT1-MMP and the resultant phenotype of renal epithelial tumors. Madin Darby canine kidney epithelial cells transfected with a MEK1 expression plasmid yielded populations with morphologic phenotypes ranging from epithelial, mixed epithelial/mesenchymal to mesenchymal. Clones were analyzed for MEK1 activity, MT1-MMP expression and extent of epithelial–mesenchymal transition. Phenotypes of the MDCK-MEK1 clones were evaluated in vivo with nu/nu mice. Tissue microarray of renal cell cancers was quantitatively assessed for expression of phosphorylated MEK1 and MT1-MMP proteins and correlations drawn to Fuhrman nuclear grade. Graded increases in the MEK signaling module were associated with graded induction of epithelial–mesenchymal transition of the MDCK cells and induction of MT1-MMP transcription and synthesis. Inhibition of MEK1 and MT1-MMP activity reversed the epithelial–mesenchymal transition. Tumors generated by epithelial, mixed epithelial/mesenchymal and mesenchymal MDCK clones demonstrated a gradient of phenotypes extending from well-differentiated, fully encapsulated non-invasive tumors to tumors with an anaplastic morphology, high Fuhrman nuclear score, neoangiogenesis and invasion. Tumor microarray demonstrated a statistically significant association between the extent of phosphorylated MEK1, MT1-MMP expression and nuclear grade. We conclude that graded increases in the MEK1 signaling module are correlated with M1-MMP expression, renal epithelial cell tumor phenotype, invasive activity and nuclear grade. Phosphorylated MEK1 and MT1-MMP may represent novel, and mechanistic, biomarkers for the assessment of renal

  6. Kindlin-2 inhibits serous epithelial ovarian cancer peritoneal dissemination and predicts patient outcomes.

    PubMed

    Ren, Caixia; Du, Juan; Xi, Chenguang; Yu, Yu; Hu, Ajin; Zhan, Jun; Guo, Hongyan; Fang, Weigang; Liu, Congrong; Zhang, Hongquan

    2014-03-28

    Kindlin-2 has been known to promote most cancer progression through regulation of multiple signaling pathways. However, a novel tumor suppressive role of Kindlin-2 was identified in serous epithelial ovarian cancer progression, which sharply contrasts to the tumor promoting roles for Kindlin-2 in most other cancers. While we demonstrated that Kindlin-2 was highly expressed in control tissues, a drastic low expression of Kindlin-2 was found in the tumor tissues of serous epithelial ovarian cancer, especially in the high-grade serous epithelial ovarian cancer. Importantly, Kindlin-2 inhibited serous epithelial ovarian cancer cell peritoneal dissemination in a mouse model. For clinical relevance, low Kindlin-2 expression correlated with higher tumor grade and older patients. Intriguingly, decreased Kindlin-2 expression predicts poor overall and progression-free survivals in serous epithelial ovarian cancer patients. Mechanistically, Kindlin-2 induced a mesenchymal to epithelial transition in serous epithelial ovarian cancer cells, at least in part, by up-regulation of estrogen receptor α which was recruited to the promoter of E-cadherin and thereby enhanced the transcription of E-cadherin. Collectively, we concluded that inadequate Kindlin-2 is an independent risk factor for serous epithelial ovarian cancer patients.

  7. Epithelial cell tumors of the hen reproductive tract.

    PubMed

    Harris, Elizabeth A; Fletcher, Oscar J; Anderson, Kenneth E; Petitte, James N; Kopelovich, Levy; Mozdziak, Paul E

    2014-03-01

    There is a paucity of preclinical models that simulate the development of ovarian tumors in humans. At present, the egg-laying hen appears to be the most promising model to study the spontaneous occurrence of ovarian tumors in the clinical setting. Although gross classification and histologic grade of tumors have been used prognostically in women with ovarian tumors, there is currently no single system that is universally used to classify reproductive tumors in the hen. Four hundred and one 192-wk-old egg-laying hens were necropsied to determine the incidence of reproductive tumors using both gross pathology and histologic classification. Gross pathologic classifications were designated as follows: birds presenting with ovarian tumors only (class 1), those presenting with oviductal and ovarian tumors (class 2), those with ovarian and oviductal tumors that metastasized to the gastrointestinal tract (class 3), those with ovarian and oviductal tumors that metastasized to the gastrointestinal tract and other distant organs (class 4), those with oviductal tumors only (class 5), those with oviductal tumors that metastasized to other organs with no ovarian involvement (class 6), and those with ovarian tumors that metastasized to other organs with no oviductal involvement (class 7), including birds with gastrointestinal tumors and no reproductive involvement (GI only) and those with no tumors (normal). Histopathologic classifications range from grades 1 to 3 and are based on mitotic developments and cellular differentiation. An updated gross pathology and histologic classification systems for the hen reproductive malignancies provides a method to report the range of reproductive tumors revealed in a flock of aged laying hens.

  8. The Impact of Epithelial Stromal Interactions on Human Breast Tumor Heterogeneity

    DTIC Science & Technology

    2016-12-01

    AWARD NUMBER: W81XWH-13-1-0357 TITLE: The Impact of Epithelial-Stromal Interactions on Human Breast Tumor Heterogeneity PRINCIPAL INVESTIGATOR...2013 – 14 Sept 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-13-1-0357 The Impact of Epithelial-Stromal Interactions on Human Breast...crista.thompson@mail.mcgill.ca 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER Royal

  9. Utility of Electrocardiography (ECG)-Gated Computed Tomography (CT) for Preoperative Evaluations of Thymic Epithelial Tumors.

    PubMed

    Ozawa, Yoshiyuki; Hara, Masaki; Nakagawa, Motoo; Shibamoto, Yuta

    2016-01-01

    Preoperative evaluation of invasion to the adjacent organs is important for the thymic epithelial tumors on CT. The purpose of our study was to evaluate the utility of electrocardiography (ECG)-gated CT for assessing thymic epithelial tumors with regard to the motion artifacts produced and the preoperative diagnostic accuracy of the technique. Forty thymic epithelial tumors (36 thymomas and 4 thymic carcinomas) were examined with ECG-gated contrast-enhanced CT using a dual source scanner. The scan delay after the contrast media injection was 30 s for the non-ECG-gated CT and 100 s for the ECG-gated CT. Two radiologists blindly evaluated both the non-ECG-gated and ECG-gated CT images for motion artifacts and determined whether the tumors had invaded adjacent structures (mediastinal fat, superior vena cava, brachiocephalic veins, aorta, pulmonary artery, pericardium, or lungs) on each image. Motion artifacts were evaluated using a 3-grade scale. Surgical and pathological findings were used as a reference standard for tumor invasion. Motion artifacts were significantly reduced for all structures by ECG gating (p=0.0089 for the lungs and p<0.0001 for the other structures). Non-ECG-gated CT and ECG-gated CT demonstrated 79% and 95% accuracy, respectively, during assessments of pericardial invasion (p=0.03). ECG-gated CT reduced the severity of motion artifacts and might be useful for preoperative assessment whether thymic epithelial tumors have invaded adjacent structures.

  10. FGFR3 has tumor suppressor properties in cells with epithelial phenotype

    PubMed Central

    2013-01-01

    Background Due to frequent mutations in certain cancers, FGFR3 gene is considered as an oncogene. However, in some normal tissues, FGFR3 can limit cell growth and promote cell differentiation. Thus, FGFR3 action appears paradoxical. Results FGFR3 expression was forced in pancreatic cell lines. The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells. Distinct exclusive pathways were activated, STATs in epithelial-like cells and MAP Kinases in mesenchymal-like cells. Both FGFR3 splice variants had similar effects and used the same intracellular signaling. In human pancreatic carcinoma tissues, levels of FGFR3 dropped in tumors. Conclusion In tumors from epithelial origin, FGFR3 signal can limit tumor growth, explaining why the 4p16.3 locus bearing FGFR3 is frequently lost and why activating mutations of FGFR3 in benign or low grade tumors of epithelial origin are associated with good prognosis. The new hypothesis that FGFR3 can harbor both tumor suppressive and oncogenic properties is crucial in the context of targeted therapies involving specific tyrosine kinase inhibitors (TKIs). TKIs against FGFR3 might result in adverse effects if used in the wrong cell context. PMID:23902722

  11. Benign phyllodes tumor with tubular adenoma-like epithelial component in FNAC: A diagnostic pitfall.

    PubMed

    Panda, Kishori M

    2016-01-01

    Benign phyllodes tumor (BPT) is a biphasic neoplasm composed of bland stromal and epithelial elements. Cytologic diagnostic criteria of BPT, though documented in the literature, diagnostic pitfalls in fine-needle aspiration cytology (FNAC) may occur due to sampling error, high cellularity, ductal hyperplasia, paucity of stromal component, and occasional dissociation of epithelial cells. Here, we describe a case of BPT diagnosed by histology in a 19-year-old female, where FNAC features were inconclusive due to paucity of stromal component, predominance of tubular adenoma-like epithelial component, and due to the presence of other overlapping features with fibroadenoma.

  12. Benign phyllodes tumor with tubular adenoma-like epithelial component in FNAC: A diagnostic pitfall

    PubMed Central

    Panda, Kishori M

    2016-01-01

    Benign phyllodes tumor (BPT) is a biphasic neoplasm composed of bland stromal and epithelial elements. Cytologic diagnostic criteria of BPT, though documented in the literature, diagnostic pitfalls in fine-needle aspiration cytology (FNAC) may occur due to sampling error, high cellularity, ductal hyperplasia, paucity of stromal component, and occasional dissociation of epithelial cells. Here, we describe a case of BPT diagnosed by histology in a 19-year-old female, where FNAC features were inconclusive due to paucity of stromal component, predominance of tubular adenoma-like epithelial component, and due to the presence of other overlapping features with fibroadenoma. PMID:28028339

  13. Microvesicles released from tumor cells disrupt epithelial cell morphology and contractility.

    PubMed

    Bordeleau, Francois; Chan, Bryan; Antonyak, Marc A; Lampi, Marsha C; Cerione, Richard A; Reinhart-King, Cynthia A

    2016-05-24

    During tumor progression, cancer cells interact and communicate with non-malignant cells within their local microenvironment. Microvesicles (MV) derived from human cancer cells play an important role in mediating this communication. Another critical aspect of cancer progression involves widespread ECM remodeling, which occur both at the primary and metastatic sites. ECM remodeling and reorganization within the tumor microenvironment is generally attributed to fibroblasts. Here, using MCF10a cells, a well-characterized breast epithelial cell line that exhibits a non-malignant epithelial phenotype, and MVs shed by aggressive MDA-MB-231 carcinoma cells, we show that non-malignant epithelial cells can participate in ECM reorganization of 3D collagen matrices following their treatment with cancer cell-derived MVs. In addition, MVs trigger several changes in epithelial cells under 3D culture conditions. Furthermore, we show that this ECM reorganization is associated with an increase in cellular traction force following MV treatment, higher acto-myosin contractility, and higher FAK activity. Overall, our findings suggest that MVs derived from tumor cells can contribute to ECM reorganization occurring within the tumor microenvironment by enhancing the contractility of non-malignant epithelial cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Epithelial Junction Opener Improves Oncolytic Adenovirus Therapy in Mouse Tumor Models

    PubMed Central

    Yumul, Roma; Richter, Maximilian; Lu, Zhuo-Zhuang; Saydaminova, Kamola; Wang, Hongjie; Wang, Chung-Huei Katherine; Carter, Darrick; Lieber, André

    2016-01-01

    A central resistance mechanism in solid tumors is the maintenance of epithelial junctions between malignant cells that prevent drug penetration into the tumor. Human adenoviruses (Ads) have evolved mechanisms to breach epithelial barriers. For example, during Ad serotype 3 (Ad3) infection of epithelial tumor cells, massive amounts of subviral penton-dodecahedral particles (PtDd) are produced and released from infected cells to trigger the transient opening of epithelial junctions, thus facilitating lateral virus spread. We show here that an Ad3 mutant that is disabled for PtDd production is significantly less effective in killing of epithelial human xenograft tumors than the wild-type Ad3 virus. Intratumoral spread and therapeutic effect of the Ad3 mutant was enhanced by co-administration of a small recombinant protein (JO; produced in Escherichia coli) that incorporated the minimal junction opening domains of PtDd. We then demonstrated that co-administration of JO with replication-competent Ads that do not produce PtDd (Ad5, Ad35) resulted in greater attenuation of tumor growth than virus injection alone. Furthermore, we genetically modified a conditionally replicating Ad5-based oncolytic Ad (Ad5Δ24) to express a secreted form of JO upon replication in tumor cells. The JO-expressing virus had a significantly greater antitumor effect than the unmodified AdΔ24 version. Our findings indicate that epithelial junctions limit the efficacy of oncolytic Ads and that this problem can be address by co-injection or expression of JO. JO has also the potential for improving cancer therapy with other types of oncolytic viruses. PMID:26993072

  15. Cytomorphologic Attributes of Epithelial Myoepithelial Carcinoma of Nasal Cavity - A Rare Tumor with Unusual Clinical Presentation

    PubMed Central

    Vijayshankar, Shivshankar; Abhishek, MG; Kumari, Amita

    2016-01-01

    Epithelial-Myoepithelial Carcinoma (EMC) is a rare low grade epithelial malignancy of major Salivary Glands (SG). Though the histomorphology of this tumor is distinct, unusual location and clinical presentation may pose diagnostic difficulties especially when this lesion is first encountered at cytology. We report a case of 60-year-old female presenting with nasal obstruction of three months duration. At FNAC the diagnosis of EMC was suggested and it was confirmed on histopathology. We present this case highlighting the cytomorphologic attributes of this rare tumor occurring at an extremely uncommon location – Nasal cavity. PMID:27790447

  16. Lead, selenium and nickel concentrations in epithelial ovarian cancer, borderline ovarian tumor and healthy ovarian tissues.

    PubMed

    Canaz, Emel; Kilinc, Metin; Sayar, Hamide; Kiran, Gurkan; Ozyurek, Eser

    2017-09-01

    Wide variation exists in ovarian cancer incidence rates suggesting the importance of environmental factors. Due to increasing environmental pollution, trace elements and heavy metals have drawn attention in studies defining the etiology of cancer, but scant data is available for ovarian cancer. Our aim was to compare the tissue concentrations of lead, selenium and nickel in epithelial ovarian cancer, borderline tumor and healthy ovarian tissues. The levels of lead, selenium and nickel were estimated using atomic absorption spectrophotometry in formalin-fixed paraffin-embedded tissue samples. Tests were carried out in 20 malignant epithelial ovarian cancer, 15 epithelial borderline tumor and 20 non-neoplastic healthy ovaries. Two samples were collected for borderline tumors, one from papillary projection and one from the smooth surface of cyst wall. Pb and Ni concentrations were found to be higher both in malignant and borderline tissues than those in healthy ovaries. Concentrations of Pb and Ni in malignant tissues, borderline papillary projections and capsular tissue samples were not different. Comparison of Se concentrations of malignant, borderline and healthy ovarian tissues did not reveal statistical difference. Studied metal levels were not found to be different in either papillary projection or in cyst wall of the borderline tumors. This study revealed the accumulation of lead and nickel in ovarian tissue is associated with borderline and malignant proliferation of the surface epithelium. Accumulation of these metals in epithelial ovarian cancer and borderline ovarian tumor has not been demonstrated before. Copyright © 2017 Elsevier GmbH. All rights reserved.

  17. Epithelial to mesenchymal transition correlates with tumor budding and predicts prognosis in esophageal squamous cell carcinoma.

    PubMed

    Niwa, Yukiko; Yamada, Suguru; Koike, Masahiko; Kanda, Mitsuro; Fujii, Tsutomu; Nakayama, Goro; Sugimoto, Hiroyuki; Nomoto, Shuji; Fujiwara, Michitaka; Kodera, Yasuhiro

    2014-11-01

    Epithelial to mesenchymal transition (EMT) is considered to play an important role in cancer invasion. Tumor budding is a prognostic factor in esophageal squamous cell carcinoma (ESCC). The aim of this study was to explore the correlation between EMT and tumor budding. Surgical specimens from 78 cases of ESCC resected without preoperative treatment between 2001 and 2013 were enrolled in the study. The mRNA expressions of E-cadherin and vimentin were measured in cancerous tissues using real-time PCR, and each tumor was classified into either epithelial or mesenchymal group. Tumor budding was evaluated in H&E-stained slides and divided into two groups; low-grade budding (<3) and high-grade budding (≥3). The 5-year survival rate in the epithelial group was significantly higher than that in the mesenchymal group (62.0% vs. 31.5%, P = 0.021). Survival rate of patients in the low-grade budding group was significantly higher than that of patients in the high-grade budding group (75.1% vs. 25.9%, P < 0.001). High-grade tumor budding was significantly associated with the mesenchymal group (P = 0.009). EMT was found to occur in ESCC and was significantly associated with tumor budding. Tumor budding was identified as a significant independent prognostic factor among the current population of ESCC. © 2014 Wiley Periodicals, Inc.

  18. Transformed epithelial cells and fibroblasts/myofibroblasts interaction in breast tumor: a mathematical model and experiments.

    PubMed

    Kim, Yangjin; Wallace, Julie; Li, Fu; Ostrowski, Michael; Friedman, Avner

    2010-09-01

    It is well known that tumor and its microenvironment, or stroma, interact with each other and that this interaction plays a critical role in tumor initiation, growth, and metastasis. This interaction consists of complex relations between tumor cells, stromal cells such as fibroblasts, epithelial cells and immunocytes, the vascular system, the extracellular matrix, and cytokines secreted by the cells. Understanding these relationships may lead to new therapeutic approaches to cancer. In the present paper, we consider tumor-stroma crosstalk in a simple in vitro situation which involves interaction between tumor epithelial cells from breast cancer and a microenvironment consisting of just fibroblasts. The two populations of cells are separated by a semi-permeable membrane that allows only cytokines to cross over. We develop a mathematical model that includes two critical growth factors: TGF-beta, produced by the tumor cells, and EGF, secreted by the fibroblasts. The TGF-beta modifies the microenvironment by transforming fibroblasts into myofibroblasts. Myofibroblasts secrete higher concentrations of EGF than fibroblasts, thereby, increasing the proliferation of tumor cells. Thus already in this simple setup one sees a mutual interaction between tumor cells and their microenvironment. We conducted experiments which show good agreement with the model's simulations, hence confirming the model's ability to predict aspects of tumor cell behavior in response to signaling from fibroblasts.

  19. Survival outcomes and toxicity of intraoperative intraperitoneal chemotherapy in advanced epithelial ovarian cancer

    PubMed Central

    Yoon, Ji-Young; Koo, Yu-Jin; Kim, Mi-Jung; Kim, Tae-Jin; Lim, Kyung-Taek

    2014-01-01

    Objective To assess the effect of single-dose cisplatin intraperitoneally administered during cytoreductive surgery in advanced epithelial ovarian cancer. Methods Data from patients who underwent surgical management followed by intravenous (IV) chemotherapy for stage III epithelial ovarian cancer from 2003 to 2012 were retrospectively reviewed. Subjects were divided into intraperitoneal (IP) and no-intraperitoneal (NIP) groups according to the administration of IP cisplatin 100 mg during the staging surgery. Clinical results such as survival outcomes and chemotherapeutic toxicity were compared between the two groups. Results Thirty-seven patients in the IP group and 26 in the NIP group were identified. There were no significant differences between the two groups in basic characteristics such as age, histology, and surgical procedures. After the surgery with or without IP chemotherapy, there was no difference in the rate of either hematologic or gastrointestinal toxicity or in the rate of incompletion of following IV chemotherapy. Tumor recurrence occurred in 67.6% (25 patients) of IP group and 57.7% (15 patients) of NIP group (P=0.423) during the mean follow-up period of 37 months. The 3-year disease free-survival rate was 39.9% in the IP group and 35.8% in the NIP group, and the relative risk of recurrence was 0.864 (95% confidence interval, 0.447-1.673; P=0.665) in the IP group as compared with the NIP group. Conclusion IP chemotherapy with single-dose cisplatin during cytoreductive surgery is safe and feasible with little chemotherapeutic toxicity in advanced epithelial ovarian cancer, but no distinct improvement in survival could be demonstrated in the present study. PMID:25469337

  20. Review of the touch preparation cytology of spindle epithelial tumor with thymus-like differentiation

    PubMed Central

    Yi, Kijong; Rehman, Abdul; Jang, Se Min; Paik, Seung Sam

    2016-01-01

    We experienced a case of spindle epithelial tumor with thymus-like differentiation (SETTLE) with touch preparation cytology performed during the intraoperative frozen section diagnosis in a 22-year-old woman. The tumor was partially encapsulated by fibrous capsule. It was a highly cellular biphasic tumor characterized by fasciculated spindle cells with streaming pattern and tubulopapillary epithelial component. The tumor cells were positive for cytokeratin, vimentin, c-kit, epithelial membrane antigen (EMA), and thyroid transcription factor-1 (TTF-1). However, the tumor cells were negative for thyroglobulin, calcitonin, CD99, S-100 protein, CD34, smooth muscle actin, HBME-1, and galectin-3. The reviewed touch smears showed tight clusters with high cellularity. Most cellular clusters showed papillary configuration. However, some clusters showed spindle cells with streaming pattern. The spindle tumor cells showed elongated and cigar-shaped nuclei. Although the incidence is very rare, SETLLE should be included in the differential diagnosis when a spindle cell neoplasm is encountered in touch preparation cytology in young patients with a thyroid mass. PMID:27011438

  1. ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer

    PubMed Central

    Hedditch, Ellen L.; Gao, Bo; Russell, Amanda J.; Lu, Yi; Emmanuel, Catherine; Beesley, Jonathan; Johnatty, Sharon E.; Chen, Xiaoqing; Harnett, Paul; George, Joshy; Williams, Rebekka T.; Flemming, Claudia; Lambrechts, Diether; Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace; Karlan, Beth; Lester, Jenny; Orsulic, Sandra; Walsh, Christine; Fasching, Peter; Beckmann, Matthias W.; Ekici, Arif B.; Hein, Alexander; Matsuo, Keitaro; Hosono, Satoyo; Nakanishi, Toru; Yatabe, Yasushi; Pejovic, Tanja; Bean, Yukie; Heitz, Florian; Harter, Philipp; du Bois, Andreas; Schwaab, Ira; Hogdall, Estrid; Kjaer, Susan K.; Jensen, Allan; Hogdall, Claus; Lundvall, Lene; Engelholm, Svend Aage; Brown, Bob; Flanagan, James; Metcalf, Michelle D; Siddiqui, Nadeem; Sellers, Thomas; Fridley, Brooke; Cunningham, Julie; Schildkraut, Joellen; Iversen, Ed; Weber, Rachel P.; Berchuck, Andrew; Goode, Ellen; Bowtell, David D.; Chenevix-Trench, Georgia; deFazio, Anna; Norris, Murray D.; MacGregor, Stuart; Haber, Michelle; Henderson, Michelle J.

    2014-01-01

    Background ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. Methods The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA–mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan–Meier analysis and log-rank tests. All statistical tests were two-sided. Results Associations with outcome were observed with ABC transporters of the “A” subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e−6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. Conclusions Expression of ABCA transporters was associated with poor

  2. ABCA transporter gene expression and poor outcome in epithelial ovarian cancer.

    PubMed

    Hedditch, Ellen L; Gao, Bo; Russell, Amanda J; Lu, Yi; Emmanuel, Catherine; Beesley, Jonathan; Johnatty, Sharon E; Chen, Xiaoqing; Harnett, Paul; George, Joshy; Williams, Rebekka T; Flemming, Claudia; Lambrechts, Diether; Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace; Karlan, Beth; Lester, Jenny; Orsulic, Sandra; Walsh, Christine; Fasching, Peter; Beckmann, Matthias W; Ekici, Arif B; Hein, Alexander; Matsuo, Keitaro; Hosono, Satoyo; Nakanishi, Toru; Yatabe, Yasushi; Pejovic, Tanja; Bean, Yukie; Heitz, Florian; Harter, Philipp; du Bois, Andreas; Schwaab, Ira; Hogdall, Estrid; Kjaer, Susan K; Jensen, Allan; Hogdall, Claus; Lundvall, Lene; Engelholm, Svend Aage; Brown, Bob; Flanagan, James; Metcalf, Michelle D; Siddiqui, Nadeem; Sellers, Thomas; Fridley, Brooke; Cunningham, Julie; Schildkraut, Joellen; Iversen, Ed; Weber, Rachel P; Berchuck, Andrew; Goode, Ellen; Bowtell, David D; Chenevix-Trench, Georgia; deFazio, Anna; Norris, Murray D; MacGregor, Stuart; Haber, Michelle; Henderson, Michelle J

    2014-07-01

    ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided. Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid

  3. Mixed epithelial and stromal tumor of the middle ear: The first case report.

    PubMed

    Michal, Michael; Skálová, Alena; Kazakov, Dmitry V; Pecková, Květoslava; Heidenreich, Filip; Grossmann, Petr; Michal, Michal

    2017-03-01

    We report a tumor arising in the middle ear of a 65-year-old female patient that was composed of an ovarian-type stroma (OS) and an epithelial component. The tumor consisted of irregular, polypoid masses containing multiple variably sized cystic spaces, which were invariably surrounded by the OS. The cystic spaces were lined by flat, cuboidal, or columnar epithelial cells, in most parts showing mucinous differentiation. The epithelial lining of the cysts strongly expressed cytokeratins AE1-3, CK7, CK8, CK18, CK19, EMA, and S100 protein. The stroma expressed CD34 and smooth muscle actin. No cytological atypia or mitoses were present, and the proliferative activity was less than 1% in both components. The clonality analysis proved the clonal nature of the neoplasm. We believe that this tumor is a new member in the family of neoplasms containing the OS, and therefore we propose the term mixed epithelial and stromal tumor of the middle ear. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Mammary Tumor Development: Stromal-Epithelial Interactions in Oncogenesis.

    DTIC Science & Technology

    1996-09-01

    address experimentally the strong association of p53 mutations with human breast cancers, and to test whether this association holds for experimental...may develop secretory tumors (32,45,46). MG tumors are reported in transgenic mice expressing c-myc, c- erbB2 /neu, int-1, int-3 and Ha-ras, and in F1...Yasui, W, Takekura, N, Kameda, T, Oda, N, Ito, M, Ito, H, Tahara, E: Effect of epider- mal growth factor on rat stomach carcinogenesis induced by N

  5. Belinostat in Treating Patients With Advanced Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer or Ovarian Low Malignant Potential Tumors

    ClinicalTrials.gov

    2016-10-20

    Fallopian Tube Carcinoma; Primary Peritoneal Carcinoma; Recurrent Borderline Ovarian Surface Epithelial-Stromal Tumor; Recurrent Ovarian Carcinoma; Stage III Borderline Ovarian Surface Epithelial-Stromal Tumor; Stage III Ovarian Cancer; Stage IV Borderline Ovarian Surface Epithelial-Stromal Tumor; Stage IV Ovarian Cancer

  6. Utility of Electrocardiography (ECG)-Gated Computed Tomography (CT) for Preoperative Evaluations of Thymic Epithelial Tumors

    PubMed Central

    Ozawa, Yoshiyuki; Hara, Masaki; Nakagawa, Motoo; Shibamoto, Yuta

    2016-01-01

    Summary Background Preoperative evaluation of invasion to the adjacent organs is important for the thymic epithelial tumors on CT. The purpose of our study was to evaluate the utility of electrocardiography (ECG)-gated CT for assessing thymic epithelial tumors with regard to the motion artifacts produced and the preoperative diagnostic accuracy of the technique. Material/Methods Forty thymic epithelial tumors (36 thymomas and 4 thymic carcinomas) were examined with ECG-gated contrast-enhanced CT using a dual source scanner. The scan delay after the contrast media injection was 30 s for the non-ECG-gated CT and 100 s for the ECG-gated CT. Two radiologists blindly evaluated both the non-ECG-gated and ECG-gated CT images for motion artifacts and determined whether the tumors had invaded adjacent structures (mediastinal fat, superior vena cava, brachiocephalic veins, aorta, pulmonary artery, pericardium, or lungs) on each image. Motion artifacts were evaluated using a 3-grade scale. Surgical and pathological findings were used as a reference standard for tumor invasion. Results Motion artifacts were significantly reduced for all structures by ECG gating (p=0.0089 for the lungs and p<0.0001 for the other structures). Non-ECG-gated CT and ECG-gated CT demonstrated 79% and 95% accuracy, respectively, during assessments of pericardial invasion (p=0.03). Conclusions ECG-gated CT reduced the severity of motion artifacts and might be useful for preoperative assessment whether thymic epithelial tumors have invaded adjacent structures. PMID:27920842

  7. MiR-7 Promotes Epithelial Cell Transformation by Targeting the Tumor Suppressor KLF4

    PubMed Central

    Meza-Sosa, Karla F.; Pérez-García, Erick I.; Camacho-Concha, Nohemí; López-Gutiérrez, Oswaldo; Pedraza-Alva, Gustavo; Pérez-Martínez, Leonor

    2014-01-01

    MicroRNAs (miRNAs) are endogenous small non-coding RNAs that have a pivotal role in the post-transcriptional regulation of gene expression and their misregulation is common in different types of cancer. Although it has been shown that miR-7 plays an oncogenic role in different cellular contexts, the molecular mechanisms by which miR-7 promotes cell transformation are not well understood. Here we show that the transcription factor KLF4 is a direct target of miR-7 and present experimental evidence indicating that the regulation of KLF4 by miR-7 has functional implications in epithelial cell transformation. Stable overexpression of miR-7 into lung and skin epithelial cells enhanced cell proliferation, cell migration and tumor formation. Alteration of these cellular functions by miR-7 resulted from misregulation of KLF4 target genes involved in cell cycle control. miR-7-induced tumors showed decreased p21 and increased Cyclin D levels. Taken together, these findings indicate that miR-7 acts as an oncomiR in epithelial cells in part by directly regulating KLF4 expression. Thus, we conclude that miR-7 acts as an oncomiR in the epithelial cellular context, where through the negative regulation of KLF4-dependent signaling pathways, miR-7 promotes cellular transformation and tumor growth. PMID:25181544

  8. MiR-7 promotes epithelial cell transformation by targeting the tumor suppressor KLF4.

    PubMed

    Meza-Sosa, Karla F; Pérez-García, Erick I; Camacho-Concha, Nohemí; López-Gutiérrez, Oswaldo; Pedraza-Alva, Gustavo; Pérez-Martínez, Leonor

    2014-01-01

    MicroRNAs (miRNAs) are endogenous small non-coding RNAs that have a pivotal role in the post-transcriptional regulation of gene expression and their misregulation is common in different types of cancer. Although it has been shown that miR-7 plays an oncogenic role in different cellular contexts, the molecular mechanisms by which miR-7 promotes cell transformation are not well understood. Here we show that the transcription factor KLF4 is a direct target of miR-7 and present experimental evidence indicating that the regulation of KLF4 by miR-7 has functional implications in epithelial cell transformation. Stable overexpression of miR-7 into lung and skin epithelial cells enhanced cell proliferation, cell migration and tumor formation. Alteration of these cellular functions by miR-7 resulted from misregulation of KLF4 target genes involved in cell cycle control. miR-7-induced tumors showed decreased p21 and increased Cyclin D levels. Taken together, these findings indicate that miR-7 acts as an oncomiR in epithelial cells in part by directly regulating KLF4 expression. Thus, we conclude that miR-7 acts as an oncomiR in the epithelial cellular context, where through the negative regulation of KLF4-dependent signaling pathways, miR-7 promotes cellular transformation and tumor growth.

  9. p14 expression differences in ovarian benign, borderline and malignant epithelial tumors.

    PubMed

    Cabral, Vinicius Duarte; Cerski, Marcelle Reesink; Sa Brito, Ivana Trindade; Kliemann, Lucia Maria

    2016-10-22

    Abnormalities in tumor suppressors p14, p16 and p53 are reported in several human cancers. In ovarian epithelial carcinogenesis, p16 and p53 show higher immunohistochemical staining frequencies in malignant tumors and are associated with poor prognoses. p14 was only analyzed in carcinomas, with conflicting results. There are no reports on its expression in benign and borderline tumors. This study aims to determine p14, p16 and p53 expression frequencies in ovarian benign, borderline and malignant tumors and their associations with clinical parameters. A cross-sectional study utilizing immunohistochemistry was performed on paraffin-embedded ovarian epithelial tumor samples. Clinical data were collected from medical records. Fisher's exact test and the Bonferroni correction were performed for frequency associations. Survival comparisons utilized Kaplan-Meier and log rank testing. Associations were considered significant when p < 0.05. p14 absent expression was associated with malignant tumors (60 % positive) (p = 0.000), while 93 % and 94 % of benign and borderline tumors, respectively, were positive. p16 was positive in 94.6 % of carcinomas, 75 % of borderline and 45.7 % of benign tumors (p = 0.000). p53 negative staining was associated with benign tumors (2.9 % positive) (p = 0.016) but no difference was observed between borderline (16.7 %) and malignant tumors (29.7 %) (p = 0.560). No associations were found between expression rates, disease-free survival times or clinical variables. Carcinoma subtypes showed no difference in expression. This is the first description of p14 expression in benign and borderline tumors. It remains stable in benign and borderline tumors, while carcinomas show a significant absence of staining. This may indicate that p14 abnormalities occur later in carcinogenesis. p16 and p53 frequencies increase from benign to borderline and malignant tumors, similarly to previous reports, possibly reflecting the

  10. Expression of RAGE and HMGB1 in thymic epithelial tumors, thymic hyperplasia and regular thymic morphology.

    PubMed

    Moser, Bernhard; Janik, Stefan; Schiefer, Ana-Iris; Müllauer, Leonhard; Bekos, Christine; Scharrer, Anke; Mildner, Michael; Rényi-Vámos, Ferenc; Klepetko, Walter; Ankersmit, Hendrik Jan

    2014-01-01

    Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (p<0.001). HMGB1 nuclear staining was strongest in A and AB, and gradually less in B1 = B2>B3>thymic carcinoma (p<0.001). Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none), B1 (strong), B2 (moderate), B3 and thymic carcinoma (weak); (p<0.001). Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.

  11. Expression of RAGE and HMGB1 in Thymic Epithelial Tumors, Thymic Hyperplasia and Regular Thymic Morphology

    PubMed Central

    Moser, Bernhard; Janik, Stefan; Schiefer, Ana-Iris; Müllauer, Leonhard; Bekos, Christine; Scharrer, Anke; Mildner, Michael; Rényi-Vámos, Ferenc; Klepetko, Walter; Ankersmit, Hendrik Jan

    2014-01-01

    Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (p<0.001). HMGB1 nuclear staining was strongest in A and AB, and gradually less in B1 = B2>B3>thymic carcinoma (p<0.001). Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none), B1 (strong), B2 (moderate), B3 and thymic carcinoma (weak); (p<0.001). Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer. PMID:24705787

  12. Inflammatory markers in blood and serum tumor markers predict survival in patients with epithelial appendiceal neoplasms undergoing surgical cytoreduction and intraperitoneal chemotherapy.

    PubMed

    Chua, Terence C; Chong, Chanel H; Liauw, Winston; Zhao, Jing; Morris, David L

    2012-08-01

    The study examines the role inflammatory and tumor markers as biomarkers to preoperatively predict outcome in patients with epithelial appendiceal neoplasm undergoing cytoreduction and intraperitoneal chemotherapy. Associations between baseline variables, tumor markers [CEA (carcinoembyronic antigen], CA125, CA199), inflammatory markers including neutrophils-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and C-reactive protein (CRP) with progression-free survival (PFS) and overall survival (OS) were examined in patients undergoing surgical cytoreduction and intraperitoneal chemotherapy for epithelial appendiceal neoplasm. A total of 174 patients with epithelial appendiceal neoplasm (low-grade pseudomyxoma, n = 117; appendiceal cancer, n = 57) underwent cytoreduction. On univariate analysis, all 3 inflammatory and tumor markers predicted for both PFS and OS, respectively; NLR ≤ 2.6 (P = 0.01, P = 0.002), PLR ≤ 166 (P = 0.006, P = 0.016), CRP ≤ 12.5 (P = 0.001, P = 0.008), CEA (P < 0.001, P = 0.001), CA125 (P = 0.004, P < 0.001), CA199 (P < 0.001, P < 0.001). On multivariate analysis, there were no independent predictors of OS. PFS was independently associated with the presence of lymph node metastasis (P = 0.02), CA199 > 37 (P = 0.003), and a CRP > 12.5 (P = 0.013). A higher peritoneal cancer index (PCI > 24) was associated with elevation in CEA > 12, CA125 > 39, CA199 > 37, PLR > 166 and CRP > 12. The tumor histologic subtype was associated with CA 199 levels. The results from this investigation suggest that preoperative inflammatory markers in blood and serologic tumor markers may predict outcomes and are associated with tumor biology in patients with epithelial appendiceal neoplasm undergoing cytoreduction and intraperitoneal chemotherapy treatment.

  13. Cancer-testis antigen expression is shared between epithelial ovarian cancer tumors.

    PubMed

    Garcia-Soto, Arlene E; Schreiber, Taylor; Strbo, Natasa; Ganjei-Azar, Parvin; Miao, Feng; Koru-Sengul, Tulay; Simpkins, Fiona; Nieves-Neira, Wilberto; Lucci, Joseph; Podack, Eckhard R

    2017-06-01

    Cancer-testis (CT) antigens have been proposed as potential targets for cancer immunotherapy. Our objective was to evaluate the expression of a panel of CT antigens in epithelial ovarian cancer (EOC) tumor specimens, and to determine if antigen sharing occurs between tumors. RNA was isolated from EOC tumor specimens, EOC cell lines and benign ovarian tissue specimens. Real time-PCR analysis was performed to determine the expression level of 20 CT antigens. A total of 62 EOC specimens, 8 ovarian cancer cell lines and 3 benign ovarian tissues were evaluated for CT antigen expression. The majority of the specimens were: high grade (62%), serous (68%) and advanced stage (74%). 58 (95%) of the EOC tumors analyzed expressed at least one of the CT antigens evaluated. The mean number of CT antigen expressed was 4.5 (0-17). The most frequently expressed CT antigen was MAGE A4 (65%). Antigen sharing analysis showed the following: 9 tumors shared only one antigen with 62% of the evaluated specimens, while 37 tumors shared 4 or more antigens with 82%. 5 tumors expressed over 10 CT antigens, which were shared with 90% of the tumor panel. CT antigens are expressed in 95% of EOC tumor specimens. However, not a single antigen was universally expressed across all samples. The degree of antigen sharing between tumors increased with the total number of antigens expressed. These data suggest a multi-epitope approach for development of immunotherapy for ovarian cancer treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Modulating malignant epithelial tumor cell adhesion, migration and mechanics with nanorod surfaces.

    PubMed

    Lee, Jiyeon; Chu, Byung Hwan; Sen, Shamik; Gupte, Anand; Chancellor, T J; Chang, Chih-Yang; Ren, Fan; Kumar, Sanjay; Lele, Tanmay P

    2011-02-01

    The failure of tumor stents used for palliative therapy is due in part to the adhesion of tumor cells to the stent surface. It is therefore desirable to develop approaches to weaken the adhesion of malignant tumor cells to surfaces. We have previously developed SiO₂ coated nanorods that resist the adhesion of normal endothelial cells and fibroblasts. The adhesion mechanisms in malignant tumor cells are significantly altered from normal cells; therefore, it is unclear if nanorods can similarly resist tumor cell adhesion. In this study, we show that the morphology of tumor epithelial cells cultured on nanorods is rounded compared to flat surfaces and associated with decreased cellular stiffness and non-muscle myosin II phosphorylation. Tumor cell viability and proliferation was unchanged on nanorods. Adherent cell numbers were significantly decreased while single tumor cell motility was increased on nanorods compared to flat surfaces. Together, these results suggest that nanorods can be used to weaken malignant tumor cell adhesion, and therefore potentially improve tumor stent performance.

  15. Alternative inclusion of fibroblast growth factor receptor 2 exon IIIc in Dunning prostate tumors reveals unexpected epithelial mesenchymal plasticity.

    PubMed

    Oltean, Sebastian; Sorg, Brian S; Albrecht, Todd; Bonano, Vivian I; Brazas, Robert M; Dewhirst, Mark W; Garcia-Blanco, Mariano A

    2006-09-19

    In epithelial cells, alternative splicing of fibroblast growth factor receptor 2 (FGFR2) transcripts leads to the expression of the FGFR2(IIIb) isoform, whereas in mesenchymal cells, the same process results in the synthesis of FGFR2(IIIc). Expression of the FGFR2(IIIc) isoform during prostate tumor progression suggests a disruption of the epithelial character of these tumors. To visualize the use of FGFR2 exon IIIc in prostate AT3 tumors in syngeneic rats, we constructed minigene constructs that report on alternative splicing. Imaging these alternative splicing decisions revealed unexpected mesenchymal-epithelial transitions in these primary tumors. These transitions were observed more frequently where tumor cells were in contact with stroma. Indeed, these transitions were frequently observed among lung micrometastases in the organ parenchyma and immediately adjacent to blood vessels. Our data suggest an unforeseen relationship between epithelial mesenchymal plasticity and malignant fitness.

  16. Mitochondrial biogenesis in epithelial cancer cells promotes breast cancer tumor growth and confers autophagy resistance.

    PubMed

    Salem, Ahmed F; Whitaker-Menezes, Diana; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

    2012-11-15

    Here, we set out to test the novel hypothesis that increased mitochondrial biogenesis in epithelial cancer cells would "fuel" enhanced tumor growth. For this purpose, we generated MDA-MB-231 cells (a triple-negative human breast cancer cell line) overexpressing PGC-1α and MitoNEET, which are established molecules that drive mitochondrial biogenesis and increased mitochondrial oxidative phosphorylation (OXPHOS). Interestingly, both PGC-1α and MitoNEET increased the abundance of OXPHOS protein complexes, conferred autophagy resistance under conditions of starvation and increased tumor growth by up to ~3-fold. However, this increase in tumor growth was independent of neo-angiogenesis, as assessed by immunostaining and quantitation of vessel density using CD31 antibodies. Quantitatively similar increases in tumor growth were also observed by overexpression of PGC-1β and POLRMT in MDA-MB-231 cells, which are also responsible for mediating increased mitochondrial biogenesis. Thus, we propose that increased mitochondrial "power" in epithelial cancer cells oncogenically promotes tumor growth by conferring autophagy resistance. As such, PGC-1α, PGC-1β, mitoNEET and POLRMT should all be considered as tumor promoters or "metabolic oncogenes." Our results are consistent with numerous previous clinical studies showing that metformin (a weak mitochondrial "poison") prevents the onset of nearly all types of human cancers in diabetic patients. Therefore, metformin (a complex I inhibitor) and other mitochondrial inhibitors should be developed as novel anticancer therapies, targeting mitochondrial metabolism in cancer cells.

  17. The Network of Epithelial-mesenchymal transition: potential new targets for tumor resistance

    PubMed Central

    Nantajit, Danupon; Lin, Dong; Li, Jian Jian

    2014-01-01

    Purpose In multiple cell metazoans, the ability of polarized epithelial cells to convert to motile mesenchymal cells in order to relocate to another location is governed by a unique process termed epithelial-mesenchymal transition (EMT). While being an essential process of cellular plasticity for normal tissue and organ developments, EMT is found to be involved in an array of malignant phenotypes of tumor cells including proliferation and invasion, angiogenesis, stemness of cancer cells and resistance to chemo-radiotherapy. Although EMT is being extensively studied and demonstrated to play a key role in tumor metastasis and in sustaining tumor hallmarks, there is a lack of clear picture of the overall EMT signaling network, wavering the potential clinical trials targeting EMT. Methods In this review, we highlight the potential key therapeutic targets of EMT linked with tumor aggressiveness, hypoxia, angiogenesis and cancer stem cells, emphasizing on an emerging EMT-associated NF-κB/HER2/STAT3 pathway in radioresistance of breast cancer stem cells. Results Further definition of cancer stem cell repopulation due to EMT-controlled tumor microenvironment will help to understand how tumors exploit the EMT mechanisms for their survival and expansion advantages. Conclusions The knowledge of EMT will offer more effective targets in clinical trials to treat therapy-resistant metastatic lesions. PMID:25270087

  18. Endothelial Caveolin-1 regulates the radiation response of epithelial prostate tumors

    PubMed Central

    Klein, D; Schmitz, T; Verhelst, V; Panic, A; Schenck, M; Reis, H; Drab, M; Sak, A; Herskind, C; Maier, P; Jendrossek, V

    2015-01-01

    The membrane protein caveolin-1 (Cav1) recently emerged as a novel oncogene involved in prostate cancer progression with opposed regulation in epithelial tumor cells and the tumor stroma. Here we examined the role of stromal Cav1 for growth and radiation response of MPR31-4 prostate cancer xenograft tumors using Cav1-deficient C57Bl/6 mice. Syngeneic MPR31-4 tumors grew faster when implanted into Cav1-deficient mice. Increased tumor growth on Cav1-deficient mice was linked to decreased integration of smooth muscle cells into the wall of newly formed blood vessels and thus with a less stabilized vessel phenotype compared with tumors from Cav1 wild-type animals. However, tumor growth delay of MPR31-4 tumors grown on Cav1 knockout mice to a single high-dose irradiation with 20 Gray was more pronounced compared with tumors grown on wild-type mice. Increased radiation-induced tumor growth delay in Cav1-deficient mice was associated with an increased endothelial cell apoptosis. In vitro studies using cultured endothelial cells (ECs) confirmed that the loss of Cav1 expression increases sensitivity of ECs to radiation-induced apoptosis and reduces their clonogenic survival after irradiation. Immunohistochemical analysis of human tissue specimen further revealed that although Cav1 expression is mostly reduced in the tumor stroma of advanced and metastatic prostate cancer, the vascular compartment still expresses high levels of Cav1. In conclusion, the radiation response of MPR31-4 prostate tumors is critically regulated by Cav1 expression in the tumor vasculature. Thus, Cav1 might be a promising therapeutic target for combinatorial therapies to counteract radiation resistance of prostate cancer at the level of the tumor vasculature. PMID:25985209

  19. Risk and survival outcomes of radiation-induced CNS tumors.

    PubMed

    Lee, Jessica W; Wernicke, A Gabriella

    2016-08-01

    Patients treated with cranial radiation are at risk of developing secondary CNS tumors. Understanding the incidence, treatment, and long-term outcomes of radiation-induced CNS tumors plays a role in clinical decision-making and patient education. Additionally, as meningiomas and pituitary tumors have been detected at increasing rates across all ages and may potentially be treated with radiation, it is important to know and communicate the risk of secondary tumors in children and adults. After conducting an extensive literature search, we identified publications that report incidence and long-term outcomes of radiation-induced CNS tumors. We reviewed 14 studies in children, which reported that radiation confers a 7- to 10-fold increase in subsequent CNS tumors, with a 20-year cumulative incidence ranging from 1.03 to 28.9 %. The latency period for secondary tumors ranged from 5.5 to 30 years, with gliomas developing in 5-10 years and meningiomas developing around 15 years after radiation. We also reviewed seven studies in adults, where the two strongest studies showed no increased risk while the remaining studies found a higher risk compared to the general population. The latency period for secondary CNS tumors in adults ranged from 5 to 34 years. Treatment and long-term outcomes of radiation-induced CNS tumors have been documented in four case series, which did not conclusively demonstrate that secondary CNS tumors fared worse than primary CNS tumors. Radiation-induced CNS tumors remain a rare occurrence that should not by itself impede radiation treatment. Additional investigation is needed on the risk of radiation-induced tumors in adults and the long-term outcomes of these tumors.

  20. Critical tumor suppressor function mediated by epithelial Mig-6 in endometrial cancer

    PubMed Central

    Kim, Tae Hoon; Lee, Dong-Kee; Cho, Sung-Nam; Orvis, Grant D.; Behringer, Richard R.; Lydon, John P.; Ku, Bon Jeong; McCampbell, Adrienne S.; Broaddus, Russell R.; Jeong, Jae-Wook

    2013-01-01

    Endometrial cancer is preceded by endometrial hyperplasia, unopposed estrogen exposure and genetic alterations, but the precise causes of endometrial cancer remain uncertain. Mig-6, mainly known as a negative regulator of the EGF receptor, is an important mediator of progesterone signaling in the uterus, where it mediates tumor suppression by modulating endometrial stromal-epithelial communications. In this study, we investigated the function of Mig-6 in the uterine epithelium using a tissue-specific gene knockout strategy, in which floxed Mig-6 (Mig-6f/f) mice were crossed to Wnt7a-Cre mice (Wnt7acre+ Mig-6f/f). Wnt7acre+ Mig-6f/f mice developed endometrial hyperplasia and estrogen-dependent endometrial cancer, exhibiting increased proliferation in epithelial cells as well as apoptosis in sub-epithelial stromal cells. We documented increased expression of NOTCH1 and BIRC3 in epithelial cells of Wnt7acre+ Mig-6f/f mice and decreased expression of the progesterone receptor (PR) in stromal cells. Progesterone therapy controls endometrial growth and prevents endometrial cancer, but the effectiveness of progesterone as a treatment for women with endometrial cancer is less clear. We noted that the hyperplasic phenotype of Wnt7acre+ Mig-6f/f mice was prevented by progesterone treatment, whereas this treatment had no effect in PRcre/+ Mig-6f/f mice where Mig-6 was deleted in both the epithelial and stromal compartments of the uterus. In contrast, activation of progesterone signaling in the stroma regulated proliferation and apoptosis in the epithelium via suppression of ERα signaling there. In summary, our results establish that epithelial Mig-6 functions as a critical tumor suppressor that mediates the ability of progesterone to prevent the development of endometrial cancer. PMID:23811943

  1. CCL18 from tumor-cells promotes epithelial ovarian cancer metastasis via mTOR signaling pathway.

    PubMed

    Wang, Qi; Tang, Yong; Yu, Hongjing; Yin, Qiaoyun; Li, Mengdi; Shi, Lijun; Zhang, Wei; Li, Danrong; Li, Li

    2016-11-01

    CCL18 is a chemotactic cytokine involved in the pathogenesis and progression of various disorders, including cancer. Previously, our results showed high levels of CCL18 in the serum of epithelial ovarian carcinoma patients suggesting its potential as a circulating biomarker. In this study, we determined that CCL18 expression was up-regulated in ovarian carcinoma compared with adjacent tissue and was expressed in carcinoma cells in the tumor and not in normal ovarian epithelial cells by laser capture microdissection coupled with real-time RT-PCR. Moreover, correlation analysis showed that the CCL18 level was positively correlated with the metastasis of patients with ovarian cancer. Survival analysis also revealed that an increased level of CCL18 was associated with worse survival time in ovarian cancer patients. Over-expression of CCL18 led to enhanced migration and invasion of the Skov3 ovarian cancer cell line in vitro and in vivo. Finally, proteomics analysis demonstrated that CCL18-mediated ovarian cancer invasiveness was strongly correlated with the mTORC2 pathway. These findings suggest that the CCL18 chemokine has an important role in chemokine-mediated tumor metastasis, and may serve as a potential predictor for poor survival outcomes for ovarian cancer. © 2015 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc. © 2015 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.

  2. Transient Low Doses of DNA Demethylating Agents Exert Durable Anti-tumor Effects on Hematological and Epithelial Tumor Cells

    PubMed Central

    Tsai, Hsing-Chen; Li, Huili; Van Neste, Leander; Cai, Yi; Robert, Carine; Rassool, Feyruz V.; Shin, James J.; Harbom, Kirsten M.; Beaty, Robert; Pappou, Emmanouil; Harris, James; Yen, Ray-Whay Chiu; Ahuja, Nita; Brock, Malcolm V.; Stearns, Vered; Feller-Kopman, David; Yarmus, Lonny B.; Lin, Yi-Chun; Welm, Alana L.; Issa, Jean-Pierre; Minn, Il; Matsui, William; Jang, Yoon-Young; Sharkis, Saul J.; Baylin, Stephen B.; Zahnow, Cynthia A.

    2012-01-01

    SUMMARY Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically-relevant nanomolar doses, without causing immediate cytotoxicity, produce an anti-tumor “memory” response, including inhibition of subpopulations of cancer stem-like cells. These effects are accompanied by sustained decreases in genome-wide promoter DNA methylation, gene re-expression, and anti-tumor changes in key cellular regulatory pathways. Low dose decitabine and azacitidine may have broad applicability for cancer management. PMID:22439938

  3. ADA3 regulates normal and tumor mammary epithelial cell proliferation through c-MYC.

    PubMed

    Griffin, Nicolas I; Sharma, Gayatri; Zhao, Xiangshan; Mirza, Sameer; Srivastava, Shashank; Dave, Bhavana J; Aleskandarany, Mohammed; Rakha, Emad; Mohibi, Shakur; Band, Hamid; Band, Vimla

    2016-11-16

    We have established the critical role of ADA3 as a coactivator of estrogen receptor (ER), as well as its role in cell cycle progression. Furthermore, we showed that ADA3 is predominantly nuclear in mammary epithelium, and in ER+, but is cytoplasmic in ER- breast cancers, the latter correlating with poor survival. However, the role of nuclear ADA3 in human mammary epithelial cells (hMECs), and in ER+ breast cancer cells, as well as the importance of ADA3 expression in relation to patient prognosis and survival in ER+ breast cancer have remained uncharacterized. We overexpressed ADA3 in hMECs or in ER+ breast cancer cells and assessed the effect on cell proliferation. The expression of ADA3 was analyzed then correlated with the expression of various prognostic markers, as well as survival of breast cancer patients. Overexpression of ADA3 in ER- hMECs as well as in ER+ breast cancer cell lines enhanced cell proliferation. These cells showed increased cyclin B and c-MYC, decreased p27 and increased SKP2 levels. This was accompanied by increased mRNA levels of early response genes c-FOS, EGR1, and c-MYC. Analysis of breast cancer tissue specimens showed a significant correlation of ADA3 nuclear expression with c-MYC expression. Furthermore, nuclear ADA3 and c-MYC expression together showed significant correlation with tumor grade, mitosis, pleomorphism, NPI, ER/PR status, Ki67 and p27 expression. Importantly, within ER+ cases, expression of nuclear ADA3 and c-MYC also significantly correlated with Ki67 and p27 expression. Univariate Kaplan Meier analysis of four groups in the whole, as well as the ER+ patients showed that c-MYC and ADA3 combinatorial phenotypes showed significantly different breast cancer specific survival with c-MYC-high and ADA3-Low subgroup had the worst outcome. Using multivariate analyses within the whole cohort and the ER+ subgroups, the significant association of ADA3 and c-MYC expression with patients' outcome was independent of tumor grade

  4. Usefulness of fluorine-18 fluorodeoxyglucose-positron emission tomography in management strategy for thymic epithelial tumors.

    PubMed

    Matsumoto, Isao; Oda, Makoto; Takizawa, Masaya; Waseda, Ryuichi; Nakajima, Kenichi; Kawano, Masaya; Mochizuki, Takafumi; Ikeda, Hiroko; Watanabe, Go

    2013-01-01

    This study investigated the usefulness of fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) during the treatment of thymic epithelial tumors in combination with Ki-67 evaluation based on surgical cases in our department. Between November 2003 and May 2011, 39 patients with thymic epithelial tumor underwent preoperative FDG-PET. The maximum standardized uptake value (SUVmax) of each category within Masaoka stage, World Health Organization classification, tumor diameter, myasthenia gravis, and Ki-67 label index were compared. To examine risk factors for relapse, SUVmax, age, sex, and surgical radicality were investigated in addition to those items. The mean SUVmax was 4.5 (range, 1.2 to 14.6) and was significantly higher for Masaoka stage IV than for I and II (all p < 0.008) and for World Health Organization classified thymic cancer compared with all other types (all p < 0.0001). Mean SUVmax revealed significantly higher values for large tumors than for small tumors (p = 0.02). Mean SUVmax was significantly higher for high Ki-67-positive samples (p = 0.0004), indicating a strong correlation between SUVmax and the Ki-67 label index (ρ = 0.77, p = 0.0001). SUVmax accurately reflected therapeutic efficacy in patients with induction therapy. Univariate analysis revealed Masaoka stages III and IV and pathologically incomplete resection as risk factors for relapse. On multivariate analysis, independent risk factors for relapse comprised only Masaoka stages III and IV. FDG-PET SUVmax does reflect proliferation and invasiveness of thymic epithelial tumors and can provide an index for diagnosis and treatment, although it is not a risk factor for relapse. FDG-PET is also useful for evaluating induction therapy efficacy and detecting relapse. Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  5. Distinctive clinical presentation of a NF-1 patient with loss of heterozygosity of PTCH in his epithelial tumors.

    PubMed

    Jacobson, Elizabeth; Toms, Catherine; Huang, Conway; Skelton, Henry; Smith, Kathleen

    2005-10-01

    Although patients with neurofibromatosis (NF) have an increased incidence of tumors, there is only one study that suggests that NF1 patients may have an increased risk for epithelial malignancies. We present a patient with known NF1 who had developed multiple epithelial tumors since early in his life. All but one of these tumors were morphologically most consistent with trichoepitheliomas. Loss of heterozygosity (LOH) for Patched 1 gene (PTCH) was demonstrated within two of the trichoepitheloma-like tumors and one tumor diagnosed as basal cell carcinoma, and the patient was show to have a PTCH gene deletion. To our knowledge, a patient presenting with both NF1 and multiple trichoepitheliomas (MTE) has not previously been reported. The dysregulation in cellular proliferation and signaling induced by decreased NF1 along with the PTCH gene mutation may explain the pattern of immunohistochemical staining within these tumors, and the rare association of NF1 with epithelial neoplasms.

  6. Keratins as markers that distinguish normal and tumor-derived mammary epithelial cells

    SciTech Connect

    Trask, D.K.; Band, V.; Zajchowski, D.A.; Yaswen, P.; Suh, T.; Sager, R. )

    1990-03-01

    Keratin 5 (K5) mRNA and protein are shown to be expressed in normal mammary epithelial cells in culture and are absent from tumor-derived dell lines. To extend these findings, the full complements of keratins in normal, immortalized, and tumor cells were compared. It is shown here that normal cells produce keratins K5, K6, K7, K14, and K17, whereas tumor cells produce mainly keratins K8, K18, and K19. In immortalized cells, which are preneoplastic or partially transformed, the levels of K5 mRNA and protein are lower than in normal cells, whereas the amount of K18 is increased. Thus, K5 is an important marker in the tumorigenic process, distinguishing normal from tumor cells, and decrease K5 expression correlates with tumorigenic progression.

  7. Effect of reproductive hormones on ovarian epithelial tumors: II. Effect on angiogenic activity.

    PubMed

    Chen, Chen; Petitclerc, Eric; Zhou, Hong; Brooks, Peter C; Sun, Tong; Yu, Mimi C; Zheng, Wenxin; Dubeau, Louis

    2002-01-01

    Menstrual cycle activity predisposes to ovarian epithelial tumors based on numerous epidemiological studies. We showed that the hormones involved in menstrual cycle regulation modulate cell cycle activity in these tumors in an accompanying paper. We investigated whether such hormones could also influence angiogenesis, an important determinant of tumor progression, in the same tumors. Treatment with progesterone (P4) stimulated VEGF protein secretion in 4 of 5 ovarian carcinoma cell lines examined. Northern blot analyses performed in MCV50 cells showed that this effect was accompanied by increased VEGF mRNA levels. P4 also stimulated VEGF promoter activity in these cells. Estradiol (E2) showed a similar, but substantially smaller effect on VEGF secretion which was additive to that of P4. Conditioned medium from P4-treated cells strongly stimulated angiogenesis on chicken chorio-allantoic membranes. Incubating the conditioned medium with a neutralizing anti-VEGF antibody, but not with non-specific immunoglobulins abolished this effect. Angiogenic activity was not altered by treatment of the membranes with P4 directly. We conclude that P4 can stimulate angiogenic activity via induction of VEGF secretion in some ovarian epithelial tumors. Therapeutic use of progestins may be most effective when administered in combination with an anti-angiogenic agent, at least against a subset of ovarian carcinomas.

  8. Pediatric epithelial salivary gland tumors: spectrum of histologies and cytogenetics at a children's hospital.

    PubMed

    Craver, Randall D; Fonseca, Paula; Carr, Ronald

    2010-01-01

    There are conflicting reports regarding the relative frequency of benign and malignant epithelial salivary gland tumors in children. There are only a few reports of the cytogenetic abnormalities in the pleomorphic adenomas (PA) that arise in children, and even less information regarding the pleomorphic adenoma gene 1 (PLAG1) and high motility group A2 (HMGA2 ) histochemical staining in PAs, or their correlation with histologic types (stromal vs epithelial predominance). A retrospective 14 year review of epithelial salivary gland tumors encountered at a children's hospital identified 13 tumors: 12 PAs and 1 acinic cell carcinoma (ACC). No mucoepidermoid carcinomas were identified. Tumors arose in the parotid (7) and other sites (2 submandibular, 4 minor). Ten PAs in our cohort had cytogenetic studies. Four were normal, 5 involved 8q12, and 1 involved 12q13. Immunohistochemistry identified an additional 2 PAs with PLAG1 staining, and 5 additional PAs with HMGA2 staining. One tumor with ins(18;8)(q21.1;q12q22.2) had no PLAG1 staining, but stained with HMGA2. This ins(18;8) may not have involved the PLAG1 gene. There was no demonstrable correlation of 8q12/PLAG1 staining or 12q13/HMGA2 staining with histologic type. Thus we found abnormalities in either 8q12/PLAG1 staining or 12q13/HMGA2 staining in all PAs. The HMGA2 staining in 50% of PAs suggests that it may be more frequently involved in PAs than previously thought based on cytogenetic studies, at least in children.

  9. Feto-maternal outcomes of pregnancy complicated by epithelial ovarian cancer: a systematic review of literature.

    PubMed

    Blake, Erin A; Kodama, Michiko; Yunokawa, Mayu; Ross, Malcolm S; Ueda, Yutaka; Grubbs, Brendan H; Matsuo, Koji

    2015-03-01

    Although cancer diagnosed during pregnancy is rare, epithelial cell type ovarian cancers (EOCs) comprise approximately one quarter to one half of cases of ovarian malignancy diagnosed during pregnancy. The behavior of EOC during pregnancy and its implications for maternal and fetal outcomes is not well understood. In order to better define these outcomes, a systematic literature search was conducted in PubMed/MEDLINE using entry keywords "pregnancy" and "ovarian cancer" for the period from 1955 to 2013. The literature search identified 105 cases eligible for analysis. Clinical characteristics, pregnancy outcome, tumor characteristics, clinical management, and survival outcomes were all evaluated. Serious adverse events were defined as complications related to EOC that resulted in severe morbidity or mortality for the mother and/or fetus. The mean age of cases was 31.6 years. The most common histology was serous (47.6%), followed by mucinous (27.6%) and endometrioid types (10.5%). The most common presenting symptom was abdominal or pelvic pain (26.7%) while incidentally detected tumors accounted for one third of cases. The majority of cases were stage I at diagnosis (63.8%) followed by stage III disease (24.8%), and the median tumor size was 12cm. Live births occurred in 81.3% of cases, and of the remainder 72.2% were due to elective termination. Intrapartum surgery primarily took place in the second trimester (43%) with fetal conservation in 61.9% of operations. Over half of cases received chemotherapy (55.2%), approximately one third of which received it during the pregnancy (36.2%). Among the 21 cases treated with chemotherapy during pregnancy, there was no association with small for gestational age or fetal malformations. Serious adverse events occurred in 21.9% of cases, of which the most common was tumor rupture during pregnancy (10.5%). Three (2.9%) maternal death following surgery during pregnancy and five (6.4%) neonatal deaths were reported. Gestational

  10. Critical tumor suppressor function mediated by epithelial Mig-6 in endometrial cancer.

    PubMed

    Kim, Tae Hoon; Lee, Dong-Kee; Cho, Sung-Nam; Orvis, Grant D; Behringer, Richard R; Lydon, John P; Ku, Bon Jeong; McCampbell, Adrienne S; Broaddus, Russell R; Jeong, Jae-Wook

    2013-08-15

    Endometrial cancer is preceded by endometrial hyperplasia, unopposed estrogen exposure, and genetic alterations, but the precise causes of endometrial cancer remain uncertain. Mig-6, mainly known as a negative regulator of the EGF receptor, is an important mediator of progesterone signaling in the uterus, where it mediates tumor suppression by modulating endometrial stromal-epithelial communications. In this study, we investigated the function of Mig-6 in the uterine epithelium using a tissue-specific gene knockout strategy, in which floxed Mig-6 (Mig-6(f/f)) mice were crossed to Wnt7a-Cre mice (Wnt7a(cre+)Mig-6(f/f)). Wnt7a(cre+)Mig-6(f/f) mice developed endometrial hyperplasia and estrogen-dependent endometrial cancer, exhibiting increased proliferation in epithelial cells as well as apoptosis in subepithelial stromal cells. We documented increased expression of NOTCH1 and BIRC3 in epithelial cells of Wnt7a(cre+)Mig-6(f/f) mice and decreased expression of the progesterone receptor (PR) in stromal cells. Progesterone therapy controls endometrial growth and prevents endometrial cancer, but the effectiveness of progesterone as a treatment for women with endometrial cancer is less clear. We noted that the hyperplasic phenotype of Wnt7a(cre+)Mig-6(f/f) mice was prevented by progesterone treatment, whereas this treatment had no effect in PR(cre/+)Mig-6(f/f) mice where Mig-6 was deleted in both the epithelial and stromal compartments of the uterus. In contrast, activation of progesterone signaling in the stroma regulated proliferation and apoptosis in the epithelium via suppression of ERα signaling. In summary, our results establish that epithelial Mig-6 functions as a critical tumor suppressor that mediates the ability of progesterone to prevent the development of endometrial cancer.

  11. Cystic nephroma/mixed epithelial stromal tumor: a benign neoplasm with potential for recurrence.

    PubMed

    Sun, Belinda L; Abern, Michael; Garzon, Steven; Setty, Suman

    2015-05-01

    Cystic nephroma (CN) is a rare, benign, renal neoplasm composed of epithelial and stromal elements. Only about 200 cases have been reported since 1892 and recurrence has rarely been observed. We report a 32-year-old Hispanic woman, with a history of a right, complex cystic, renal mass treated by robotic decortication 2 years ago, who presented with flank pain, hematuria, and recurrent urinary tract infection. A magnetic resonance imaging study showed a 3.4-cm multicystic lesion with thickened septa and enhancement at the right kidney. The partial nephrectomy specimen revealed a well-circumscribed, multicystic tumor abutting the renal pelvis, with thick septa and smooth walls, filled with clear fluid. Microscopic examination showed variably sized cysts lined by cuboidal epithelium with focal hobnailing, without significant cytologic atypia and mitosis. The epithelial lining was positive for CK19, high molecular weight cytokeratin, and α-methylacyl-CoA racemase suggesting a primitive tubular epithelial phenotype. Primitive glomeruli-like structures were also present. The ovarian-like stroma was condensed around the cysts and was variably cellular with areas of muscle differentiation and thick-walled vessels. The stroma was positive for desmin, estrogen receptor, progesterone receptor, and CD10. We suggest that CN represents a variable mixture of epithelial and stromal elements, immature glomerular, tubular, muscle, and vascular elements, which may be present in variable proportions creating a spectrum of lesions previously described as CN and mixed epithelial and stromal tumors (MEST). This case emphasizes that CN/MEST clinically/radiologically mimics other cystic renal neoplasms, especially cystic renal cell carcinoma and tubulocystic carcinoma, necessitating histopathological examination and immunohistochemial studies for definitive diagnosis. Additionally, CN has the tendency to recur when not completely excised initially.

  12. Classification of circulating tumor cells by epithelial-mesenchymal transition markers.

    PubMed

    Wu, Shiyang; Liu, Suyan; Liu, Zhiming; Huang, Jiefeng; Pu, Xiaoyu; Li, Jing; Yang, Dinghua; Deng, Haijun; Yang, Ning; Xu, Jiasen

    2015-01-01

    In cancer, epithelial-mesenchymal transition (EMT) is associated with metastasis. Characterizing EMT phenotypes in circulating tumor cells (CTCs) has been challenging because epithelial marker-based methods have typically been used for the isolation and detection of CTCs from blood samples. The aim of this study was to use the optimized CanPatrol CTC enrichment technique to classify CTCs using EMT markers in different types of cancers. The first step of this technique was to isolate CTCs via a filter-based method; then, an RNA in situ hybridization (RNA-ISH) method based on the branched DNA signal amplification technology was used to classify the CTCs according to EMT markers. Our results indicated that the efficiency of tumor cell recovery with this technique was at least 80%. When compared with the non-optimized method, the new method was more sensitive and more CTCs were detected in the 5-ml blood samples. To further validate the new method, 164 blood samples from patients with liver, nasopharyngeal, breast, colon, gastric cancer, or non-small-cell lung cancer (NSCLC) were collected for CTC isolation and characterization. CTCs were detected in 107 (65%) of 164 blood samples, and three CTC subpopulations were identified using EMT markers, including epithelial CTCs, biophenotypic epithelial/mesenchymal CTCs, and mesenchymal CTCs. Compared with the earlier stages of cancer, mesenchymal CTCs were more commonly found in patients in the metastatic stages of the disease in different types of cancers. Circulating tumor microemboli (CTM) with a mesenchymal phenotype were also detected in the metastatic stages of cancer. Classifying CTCs by EMT markers helps to identify the more aggressive CTC subpopulation and provides useful evidence for determining an appropriate clinical approach. This method is suitable for a broad range of carcinomas.

  13. Neutrophil Granulocytes in Ovarian Cancer - Induction of Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration

    PubMed Central

    Mayer, Christine; Darb-Esfahani, Silvia; Meyer, Anne-Sophie; Hübner, Katrin; Rom, Joachim; Sohn, Christof; Braicu, Ioana; Sehouli, Jalid; Hänsch, G. Maria; Gaida, Matthias M.

    2016-01-01

    Background: Ovarian cancer (OvCa) is a highly aggressive malignoma with a tumor-promoting microenvironment. Infiltration of polymorphonuclear neutrophils (PMN) is frequently seen, raising the question of their impact on tumor development. In that context, effects of PMN on human ovarian cancer cells were assessed. Methods: Human epithelial ovarian cancer cells were incubated with human PMN, lysate of PMN, or neutrophil elastase. Morphological alterations were observed by time-lapse video-microscopy, and the underlying molecular mechanism was analyzed by flow cytometry and Western blotting. Functional alternations were assessed by an in vitro wound healing assay. In parallel, a large cohort of n=334 primary OvCa tissue samples of various histological subtypes was histologically evaluated. Results: Co-cultivation of cancer cells with either PMN or PMN lysate causes a change of the polygonal epithelial phenotype of the cells towards a spindle shaped morphology, causing a cribriform cell growth. The PMN-induced alteration could be attributed to elastase, a major protease of PMN. Elastase-induced shape change was most likely due to the degradation of membranous E-cadherin, which results in loss of cell contacts and polarity. Moreover, in response to elastase, epithelial cytokeratins were downmodulated, in parallel with a nuclear translocation of β-catenin. These PMN-elastase induced alterations of cells are compatible with an epithelial-to-mesenchymal transition (EMT) of the cancer cells. Following EMT, the cells displayed a more migratory phenotype. In human biopsies, neutrophil infiltration was seen in 72% of the cases. PMN infiltrates were detected preferentially in areas with low E-cadherin expression. Conclusion: PMN in the microenvironment of OvCa can alter tumor cells towards a mesenchymal and migratory phenotype. PMID:27053953

  14. Targeting myeloid cells in the tumor microenvironment enhances vaccine efficacy in murine epithelial ovarian cancer.

    PubMed

    Khan, Anm Nazmul H; Kolomeyevskaya, Nonna; Singel, Kelly L; Grimm, Melissa J; Moysich, Kirsten B; Daudi, Sayeema; Grzankowski, Kassondra S; Lele, Sashikant; Ylagan, Lourdes; Webster, Gill A; Abrams, Scott I; Odunsi, Kunle; Segal, Brahm H

    2015-05-10

    Epithelial ovarian cancer (EOC) is typically diagnosed at advanced stages, and is associated with a high relapse rate. Patients in remission are ideal candidates for immunotherapy aimed at cure or prolonging disease-free periods. However, immunosuppressive pathways in the tumor microenvironment are obstacles to durable anti-tumor immunity. In a metastatic syngeneic mouse model of EOC, immunosuppressive macrophages and myeloid-derived suppressor cells (MDSCs) accumulate in the local tumor environment. In addition, resident peritoneal macrophages from non-tumor-bearing mice were highly immunosuppressive, abrogating stimulated T cell proliferation in a cell contact-dependent manner. Immunization with microparticles containing TLR9 and NOD-2 ligands (MIS416) significantly prolonged survival in tumor-bearing mice. The strategy of MIS416 immunization followed by anti-CD11b administration further delayed tumor progression, thereby establishing the proof of principle that myeloid depletion can enhance vaccine efficacy. In patients with advanced EOC, ascites analysis showed substantial heterogeneity in the relative proportions of myeloid subsets and their immunosuppressive properties. Together, these findings point to immunosuppressive myeloid cells in the EOC microenvironment as targets to enhance vaccination. Further studies of myeloid cell accumulation and functional phenotypes in the EOC microenvironment may identify patients who are likely to benefit from vaccination combined with approaches that deplete tumor-associated myeloid cells.

  15. Regulation of epithelial-mesenchymal transition by tumor-associated macrophages in cancer

    PubMed Central

    Zhang, Jia; Yao, Hongmei; Song, Ge; Liao, Xia; Xian, Yao; Li, Weimin

    2015-01-01

    It should be urgently better understood of the mechanism that contributes cancer aggressiveness. Epithelial-mesenchymal transition (EMT) plays a fundamental role in tumor progression and metastasis formation by invasion, resistance to cell death and senescence, resistance to chemotherapy and immunotherapy, immune surveillance, immunosuppression and inflammation, confers stem cell properties. Tumor-associated macrophages (TAMs) are key orchestrators and a set of macrophages in tumor microenvironment. They are major players in the connection between inflammation and cancer. TAMs could promote proliferation, invasion and metastasis of tumor cells, stimulate tumor angiogenesis, and inhibit anti-tumor immune response mediated by T cell followed by promoting tumor progression. Recently, studies showed that TAMs played critical role in the regulation of EMT in cancer, although the underlying mechanism of TAMs-mediated acquisition of EMT has been largely unclear. This review will discuss recent advances in our understanding of the role of TAMs in the regulation of EMT during tumorigenesis and summarize the recent ongoing experimental and pre-clinical TAMs targeted studies. PMID:26692918

  16. A Multidisciplinary Orbit-Sparing Treatment Approach That Includes Proton Therapy for Epithelial Tumors of the Orbit and Ocular Adnexa.

    PubMed

    Holliday, Emma B; Esmaeli, Bita; Pinckard, Jamie; Garden, Adam S; Rosenthal, David I; Morrison, William H; Kies, Merrill S; Gunn, G Brandon; Fuller, C David; Phan, Jack; Beadle, Beth M; Zhu, Xiarong Ronald; Zhang, Xiaodong; Frank, Steven J

    2016-05-01

    Postoperative radiation is often indicated in the treatment of malignant epithelial tumors of the orbit and ocular adnexa. We present details of radiation technique and toxicity data after orbit-sparing surgery followed by adjuvant proton radiation therapy. Twenty patients underwent orbit-sparing surgery followed by proton therapy for newly diagnosed malignant epithelial tumors of the lacrimal gland (n=7), lacrimal sac/nasolacrimal duct (n=10), or eyelid (n=3). Tumor characteristics, treatment details, and visual outcomes were obtained from medical records. Acute and chronic toxicity were prospectively scored using Common Terminology Criteria for Adverse Events version 4.0. The median radiation dose was 60 Gy(RBE) (relative biological effectiveness; [range 50-70 Gy]); 11 patients received concurrent chemotherapy. Dose to ipsilateral anterior optic structures was reduced in 13 patients by having them gaze away from the target during treatment. At a median follow-up time of 27.1 months (range 2.6-77.2 months), no patient had experienced local recurrence; 1 had regional and 1 had distant recurrence. Three patients developed chronic grade 3 epiphora, and 3 developed grade 3 exposure keratopathy. Four patients experienced a decrease in visual acuity from baseline but maintained vision sufficient to perform all activities of daily living without difficulty. Patients with grade ≥3 chronic ocular toxicity had higher maximum dose to the ipsilateral cornea (median 46.3 Gy[RBE], range 36.6-52.7 Gy[RBE] vs median 37.4 Gy[RBE], range 9.0-47.3 Gy(RBE); P=.017). Orbit-sparing surgery for epithelial tumors of the orbit and ocular adnexa followed by proton therapy successfully achieved disease control and was well tolerated. No patient required orbital exenteration or enucleation. Chronic grade 3 toxicity was associated with high maximum dose to the cornea. An eye-deviation technique can be used to limit the maximum corneal dose to <35 Gy(RBE). Copyright © 2016 Elsevier Inc. All

  17. Factors affecting intellectual outcome in pediatric brain tumor patients

    SciTech Connect

    Ellenberg, L.; McComb, J.G.; Siegel, S.E.; Stowe, S.

    1987-11-01

    A prospective study utilizing repeated intellectual testing was undertaken in 73 children with brain tumors consecutively admitted to Childrens Hospital of Los Angeles over a 3-year period to determine the effect of tumor location, extent of surgical resection, hydrocephalus, age of the child, radiation therapy, and chemotherapy on cognitive outcome. Forty-three patients were followed for at least two sequential intellectual assessments and provide the data for this study. Children with hemispheric tumors had the most general cognitive impairment. The degree of tumor resection, adequately treated hydrocephalus, and chemotherapy had no bearing on intellectual outcome. Age of the child affected outcome mainly as it related to radiation. Whole brain radiation therapy was associated with cognitive decline. This was especially true in children below 7 years of age, who experienced a very significant loss of function after whole brain radiation therapy.

  18. Tumor-infiltrating T lymphocytes improve clinical outcome of therapy-resistant neuroblastoma

    PubMed Central

    Mina, Marco; Boldrini, Renata; Citti, Arianna; Romania, Paolo; D'Alicandro, Valerio; De Ioris, Maretta; Castellano, Aurora; Furlanello, Cesare; Locatelli, Franco; Fruci, Doriana

    2015-01-01

    Neuroblastoma grows within an intricate network of different cell types including epithelial, stromal and immune cells. The presence of tumor-infiltrating T cells is considered an important prognostic indicator in many cancers, but the role of these cells in neuroblastoma remains to be elucidated. Herein, we examined the relationship between the type, density and organization of infiltrating T cells and clinical outcome within a large collection of neuroblastoma samples by quantitative analysis of immunohistochemical staining. We found that infiltrating T cells have a prognostic value greater than, and independent of, the criteria currently used to stage neuroblastoma. A variable in situ structural organization and different concurrent infiltration of T-cell subsets were detected in tumors with various outcomes. Low-risk neuroblastomas were characterized by a higher number of proliferating T cells and a more structured T-cell organization, which was gradually lost in tumors with poor prognosis. We defined an immunoscore based on the presence of CD3+, CD4+ and CD8+ infiltrating T cells that associates with favorable clinical outcome in MYCN-amplified tumors, improving patient survival when combined with the v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) status. These findings support the hypothesis that infiltrating T cells influence the behavior of neuroblastoma and might be of clinical importance for the treatment of patients. PMID:26405592

  19. Tumor necrosis factor-alpha is expressed by glomerular visceral epithelial cells in human membranous nephropathy.

    PubMed Central

    Neale, T. J.; Rüger, B. M.; Macaulay, H.; Dunbar, P. R.; Hasan, Q.; Bourke, A.; Murray-McIntosh, R. P.; Kitching, A. R.

    1995-01-01

    The role of tumor necrosis factor alpha (TNF-alpha) was examined in biopsy-proven glomerulonephritis by immunohistochemistry, in situ hybridization, immunogold electron microscopy, immunoassay in serum and urine, and urinary immunoblot. Striking glomerular capillary wall and visceral glomerular epithelial cell TNF-alpha protein staining was observed in all cases of membranous nephropathy and membranous lupus nephropathy. Staining was less frequently observed in crescentic glomerulonephritis and in isolated cases of other histological subtypes of glomerulonephritis, usually in association with glomerular macrophages. By immunogold electron microscopy TNF-alpha was localized in membranous nephropathy within the visceral glomerular epithelial cells, and also in the glomerular basement membrane, especially in relation to immune deposits. In situ hybridization localized TNF-alpha mRNA exclusively to glomerular epithelial cells in all biopsies with membranous morphology but not in other histological subtypes. Concentrations of TNF-alpha were significantly increased compared with normal controls in the urine of patients with membranous nephropathy and with crescentic glomerulonephritis. The expression of TNF-alpha by glomerular epithelial cells exclusively and universally in biopsies showing a membranous morphology strongly suggests this cytokine has a role in the pathogenesis of membranous nephropathy. Images Figure 1 Figure 2 Figure 3 Figure 5 PMID:7778683

  20. Early dental epithelial transcription factors distinguish ameloblastoma from keratocystic odontogenic tumor.

    PubMed

    Heikinheimo, K; Kurppa, K J; Laiho, A; Peltonen, S; Berdal, A; Bouattour, A; Ruhin, B; Catón, J; Thesleff, I; Leivo, I; Morgan, P R

    2015-01-01

    The aim of the study was to characterize the molecular relationship between ameloblastoma and keratocystic odontogenic tumor (KCOT) by means of a genome-wide expression analysis. Total RNA from 27 fresh tumor samples of 15 solid/multicystic intraosseous ameloblastomas and 12 sporadic KCOTs was hybridized on Affymetrix whole genome arrays. Hierarchical clustering separated ameloblastomas and KCOTs into 2 distinct groups. The gene set enrichment analysis based on 303 dental genes showed a similar separation of ameloblastomas and KCOTs. Early dental epithelial markers PITX2, MSX2, DLX2, RUNX1, and ISL1 were differentially overexpressed in ameloblastoma, indicating its dental identity. Also, PTHLH, a hormone involved in tooth eruption and invasive growth, was one of the most differentially upregulated genes in ameloblastoma. The most differentially overexpressed genes in KCOT were squamous epithelial differentiation markers SPRR1A, KRTDAP, and KRT4, as well as DSG1, a component of desmosomal cell-cell junctions. Additonally, the epithelial stem cell marker SOX2 was significantly upregulated in KCOT when compared with ameloblastoma. Taken together, the gene expression profile of ameloblastoma reflects differentiation from dental lamina toward the cap/bell stage of tooth development, as indicated by dental epithelium-specific transcription factors. In contrast, gene expression of KCOT indicates differentiation toward keratinocytes. © International & American Associations for Dental Research 2014.

  1. Grhl3 induces human epithelial tumor cell migration and invasion via downregulation of E-cadherin.

    PubMed

    Zhao, Pan; Guo, Sijia; Tu, Zhenzhen; Di, Lijun; Zha, Xiaojun; Zhou, Haisheng; Zhang, Xuejun

    2016-03-01

    Grainyhead genes are involved in wound healing and developmental neural tube closure. Metastasis is a multistep process during which cancer cells disseminate from the site of primary tumors and establish secondary tumors in distant organs. The adhesion protein E-cadherin plays an essential role in metastasis. In light of the high degree of similarity between the epithelial-mesenchymal transition (EMT) occurring in wound-healing processes and the EMT occurring during the acquisition of invasiveness in skin or breast cancer, we investigated the role of the Grainyhead genes in cancer invasion. Here, we show that there is an inverse relationship between Grainyhead-like 3 (Grhl3) and E-cadherin expression in some epithelial tumor cell lines. Overexpression of Grhl3 in the E-cadherin-positive epithelial tumor cell line, characterized by less invasiveness, generated a transcriptional blockage of the E-cadherin gene and promoted cell migration and cell invasion. Conversely, Grhl3 depletion inhibited cell migration and cell invasion and was associated with a gain of E-cadherin expression. To further explore the mechanism by which Grhl3 regulated E-cadherin expression, an E-cadherin promoter report analysis was performed and results showed that Grhl3 repressed E-cadherin gene expression by directly or indirectly binding to the E-boxes present in the proximal E-cadherin promoter. Taken together, our findings define a major role for Grhl3 in the induction of migration and invasion by the downregulation of E-cadherin in cancer cells.

  2. TGFβ Signaling in Tumor Initiation, Epithelial-to-Mesenchymal Transition, and Metastasis

    PubMed Central

    2015-01-01

    Retaining the delicate balance in cell signaling activity is a prerequisite for the maintenance of physiological tissue homeostasis. Transforming growth factor-beta (TGFβ) signaling is an essential pathway that plays crucial roles during embryonic development as well as in adult tissues. Aberrant TGFβ signaling activity regulates tumor progression in a cancer cell-autonomous or non-cell-autonomous fashion and these effects may be tumor suppressing or tumor promoting depending on the cellular context. The fundamental role of this pathway in promoting cancer progression in multiple stages of the metastatic process, including epithelial-to-mesenchymal transition (EMT), is also becoming increasingly clear. In this review, we discuss the latest advances in the effort to unravel the inherent complexity of TGFβ signaling and its role in cancer progression and metastasis. These findings provide important insights into designing personalized therapeutic strategies against advanced cancers. PMID:25883652

  3. Outcomes of laparoscopic fertility-sparing surgery in clinically early-stage epithelial ovarian cancer

    PubMed Central

    Park, Jin-Young; Lee, Yoo-Young; Kim, Tae-Joong; Kim, Byoung-Gie; Bae, Duk-Soo

    2016-01-01

    Objective Fertility-sparing surgery (FSS) is becoming an important technique in the surgical management of young women with early-stage epithelial ovarian cancer (EOC). We retrospectively evaluated the outcome of laparoscopic FSS in presumed clinically early-stage EOC. Methods We retrospectively searched databases of patients who received laparoscopic FSS for EOC between January 1999 and December 2012 at Samsung Medical Center. Women aged ≤40 years were included. The perioperative, oncological, and obstetric outcomes of these patients were evaluated. Results A total of 18 patients was evaluated. The median age of the patients was 33.5 years (range, 14 to 40 years). The number of patients with clinically stage IA and IC was 6 (33.3%) and 12 (66.7%), respectively. There were 7 (38.9%), 5 (27.8%), 3 (16.7%), and 3 patients (16.7%) with mucinous, endometrioid, clear cell, and serous tumor types, respectively. Complete surgical staging to preserve the uterus and one ovary with adnexa was performed in 4 patients (22.2%). Two out of them were upstaged to The International Federation of Gynecology and Obstetrics stage IIIA1. During the median follow-up of 47.3 months (range, 11.5 to 195.3 months), there were no perioperative or long term surgical complications. Four women (22.2%) conceived after their respective ovarian cancer treatments. Three (16.7%) of them completed full-term delivery and one is expecting a baby. One patient had disease recurrence. No patient died of the disease. Conclusion FSS in young patients with presumed clinically early-stage EOC is a challenging and cautious procedure. Further studies are urgent to determine the safety and feasibility of laparoscopic FSS in young patients with presumed clinically early-stage EOC. PMID:26768783

  4. RBSP3 (HYA22) is a tumor suppressor gene implicated in major epithelial malignancies

    PubMed Central

    Kashuba, Vladimir I.; Li, Jingfeng; Wang, Fuli; Senchenko, Vera N.; Protopopov, Alexey; Malyukova, Alena; Kutsenko, Alexey S.; Kadyrova, Elena; Zabarovska, Veronika I.; Muravenko, Olga V.; Zelenin, Alexander V.; Kisselev, Lev L.; Kuzmin, Igor; Minna, John D.; Winberg, Gösta; Ernberg, Ingemar; Braga, Eleonora; Lerman, Michael I.; Klein, George; Zabarovsky, Eugene R.

    2004-01-01

    Chromosome 3p21.3 region is frequently (>90%) deleted in lung and other major human carcinomas. We subdivided 3p21.3 into LUCA and AP20 subregions and discovered frequent homozygous deletions (10-18%) in both subregions. This finding strongly implies that they harbor multiple tumor suppressor genes involved in the origin and/or development of major epithelial cancers. In this study, we performed an initial analysis of RBSP3/HYA22, a candidate tumor suppressor genes located in the AP20 region. Two sequence splice variants of RBSP3/HYA22 (A and B) were identified, and we provide evidence for their tumor suppressor function. By sequence analysis RBSP3/HYA22 belongs to a gene family of small C-terminal domain phosphatases that may control the RNA polymerase II transcription machinery. Expression of the gene was drastically (>20-fold) decreased in 11 of 12 analyzed carcinoma cell lines and in three of eight tumor biopsies. We report missense and nonsense mutations in tumors where RBSP3/HYA22 was expressed, growth suppression with regulated transgenes in culture, suppression of tumor formation in severe combined immunodeficient mice, and dephosphorylation of ppRB by RBSP3/HYA22, presumably leading to a block of the cell cycle at the G1/S boundary. PMID:15051889

  5. Neuroendoscopic Resection of Intraventricular Tumors: A Systematic Outcomes Analysis

    PubMed Central

    Barber, Sean M.; Baskin, David

    2013-01-01

    Introduction. Though traditional microsurgical techniques are the gold standard for intraventricular tumor resection, the morbidity and invasiveness of microsurgical approaches to the ventricular system have galvanized interest in neuroendoscopic resection. We present a systematic review of the literature to provide a better understanding of the virtues and limitations of endoscopic tumor resection. Materials and Methods. 40 articles describing 668 endoscopic tumor resections were selected from the Pubmed database and reviewed. Results. Complete or near-complete resection was achieved in 75.0% of the patients. 9.9% of resected tumors recurred during the follow-up period, and procedure-related complications occurred in 20.8% of the procedures. Tumor size ≤ 2cm (P = 0.00146), the presence of a cystic tumor component (P < 0.0001), and the use of navigation or stereotactic tools during the procedure (P = 0.0003) were each independently associated with a greater likelihood of complete or near-complete tumor resection. Additionally, the complication rate was significantly higher for noncystic masses than for cystic ones (P < 0.0001). Discussion. Neuroendoscopic outcomes for intraventricular tumor resection are significantly better when performed on small, cystic tumors and when neural navigation or stereotaxy is used. Conclusion. Neuroendoscopic resection appears to be a safe and reliable treatment option for patients with intraventricular tumors of a particular morphology. PMID:24191196

  6. An intraosseous sclerosing odontogenic tumor predominantly composed of epithelial cells: relation to (so-called) sclerosing odontogenic carcinoma and epithelial-rich central odontogenic fibroma.

    PubMed

    Tan, Sze Hwa; Yeo, Jin Fei; Kheem Pang, Brendan Nghee; Petersson, Fredrik

    2014-10-01

    We report a case of an asymptomatic sclerosing odontogenic tumor in a 31-year-old woman. Radiologically, the tumor was well circumscribed, was predominantly radiolucent, and had a peripheral sclerotic margin. Histopathologically, the tumor showed small clusters, strands, and cords of small to medium-sized epithelial tumor cells in a sclerotic collagenous stroma. Immunohistochemically, the tumor cells were positive for broad-spectrum cytokeratins (CKs) (CK7, CK5/6, CK19, and CAM 5.2) and p63. Membranous staining for E-cadherin was present. There was weak to moderate nuclear expression of p16 in 30% of cells. Rare tumor cells were positive for p53. Progesterone receptors were expressed in about 60% of the tumor cells. The proliferative activity (Ki-67) was approximately 2%. A molecular genetic (fluorescence in situ hybridization) study showed no EWSR1 (EWS RNA-binding protein 1) gene rearrangement. No recurrence or metastatic events have been documented at 1-year follow-up. This tumor represents a classification dilemma mainly between epithelial-rich central odontogenic fibroma and the so-called sclerosing odontogenic carcinoma.

  7. Tumor-specific p53 sequences in blood and peritoneal fluid of women with epithelial ovarian cancer.

    PubMed

    Swisher, Elizabeth M; Wollan, Melissa; Mahtani, Sarita M; Willner, Julia B; Garcia, Rochelle; Goff, Barbara A; King, Mary-Claire

    2005-09-01

    Free tumor DNA in body fluids may be an important biomarker. We tested whether tumor-specific mutated p53 DNA can be detected in blood and peritoneal fluid from women with epithelial ovarian cancer. Sequencing of tumor DNA identified somatic p53 mutations. Free DNA from matched blood or peritoneal fluid was evaluated for the tumor-specific p53 mutation using a ligase detection reaction. Sixty-nine of 137 tumors (50%) had p53 mutations. Plasma or serum from 21 (30%) of the 69 informative cases contained the tumor-specific p53 mutation. Circulating tumor was an independent predictor of decreased survival in multivariate analysis (P=.02). We detected tumor DNA in peritoneal fluid in 28 of 30 (93%) cases, including all 6 cases with negative cytology. One third of women with ovarian cancer have circulating tumor DNA and an associated reduced survival. Free tumor DNA can be detected in the majority of peritoneal fluid samples.

  8. Tumor suppressor roles of CENP-E and Nsl1 in Drosophila epithelial tissues.

    PubMed

    Clemente-Ruiz, Marta; Muzzopappa, Mariana; Milán, Marco

    2014-01-01

    Depletion of spindle assembly checkpoint (SAC) genes in Drosophila epithelial tissues leads to JNK-dependent programmed cell death and additional blockade of the apoptotic program drives tumorigenesis. A recent report proposes that chromosomal instability (CIN) is not the driving force in the tumorigenic response of the SAC-deficient tissue, and that checkpoint proteins exert a SAC-independent tumor suppressor role. This notion is based on observations that the depletion of CENP-E levels or prevention of Bub3 from binding to the kinetochore in Drosophila tissues unable to activate the apoptotic program induces CIN but does not cause hyperproliferation. Here we re-examined this proposal. In contrast to the previous report, we observed that depletion of CENP-E or Nsl1-the latter mediating kinetochore targeting of Bub3-in epithelial tissues unable to activate the apoptotic program induces significant levels of aneuploidy and drives tumor-like growth. The induction of the JNK transcriptional targets Wingless, a mitogenic molecule, and MMP1, a matrix metaloproteinase 1 involved in basement membrane degradation was also observed in these tumors. An identical response of the tissue was previously detected upon depletion of several SAC genes or genes involved in spindle assembly, chromatin condensation, and cytokinesis, all of which have been described to cause CIN. All together, these results reinforce the role of CIN in driving tumorigenesis in Drosophila epithelial tissues and question the proposed SAC-independent roles of checkpoint proteins in suppressing tumorigenesis. Differences in aneuploidy rates might explain the discrepancy between the previous report and our results.

  9. Spindle epithelial tumor with thymus-like differentiation: a case report and review of literature.

    PubMed

    Misra, R K; Mitra, Shaila; Yadav, Rajesh; Bundela, Alpana

    2013-01-01

    Spindle epithelial tumor with thymus-like differentiation (SETTLE) is an extremely rare type of thyroid tumor with fewer than 35 reported cases available in the literature so far, most of them having been diagnosed histologically after resection. The tumor is believed to be derived from branchial-pouch or thymic remnants, occurring in young adults, predominantly in males, with a male:female ratio 1.8:1. A 14-year-old girl presented with a nodular mass in her right thyroid that had been present for 1 year. Ultrasonological study revealed a heterogeneous solid mass (2.5 × 1.5 × 1.5 cm) in the right lobe of the thyroid. Fine-needle aspiration (FNA) smears were highly cellular and comprised of predominantly dissociated uniform spindle cells with naked oval nuclei along with some aggregates and groups. Occasional islands of epithelial cells were also present. Cytologically, the spindle cells had bland nuclear chromatin, with very scanty mitotic figures. Upon examination of the FNA smears, a provisional diagnosis of SETTLE was suggested along with a request for an incisional biopsy to rule out another differential diagnosis of medullary carcinoma thyroid. On the resected tissue specimen, diagnosis was histologically confirmed to be SETTLE. Immunohistochemical study revealed a strong and diffuse positivity for high-molecular-weight keratin and vimentin, and negativity for thyroglobulin, calcitonin, S-100 protein, desmin, chromogranin and synaptophysin. Cytologically, SETTLE can safely be considered, especially if spindle elements are observed along with the occasional group of epithelial cells in FNA smears from the thyroid of young adults. It can help in the preoperative recognition of lesions based on distinctive cytomorphological features and immunohistochemical characteristics, allowing a more sound therapeutic approach because these patients can present with delayed metastasis. Copyright © 2013 S. Karger AG, Basel.

  10. Evidence for a stromal-epithelial “lactate shuttle” in human tumors

    PubMed Central

    Lin, Zhao; Ertel, Adam; Flomenberg, Neal; Witkiewicz, Agnieszka K; Birbe, Ruth C; Howell, Anthony; Pavlides, Stephanos; Gandara, Ricardo; Pestell, Richard G; Sotgia, Federica

    2011-01-01

    Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. In this new paradigm, cancer-associated fibroblasts undergo aerobic glycolysis, and extrude lactate to “feed” adjacent cancer cells, which then drives mitochondrial biogenesis and oxidative mitochondrial metabolism in cancer cells. Thus, there is vectorial transport of energy-rich substrates from the fibroblastic tumor stroma to anabolic cancer cells. A prediction of this hypothesis is that cancer-associated fibroblasts should express MCT4, a mono-carboxylate transporter that has been implicated in lactate efflux from glycolytic muscle fibers and astrocytes in the brain. To address this issue, we co-cultured MCF7 breast cancer cells with normal fibroblasts. Interestingly, our results directly show that breast cancer cells specifically induce the expression of MCT4 in cancer-associated fibroblasts; MCF7 cells alone and fibroblasts alone, both failed to express MCT4. We also show that the expression of MCT4 in cancer-associated fibroblasts is due to oxidative stress, and can be prevented by pre-treatment with the anti-oxidant N-acetyl-cysteine. In contrast to our results with MCT4, we see that MCT1, a transporter involved in lactate uptake, is specifically upregulated in MCF7 breast cancer cells when co-cultured with fibroblasts. Virtually identical results were also obtained with primary human breast cancer samples. In human breast cancers, MCT4 selectively labels the tumor stroma, e.g., the cancer-associated fibroblast compartment. Conversely, MCT1 was selectively expressed in the epithelial cancer cells within the same tumors. Functionally, we show that overexpression of MCT4 in fibroblasts protects both MCF7 cancer cells and fibroblasts against cell death, under co-culture conditions. Thus, we provide the first evidence for the existence of a stromal-epithelial lactate shuttle in human tumors, analogous to the lactate shuttles that are essential for the normal

  11. Outcome after resection of one hundred gastrointestinal stromal tumors.

    PubMed

    Krajinovic, K; Germer, C T; Agaimy, A; Wünsch, P H; Isbert, C

    2010-01-01

    To evaluate the outcome after surgical resection in patients with gastrointestinal stromal tumors and to determine the factors influencing local tumor recurrence or distant metastatic disease after locally complete tumor resection (R0). Outcomes of 100 patients with primary gastrointestinal stromal tumors (GIST) surgically managed between 1997 and 2006 at a single institution were reviewed. Univariate and bivariate analyses were used to determine factors affecting recurrence-free and tumor-free survival. All patients (n = 100) had c-kit-positive GIST. There were 17% (n = 17) very low risk, 41% (n = 41) low risk, 19% (n = 19) intermediate risk and 23% (n = 23) high risk GIST originating from the stomach, small bowel, colon and rectum. The median patient age was 68 years (range 39-92). Seventy-three percent of the patients had symptomatic local disease. Most (94%; n = 94) of them underwent R0 resections of their primary tumor. R0 resection was significantly associated with a lower tumor-related mortality rate (p = 0.0001). The patients with recurrence/metastases had significantly larger tumors (p = 0.0017) and a mitotic index higher than 5/50 HPF (p = 0.0001). Seven of 20 patients from the high-risk group and 2 of 7 patients with metastatic disease developed local recurrence or further metastatatic tumor spread following R0 resection. Surgical removal continues to be the mainstay of GIST treatment. R0 resection, tumor size and mitotic index are significant prognostic factors. Overall, more than 30% of the patients with high-risk GIST develop local recurrences and distant metastases despite R0 resection. Additional molecular pathological markers are needed to yield a more accurate tumor profile and to thus achieve a better predictability of the biological behavior of GIST. Copyright 2010 S. Karger AG, Basel.

  12. Grepafloxacin inhibits tumor necrosis factor-alpha-induced interleukin-8 expression in human airway epithelial cells.

    PubMed

    Hashimoto, S; Matsumoto, K; Gon, Y; Maruoka, S; Hayashi, S; Asai, Y; Machino, T; Horie, T

    2000-01-01

    We examined the effect of grepafloxacin (GPFX), a new fluoroquinolone antimicrobial agent, on interleukin-8 (IL-8) expression in tumor necrosis factor-alpha (TNF-alpha)-stimulated human airway epithelial cells (AEC). GPFX inhibited IL-8 protein production as well as mRNA expression in a concentration-dependent manner (2.5 - 25 micro g/ml), but the inhibition of IL-8 expression by corresponding concentrations of GPFX to serum and airway lining fluids was not complete. We discuss the modulatory effect of GPFX on IL-8 production in the context of its efficacy on controlling chronic airway inflammatory diseases.

  13. Heterogeneity of keratin expression in epithelial tumor cells of adenolymphoma in paraffin sections.

    PubMed

    Orito, T; Shinohara, H; Okada, Y; Mori, M

    1989-06-01

    Immunohistochemical expressions of keratin polypeptides detected by monoclonal antibodies were described in tumor cells of adenolymphoma, and the possibility of intercalated duct and ductal basal cells in the salivary glands being the progenitors was discussed. Basal cells in the tumor showed positive staining for keratin nos. 8, 13, 16, 18 and 19 detecting for monoclonal keratin antibodies (PKK 1, K 4.62, K 8.12, K 8.13), columnar tumor cells displayed strongly positive reactions with RPN 1164 and K4.62 suggesting keratin nos. 8 and 19. Great heterogeneity of distribution for keratin polypeptides was displayed by epithelial cells of adenolymphoma. Intercalated duct cells of normal salivary glands reacted with RPN 1164, RPN 1165, K 4.62 and K 8.13 monoclonal antibodies, which indicates the presence of keratins 8 and 19; and ductal basal cells reacted with PKK 1, K 4.62 and K 8.12, suggesting nos. 8, 13, 16, 18 and 19 keratins. Distribution of involucrin was variable in tumor epithelium of adenolymphoma, and was negative in the normal gland. The immunohistochemical distribution of keratin types between basal tumor cells of adenolymphoma and ductal basal cells of the normal salivary gland was compared.

  14. Prognostic Significance of the Tumor-Stroma Ratio in Epithelial Ovarian Cancer

    PubMed Central

    Chen, Ying; Zhang, Lei; Liu, Wenxin; Liu, Xiangyu

    2015-01-01

    Tumor-stroma ratio (TSR) has recently been identified as a promising prognostic parameter for several solid tumors. This study aimed to evaluate the prognostic role of TSR in epithelial ovarian cancer (EOC) and 838 EOC patients were enrolled in this study. TSR was estimated on hematoxylin-and-eosin-stained tissue sections from the most invasive part of the primary tumor. Patients were classified as stroma-rich or stroma-poor according to the proportion of stroma ≥50% or <50%. Chi-square test analysis revealed that TSR were significantly associated with FIGO stage, LN status, and recurrence or not (all of them P < 0.001). The higher stroma-rich proportions were found in EOC patients with advanced stage (36.13% versus 19.75%), LN metastasis (51.93% versus 27.25%), and recurrence (34.27% versus 6.82%). Stroma-rich EOC patients had obvious shorter median time of progression-free survival (29 versus 39 months) and overall survival (50 versus 58 months), respectively. TSR was an independent prognostic factor for the evaluation of PFS in EOC. Stroma-rich tumors had worse prognosis and higher risk of relapse compared with those in stroma-poor tumors in EOC patients. Considered easy to determine for routine pathological examination, TSR may serve as a new prognostic histological parameter in EOC. PMID:26609529

  15. Diagnostically Challenging Epithelial Odontogenic Tumors: A Selective Review of 7 Jawbone Lesions

    PubMed Central

    Mishima, Kenji; Saito, Ichiro; Kusama, Kaoru

    2009-01-01

    Considerable variation in the clinicopathologic presentation of epithelial odontogenic tumors can sometimes be confusing and increase the chance of misdiagnosis. Seven diagnostically challenging jawbone lesions are described. There were 2 cases of mistaken identity in our ameloblastoma file. One unicystic type, initially diagnosed and treated as a lateral periodontal cyst, showed destructive recurrence 6 years postoperatively. The other globulomaxillary lesion was managed under the erroneous diagnosis of adenomatoid odontogenic tumor and recurred 4 times over an 11-year period. This tumor was found in retrospect to be consistent with an adenoid ameloblastoma with dentinoid. The diagnosis of cystic squamous odontogenic tumor (SOT) occurring as a radicular lesion of an impacted lower third molar was one of exclusion. Of two unsuspected keratocystic odontogenic tumors, one depicted deceptive features of pericoronitis, while the other case has long been in our files with the diagnosis of globulomaxillary SOT. Two cases of primary intraosseous squamous cell carcinoma appeared benign clinically and exhibited unexpected findings; an impacted third molar began to erupt in association with the growth of carcinoma and another periradicular carcinoma showed dentinoid formation. Cases selectively reviewed in this article present challenging problems which require clinical and radiographic correlation to avoid potential diagnostic pitfalls. PMID:20596984

  16. EMT Inducers Catalyze Malignant Transformation of Mammary Epithelial Cells and Drive Tumorigenesis towards Claudin-Low Tumors in Transgenic Mice

    PubMed Central

    Fauvet, Frédérique; Courtois-Cox, Stéphanie; Wierinckx, Anne; Devouassoux-Shisheboran, Mojgan; Treilleux, Isabelle; Tissier, Agnès; Gras, Baptiste; Pourchet, Julie; Puisieux, Isabelle; Browne, Gareth J.; Spicer, Douglas B.; Lachuer, Joël; Ansieau, Stéphane; Puisieux, Alain

    2012-01-01

    The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMT–inducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cell–like characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation. PMID:22654675

  17. Mesenchymal-epithelial transitions: spontaneous and cumulative syntheses of epithelial marker molecules and their assemblies to novel cell junctions connecting human hematopoietic tumor cells to carcinomatoid tissue structures.

    PubMed

    Franke, Werner W; Rickelt, Steffen

    2011-12-01

    Using biochemical as well as light- and electron-microscopic immunolocalization methods, in cultures of unicellular human blood tumor cells, we have studied the phenomenon of spontaneous and cumulative syntheses of certain epithelial proteins and glycoproteins and their assemblies to two major kinds of novel cell-cell junctions, adhering junctions (AJs) and junctions based on the epithelial cell adhesion molecule (EpCAM). More than two decades, we have selected and characterized clonal sublines of multipotential hematopoietic K562 cells, which are enriched in newly formed AJs based on cis-clusters of desmoglein Dsg2, in some sublines accompanied by desmocollin Dsc2. Both desmosomal cadherins can be anchored in a submembranous plaque containing plakoglobin and plakophilins Pkp2 and Pkp3, with or without other armadillo proteins and desmoplakin. Also, these cells are often connected by an additional, extended junction system, in which the transmembrane epithelial glycoprotein EpCAM is associated with a cytoplasmic plaque rich in several actin-binding proteins such as afadin, α-actinin, ezrin and vinculin. Both kinds of junctions contribute to connections of K562 cells into epithelioid monolayers or even three-dimensional, tissue-like structures, thus markedly changing the cell biological nature and behavior of the resulting tumor subforms (mesenchymal-epithelial transitions). We discuss molecular mechanisms involved in the formation and function of these junctions, also with respect to tumor spread and metastasis, as well as diagnostic and therapeutic consequences.

  18. Surface modification of microparticles causes differential uptake responses in normal and tumoral human breast epithelial cells

    NASA Astrophysics Data System (ADS)

    Patiño, Tania; Soriano, Jorge; Barrios, Lleonard; Ibáñez, Elena; Nogués, Carme

    2015-06-01

    The use of micro- and nanodevices as multifunctional systems for biomedical applications has experienced an exponential growth during the past decades. Although a large number of studies have focused on the design and fabrication of new micro- and nanosystems capable of developing multiple functions, a deeper understanding of their interaction with cells is required. In the present study, we evaluated the effect of different microparticle surfaces on their interaction with normal and tumoral human breast epithelial cell lines. For this, AlexaFluor488 IgG functionalized polystyrene microparticles (3 μm) were coated with Polyethyleneimine (PEI) at two different molecular weights, 25 and 750 kDa. The effect of microparticle surface properties on cytotoxicity, cellular uptake and endocytic pathways were assessed for both normal and tumoral cell lines. Results showed a differential response between the two cell lines regarding uptake efficiency and mechanisms of endocytosis, highlighting the potential role of microparticle surface tunning for specific cell targeting.

  19. Human endometrial mesenchymal stem cells exhibit intrinsic anti-tumor properties on human epithelial ovarian cancer cells

    PubMed Central

    Bu, Shixia; Wang, Qian; Zhang, Qiuwan; Sun, Junyan; He, Biwei; Xiang, Charlie; Liu, Zhiwei; Lai, Dongmei

    2016-01-01

    Epithelial ovarian cancer (EOC) is the most lethal tumor of all gynecologic tumors. There is no curative therapy for EOC thus far. The tumor-homing ability of adult mesenchymal stem cells (MSCs) provide the promising potential to use them as vehicles to transport therapeutic agents to the site of tumor. Meanwhile, studies have showed the intrinsic anti-tumor properties of MSCs against various kinds of cancer, including epithelial ovarian cancer. Human endometrial mesenchymal stem cells (EnSCs) derived from menstrual blood are a novel source for adult MSCs and exert restorative function in some diseases. Whether EnSCs endow innate anti-tumor properties on EOC cells has never been reported. By using tumor-bearing animal model and ex vivo experiments, we found that EnSCs attenuated tumor growth by inducing cell cycle arrest, promoting apoptosis, disturbing mitochondria membrane potential and decreasing pro-angiogenic ability in EOC cells in vitro and/or in vivo. Furthermore, EnSCs decreased AKT phosphorylation and promoted nuclear translocation of Forkhead box O-3a (FoxO3a) in EOC cells. Collectively, our findings elucidated the potential intrinsic anti-tumor properties of EnSCs on EOC cells in vivo and in vitro. This research provides a potential strategy for EnSC-based anti-cancer therapy against epithelial ovarian cancer. PMID:27845405

  20. Epithelial splicing regulatory protein 1 and 2 paralogues correlate with splice signatures and favorable outcome in human colorectal cancer

    PubMed Central

    Deloria, Abigail J.; Höflmayer, Doris; Kienzl, Philip; Łopatecka, Justyna; Sampl, Sandra; Klimpfinger, Martin; Braunschmid, Tamara; Bastian, Fabienne; Lu, Lingeng; Marian, Brigitte; Stättner, Stefan; Holzmann, Klaus

    2016-01-01

    ESRPs are master splice regulators implicated in alternative mRNA splicing programs important for epithelial-mesenchymal transition (EMT) and tumor progression. ESRP1 was identified in some tumors as good or worse predictor of outcome, but in colorectal cancer (CRC) the prognostic value of ESRPs and relation with mesenchymal splice variants is not clear. Here, we studied 68 CRC cases, compared tissue expression of ESRPs with clinical data and with EMT gene splice patterns of conditional CRC cells with deficient ESRP1 expression. Around 72% of patients showed global decreased transcript expression of both ESRPs in tumor as compared to matched non-neoplastic colorectal epithelium. Reduction of ESRP1 in tumor cells was evaluated by immunohistochemistry, associated with microsatellite stability and switch to mesenchymal splice signatures of FGFRs, CD44, ENAH and CTNND1(p120-catenin). Expression of ESRPs was significantly associated with favorable overall survival (log-rank test, P=0.0186 and 0.0408), better than prognostic stratification by tumor staging; and for ESRP1 confirmed with second TCGA cohort (log-rank test, P=0.0435). Prognostic value is independent of the pathological stage and microsatellite instability (ESRP1: HR=0.36, 95%CI 0.15–0.91, P=0.032; ESRP2: HR=0.23, 95%CI 0.08–0.65, P=0.006). Our study supports the role of ESRP1 as tumor suppressor and strongly suggests that ESRPs are candidate markers for early detection, diagnosis, and prognosis of CRC. PMID:27650542

  1. Grhl3 induces human epithelial tumor cell migration and invasion via downregulation of E-cadherin

    PubMed Central

    Zhao, Pan; Guo, Sijia; Tu, Zhenzhen; Di, Lijun; Zha, Xiaojun; Zhou, Haisheng; Zhang, Xuejun

    2016-01-01

    Grainyhead genes are involved in wound healing and developmental neural tube closure. Metastasis is a multistep process during which cancer cells disseminate from the site of primary tumors and establish secondary tumors in distant organs. The adhesion protein E-cadherin plays an essential role in metastasis. In light of the high degree of similarity between the epithelial–mesenchymal transition (EMT) occurring in wound-healing processes and the EMT occurring during the acquisition of invasiveness in skin or breast cancer, we investigated the role of the Grainyhead genes in cancer invasion. Here, we show that there is an inverse relationship between Grainyhead-like 3 (Grhl3) and E-cadherin expression in some epithelial tumor cell lines. Overexpression of Grhl3 in the E-cadherin-positive epithelial tumor cell line, characterized by less invasiveness, generated a transcriptional blockage of the E-cadherin gene and promoted cell migration and cell invasion. Conversely, Grhl3 depletion inhibited cell migration and cell invasion and was associated with a gain of E-cadherin expression. To further explore the mechanism by which Grhl3 regulated E-cadherin expression, an E-cadherin promoter report analysis was performed and results showed that Grhl3 repressed E-cadherin gene expression by directly or indirectly binding to the E-boxes present in the proximal E-cadherin promoter. Taken together, our findings define a major role for Grhl3 in the induction of migration and invasion by the downregulation of E-cadherin in cancer cells. PMID:26837418

  2. Synchronous sertoli cell and serous cystadenoma tumors of the ovaries with mixed epithelial and stromal tumor of the kidney: a case report.

    PubMed

    da Silva, Cléber Sérgio; Adad, Sheila Jorge; Saldanha, João Cristiane; Cançado, Cristiane Gobbo; Bachi, Carlos; Murta, Eddie Fernando Candido

    2007-06-01

    We present a rare case of a 68-year-old postmenopausal woman with a mobile, hard, and painless pelvic abdominal mass that was palpated to the umbilical scar. Ultrasonography demonstrated a solid mass in the upper pole of the right kidney and a predominantly solid pelvic abdominal mass. Serum testosterone was 413 ng/dL. The patient underwent laparotomy on the renal tumor, which was thought to have a probable ovarian metastasis. Bilateral ovariectomy and right nephrectomy were performed. Immunohistochemical and histopathologic assessment identified a right ovarian Sertoli cell tumor, a left ovarian serous cystadenoma, and a mixed epithelial-stromal tumor in the kidney with positive hormonal receptor. Because our patient had an ovarian neoplasm producing steroids and a kidney tumor expressing hormonal receptors, the hypothesis of possible endocrine dependence in the pathogenesis of mixed epithelial stromal tumor is reinforced.

  3. The Role of BRCA1 in Suppressing Epithelial-Mesenchymal Transition in Mammary Gland and Tumor Development

    DTIC Science & Technology

    2015-09-01

    in p18- deficient mice activates epithelial -to-mesenchymal transition (EMT) and induces dedifferentiation of luminal stem cells (LSCs), which...tumorigenesis. 15. SUBJECT TERMS Brca1 suppresses EMT and stem cell dedifferentiation 16. SECURITY CLASSIFICATION OF: U 17. LIMITATION OF ABSTRACT 18... epithelial -mesenchymal transition (EMT)-inducing transcription factors in p18 deficient luminal and tumor cells . Germline mutation of Brca1 converts p18

  4. Bilateral epithelial defects after laser in situ keratomileusis. Clinical features, management and outcome.

    PubMed

    Rao, Srinivas K; Shome, Debraj; Iyer, Geetha K; Fogla, Rajesh; Padmanabhan, Prema

    2005-03-01

    To describe the preoperative characteristics, intraoperative details, management, and postoperative in patients with bilateral epithelial defects after laser in situ keratomileusis (LASIK). Retrospective non-comparative case series. Six patients with bilateral epithelial defects after LASIK were part of a cohort of 605 patients undergoing bilateral LASIK at our center from December 2001 to April 2003. The mean age of the patients (5M:1F) was 28.5 +/- 7.9 years, and the average pretreatment myopic spherical equivalent (SE) refraction was 7.3 +/- 0.7 D (-4, -12.25D). An epithelial flap was present in 6 eyes and an epithelial defect with a mean diameter of 3 mm (2mm, 6mm) was seen in 6 eyes. In four patients the epithelial disturbance was bilaterally similar. All defects occurred in the inferior cornea and the epithelial flaps had the hinge positioned superiorly. None of the patients had ocular or systemic risk factors that could have resulted in this complication. A bandage contact lens was used in 6 eyes. At last follow-up of 5.5 +/- 9.5 months (0.25, 21 months), unaided visual acuity was 6/9 or better in 10 eyes. Best spectacle-corrected visual acuity (BSCVA) was maintained in 8 eyes, while 4 eyes lost one line of BSCVA. Recurrent corneal erosions were not reported in the follow-up period. These patients represent a hitherto unrecognised group of individuals who appear to have a subclinical weakness of adhesion of the corneal epithelium to the underlying structures, which is not evident on clinical examination. This results in bilateral epithelial disturbances after LASIK. Appropriate management results in satisfactory clinical outcomes. Other options for treatment of the fellow eye of such patients include the use of a different microkeratome, release of suction during the reverse pass of the Hansatome microkeratome, and photorefractive keratectomy if the refractive error is low.

  5. Keratin 8 phosphorylation regulates keratin reorganization and migration of epithelial tumor cells

    PubMed Central

    Busch, Tobias; Armacki, Milena; Eiseler, Tim; Joodi, Golsa; Temme, Claudia; Jansen, Julia; von Wichert, Götz; Omary, M. Bishr; Spatz, Joachim; Seufferlein, Thomas

    2012-01-01

    Cell migration and invasion are largely dependent on the complex organization of the various cytoskeletal components. Whereas the role of actin filaments and microtubules in cell motility is well established, the role of intermediate filaments in this process is incompletely understood. Organization and structure of the keratin cytoskeleton, which consists of heteropolymers of at least one type 1 and one type 2 intermediate filament, are in part regulated by post-translational modifications. In particular, phosphorylation events influence the properties of the keratin network. Sphingosylphosphorylcholine (SPC) is a bioactive lipid with the exceptional ability to change the organization of the keratin cytoskeleton, leading to reorganization of keratin filaments, increased elasticity, and subsequently increased migration of epithelial tumor cells. Here we investigate the signaling pathways that mediate SPC-induced keratin reorganization and the role of keratin phosphorylation in this process. We establish that the MEK–ERK signaling cascade regulates both SPC-induced keratin phosphorylation and reorganization in human pancreatic and gastric cancer cells and identify Ser431 in keratin 8 as the crucial residue whose phosphorylation is required and sufficient to induce keratin reorganization and consequently enhanced migration of human epithelial tumor cells. PMID:22344252

  6. Cell-Type-Specific Chromatin States Differentially Prime Squamous Cell Carcinoma Tumor-Initiating Cells for Epithelial to Mesenchymal Transition.

    PubMed

    Latil, Mathilde; Nassar, Dany; Beck, Benjamin; Boumahdi, Soufiane; Wang, Li; Brisebarre, Audrey; Dubois, Christine; Nkusi, Erwin; Lenglez, Sandrine; Checinska, Agnieszka; Vercauteren Drubbel, Alizée; Devos, Michael; Declercq, Wim; Yi, Rui; Blanpain, Cédric

    2017-02-02

    Epithelial to mesenchymal transition (EMT) in cancer cells has been associated with metastasis, stemness, and resistance to therapy. Some tumors undergo EMT while others do not, which may reflect intrinsic properties of their cell of origin. However, this possibility is largely unexplored. By targeting the same oncogenic mutations to discrete skin compartments, we show that cell-type-specific chromatin and transcriptional states differentially prime tumors to EMT. Squamous cell carcinomas (SCCs) derived from interfollicular epidermis (IFE) are generally well differentiated, while hair follicle (HF) stem cell-derived SCCs frequently exhibit EMT, efficiently form secondary tumors, and possess increased metastatic potential. Transcriptional and epigenomic profiling revealed that IFE and HF tumor-initiating cells possess distinct chromatin landscapes and gene regulatory networks associated with tumorigenesis and EMT that correlate with accessibility of key epithelial and EMT transcription factor binding sites. These findings highlight the importance of chromatin states and transcriptional priming in dictating tumor phenotypes and EMT.

  7. Modulatory effects of metformin on mutagenicity and epithelial tumor incidence in doxorubicin-treated Drosophila melanogaster.

    PubMed

    Oliveira, Victor Constante; Constante, Sarah Alves Rodrigues; Orsolin, Priscila Capelari; Nepomuceno, Júlio César; de Rezende, Alexandre Azenha Alves; Spanó, Mário Antônio

    2017-08-01

    Metformin (MET) is an anti-diabetic drug used to prevent hepatic glucose release and increase tissue insulin sensitivity. Diabetic cancer patients are on additional therapy with anticancer drugs. Doxorubicin (DXR) is a cancer chemotherapeutic agent that interferes with the topoisomerase II enzyme and generates free radicals. MET (2.5, 5, 10, 25 or 50 mM) alone was examined for mutagenicity, recombinogenicity and carcinogenicity, and combined with DXR (0.4 mM) for antimutagenicity, antirecombinogenicity and anticarcinogenicity, using the Somatic Mutation and Recombination Test and the Test for Detecting Epithelial Tumor Clones in Drosophila melanogaster. MET alone did not induce mutation or recombination. Modulating effects of MET on DXR-induced DNA damage were observed at the highest concentrations. In the evaluation of carcinogenesis, MET alone did not induce tumors. When combined with DXR, MET also reduced the DXR-induced tumors at the highest concentrations. Therefore, in the present experimental conditions, MET alone did not present mutagenic/recombinogenic/carcinogenic effects, but it was able to modulate the effect of DXR in the induction of DNA damage and of tumors in D. melanogaster. It is believed that this modulating effect is mainly related to the antioxidant, anti-inflammatory and apoptotic effects of this drug, although such effects have not been directly evaluated. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Nanoparticle-based sorting of circulating tumor cells by epithelial antigen expression during disease progression in an animal model.

    PubMed

    Muhanna, Nidal; Mepham, Adam; Mohamadi, Reza M; Chan, Harley; Khan, Tahsin; Akens, Margarete; Besant, Justin D; Irish, Jonathan; Kelley, Shana O

    2015-10-01

    Circulating tumor cells (CTCs) can be used as markers for the detection, characterization, and targeted therapeutic management of cancer. We recently developed a nanoparticle-mediated approach for capture and sorting of CTCs based on their specific epithelial phenotype. In the current study, we investigate the phenotypic transition of tumor cells in an animal model and show the correlation of this transition with tumor progression. VX2 tumor cells were injected into rabbits, and CTCs were evaluated during tumor progression and correlated with computerized tomography (CT) measurements of tumor volume. The results showed a dramatic increase of CTCs during the four weeks of tumor growth. Following resection, CTC levels dropped but then rebounded, likely due to lymph node metastases. Additionally, CTCs showed a marked loss of the epithelial cell adhesion molecule (EpCAM) relative to precursor cells. In conclusion, the device accurately traces disease progression and CTC phenotypic shift in an animal model. The detection of circulating tumor cells (CTCs) has been used to predict disease prognosis. In this study, the authors developed a nanoparticle-mediated platform based on microfluidics to analyze the differential expressions of epithelial cell adhesion molecule (EpCAM) on CTCs in an animal model. It was found that the loss of EpCAM correlated with disease progression. Hence, the use of this platform may be further applied in other cancer models in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Radiation therapy for epithelial ovarian cancer brain metastases: clinical outcomes and predictors of survival

    PubMed Central

    2013-01-01

    Background Brain metastases (BM) and leptomeningeal disease (LMD) are uncommon in epithelial ovarian cancer (EOC). We investigate the outcomes of modern radiation therapy (RT) as a primary treatment modality in patients with EOC BM and LMD. Methods We evaluated 60 patients with EOC treated at our institution from 1996 to 2010 who developed BM. All information was obtained from chart review. Results At EOC diagnosis, median age was 56.1 years and 88% of patients were stage III-IV. At time of BM diagnosis, 46.7% of patients had 1 BM, 16.7% had two to three, 26.7% had four or more, and 10% had LMD. Median follow-up after BM was 9.3 months (range, 0.3-82.3). All patients received RT, and 37% had surgical resection. LMD occurred in the primary or recurrent setting in 12 patients (20%), 9 of whom received RT. Median overall survival (OS) after BM was 9.7 months for all patients (95% CI 5.9–13.5), and 16.1 months (95% CI 3.8-28.3) in patients with one BM. On multivariate analysis, Karnofsky performance status less than 70 (hazard ratio [HR] 2.86, p = 0.018), four or more BM (HR 3.18, p = 0.05), LMD (HR 8.22, p = 0.013), and uncontrolled primary tumor (HR 2.84, p = 0.008) were significantly associated with inferior OS. Use of surgery was not significant (p = 0.31). Median central nervous system freedom from progression (CNS-FFP) in 47 patients with follow-up was 18.5 months (95% CI, 9.3–27.9). Only four or more BM (HR 2.56, p = 0.04) was significantly associated with poorer CNS-FFP. Conclusions Based on our results, RT appears to be an effective treatment modality for brain metastases from EOC and should be routinely offered. Karnofsky performance status less than 70, four or more BM, LMD, and uncontrolled primary tumor predict for worse survival after RT for EOC BM. Whether RT is superior to surgery or chemotherapy for EOC BM remains to be seen in a larger cohort. PMID:23414446

  10. Outcome of pregnancy in survivors of Wilms' tumor

    SciTech Connect

    Li, F.P.; Gimbrere, K.; Gelber, R.D.; Sallan, S.E.; Flamant, F.; Green, D.M.; Heyn, R.M.; Meadows, A.T.

    1987-01-09

    Outcome of pregnancy was reported by 99 patients who were cured of childhood Wilms' tumor at seven pediatric cancer centers during 1931 to 1979. These patients carried or sired 191 singleton pregnancies of at least 20 weeks in duration. Among the 114 pregnancies in women who had received abdominal radiotherapy for Wilms' tumor, an adverse outcome occurred in 34 (30%). There were 17 perinatal deaths (five in premature low-birth-weight infants) and 17 other low-birth-weight infants. Compared with white women in the United States, the irradiated women had an increased perinatal mortality rate (relative risk, 7.9) and an excess of low-birth-weight infants (relative risk, 4.0). In contrast, an adverse outcome was found in two (3%) of the 77 pregnancies in nonirradiated female patients with Wilms' tumor and wives of male patients. The high risk of adverse pregnancy outcome should be considered in the counseling and prenatal care of women who have received abdominal radiotherapy for Wilms' tumor.

  11. [Frozen-section biopsy in ovarian neoplasm diagnosis: diagnostic correlation according to diameter and weight in tumors of epithelial origin].

    PubMed

    Cuello, M; Galleguillos, G; Zárate, C; Córdova, M; Brañes, J; Chuaqui, R; Wild, R

    1999-10-01

    Adequate management and treatment of ovarian carcinoma requires a complete surgical staging supported by frozen-section examination. To achieve this goal it is necessary a high level of accuracy. To evaluate the accuracy of frozen-sections in ovarian carcinoma considering the influence of tumor diameter and weight. Retrospective study of frozen-sections performed in patients with ovarian tumors who underwent surgery. Frozen- and permanent-sections were divided into three categories (benign, borderline and malignant) and stratified by diameter (< 10 cm, 10 to 20 cm, > 20 cm) and weight (< 700 g, 700 a 1400 g, > 1400 g). The diagnostic correlation, sensitivity, specificity, predictive values and accuracy of each frozen-section diagnosis were determined. Eight hundred forty two ovarian tumors that underwent frozen-sections between January 1988 and October 1998 were studied. Final diagnosis was 86.7% benign, 2.7% low malignant potential (LMP) and 10.6% malignant. The diagnosis correlation between frozen- and permanent-sections was 98.2%. Misdiagnosis was in epithelial ovarian tumors, particularly in LMP tumors. Sensitivity, specificity, positive- and negative-predictive values and accuracy of the four hundred eighty nine epithelial tumor were 92.6%, 99.2%, 96.7%, 98.2% and 97.9%, respectively. Diagnostic correlation was higher in epithelial ovarian tumors with diameter < 10 cm (98.2% v/s 93.8%) and weight < 700 g (96.9% v/s 88.9%). Diagnostic correlation with permanent-section examination, sensitivity, specificity and predictive values of frozen-sections are high in ovarian tumors. Accurate diagnosis at frozen sections of epithelial ovarian tumors with diameter > 10 cm or weight > 700 g (particularly in LMP tumors) is difficult because of the extensive sampling required. Frozen-sections diagnoses are important to determine the type and extent of surgery performed at the initial operation.

  12. Oxystressed tumor microenvironment potentiates epithelial to mesenchymal transition and alters cellular bioenergetics towards cancer progression.

    PubMed

    Sridaran, Dhivya; Ramamoorthi, Ganesan; MahaboobKhan, Rasool; Kumpati, Premkumar

    2016-10-01

    During tumorigenesis, cancer cells generate complex, unresolved interactions with the surrounding oxystressed cellular milieu called tumor microenvironment (TM) that favors spread of cancer to other body parts. This dissemination of cancer cells from the primary tumor site is the main clinical challenge in cancer treatment. In addition, the significance of enhanced oxidative stress in TM during cancer progression still remains elusive. Thus, the present study was performed to investigate the molecular and cytoskeletal alterations in breast cancer cells associated with oxystressed TM that potentiates metastasis. Our results showed that depending on the extent of oxidative stress in TM, cancer cells exhibited enhanced migration and survival with reduction of chemosensitivity. Corresponding ultrastructural analysis showed radical cytoskeletal modifications that reorganize cell-cell interactions fostering transition of epithelial cells to mesenchymal morphology (EMT) marking metastasis, which was reversed upon antioxidant treatment. Decreased E-cadherin and increased vimentin, Twist1/2 expression corroborated the initiation of EMT in oxystressed TM-influenced cells. Further evaluation of cellular energetics demonstrated significant metabolic reprogramming with inclination towards glucose or external glutamine from TM as energy source depending on the breast cancer cell type. These observations prove the elemental role of oxystressed TM in cancer progression, initiating EMT and metabolic reprogramming. Further cell-type specific metabolomic analysis would unravel the alternate mechanisms in cancer progression for effective therapeutic intervention. Graphical abstract Schematic representation of the study and proposed mechanism of oxystressed TM influenced cancer progression. Cancer cells exhibit a close association with tumor microenvironment (TM), and oxystressed TM enhances cancer cell migration and survival and reduces chemosensitivity. Oxystressed TM induces dynamic

  13. Inhibition of histamine receptor 3 suppresses glioblastoma tumor growth, invasion, and epithelial-to-mesenchymal transition

    PubMed Central

    Cai, Wen-Ke; Yang, Yong-Xiang; Sun, Chao; Zhang, Zhuo; Xu, Yu-Qiao; Chang, Ting; Li, Zhu-Yi

    2015-01-01

    Histamine receptor 3 (H3R) is expressed in various tumors and correlated with malignancy and tumor proliferation. However, the role of H3R in tumor invasion and epithelial to mesenchymal transition (EMT) remains unknown. Here, we explored the H3R in the highly invasive glioblastoma (GBM) and U87MG cells. We found that H3R mRNA and protein levels were up-regulated in the GBM and glioma cell lines compared to normal brain tissue and astrocytes. In U87MG cell line, inhibition of H3R by siRNA or the antagonist ciproxifan (CPX) suppressed proliferation, invasiveness, and the expression of EMT activators (Snail, Slug and Twist). In addition, expression of epithelial markers (E-cadherin and ZO-1) was up-regulated and expression of mesenchymal markers (vimentin and N-cadherin) was down-regulated in vitro and in vivo in a xenograft model. In addition, we also showed that inhibition of H3R by siRNA or CPX inactivated the PI3K/Akt and MEK/ERK signaling pathways, while inhibition of Akt or ERK activity with antagonists or siRNAs suppressed H3R agonist (R)-(α)-(−)- methylhistamine dihydrobromide (RAMH) mediated invasion and reorganization of cadherin-household. In conclusion, overexpression of H3R is associated with glioma progression. Inhibition of H3R leads to suppressed invasion and EMT of GBM by inactivating the PI3K/Akt and MEK/ERK pathways in gliomas. PMID:25940798

  14. Validity of the semi-infinite tumor model in diffuse reflectance spectroscopy for epithelial cancer diagnosis: a Monte Carlo study

    NASA Astrophysics Data System (ADS)

    Zhu, Caigang; Liu, Quan

    2011-08-01

    The accurate understanding of optical properties of human tissues plays an important role in the optical diagnosis of early epithelial cancer. Many inverse models used to determine the optical properties of a tumor have assumed that the tumor was semi-infinite, which infers infinite width and length but finite thickness. However, this simplified assumption could lead to large errors for small tumor, especially at the early stages. We used a modified Monte Carlo code, which is able to simulate light transport in a layered tissue model with buried tumor-like targets, to investigate the validity of the semi-infinite tumor assumption in two common epithelial tissue models: a squamous cell carcinoma (SCC) tissue model and a basal cell carcinoma (BCC) tissue model. The SCC tissue model consisted of three layers, i.e. the top epithelium, the middle tumor and the bottom stroma. The BCC tissue model also consisted of three layers, i.e. the top epidermis, the middle tumor and the bottom dermis. Diffuse reflectance was simulated for two common fiber-optic probes. In one probe, both source and detector fibers were perpendicular to the tissue surface; while in the other, both fibers were tilted at 45 degrees relative to the normal axis of the tissue surface. It was demonstrated that the validity of the semi-infinite tumor model depends on both the fiber-optic probe configuration and the tumor dimensions. Two look-up tables, which relate the validity of the semi-infinite tumor model to the tumor width in terms of the source-detector separation, were derived to guide the selection of appropriate tumor models and fiber optic probe configuration for the optical diagnosis of early epithelial cancers.

  15. Glut-1 intensity and pattern of expression in thymic epithelial tumors are predictive of WHO subtypes.

    PubMed

    Thomas de Montpréville, Vincent; Quilhot, Pauline; Chalabreysse, Lara; De Muret, Anne; Hofman, Véronique; Lantuéjoul, Sylvie; Parrens, Marie; Payan, Marie-José; Rouquette, Isabelle; Secq, Véronique; Girard, Nicolas; Besse, Benjamin; Marx, Alexander; Molina, Thierry Jo

    2015-12-01

    Glucose-transporter-1 (Glut-1) may be a useful marker for differentiating B3 thymomas and thymic carcinomas. Since the literature is limited, we undertook a study to evaluate its diagnostic value in a series of thymic epithelial tumors. Glut-1 expression was studied by the group of pathologists linked to the French national oncological network RYTHMIC. Immunostaining was performed on a whole section of one paraffin block in a series of 92 successive surgical specimens. Patterns (focal, zonal, diffuse) and intensity of Glut-1 expression were assessed and compared with WHO histological subtypes. Expression was mainly restricted to epithelial cells. Immature T-lymphocytes were negative. A diffuse, moderate or strong staining was observed in most thymic carcinomas (15/16). In B3 thymomas (10/11) and in B3 thymomas borderline to thymic carcinomas (5/6), a moderate to strong zonal staining was observed at distance from vessels and fibrous septa. This pattern sometimes created the aspect of an anastomosing network in large cellular lobules. In B1 thymomas, immunostaining highlighted foci of medullary differentiation (7/8). B2 thymomas (n=25) were heterogeneous, with a spectrum of patterns ranging between those of B1 and B3 thymomas. Type A thymomas (n=5) mostly presented a weak positivity but one aggressive case showed zonal moderate/strong positivity. Most AB thymomas (15/17) showed weak to moderate immunostaining in spindle cell areas. In micronodular thymomas (n=3), epithelial cells and B-lymphocytes were weakly positive while follicular dendritic cells were strongly highlighted. One metaplastic thymoma displayed diffuse and moderate positivity. Glut-1 expression globally depended on histological subtypes and the staining patterns (diffuse or zonal) were different between thymic carcinomas and type B3 thymomas. A comparative study of Glut-1 expression in atypical versus conventional type A thymomas appears warranted. Otherwise, restriction to epithelial cells makes

  16. TRAF-4 expression in epithelial progenitor cells. Analysis in normal adult, fetal, and tumor tissues.

    PubMed Central

    Krajewska, M.; Krajewski, S.; Zapata, J. M.; Van Arsdale, T.; Gascoyne, R. D.; Berern, K.; McFadden, D.; Shabaik, A.; Hugh, J.; Reynolds, A.; Clevenger, C. V.; Reed, J. C.

    1998-01-01

    TRAF-4 was discovered because of its expression in breast cancers and is a member of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) family of putative signal-transducing proteins. In vitro binding assays demonstrated that TRAF-4 interacts with the cytosolic domain of the lymphotoxin-beta receptor (LT beta R) and weakly with the p75 nerve growth factor receptor (NGFR) but not with TNFR1, TNFR2, Fas, or CD40. Immunofluorescence analysis of TRAF-4 in transfected cells demonstrated localization to cytosol but not nucleus. Immunohistochemical assays of normal human adult tissues revealed prominent cytosolic immunostaining in thymic epithelial cells and lymph node dendritic cells but not in lymphocytes or thymocytes, paralleling the reported patterns of LT beta R expression. The basal cell layer of most epithelia in the body was very strongly TRAF-4 immunopositive, including epidermis, nasopharynx, respiratory tract, salivary gland, and esophagus. Similar findings were obtained in 12- to 18-week human fetal tissue, indicating a highly restricted pattern of expression even during development in the mammary gland, epithelial cells of the terminal ducts were strongly TRAF-4 immunopositive whereas myoepithelial cells and most of the mammary epithelial cells lining the extralobular ducts were TRAF-4 immunonegative. Of 84 primary breast cancers evaluated, only 7 expressed TRAF-4. Ductal carcinoma in situ (DCIS) lesions were uniformly TRAF-4 immunonegative (n = 21). In the prostate, the basal cells were strongly immunostained for TRAF-4, whereas the secretory epithelial cells were TRAF-4 negative. Basal cells in prostate hypertrophy (n = 6) and prostatic intraepithelial neoplasia (PIN; n = 6) were strongly TRAF-4 positive, but none of the 32 primary and 16 metastatic prostate cancer specimens examined contained TRAF-4-positive malignant cells. Although also expressed in some types of mesenchymal cells, these findings suggest that TRAF-4 is a marker of normal

  17. Epidemiologic and molecular characteristics of borderline and malignant epithelial ovarian tumors

    NASA Astrophysics Data System (ADS)

    Bastos, Eugenia Maria Chaves De Moraes

    Data from the Cancer and Steroid Hormone Study, a multicenter, population-based, case-control study were used to identify risk factors for epithelial ovarian cancer according to tumor behavior, histologic types, as well as p53 expression. Cases were women between 20 to 54 years old diagnosed with epithelial ovarian cancer from 1980 to 1982. Controls were women selected by random digit dialing. Tumor samples were analyzed for p53 overexpression using immunohistochemistry. Case-case and case-control conditional logistic regression models matched on age and diagnosing centers were used to calculate odds ratios (OR's) and 95% confidence intervals (CI's) for borderline, malignant, mucinous, and nonmucinous tumors, and p53 positive and p53 negative cases. The OR's for high number of lifetime ovulatory cycles (376-533 compared with less than 234) were 3.1 (95% CI 1.6-6.1) for malignant and 1.4 (95% CI 0.5-3.7) for borderline cases. The high number of ovulatory cycles was also a strong risk factor among nonmucinous cases. OR's for current and recent ex-smokers compared with never smokers were 2.8 (95% CI 1.7-4.8) for mucinous and 0.9 (95% CI 0.7-1.1) for nonmucinous types. Infertility showed a positive association with borderline ovarian cancer. Family history of ovarian or breast cancer was positively associated with malignant and nonmucinous cases. Parity had an inverse association with malignant ovarian cancer cases. When cases were subdivided by p53 results, the OR for tobacco smoking and p53 positive ovarian cancer was elevated for mucinous (OR = 3.9; 95% CI 0.8-18) at localized stage. Alcohol use showed a positive association with p53 positive malignant cases at advanced stage (OR = 2.0; 95% CI 1.2-3.2) and with p53 positive nonmucinous cases at advanced stage (OR = 2.1; 95% CI 1.2-3.4). A positive association between high number of ovulatory cycles and p53 positive malignant cases was observed in cases with localized stage (OR = 6.6; 95% CI 1.0-45) and advanced

  18. 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

  19. Tumor progression, metastasis, and modulators of epithelial-mesenchymal transition in endometrioid endometrial carcinoma: an update.

    PubMed

    Makker, Annu; Goel, Madhu Mati

    2016-02-01

    Endometrioid endometrial carcinoma (EEC), also known as type 1 endometrial cancer (EC), accounts for over 70-80% of all cases that are usually associated with estrogen stimulation and often develops in a background of atypical endometrial hyperplasia. The increased incidence of EC is mainly confined to this type of cancer. Most EEC patients present at an early stage and generally have a favorable prognosis; however, up to 30% of EEC present as high risk tumors, which have invaded deep into the myometrium at diagnosis and progressively lead to local or extra pelvic metastasis. The poor survival of advanced EC is related to the lack of effective therapies, which can be attributed to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis. Multiple lines of evidence illustrate that epithelial-mesenchymal transition (EMT)-like events are central to tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. The aim of this review is to summarize the current knowledge on molecular events associated with EMT in progression, invasion, and metastasis of EEC. Further, the role of epigenetic modifications and microRNA regulation, tumor microenvironment, and microcystic elongated and fragmented glands like invasion pattern have been discussed. We believe this article may perhaps stimulate further research in this field that may aid in identifying high risk patients within this clinically challenging patient group and also lead to the recognition of novel targets for the prevention of metastasis - the most fatal consequence of endometrial carcinogenesis.

  20. Targeting epithelial-mesenchymal transition: Metal organic network nano-complexes for preventing tumor metastasis.

    PubMed

    Fan, Jin-Xuan; Zheng, Di-Wei; Rong, Lei; Zhu, Jing-Yi; Hong, Sheng; Li, Cao; Xu, Zu-Shun; Cheng, Si-Xue; Zhang, Xian-Zheng

    2017-09-01

    Tumor metastasis is the leading cause of death in cancer patients, and epithelial-mesenchymal transition (EMT) is an essential step in tumor metastasis. Unfortunately, during the chemotherapy, EMT could be induced under the selective pressure of clinical cytotoxic drugs. Here, to solve this problem, we have synthesized multi-functional epigallocatechin gallate/iron nano-complexes (EIN) as a versatile coating material to improve conventional therapies. In vitro studies showed that this strategy could eliminate EMT-type cancer cells. Mechanism studies also revealed that EIN was able to down-regulate the downstream expression of metastasis-associated factors, decrease the migration ability of cancer cells and prevent cancer cells from gaining drug resistance. In vivo investigation revealed that EIN had superior ability to enhance the therapeutic effect of conventional nanomedicines and inhibit the EMT process. Our study indicates the promising use of EIN to make up for the deficiencies of chemotherapy may provide insights into systematic cancer therapy to overcome tumor metastasis and drug resistance. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Autophagy regulates keratin 8 homeostasis in mammary epithelial cells and in breast tumors

    PubMed Central

    Kongara, Sameera; Kravchuk, Olga; Teplova, Irina; Lozy, Fred; Schulte, Jennifer; Moore, Dirk; Barnard, Nicola; Neumann, Carola A.; White, Eileen; Karantza, Vassiliki

    2010-01-01

    Autophagy is activated in response to cellular stressors and mediates lysosomal degradation and recycling of cytoplasmic material and organelles as a temporary cell survival mechanism. Defective autophagy is implicated in human pathology, as disruption of protein and organelle homeostasis enables disease-promoting mechanisms such as toxic protein aggregation, oxidative stress, genomic damage and inflammation. We previously showed that autophagy-defective immortalized mouse mammary epithelial cells (iMMECs) are susceptible to metabolic stress, DNA damage and genomic instability. We now report that autophagy deficiency was associated with ER and oxidative stress, and deregulation of p62-mediated keratin homeostasis in mammary cells and allograft tumors and in mammary tissues from genetically engineered mice. In human breast tumors, high phospho(Ser73)-K8 levels inversely correlated with Beclin 1 expression. Thus, autophagy preserves cellular fitness by limiting ER and oxidative stress, a function potentially important in autophagy-mediated suppression of mammary tumorigenesis. Furthermore, autophagy regulates keratin homeostasis in the mammary gland via a p62-dependent mechanism. High phospho(Ser73)-K8 expression may be a marker of autophagy functional status in breast tumors and, as such, could have therapeutic implications for breast cancer patients. PMID:20530580

  2. Melanoma Proteoglycan Modifies Gene Expression to Stimulate Tumor Cell Motility, Growth and Epithelial to Mesenchymal Transition

    PubMed Central

    Yang, Jianbo; Price, Matthew A.; Li, GuiYuan; Bar-Eli, Menashe; Salgia, Ravi; Jagedeeswaran, Ramasamy; Carlson, Jennifer H.; Ferrone, Soldano; Turley, Eva A.; McCarthy, James B.

    2009-01-01

    Melanoma chondroitin sulfate proteoglycan (MCSP) is a plasma membrane-associated proteoglycan that facilitates the growth, motility and invasion of tumor cells. MCSP expression in melanoma cells enhances integrin function and constitutive activation of Erk 1,2. The current studies were performed to determine the mechanism by which MCSP expression promotes tumor growth and motility. The results demonstrate that MCSP expression in radial growth phase (RGP), vertical growth phase (VGP) or metastatic cell lines causes sustained activation of Erk 1,2, enhanced growth and motility which all require the cytoplasmic domain of the MCSP core protein. MCSP expression in an RGP cell line also promotes an epithelial to mesenchymal transition (EMT) based on changes in cell morphology and the expression of several EMT markers. Finally MCSP enhances the expression of c-Met and HGF, and inhibiting c-Met expression or activation limits the increased growth and motility of multiple melanoma cell lines. The studies collectively demonstrate an importance for MCSP in promoting progression by an epigenetic mechanism and they indicate that MCSP could be targeted to delay or inhibit tumor progression in patients. PMID:19738072

  3. Stonin 2 Overexpression is Correlated with Unfavorable Prognosis and Tumor Invasion in Epithelial Ovarian Cancer

    PubMed Central

    Zhang, Weijing; Li, Han; Ou, Yulan; Song, Libing

    2017-01-01

    Stonin 2 (STON2), which functions in adjusting endocytotic complexes, is probably involved in the monitoring of the internalization of dopamine D2 receptors which have an inhibitory action of dopamine on tumor progression. However, its clinical significance in tumor progression and prognosis remains unclear. We explored the association between STON2 and the clinicopathological characteristics of epithelial ovarian cancer (EOC). The STON2 levels in ovarian cancer and normal cell lines and tissues were detected by real-time PCR and Western blot analyses. STON2 protein expression was also detected by an immunohistochemical analysis. The clinical significance of STON2 expression in ovarian cancer was statistically analyzed. STON2 significantly increased in the ovarian cancer cell lines and tissues compared to the normal ones. In the 89 EOC samples tested, STON2 expression was significantly correlated with intraperitoneal metastasis, intestinal metastasis, intraperitoneal recurrence, ascites containing tumor cells, and CA153 level. Moreover, patients with STON2 protein overexpression were more likely to exhibit platinum resistance and to have undergone neoadjuvant chemotherapy. Patients with high STON2 protein expression had a tendency to have a shorter overall survival and a poor prognosis. A multivariate analysis showed that STON2 was an independent prognostic predictor for EOC patients. In conclusion, STON2 plays an important role in the progression and prognosis of ovarian carcinoma, especially in platinum resistance, intraperitoneal metastasis, and recurrence. STON2 can be a novel antitumor drug target and biomarker which predicts an unfavorable prognosis for EOC patients. PMID:28758939

  4. Dclk1 facilitates intestinal tumor growth via enhancing pluripotency and epithelial mesenchymal transition

    PubMed Central

    Chandrakesan, Parthasarathy; Weygant, Nathaniel; May, Randal; Qu, Dongfeng; Chinthalapally, Harisha R.; Sureban, Sripathi M.; Ali, Naushad; Lightfoot, Stan A.; Umar, Shahid; Houchen, Courtney W.

    2014-01-01

    Doublecortin-like kinase 1 (Dclk1) is overexpressed in many cancers including colorectal cancer (CRC) and it specifically marks intestinal tumor stem cells. However, the role of Dclk1 in intestinal tumorigenesis in Apc mutant conditions is still poorly understood. We demonstrate that Dclk1 expression and Dclk1+ cells are significantly increased in the intestinal epithelium of elderly ApcMin/+ mice compared to young ApcMin/+ mice and wild type mice. Intestinal epithelial cells of ApcMin/+ mice demonstrate increased pluripotency, self-renewing ability, and EMT. Furthermore, miRNAs are dysregulated, expression of onco-miRNAs are significantly increased with decreased tumor suppressor miRNAs. In support of these findings, knockdown of Dclk1 in elderly ApcMin/+ mice attenuates intestinal adenomas and adenocarcinoma by decreasing pluripotency, EMT and onco-miRNAs indicating that Dclk1 overexpression facilitates intestinal tumorigenesis. Knocking down Dclk1 weakens Dclk1-dependent intestinal processes for tumorigenesis. This study demonstrates that Dclk1 is critically involved in facilitating intestinal tumorigenesis by enhancing pluripotency and EMT factors in Apc mutant intestinal tumors and it also provides a potential therapeutic target for the treatment of colorectal cancer. PMID:25211188

  5. Regulatory T lymphocytes and transforming growth factor beta in epithelial ovarian tumors-prognostic significance.

    PubMed

    Winkler, Izabela; Wilczynska, Barbara; Bojarska-Junak, Agnieszka; Gogacz, Marek; Adamiak, Aneta; Postawski, Krzysztof; Darmochwal-Kolarz, Dorota; Rechberger, Tomasz; Tabarkiewicz, Jacek

    2015-06-17

    Regulatory T lymphocytes (Treg) are characterized by the presence of CD4+ surface antigen. Today the transcription factor FOXP3 is considered to be the most specific marker of Treg cells. The aim of the study was to estimate the percentage of Treg in peripheral blood and the tissue of the epithelial ovarian tumor and blood serum TGF-beta concentrations and relationships between them. Moreover, the aim of the study was to answer the question whether the percentage of Treg lymphocytes affects the time of survival in patients with ovarian cancer. The patients were divided into four groups, depending on the histopathological examination result: I--a group without any pathology within the ovaries (C; n = 20), II--a group with benign tumors (B; n = 25), III - with borderline tumors (BR; n = 11), IV--a group with cancer of the ovary (M; n = 24). The percentage of Treg lymphocytes in peripheral blood and the tissue was assessed using the flow cytometry method. TGF-beta cytokine concentration was estimated with the ELISA immunoenzymatic test. Statistical analysis of the results was conducted using the computer program Statistica 10.0PL (StatSoft, Inc). No significant differences were found in percentages of Treg lymphocytes in peripheral blood between individual groups of patients (p = 0.11). However, we observed marked differences in the tissue of malignant and non-malignant tumors between individual groups of patients (p = 0.003). The analysis with the post hoc test revealed significantly higher TGF-beta concentration in the group of women with malignant tumors. Moreover, no relationship was found between TGF-beta concentration and the percentage of Treg cells in peripheral blood and tumors of the ovary. No correlation was found between the percentage of Treg lymphocytes in peripheral blood (p = 0.4) and the tissue of ovarian tumors (p = 0.3) and the time of survival of patients with ovarian cancer. The recruitment of Treg lymphocytes

  6. Rac1 expression in epithelial ovarian cancer: effect on cell EMT and clinical outcome.

    PubMed

    Leng, Ruobing; Liao, Gang; Wang, Haixia; Kuang, Jun; Tang, Liangdan

    2015-02-01

    Ras-related C3 botulinum toxin substrate 1 (rac1) has been implicated in tumor epithelial-mesenchymal transition (EMT); however, limited information is available regarding the role of rac1 in epithelial ovarian cancer (EOC). This study aimed to evaluate the correlation of rac1 expression with EMT and EOC prognosis. Rac1 protein levels of 150 EOC specimens were evaluated by immunohistochemical staining. Survival analysis was performed to determine the correlation between rac1 expression and survival. Cellular and molecular changes were also examined after rac1 in ovarian cancer cells was silenced in vitro and in vivo. The mechanism of rac1 on EMT was investigated by Western blot analysis. Rac1 was highly expressed in EOC. Rac1 overexpression was closely associated with advanced stage based on International Federation of Gynecology and Obstetrics, poor grade, serum Ca-125, and residual tumor size. Survival analyses demonstrated that patients with high rac1 expression levels were more susceptible to early tumor recurrence with very poor prognosis. This study revealed that rac1 downregulation decreased cell EMT and proliferation capability in vitro and in vivo. Rac1 expression possibly altered cell EMT by interacting with p21-activated kinase 1 and p38 mitogen-activated protein kinase signaling pathways. The present study showed that rac1 overexpression is associated with cell EMT and poor EOC prognosis. Rac1 possibly plays an important role in predicting EOC metastasis.

  7. Characterization of circulating tumor cell aggregates identified in patients with epithelial tumors

    PubMed Central

    Cho, Edward H.; Wendel, Marco; Luttgen, Madelyn; Yoshioka, Craig; Marrinucci, Dena; Lazar, Daniel; Schram, Ethan; Nieva, Jorge; Bazhenova, Lyudmila; Morgan, Alison; Ko, Andrew H.; Korn, W. Michael; Kolatkar, Anand; Bethel, Kelly; Kuhn, Peter

    2012-01-01

    Circulating tumor cells (CTCs) have been implicated as a population of cells that may seed metastasis and venous thromboembolism (VTE), two major causes of mortality in cancer patients. Thus far, existing CTC detection technologies have been unable to reproducibly detect CTC aggregates in order to address what contribution CTC aggregates may have on metastasis or VTE. We report here an enrichment-free immunofluorescence detection method that can reproducibly detect and enumerate homotypic CTC aggregates in patient samples. We identified CTC aggregates in 43% of 86 patient samples. The fraction of CTC aggregation was investigated in blood draws from 24 breast, 14 non-small cell lung (NSCLC), 18 pancreatic, 15 prostate stage IV cancer patients, and 15 normal blood donors (NBD). Both single CTCs and CTC aggregates were measured to determine whether differences exist in the physical characteristics of these two populations. Cells contained in CTC aggregates had less area and length, on average, than single CTCs. Nuclear to cytoplasmic (N/C) ratio between single CTCs and CTC aggregates were similar. This detection method may assist future studies in determining which population of cells is more physically likely to contribute to metastasis and VTE. PMID:22306705

  8. Characterization of circulating tumor cell aggregates identified in patients with epithelial tumors

    NASA Astrophysics Data System (ADS)

    Cho, Edward H.; Wendel, Marco; Luttgen, Madelyn; Yoshioka, Craig; Marrinucci, Dena; Lazar, Daniel; Schram, Ethan; Nieva, Jorge; Bazhenova, Lyudmila; Morgan, Alison; Ko, Andrew H.; Korn, W. Michael; Kolatkar, Anand; Bethel, Kelly; Kuhn, Peter

    2012-02-01

    Circulating tumor cells (CTCs) have been implicated as a population of cells that may seed metastasis and venous thromboembolism (VTE), two major causes of mortality in cancer patients. Thus far, existing CTC detection technologies have been unable to reproducibly detect CTC aggregates in order to address what contribution CTC aggregates may make to metastasis or VTE. We report here an enrichment-free immunofluorescence detection method that can reproducibly detect and enumerate homotypic CTC aggregates in patient samples. We identified CTC aggregates in 43% of 86 patient samples. The fraction of CTC aggregation was investigated in blood draws from 24 breast, 14 non-small cell lung, 18 pancreatic, 15 prostate stage IV cancer patients and 15 normal blood donors. Both single CTCs and CTC aggregates were measured to determine whether differences exist in the physical characteristics of these two populations. Cells contained in CTC aggregates had less area and length, on average, than single CTCs. Nuclear to cytoplasmic ratios between single CTCs and CTC aggregates were similar. This detection method may assist future studies in determining which population of cells is more physically likely to contribute to metastasis and VTE.

  9. Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers.

    PubMed

    Armstrong, Andrew J; Marengo, Matthew S; Oltean, Sebastian; Kemeny, Gabor; Bitting, Rhonda L; Turnbull, James D; Herold, Christina I; Marcom, Paul K; George, Daniel J; Garcia-Blanco, Mariano A

    2011-08-01

    During cancer progression, malignant cells undergo epithelial-mesenchymal transitions (EMT) and mesenchymal-epithelial transitions (MET) as part of a broad invasion and metastasis program. We previously observed MET events among lung metastases in a preclinical model of prostate adenocarcinoma that suggested a relationship between epithelial plasticity and metastatic spread. We thus sought to translate these findings into clinical evidence by examining the existence of EMT in circulating tumor cells (CTC) from patients with progressive metastatic solid tumors, with a focus on men with castration-resistant prostate cancer (CRPC) and women with metastatic breast cancer. We showed that the majority (> 80%) of these CTCs in patients with metastatic CRPC coexpress epithelial proteins such as epithelial cell adhesion molecule (EpCAM), cytokeratins (CK), and E-cadherin, with mesenchymal proteins including vimentin, N-cadherin and O-cadherin, and the stem cell marker CD133. Equally, we found that more than 75% of CTCs from women with metastatic breast cancer coexpress CK, vimentin, and N-cadherin. The existence and high frequency of these CTCs coexpressing epithelial, mesenchymal, and stem cell markers in patients with progressive metastases has important implications for the application and interpretation of approved methods to detect CTCs.

  10. High expression of S100P is associated with unfavorable prognosis and tumor progression in patients with epithelial ovarian cancer

    PubMed Central

    Wang, Xiangyu; Tian, Tian; Li, Xukun; Zhao, Meng; Lou, Yanhui; Qian, Jingfeng; Liu, Zhihua; Chen, Hongyan; Cui, Zhumei

    2015-01-01

    Accumulating evidence has demonstrated that S100P is involved in the tumorigenesis and progression of multiple cancers. In the current study, we evaluated the expression of S100P in epithelial ovarian cancer and assessed its relevance to clinicopathological characteristics. Moreover, we investigated the biological effects of S100P using A2780 and SKOV3 cells. S100P expression was significantly increased in epithelial ovarian cancer specimens compared with fallopian tube tissues and normal ovary tissues. And high expression of S100P in epithelial ovarian cancer samples was significantly associated with tumor stage (P<0.001), serum CA125 level (P=0.026), residual tumor (P<0.001), ascites (P<0.001) and lymph nodes metastasis (P<0.001). Multivariate Cox analysis showed that S100P expression was an independent prognostic factor of overall survival (OS) and progression free survival (PFS) (P=0.017 and 0.031, respectively). Functional assays showed that overexpression of S100P promoted cell proliferation and cell cycle progression but did not affect cell migration and invasion in A2780 and SKOV3 cells. These data suggest that S100P may contribute to tumor development in epithelial ovarian cancer and could be a useful marker for the prognosis of epithelial ovarian cancer patients. PMID:26396916

  11. High expression of S100P is associated with unfavorable prognosis and tumor progression in patients with epithelial ovarian cancer.

    PubMed

    Wang, Xiangyu; Tian, Tian; Li, Xukun; Zhao, Meng; Lou, Yanhui; Qian, Jingfeng; Liu, Zhihua; Chen, Hongyan; Cui, Zhumei

    2015-01-01

    Accumulating evidence has demonstrated that S100P is involved in the tumorigenesis and progression of multiple cancers. In the current study, we evaluated the expression of S100P in epithelial ovarian cancer and assessed its relevance to clinicopathological characteristics. Moreover, we investigated the biological effects of S100P using A2780 and SKOV3 cells. S100P expression was significantly increased in epithelial ovarian cancer specimens compared with fallopian tube tissues and normal ovary tissues. And high expression of S100P in epithelial ovarian cancer samples was significantly associated with tumor stage (P<0.001), serum CA125 level (P=0.026), residual tumor (P<0.001), ascites (P<0.001) and lymph nodes metastasis (P<0.001). Multivariate Cox analysis showed that S100P expression was an independent prognostic factor of overall survival (OS) and progression free survival (PFS) (P=0.017 and 0.031, respectively). Functional assays showed that overexpression of S100P promoted cell proliferation and cell cycle progression but did not affect cell migration and invasion in A2780 and SKOV3 cells. These data suggest that S100P may contribute to tumor development in epithelial ovarian cancer and could be a useful marker for the prognosis of epithelial ovarian cancer patients.

  12. Epithelial-Mesenchymal Transition in Keratocystic Odontogenic Tumor: Possible Role in Locally Aggressive Behavior

    PubMed Central

    Zhong, Wen-Qun; Chen, Gang; Zhang, Wei; Ren, Jian-Gang; Wu, Zhong-Xing; Zhao, Yi; Liu, Bing; Zhao, Yi-Fang

    2015-01-01

    The aim of this study is to clarify whether epithelial-mesenchymal transition (EMT) is involved in the pathogenesis and development of keratocystic odontogenic tumor (KCOT). The expression levels of EMT-related proteins and genes in normal oral mucosa (OM), radicular cyst (RC), and KCOT were determined and compared by real-time quantitative PCR and immunohistochemistry. Our data showed that the expression of epithelial markers E-cadherin and Pan-cytokeratin was significantly downregulated in KCOT with upregulation of mesenchymal markers N-cadherin compared to OM and RC. Importantly, TGF-β, a potent EMT inducer, and Slug, a master transcription factor, were also found highly expressed in KCOT. In addition, the results from Spearman rank correlation test and clustering analysis revealed the close relationship between Slug and MMP-9, which was further evidenced by double-labeling immunofluorescence that revealed a synchronous distribution for Slug with MMP-9 in KCOT samples. All the data suggested EMT might be involved in the locally aggressive behavior of KCOT. PMID:25879017

  13. Homeostatic pressure, tumor growth and fingering of epithelial tissues: Some generic physics arguments

    NASA Astrophysics Data System (ADS)

    Risler, Thomas

    2011-03-01

    We propose that one aspect of homeostasis is the regulation of tissues to preferred pressures, which can lead to a competition for space of purely mechanical origin and be an underlying mechanism for tumor growth. Surface and bulk contributions to pressure lead to the existence of a critical size that must be overcome by metastases to reach macroscopic sizes. This property qualitatively explains the observed size distributions of metastases, while size-independent growth rates cannot account for clinical and experimental data. It also potentially explains the observed preferential growth of metastases on tissue surfaces and membranes, suggests a mechanism underlying the seed and soil hypothesis introduced by Stephen Paget in 1889, and yields realistic values for metastatic inefficiency. Treating epithelial tissues as viscous fluids with effective cell division, we find a novel hydrodynamic instability that leads to the formation of fingering protrusions of the epithelium into the connective tissue. Arising from a combination of viscous friction effects and proliferation of the epithelial cells, this instability provides physical insight into a potential mechanism by which interfaces between epithelia and stroma undulate, and potentially by which tissue dysplasia leads to cancerous invasion. In collaboration with M. Basan, J.-F. Joanny, X. Sastre-Garau and J. Prost.

  14. Targeting the Metabolic Reprogramming That Controls Epithelial-to-Mesenchymal Transition in Aggressive Tumors

    PubMed Central

    Morandi, Andrea; Taddei, Maria Letizia; Chiarugi, Paola; Giannoni, Elisa

    2017-01-01

    The epithelial-to-mesenchymal transition (EMT) process allows the trans-differentiation of a cell with epithelial features into a cell with mesenchymal characteristics. This process has been reported to be a key priming event for tumor development and therefore EMT activation is now considered an established trait of malignancy. The transcriptional and epigenetic reprogramming that governs EMT has been extensively characterized and reviewed in the last decade. However, increasing evidence demonstrates a correlation between metabolic reprogramming and EMT execution. The aim of the current review is to gather the recent findings that illustrate this correlation to help deciphering whether metabolic changes are causative or just a bystander effect of EMT activation. The review is divided accordingly to the catabolic and anabolic pathways that characterize carbohydrate, aminoacid, and lipid metabolism. Moreover, at the end of each part, we have discussed a series of potential metabolic targets involved in EMT promotion and execution for which drugs are either available or that could be further investigated for therapeutic intervention. PMID:28352611

  15. Targeting the Metabolic Reprogramming That Controls Epithelial-to-Mesenchymal Transition in Aggressive Tumors.

    PubMed

    Morandi, Andrea; Taddei, Maria Letizia; Chiarugi, Paola; Giannoni, Elisa

    2017-01-01

    The epithelial-to-mesenchymal transition (EMT) process allows the trans-differentiation of a cell with epithelial features into a cell with mesenchymal characteristics. This process has been reported to be a key priming event for tumor development and therefore EMT activation is now considered an established trait of malignancy. The transcriptional and epigenetic reprogramming that governs EMT has been extensively characterized and reviewed in the last decade. However, increasing evidence demonstrates a correlation between metabolic reprogramming and EMT execution. The aim of the current review is to gather the recent findings that illustrate this correlation to help deciphering whether metabolic changes are causative or just a bystander effect of EMT activation. The review is divided accordingly to the catabolic and anabolic pathways that characterize carbohydrate, aminoacid, and lipid metabolism. Moreover, at the end of each part, we have discussed a series of potential metabolic targets involved in EMT promotion and execution for which drugs are either available or that could be further investigated for therapeutic intervention.

  16. EGFR in Tumor-Associated Myeloid Cells Promotes Development of Colorectal Cancer in Mice and Associates With Outcomes of Patients.

    PubMed

    Srivatsa, Sriram; Paul, Mariel C; Cardone, Claudia; Holcmann, Martin; Amberg, Nicole; Pathria, Paulina; Diamanti, Michaela A; Linder, Markus; Timelthaler, Gerald; Dienes, Hans P; Kenner, Lukas; Wrba, Fritz; Prager, Gerald W; Rose-John, Stefan; Eferl, Robert; Liguori, Giuseppina; Botti, Gerardo; Martinelli, Erika; Greten, Florian R; Ciardiello, Fortunato; Sibilia, Maria

    2017-07-01

    Inhibitors of the epidermal growth factor receptor (EGFR) are the first-line therapy for patients with metastatic colorectal tumors without RAS mutations. However, EGFR inhibitors are ineffective in these patients, and tumor level of EGFR does not associate with response to therapy. We screened human colorectal tumors for EGFR-positive myeloid cells and investigated their association with patient outcome. We also performed studies in mice to evaluate how EGFR expression in tumor cells and myeloid cells contributes to development of colitis-associated cancer and Apc(Min)-dependent intestinal tumorigenesis. We performed immunohistochemical and immunofluorescent analyses of 116 colorectal tumor biopsies to determine levels of EGFR in tumor and stroma; we also collected information on tumor stage and patient features and outcomes. We used the Mann-Whitney U and Kruskal-Wallis tests to correlate tumor levels of EGFR with tumor stage, and the Kaplan-Meier method to estimate patients' median survival time. We performed experiments in mice lacking EGFR in intestinal epithelial cells (Villin-Cre; Egfr(f/f) and Villin-CreER(T2); Egfr(f/f) mice) or myeloid cells (LysM-Cre; Egfr(f/f) mice) on a mixed background. These mice were bred with Apc(Min/+) mice; colitis-associated cancer and colitis were induced by administration of dextran sodium sulfate (DSS), with or without azoxymethane (AOM), respectively. Villin-CreER(T2) was activated in developed tumors by administration of tamoxifen to mice. Littermates that expressed full-length EGFR were used as controls. Intestinal tissues were collected; severity of colitis, numbers and size of tumors, and intestinal barrier integrity were assessed by histologic, immunohistochemical, quantitative reverse transcription polymerase chain reaction, and flow cytometry analyses. We detected EGFR in myeloid cells in the stroma of human colorectal tumors; myeloid cell expression of EGFR associated with tumor metastasis and shorter patient

  17. Prognostic analysis of invasive circulating tumor cells (iCTCs) in epithelial ovarian cancer

    PubMed Central

    Pearl, Michael L.; Zhao, Qiang; Yang, Jie; Dong, Huan; Tulley, Shaun; Zhang, Qiao1; Golightly, Marc; Zucker, Stanley; Chen, Wen-Tien

    2014-01-01

    Goals: Circulating tumor cells (CTCs) have been introduced as a biomarker in detecting advanced Epithelial Ovarian Cancer (EOC). The goals are to examine the prevalence of the invasive subpopulation of CTCs (iCTCs) in patients at high risk of EOC and to compare this biomarker to serum CA125. Methods: We used a unique Cell Adhesion Matrix (CAM)-based, functional cell enrichment and identification platform to isolate iCTCs from 129 preoperative patients. We confirmed the identity of iCTCs using positive epithelial (Epi+) markers and negative hematopoietic lineage (HL-) markers. Sensitivity and specificity of the assays were examined and iCTCs / CA125 were correlated with overall survival (OS), progression-free survival (PFS) and clinical parameters. Results: We found a 41.2% sensitivity, 95.1% specificity and 77.8% positive predictive value (PPV) of the iCTC assay in detecting patients with stage I and II EOC malignancy, and a 83% sensitivity and 97.3% PPV in detecting all stages of EOC malignancy. However, a positive CA125 test provided weak evidence to detect stage I and II malignancy (61.6% PPV) and all EOC (92.1% PPV), because of its 76.2% specificity. A significantly stronger concordance in OS and PFS of clinical factors (tumor stage, debulking and platinum sensitivity) was noted for elevated iCTCs than for serum CA125. Conclusion: The CAM-initiated CTC enrichment / identification method enabled the detection of early stage EOC. iCTCs were better correlated with worse OS and PFS, more specific and better PPV than CA125 in detecting EOC malignancy in patients at high risk of EOC. PMID:24972191

  18. Human intestinal Vdelta1+ lymphocytes recognize tumor cells of epithelial origin

    PubMed Central

    1996-01-01

    complex restricted or to be correlated with target cell expression of heat- shock proteins. Based on the ability of some epithelial tumors, including colorectal, pancreatic, and renal cell cancers to effectively cold target inhibit the lysis of colorectal cancer cell lines by these Vdelta1+ T cell lines, we suggest that intestinal Vdelta1+ T cell lines, we suggest that intestinal Vdelta1+ T cells are capable of recognizing cell surface Ag(s) shared by tumors of epithelial origin. PMID:8666926

  19. Tumor Endothelial Inflammation Predicts Clinical Outcome in Diverse Human Cancers

    PubMed Central

    Filippo, Matthew; Labay, Edwardine; Beckett, Michael A.; Mauceri, Helena J.; Liang, Hua; Darga, Thomas E.; Perakis, Samantha; Khan, Sajid A.; Sutton, Harold G.; Zhang, Wei; Khodarev, Nikolai N.; Garcia, Joe G. N.; Weichselbaum, Ralph R.

    2012-01-01

    Background Vascular endothelial cells contribute to the pathogenesis of numerous human diseases by actively regulating the stromal inflammatory response; however, little is known regarding the role of endothelial inflammation in the growth of human tumors and its influence on the prognosis of human cancers. Methods Using an experimental model of tumor necrosis factor-alpha (TNF-α)-mediated inflammation, we characterized inflammatory gene expression in immunopurified tumor-associated endothelial cells. These genes formed the basis of a multivariate molecular predictor of overall survival that was trained and validated in four types of human cancer. Results We report that expression of experimentally derived tumor endothelial genes distinguished pathologic tissue specimens from normal controls in several human diseases associated with chronic inflammation. We trained these genes in human cancer datasets and defined a six-gene inflammatory signature that predicted significantly reduced overall survival in breast cancer, colon cancer, lung cancer, and glioma. This endothelial-derived signature predicted outcome independently of, but cooperatively with, standard clinical and pathological prognostic factors. Consistent with these findings, conditioned culture media from human endothelial cells stimulated by pro-inflammatory cytokines accelerated the growth of human colon and breast tumors in immunodeficient mice as compared with conditioned media from untreated endothelial cells. Conclusions This study provides the first prognostic cancer gene signature derived from an experimental model of tumor-associated endothelial inflammation. These findings support the notion that activation of inflammatory pathways in non-malignant tumor-infiltrating endothelial cells contributes to tumor growth and progression in multiple human cancers. Importantly, these results identify endothelial-derived factors that could serve as potential targets for therapy in diverse human cancers

  20. Inflammatory markers and risk of epithelial ovarian cancer by tumor subtypes: the EPIC cohort

    PubMed Central

    Ose, Jennifer; Schock, Helena; Tjonneland, Anne; Hansen, Louise; Overvad, Kim; Dossus, Laure; Clavel-Chapelon, Francoise; Baglietto, Laura; Boeing, Heiner; Trichopolou, Antonia; Benetou, Vassiliki; Lagiou, Pagona; Masala, Giovanna; Tagliabue, Giovanna; Tumino, Rosario; Sacerdote, Carlotta; Mattiello, Amalia; de Mesquita, H.Bas Bueno; Peeters, Petra H M; Onland-Moret, N Charlotte; Weiderpass, Elisabete; Gram, Inger T; Sánchez, Soledad; Obon-Santacana, Mireia; Sànchez-Pérez, Maria-José; Larrañaga, Nerea; Castaño, José María Huerta; Ardanaz, Eva; Brändstedt, Jenny; Lundin, Eva; Idahl, Annika; Travis, Ruth C; Khaw, Kay-Tee; Rinaldi, Sabina; Romieu, Isabelle; Merrit, Melissa A; Gunter, Marc J; Riboli, Elio; Kaaks, Rudolf; Fortner, Renée T

    2015-01-01

    Background Evidence suggests an etiologic role for inflammation in ovarian carcinogenesis and heterogeneity between tumor subtypes and anthropometric indices. Prospective studies on circulating inflammatory markers and epithelial invasive ovarian cancer (EOC) have predominantly investigated overall risk; data characterizing risk by tumor characteristics (histology, grade, stage, dualistic model of ovarian carcinogenesis) and anthropometric indices are sparse. Methods We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate C-reactive protein (CRP), interleukin-6 (IL-6), and EOC risk by tumor characteristics. A total of 754 eligible EOC cases were identified; two controls (n=1,497) were matched per case. We used multivariable conditional logistic regression to assess associations. Results CRP and IL-6 were not associated with overall EOC risk. However, consistent with prior research, CRP >10 vs. CRP ≤1 mg/L was associated with higher overall EOC risk (OR=1.67 [1.03 - 2.70]). We did not observe significant associations or heterogeneity in analyses by tumor characteristics. In analyses stratified by waist circumference, inflammatory markers were associated with higher risk among women with higher waist circumference; no association was observed for women with normal waist circumference: (e.g., IL-6: waist ≤80: ORlog2=0.97 [0.81 - 1.16]; waist >88: ORlog2=1.78 [1.28 - 2.48], pheterogeneity ≤0.01). Conclusions Our data suggest that high CRP is associated with increased risk of overall EOC, and that IL-6 and CRP may be associated with EOC risk among women with higher adiposity. Impact Our data add to global evidence that ovarian carcinogenesis may be promoted by an inflammatory milieu. PMID:25855626

  1. Clinicopathologic Features and Clinical Outcomes of Esophageal Gastrointestinal Stromal Tumor

    PubMed Central

    Feng, Fan; Tian, Yangzi; Liu, Zhen; Xu, Guanghui; Liu, Shushang; Guo, Man; Lian, Xiao; Fan, Daiming; Zhang, Hongwei

    2016-01-01

    Abstract Clinicopathologic features and clinical outcomes of gastrointestinal stromal tumors (GISTs) in esophagus are limited, because of the relatively rare incidence of esophageal GISTs. Therefore, the aim of the current study was to investigate the clinicopathologic features and clinical outcomes of esophageal GISTs, and to investigate the potential factors that may predict prognosis. Esophageal GIST cases were obtained from our center and from case reports and clinical studies extracted from MEDLINE. Clinicopathologic features and survivals were analyzed and compared with gastric GISTs from our center. The most common location was lower esophagus (86.84%), followed by middle and upper esophagus (11.40% and 1.76%). The majority of esophageal GISTs were classified as high-risk category (70.83%). Mitotic index was correlated with histologic type, mutational status, and tumor size. The 5-year disease-free survival and disease-specific survival were 65.1% and 65.9%, respectively. Tumor size, mitotic index, and National Institutes of Health risk classification were associated with prognosis of esophageal GISTs. Only tumor size, however, was the independent risk factor for the prognosis of esophageal GISTs. In comparison to gastric GISTs, the distribution of tumor size, histologic type, and National Institutes of Health risk classification were significantly different between esophageal GISTs and gastric GISTs. The disease-free survival and disease-specific survival of esophageal GISTs were significantly lower than that of gastric GISTs. The most common location for esophageal GISTs was lower esophagus, and most of the esophageal GISTs are high-risk category. Tumor size was the independent risk factor for the prognosis of esophageal GISTs. Esophageal GISTs differ significantly from gastric GISTs in respect to clinicopathologic features. The prognosis of esophageal GISTs was worse than that of gastric GISTs. PMID:26765432

  2. Higher Numbers of T-Bet+ Tumor-Infiltrating Lymphocytes Associate with Better Survival in Human Epithelial Ovarian Cancer.

    PubMed

    Xu, Yun; Chen, Lujun; Xu, Bin; Xiong, Yuqi; Yang, Min; Rui, Xiaohui; Shi, Liangrong; Wu, Changping; Jiang, Jingting; Lu, Binfeng

    2017-01-01

    T-bet, a member of the T-box family of transcription factors, is a key marker of type I immune response within the tumor microenvironment, and has been previously reported by us to serve as an important prognostic indicator for human gastric cancer patients and a potential biomarker for immunotherapy. In the present study, we aimed to assess the clinical significance and prognostic value of T-bet+ tumor-infiltrating lymphocytes in human epithelial ovarian cancer. The immunohistochemistry was used to analyze the infiltration density of T-bet+ lymphoid cells in human epithelial ovarian cancer tissues, and the flow cytometry analysis was used to further analyze the presence of T-bet+ tumor-infiltrating lymphocytes subgroups in cancer tissues. Our immunohistochemistry analysis showed increased number of T-bet+ lymphoid cells in the human epithelial ovarian cancer tissues, and the flow cytometry analysis further demonstrated the presence of T-bet+ tumor-infiltrating lymphocytes subgroups including CD4+ , CD8+ T cells and NK cells. In addition, we also observed a significant association of T-bet+ tumor-infiltrating lymphocytes density in the tumor nest of cancer with not only serum CA125 levels but also with distant metastasis. However no association was observed with other characteristics like patients' age, pathological type, FIGO stage, tumor site and tumor size. Furthermore, the survival analysis showed that higher density of T-bet+ tumor-infiltrating lymphocytes both in tumor nest and tumor stroma of cancer tissues was significantly associated with better patient survival. In addition, the density of T-bet+ tumor-infiltrating lymphocytes in tumor nest appeared to be an independent risk factor for predicting patients' postoperative prognoses. Our data indicated that the key transcription factor T-bet might play an important role in the type I immune cells mediated antitumor response, and the density of T-bet+ lymphocytes in human epithelial ovarian cancer tissues

  3. Predicting Trans-epithelial Phototherapeutic Keratectomy Outcomes Using Fourier-Domain Optical Coherence Tomography

    PubMed Central

    Cleary, Catherine; Li, Yan; Tang, Maolong; Gendy, Nehal Samy El; Huang, David

    2014-01-01

    Purpose To use Fourier-domain optical coherence tomography (FD-OCT) to predict trans-epithelial phototherapeutic keratectomy (TE-PTK) outcomes. Methods Prospective case series. Subjects with anterior stromal corneal opacities underwent excimer laser PTK combined with PRK using the VISX S4 excimer laser (AMO, Inc., Santa Ana, CA). Pre- and postoperative FD-OCT images were used to develop a simulation algorithm to predict treatment outcomes. Main Outcome Measures Pre- and postoperative uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA). Postoperative corneal thickness and manifest refraction spherical equivalent (MRSE) were analyzed using multivariate linear regression. Results Nine eyes of 8 patients were treated. Nominal ablation depth was 75 – 177 μm centrally and 62 –185 μm peripherally. Measured PTK ablation depths were 20% higher centrally and 26% higher peripherally, compared to laser settings. Postoperatively, mean UDVA was 20/41 (range 20/25 – 20/80) compared to 20/103 (range 20/60 – 20/400) preoperatively. Mean CDVA was 20/29 (range 20/15 – 20/60) compared to 20/45 (range 20/30 – 20/80) preoperatively. MRSE was +1.38±2.37 D compared to −2.59±2.83D (mean±SD). Mean astigmatism magnitude was 1.14±0.83D compared to 1.40±1.18D preoperatively. Postoperative MRSE correlated strongly with ablation settings, central and peripheral epithelial thickness (r=0.99, p<0.00001 ). Central island remained difficult to predict and limited visual outcomes in some cases. Conclusion OCT measurements of opacity depth and 3D ablation simulation provide valuable guidance PTK planning. Post-PTK refraction may be predicted with a regression formula which uses OCT epithelial thickness measurements. Laser ablation rates described in this study only apply to the VisX laser. PMID:24452208

  4. Comparison of early postoperative clinical outcomes of photorefractive keratectomy and lamellar epithelial debridement.

    PubMed

    Youm, Dong Ju; Tchah, Hungwon; Choi, Chul Young

    2009-04-01

    To compare early postoperative clinical outcomes of photorefractive keratectomy (PRK) and lamellar epithelial debridement (LED). Department of Ophthalmology, Kangbuk Samsung Hospital, Seoul, Korea. This prospective study was of patients randomly assigned to have PRK or LED. In the LED group, an epithelial flap was created using an Amadeus II epikeratome. Postoperative follow-up was at 1, 3, and 7 days and 1, 3, and 6 months. The outcome parameters were uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), higher-order aberrations (HOAs), epithelial healing time, and corneal haze. The study comprised 39 patients (76 eyes). The mean preoperative spherical equivalent (SE) was -3.96 diopters (D) +/- 1.24 (SD) in the PRK group and -4.06 +/- 1.39 D in the LED group. Postoperative UCVA was significantly better in the LED group 1 day postoperatively. The UCVA was 20/20 or better in 14.6% in the PRK group and 42.9% in the LED group (P = .006); 20/25 or better in 41.5% and 82.9%, respectively (P = .000); and 20/40 or better in 80.5% and 100%, respectively (P = .006). On subsequent follow-up visits, the UCVA was comparable between groups. No eye lost lines of BCVA at 3 months. There was no difference between groups in postoperative SE refraction, HOAs, or corneal haze. Lamellar epithelial debridement and PRK had comparable safety and efficacy in the surgical correction of low to moderate myopia. The UCVA was significantly better after LED than after PRK 1 day postoperatively and equivalent thereafter.

  5. [Influence of anesthesia procedure on malignant tumor outcome].

    PubMed

    Fukui, K; Werner, C; Pestel, G

    2012-03-01

    Malignant tumors are the second major cause of death in Germany. The essential therapy of operable cancer is surgical removal of primary tumors combined with adjuvant therapy. However, several consequences of surgery may promote metastasis, such as shedding of tumor cells into the circulation, decrease in tumor-induced antiangiogenesis factors, excessive release of growth factors for wound healing and suppression of immunity induced by surgical stress. In the last decade it has become clear that cell-mediated immunity controls the development of metastasis. Various perioperative factors, such as surgical stress, certain anesthetic and analgesic drugs and pain can suppress the patients' immune system perioperatively. On the other hand, by modifications of the anesthesia technique (e.g. regional anesthesia) and perioperative management to minimize immunosuppression, anesthesiologists can play a considerable role for a better outcome in patients having malignant tumors. Sufficient clinical evidence is not yet available to prove or disprove the hypothesis that anesthesia practice can improve cancer prognosis. Despite difficulties in study design, several prospective randomized trials are currently running and the results are awaited to elucidate this topic.

  6. Bipolar radiofrequency ablation of spinal tumors: predictability, safety and outcome.

    PubMed

    Gazis, Angelos N; Beuing, Oliver; Franke, Jörg; Jöllenbeck, Boris; Skalej, Martin

    2014-04-01

    Bone metastases are often the cause of tumor-associated pain and reduction of quality of life. For patients that cannot be treated by surgery, a local minimally invasive therapy such as radiofrequency ablation can be a useful option. In cases in which tumorous masses are adjacent to vulnerable structures, the monopolar radiofrequency can cause severe neuronal damage because of the unpredictability of current flow. The aim of this study is to show that the bipolar radiofrequency ablation provides an opportunity to safely treat such spinal lesions because of precise predictability of the emerging ablation zone. Prospective cohort study of 36 patients undergoing treatment at a single institution. Thirty-six patients in advanced tumor stage with primary or secondary tumor involvement of spine undergoing radiofrequency ablation. Prediction of emerging ablation zone. Clinical outcome of treated patients. X-ray-controlled treatment of 39 lesions by bipolar radiofrequency ablation. Magnetic resonance imaging was performed pre- and postinterventionally. Patients were observed clinically during their postinterventional stay. The extent of the ablation zones was predictable to the millimeter because it did not cross the peri-interventional planned dorsal and ventral boundaries in any case. No complications were observed. Ablation of tumorous masses adjacent to vulnerable structures is feasible and predictable by using the bipolar radiofrequency ablation. Damage of neuronal structures can be avoided through precise prediction of the ablation area. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Tumor-infiltrating CD45RO(+) Memory T Lymphocytes Predict Favorable Clinical Outcome in Solid Tumors.

    PubMed

    Hu, Guoming; Wang, Shimin

    2017-09-04

    The prognostic role of tumor-infiltrating CD45RO(+) memory T lymphocytes (CD45RO(+) T cells) in human solid tumors remains controversial. Herein, we conducted a meta-analysis including 25 published studies with 4720 patients identified from PubMed and EBSCO to assess the prognostic impact of tumor-infiltrating CD45RO(+) T cells in human solid tumors. We found that CD45RO(+) T cell infiltration was significantly associated with improved overall survival (OS) and disease-free survival (DFS) in all types of solid tumors. In stratified analyses, CD45RO(+) T cell infiltration significantly improved 1-year, 3-year and 5-year OS in colorectal, gastric and esophageal cancer, but only 5-year OS in hepatocellular carcinoma. And these cells were positively associated with 1-year, 3-year and 5-year DFS in hepatocellular, colorectal and esophageal cancer. In addition, high density of intratumoral CD45RO(+) T cells inversely correlated with TNM stage of solid tumor. In conclusion, CD45RO(+) memory T lymphocyte infiltration leads to a favorable clinical outcome in solid tumors, implicating that it is a valuable biomarker for prognostic prediction for human solid malignances.

  8. Epithelial Membrane Protein-2 Promotes Endometrial Tumor Formation through Activation of FAK and Src

    PubMed Central

    Fu, Maoyong; Rao, Rajiv; Sudhakar, Deepthi; Hogue, Claire P.; Rutta, Zach; Morales, Shawn; Gordon, Lynn K.; Braun, Jonathan; Goodglick, Lee; Wadehra, Madhuri

    2011-01-01

    Endometrial cancer is the most common gynecologic malignancy diagnosed among women in developed countries. One recent biomarker strongly associated with disease progression and survival is epithelial membrane protein-2 (EMP2), a tetraspan protein known to associate with and modify surface expression of certain integrin isoforms. In this study, we show using a xenograft model system that EMP2 expression is necessary for efficient endometrial tumor formation, and we have started to characterize the mechanism by which EMP2 contributes to this malignant phenotype. In endometrial cancer cells, the focal adhesion kinase (FAK)/Src pathway appears to regulate migration as measured through wound healing assays. Manipulation of EMP2 levels in endometrial cancer cells regulates the phosphorylation of FAK and Src, and promotes their distribution into lipid raft domains. Notably, cells with low levels of EMP2 fail to migrate and poorly form tumors in vivo. These findings reveal the pivotal role of EMP2 in endometrial cancer carcinogenesis, and suggest that the association of elevated EMP2 levels with endometrial cancer prognosis may be causally linked to its effect on integrin-mediated signaling. PMID:21637765

  9. ALA-based photodynamic therapy in epithelial tumors: in vivo and in vitro models

    NASA Astrophysics Data System (ADS)

    Casas, Adriana; Fukuda, Haydee; Batlle, Alcira

    2000-03-01

    PDT shows considerable potential as a treatment modality for superficial tumors. PDT is based on the accumulation of a photosensitizer in the target tissue. Subsequent illumination with light of an appropriate wavelength provokes a photochemical reaction that results in tumor destruction. Aminolevulinic acid (ALA) is a porphyrin precursor, and its administration result in the endogenous production of phototoxic porphyrins, which has been exploited for PDT. We assessed PDT efficacy employing both in vivo and in vitro models. We used papillomas, keratoacanthomas and in situ carcinomas chemically induced in the skin of SENCAR mice. Using ALA lotion and cream formulations, the maximal amount of porphyrin accumulation in papillomas was 5.52 (mu) g/g tissue. An energy of 150 of J/cm2 was delivered by a copper-dye laser tuned at 630 nm. Microscopically, we found several signs of tissue destruction, more markedly in the upper strata of the in situ carcinomas. Papillomas, characterized by hyperkeratinization, were resistant to PDT. In our in vitro studies, we used an epithelial adenocarcinoma cell line. We tested ALA and its hexyl and methyl derivatives with the aim of increasing porphyrin synthesis. We found that hexyl-ALA was the best compound. When cultures incubated 3 hours in 0.6 mM ALA and 0.1 mM hexyl-ALA respectively were irradiated with 3 J/cm2 only 5 percent of cells survived.

  10. Automated ensemble segmentation of epithelial proliferation, necrosis, and fibrosis using scatter tumor imaging

    NASA Astrophysics Data System (ADS)

    Garcia-Allende, P. Beatriz; Conde, Olga M.; Krishnaswamy, Venkataramanan; Hoopes, P. Jack; Pogue, Brian W.; Mirapeix, Jesus; Lopez-Higuera, Jose M.

    2010-04-01

    Conventional imaging systems used today in surgical settings rely on contrast enhancement based on color and intensity and they are not sensitive to morphology changes at the microscopic level. Elastic light scattering spectroscopy has been shown to distinguish ultra-structural changes in tissue. Therefore, it could provide this intrinsic contrast being enormously useful in guiding complex surgical interventions. Scatter parameters associated with epithelial proliferation, necrosis and fibrosis in pancreatic tumors were previously estimated in a quantitative manner. Subtle variations were encountered across the distinct diagnostic categories. This work proposes an automated methodology to correlate these variations with their corresponding tumor morphologies. A new approach based on the aggregation of the predictions of K-nearest neighbors (kNN) algorithm and Artificial Neural Networks (ANNs) has been developed. The major benefit obtained from the combination of the distinct classifiers is a significant increase in the number of pixel localizations whose corresponding tissue type is reliably assured. Pseudo-color diagnosis images are provided showing a strong correlation with sample segmentations performed by a veterinary pathologist.

  11. Surface modification of microparticles causes differential uptake responses in normal and tumoral human breast epithelial cells

    PubMed Central

    Patiño, Tania; Soriano, Jorge; Barrios, Lleonard; Ibáñez, Elena; Nogués, Carme

    2015-01-01

    The use of micro- and nanodevices as multifunctional systems for biomedical applications has experienced an exponential growth during the past decades. Although a large number of studies have focused on the design and fabrication of new micro- and nanosystems capable of developing multiple functions, a deeper understanding of their interaction with cells is required. In the present study, we evaluated the effect of different microparticle surfaces on their interaction with normal and tumoral human breast epithelial cell lines. For this, AlexaFluor488 IgG functionalized polystyrene microparticles (3 μm) were coated with Polyethyleneimine (PEI) at two different molecular weights, 25 and 750 kDa. The effect of microparticle surface properties on cytotoxicity, cellular uptake and endocytic pathways were assessed for both normal and tumoral cell lines. Results showed a differential response between the two cell lines regarding uptake efficiency and mechanisms of endocytosis, highlighting the potential role of microparticle surface tunning for specific cell targeting. PMID:26068810

  12. Cell surface syndecan-1 contributes to binding and function of macrophage migration inhibitory factor (MIF) on epithelial tumor cells.

    PubMed

    Pasqualon, Tobias; Lue, Hongqi; Groening, Sabine; Pruessmeyer, Jessica; Jahr, Holger; Denecke, Bernd; Bernhagen, Jürgen; Ludwig, Andreas

    2016-04-01

    Surface expressed proteoglycans mediate the binding of cytokines and chemokines to the cell surface and promote migration of various tumor cell types including epithelial tumor cells. We here demonstrate that binding of the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) to epithelial lung and breast tumor cell lines A549 and MDA-MB231 is sensitive to enzymatic digestion of heparan sulphate chains and competitive inhibition with heparin. Moreover, MIF interaction with heparin was confirmed by chromatography and a structural comparison indicated a possible heparin binding site. These results suggested that proteoglycans carrying heparan sulphate chains are involved in MIF binding. Using shRNA-mediated gene silencing, we identified syndecan-1 as the predominant proteoglycan required for the interaction with MIF. MIF binding was decreased by induction of proteolytic shedding of syndecan-1, which could be prevented by inhibition of the metalloproteinases involved in this process. Finally, MIF induced the chemotactic migration of A549 cells, wound closure and invasion into matrigel without affecting cell proliferation. These MIF-induced responses were abrogated by heparin or by silencing of syndecan-1. Thus, our study indicates that syndecan-1 on epithelial tumor cells promotes MIF binding and MIF-mediated cell migration. This may represent a relevant mechanism through which MIF enhances tumor cell motility and metastasis.

  13. Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton.

    PubMed

    Wicki, Andreas; Lehembre, François; Wick, Nikolaus; Hantusch, Brigitte; Kerjaschki, Dontscho; Christofori, Gerhard

    2006-04-01

    The expression of podoplanin, a small mucin-like protein, is upregulated in the invasive front of a number of human carcinomas. We have investigated podoplanin function in cultured human breast cancer cells, in a mouse model of pancreatic beta cell carcinogenesis, and in human cancer biopsies. Our results indicate that podoplanin promotes tumor cell invasion in vitro and in vivo. Notably, the expression and subcellular localization of epithelial markers are unaltered, and mesenchymal markers are not induced in invasive podoplanin-expressing tumor cells. Rather, podoplanin induces collective cell migration by filopodia formation via the downregulation of the activities of small Rho family GTPases. In conclusion, podoplanin induces an alternative pathway of tumor cell invasion in the absence of epithelial-mesenchymal transition (EMT).

  14. Assessment of the ITMIG Statement on the WHO Histological Classification and of the Eighth TNM Staging of Thymic Epithelial Tumors of a Series of 188 Thymic Epithelial Tumors.

    PubMed

    Meurgey, Alexandra; Girard, Nicolas; Merveilleux du Vignaux, Claire; Maury, Jean-Michel; Tronc, François; Thivolet-Bejui, Françoise; Chalabreysse, Lara

    2017-07-08

    Thymic epithelial tumors (TETs) are rare intrathoracic malignancies that are categorized histologically according to the WHO classification, which was recently updated in 2015 on the basis of a consensus statement of the International Thymic Malignancy Interest Group (ITMIG); at the same time, the standard Masaoka-Koga staging system is scheduled to be replaced by the eighth edition of the TNM staging classification by the American Joint Committee on Cancer/Union for International Cancer Control consortium. Our objectives were to analyze the feasibility of assessing ITMIG consensus major and minor morphological and immunohistochemical criteria and the eighth edition of the TNM staging classification in a routine practice setting. This is a single-center study conducted at the Louis-Pradel Hospital of Lyon University, one of the largest centers for TETs in France. Overall, a large surgical series of 188 TETs diagnosed in 181 patients between 2000 and 2014 at our center were analyzed. There were 89 men (49%) and 92 women (51%); 57 patients (31%) presented with myasthenia gravis at time of diagnosis. According to the WHO classification, there were nine type A thymomas (5%), 67 type AB thymomas (36%), 19 type B1 thymomas (10%), 46 type B2 thymomas (24%), 27 type B3 thymomas (14%), and 20 thymic carcinomas (11%). ITMIG consensus major criteria were identified in 100% of type A, AB, B1, and B2 thymomas. After restaging according to the eighth edition of the TNM staging classification, there were 127 stage I (84%), three stage II (2%), 17 stage IIIa (11%), no stage IIIb, two stage IVa (1%), and three stage IVb (2%) thymomas. Significant correlation between histological type and stage at diagnosis was maintained after restaging according the TNM classification. Comprehensive analysis of our well-characterized surgical series of 188 TETs indicates the feasibility and the diagnostic value of the ITMIG consensus statement on WHO histological classification and highlights the

  15. Sam68 is Overexpressed in Epithelial Ovarian Cancer and Promotes Tumor Cell Proliferation

    PubMed Central

    Dong, Lijuan; Che, Hailuo; Li, Mingmei; Li, Xuepeng

    2016-01-01

    Background Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy, and evidence is accumulating on how molecular markers may be associated with the origin and process of EOC. Sam68 (Src-associated in mitosis, of 68 kD), is a K homology domain RNA-binding protein that has been investigated as a risk factor in multiple types of tumors. The aim of the present study was to investigate the contribution of the Sam68 gene in the pathogenesis of EOC. Material/Methods Western blot assay and real-time quantitative PCR methods were performed to examine Sam68 expression in EOC tissue specimens. The association of Sam68 expression with clinic-pathologic variables of EOC was evaluated. Then gain-of-function and loss-of-function strategies were adopted to examine the regulation of Sam68 on the proliferation of EOC OVCAR-3 cells using CCK-8 and colony forming assays. Results Sam68 was overexpressed in both mRNA and protein levels in EOC tumor tissue (n=152) in an association with malignant factors of EOC such as International Federation of Gynecology and Obstetrics (FIGO) stage, residual tumor size (cm), histological grade, and lymph node metastasis. In vitro results demonstrated that Sam68 overexpression was upregulated while Sam68 knockdown downregulated the proliferation of EOC OVCAR-3 cells via regulation of cell growth and colony formation. Conclusions Sam68 was overexpressed in EOC tissue in association with such cancer malignant factors of FIGO stage, histological grade, and lymph node metastasis, and also positively regulated the proliferation of EOC cells. Our research suggests that Sam68 might accelerate cell cycle progression, and present as a prognostic marker for EOC. PMID:27623016

  16. Diffusion-weighted MR imaging in thymic epithelial tumors: correlation with World Health Organization classification and clinical staging.

    PubMed

    Abdel Razek, Ahmed Abdel Khalek; Khairy, Mohamed; Nada, Nadia

    2014-10-01

    To assess thymic epithelial tumors with diffusion-weighted magnetic resonance (MR) imaging. Informed consent from patients and institutional review board approval were obtained. Prospective study was conducted on 30 consecutive patients (21 men and nine women; age range, 35-71 years) with thymic epithelial tumors. They underwent true fast imaging with steady-state precession and single-shot echo-planar diffusion-weighted MR imaging of the mediastinum with b values of 0, 400, and 800 sec/mm(2). Apparent diffusion coefficient (ADC) of the thymic epithelial tumors was calculated by the same observer at two settings and was correlated with World Health Organization classification and clinical staging. There was significant difference in longest diameter (P = .001) and necrotic part of the tumor (P = .014) between low-risk thymoma, high-risk thymoma, and thymic carcinoma. Mean ADC value of both readings of thymic epithelial tumors (n = 30) was 1.24 × 10(-3) mm(2)/sec and 1.22 × 10(-3) mm(2)/sec, with good intraobserver agreement (κ = 0.732). There was significant difference in both readings (P = .01 and .20) of low-risk thymoma (1.30 × 10(-3) mm(2)/sec and 1.29 × 10(-3) mm(2)/sec), high-risk thymoma (1.16 × 10(-3) mm(2)/sec and 1.14 × 10(-3) mm(2)/sec), and thymic carcinoma (1.18 × 10(-3) mm(2)/sec and 1.06 × 10(-3) mm(2)/sec). Cutoff ADC values of both readings used to differentiate low-risk thymoma from high-risk thymoma and thymic carcinoma were 1.25 and 1.22 × 10(-3) mm(2)/sec with area under the curve of 0.804 and 0.851, respectively. There was significant difference in both readings of ADC value of early (stage I, II) and advanced stages (stage III, IV) of thymic epithelial tumors (P = .006 and .005, respectively). ADC value is a noninvasive, reliable, and reproducible imaging parameter that may help to assess and characterize thymic epithelial tumors. © RSNA, 2014.

  17. Gastric and small intestine gastrointestinal stromal tumors: Do outcomes differ?

    PubMed

    Giuliano, Katherine; Nagarajan, Neeraja; Canner, Joseph; Najafian, Alireza; Wolfgang, Christopher; Schneider, Eric; Meyer, Christian; Lennon, Anne Marie; Johnston, Fabian M; Ahuja, Nita

    2017-03-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Previous literature has suggested that small intestine GISTs are more aggressive than gastric GISTs. Our primary objective was to compare the outcomes of gastric and small intestine GISTs in the decade after approval of imatinib for treatment. The SEER database was queried for cases of gastric and small intestine GIST between the years 2002 and 2012, using the ICD-O-3 histology code 8936. Survival analysis was performed using generalized gamma models for time to cause-specific mortality (CSM). CSM was 14.0% for the 3,759 gastric GIST patients and 14.3% for the 1,848 small intestine GIST patients. Five-year survival was 82.2% and 83.3% for gastric and small intestine patients, respectively. The number of diagnosed cases of GIST increased over the course of this study, especially for tumors <5 cm in size and in patients over age 50 years. In this large nation-wide study, we found that patients with gastric and small intestine GISTs had similar outcomes, in contrast to previous reports. The diagnosis of GIST has significantly increased in the last decade, which may reflect the increased recognition of this entity and frequent use of imaging. J. Surg. Oncol. 2017;115:351-357. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. Cell-cycle-associated markers and clinical outcome in human epithelial cancers: a tissue microarray study.

    PubMed

    Abdulkader, I; Sánchez, L; Cameselle-Teijeiro, J; Gude, F; Chávez, J E; López-López, R; Forteza, J; Fraga, M

    2005-12-01

    The development and progression of epithelial cancers are the result of an imbalance in signals promoting and inhibiting cellular proliferation and apoptosis. The aim of this study is to evaluate the expression of cell-cycle and apoptosis regulators and correlate them with clinical outcome in the most frequent carcinomas, in order to establish common prognostic biomarkers independent of cancer origin. Using tissue microarrays (TMAs), we have analysed the immuno-expression of Ki-67, Bcl-2, Bax, cyclin D1, cyclin D3, CDK1, CDK2, CDK6, p16, p21, and p27 in a series of 205 carcinomas of the large bowel, breast, lung and prostate (80, 73, 37 and 15 cases, respectively). By univariate analysis, positivity for p27, p16 and Bcl-2 was associated with better overall survival (P<0.0135, P<0.0442 and P<0.0001, respectively). The risk of mortality was 2.3-fold greater in patients without Bcl-2 expression. TMA immunohistochemical analysis identified a subset of epithelial cancers with overlapping alterations in cell-cycle checkpoints, apoptosis regulators and tumour suppressor pathways. We found that in most common epithelial cancers, regardless of origin, Bcl-2 appears to be the key biological factor influencing clinical behaviour.

  19. Dynamic molecular changes associated with epithelial-mesenchymal transition and subsequent mesenchymal-epithelial transition in the early phase of metastatic tumor formation.

    PubMed

    Aokage, Keiju; Ishii, Genichiro; Ohtaki, Yoichi; Yamaguchi, Yoko; Hishida, Tomoyuki; Yoshida, Junji; Nishimura, Mitsuyo; Nagai, Kanji; Ochiai, Atsushi

    2011-04-01

    Metastatic tumor formation via vessel route begins with cancer cell extravasation from vessel lumen, migration into the connective tissue surrounding vessels, and invasion into target organ parenchyma. Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) have been recognized to play an important role in metastatic process, however, how and where these biological changes take place in the early phase of metastatic tumor development has never been clarified. We morphologically evaluated 34 small intrapulmonary metastases formed after cancer cell extravasation from lymphatics (lymphogenic metastasis) and 40 formed in the absence of extravasation (aerogenous metastasis) in human specimens and found that isolated or small clusters of invasive cancer cells (tumor budding) were frequently observed in lymphogenic metastasis (24/34; 71%), but were never observed within aerogenous metastasis. We immunostained 34 lymphogenic metastases for 13 molecular markers of EMT and MET and scored the immunostaining intensity of cancer cells floating in lymphatic vessels (LVs), migrating into the connective tissue surrounding vessels [bronchovascular bundle (BVB)], and growing in lung parenchyma (LP). Cancer cells within BVBs stained more weakly for E-cadherin (p < 0.001), β-catenin (p < 0.001), and Geminin (p < 0.001) and more strongly for MMP-7 (p = 0.046) and Laminin-5 γ2 (p = 0.037) than tumor cells in LVs. However, cancer cells in LP exhibited resurgent E-cadherin (p = 0.011), β-catenin (p < 0.001), and Geminin (p = 0.037) expression and reduced MMP-7 (p = 0.038) and Laminin-5 γ2 (p = 0.001) expression in comparison with cancer cells in BVBs. Our results suggested that in the early phase of metastatic tumor formation cancer cells undergo dynamic phenotypic change associated with EMT and subsequent MET. Copyright © 2010 UICC.

  20. Large and round tumor nuclei in osteosarcoma: good clinical outcome

    PubMed Central

    de Andrea, Carlos E; Petrilli, Antonio Sergio; Jesus-Garcia, Reynaldo; Bleggi-Torres, Luiz F; Alves, Maria Teresa S

    2011-01-01

    Osteosarcoma is the most frequent primary malignant bone tumor. Distinct histological features are distinguishable based on the morphology of the tumor. Differences in nuclei size and shape are often observed in osteosarcoma reflecting its broad histopathological heterogeneity. This study explores the relevance of two nuclear parameters in osteosarcoma: large area and round shape. Computerized nuclear morphometry was performed in 56 conventional osteosarcoma preoperative biopsies. The mean patient follow-up time was 35.1 months. Based on the nuclear area, no significant difference (P = 0.09) in overall survival between patients with large (> 42.5 μm2) and small (< 42.5 μm2) tumor nuclei was found. However, when cases with large and round nuclei were analyzed jointly (> 42.5 μm2 and coefficient of nuclear roundness > 0.7), these two parameters together were likely to be a predictive factor (P = 0.05). Osteosarcoma patients with large and round tumor nuclei had a better outcome than patients with small and polymorphic (ovoid or spindle-shaped) nuclei. In this study, nuclear morphometry proved to be a useful tool to shed light on the biology of osteosarcoma showing that some morphometric parameters can be easily applied to help identifying patients with a good prognosis. PMID:21326812

  1. Monoclonal antibodies to an epithelial ovarian adenocarcinoma: distinctive reactivity with xenografts of the original tumor and a cultured cell line.

    PubMed

    Baumal, R; Law, J; Buick, R N; Kahn, H; Yeger, H; Sheldon, K; Colgan, T; Marks, A

    1986-08-01

    Four monoclonal antibodies (mAb) (8C, 10B, M2A, and M2D) were produced against the human epithelial ovarian adenocarcinoma cell line, HEY. The affinity constants of binding of the mAb to cultured HEY cells were 8 X 10(8) M-1 (M2D) and 10(9) M-1 (8C and 10B). mAb 8C reacted with a major glycoprotein of Mr 90,000 on the surface of HEY cells. The four mAb differed from previously reported mAb to epithelial ovarian adenocarcinomas on the basis of their reactivity with cultured ovarian adenocarcinoma cell lines using a cell-binding radioimmunoassay, and their staining of cryostat sections of various human normal and tumor tissues using an immunoperoxidase reaction. All four mAb reacted with s.c. tumors derived by injecting cultured HEY cells into thymectomized CBA/CJ mice. However, only two of the four mAb (8C and 10B) also reacted with s.c. tumors of the original HEY xenograft from which the cultured cell line was derived. In addition, mAb 8C and 10B reacted by immunoperoxidase staining with 2 and 4 different cases, respectively, of 11 epithelial ovarian adenocarcinomas examined. Cultured HEY cells were adapted to grow i.p. in BALB/c-nu/nu mice and the i.p. tumors retained their reactivity with the monoclonal antibodies. These tumor-bearing mice offer a useful model system for studying the potential of mAb, especially 8C and 10B, for the diagnosis and treatment of patients with peritoneal extension of epithelial ovarian adenocarcinomas.

  2. Analysis of CUL-5 expression in breast epithelial cells, breast cancer cell lines, normal tissues and tumor tissues

    PubMed Central

    Fay, Michael J; Longo, Kenneth A; Karathanasis, George A; Shope, David M; Mandernach, Craig J; Leong, Jason R; Hicks, Alfred; Pherson, Kenneth; Husain, Amyna

    2003-01-01

    Background The chromosomal location of CUL-5 (11q 22-23) is associated with LOH in breast cancer, suggesting that CUL-5 may be a tumor suppressor. The purpose of this research was to determine if there is differential expression of CUL-5 in breast epithelial cells versus breast cancer cell lines, and normal human tissues versus human tumors. The expression of CUL-5 in breast epithelial cells (HMEC, MCF-10A), and breast cancer cells (MCF-7, MDA-MB-231) was examined using RT-PCR, Northern blot analysis, and Western blot analysis. The expression of mRNA for other CUL family members (CUL-1, -2, -3, -4A, and -4B) in these cells was evaluated by RT-PCR. A normal human tissue expression array and a cancer profiling array were used to examine CUL-5 expression in normal human tissues and matched normal tissues versus tumor tissues, respectively. Results CUL-5 is expressed at the mRNA and protein levels by breast epithelial cells (HMEC, MCF-10A) and breast cancer cells (MCF-7, MDA-MB-231). These cells also express mRNA for other CUL family members. The normal human tissue expression array revealed that CUL-5 is widely expressed. The cancer profiling array revealed that 82% (41/50) of the breast cancers demonstrated a decrease in CUL-5 expression versus the matched normal tissue. For the 50 cases of matched breast tissue there was a statistically significant ~2.2 fold decreased expression of CUL-5 in tumor tissue versus normal tissue (P < 0.0001). Conclusions The data demonstrate no apparent decrease in CUL-5 expression in the breast cancer cell lines (MCF-7, MDA-MB-231) versus the breast epithelial cells (HMEC, MCF-10A). The decrease in CUL-5 expression in breast tumor tissue versus matched normal tissue supports the hypothesis that decreased expression of CUL-5 may play a role in breast tumorigenesis. PMID:14641918

  3. The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome.

    PubMed

    Remark, Romain; Becker, Christian; Gomez, Jorge E; Damotte, Diane; Dieu-Nosjean, Marie-Caroline; Sautès-Fridman, Catherine; Fridman, Wolf-Herman; Powell, Charles A; Altorki, Nasser K; Merad, Miriam; Gnjatic, Sacha

    2015-02-15

    Solid tumors, beyond mere accumulation of cancer cells, form a complex ecosystem consisting of normal epithelial cells, fibroblasts, blood and lymphatic vessels, structural components, and infiltrating hematopoietic cells including myeloid and lymphoid elements that impact tumor growth, tumor spreading, and clinical outcome. The composition of the immune microenvironment is diverse, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, or macrophages. The immune contexture describes the density, location, and organization of these immune cells within solid tumors. In lung cancer, which is the deadliest type of cancer, and particularly in non-small cell lung cancer, its most prevalent form, reports have described some of the interactions between the tumor and the host. These data, in addition to articles on various types of tumors, provide a greater understanding of the tumor-host microenvironment interaction and stimulate the development of prognostic and predictive biomarkers, the identification of novel target antigens for therapeutic intervention, and the implementation of tools for long-term management of patients with cancer.

  4. JOURNAL CLUB: Doubling Time of Thymic Epithelial Tumors Correlates With World Health Organization Histopathologic Classification.

    PubMed

    Jeong, Dong Young; Lee, Kyung Soo; Chung, Myung Jin; Zo, Jae Ill; Shim, Young Mog; Moon, Jung Won

    2017-10-01

    Awareness of volume doubling times (VDTs) of different thymic epithelial tumors (TETs), including low- and high-grade thymomas and thymic carcinomas, is important for their management. The purpose of this study was to evaluate the VDTs of incidentally found TETs using 3D volumetry (3D-VDT) and longest diameter (LD-VDT). This retrospective study included 50 patients (30 men, 20 women) who had histologically proven TETs and who underwent at least two serial CT studies at greater than 2-month intervals. TETs were classified into World Health Organization subtypes and further divided into low-grade (group A [A-B1]) and high-grade (group B [B2, B3]) thymoma and thymic carcinoma (group C). Tumor volumetry was performed by either manual segmentation (3D-VDT) or longest diameter measurement (LD-VDT). Groups A, B, and C accounted for 15, 26, and nine tumors. The median LDVDT in group A was 703.6 days (range, 286.7-1855.9 days); group B, 412.1 days (range, 130.9-716.9 days), and group C, 146.3 days (range, 68.9-448.3 days) (p < 0.01). The median 3D-VDTs were 1138.8 days (range, 350.1-3915.3 days), 711.0 days (range, 145.5-7209.5 days), and 203.1 days (range, 58.9-766.9 days) (p < 0.01). In ROC analysis, both LD-VDT (AUC, 0.873; p < 0.01; optimal cutoff value, 222.6 days; 90.2% sensitivity, 77.8% specificity) and 3DVDT (AUC, 0.859; p < 0.01; optimal cutoff value, 218.0 days; 92.7% sensitivity; 66.7% specificity) differentiated group C from groups A and B. VDTs differ among TETs according to tumor grade. Measurement of either LD-VDT or 3D-VDT is sensitive for differentiating carcinomas from thymomas (cutoff value, ≈ 220 days).

  5. Novel Prognostic Groups in Thymic Epithelial Tumors: Assessment of Risk and Therapeutic Strategy Selection

    SciTech Connect

    D'Angelillo, Rolando M. Trodella, Lucio; Ramella, Sara; Cellini, Numa; Balducci, Mario; Mantini, Giovanna; Cellini, Francesco; Ciresa, Marzia; Fiore, Michele; Evoli, Amelia; Sterzi, Silvia; Russo, Patrizia; Grozio, Alessia; Cesario, Alfredo; Granone, Pierluigi

    2008-06-01

    Purpose: To assess the role of multimodality treatment on patients with thymic epithelial tumors (TETs) (i.e., thymomas and thymic squamous cell carcinoma) and to define the prognostic classes according to the Masaoka and World Health Organization histologic classification systems. Methods and Materials: Primary surgery was the mainstay of therapy. Extended thymectomy was performed in all cases. The cases were primarily staged according to the Masaoka system. Adjuvant radiotherapy was given to patients diagnosed with Masaoka Stage II, III, and IVA TET. Adjuvant chemotherapy was administered in selected cases. Results: We reviewed the records of 120 patients with TETs, with a mean follow-up of 13.8 years. Of the 120 patients, 98 (81.6%) received adjuvant radiotherapy. Of these 98 patients, Grade 1-2 pulmonary or esophageal toxicity was acute in 12 (12.2%) and late in 8 (8.2%). The median overall survival was 21.6 years. Of the 120 patients, 106 were rediagnosed and reclassified according to the World Health Organization system, and the survival rate was correlated with it. Three different prognostic classes were defined: favorable, Masaoka Stage I and histologic grade A, AB, B1, B2 or Masaoka Stage II and histologic grade A, AB, B1; unfavorable, Stage IV disease or histologic grade C or Stage III and histologic grade B3; intermediate, all other combinations. The 10- and 20-year survival rate was 95% and 81% for the favorable group, 90% and 65% for the intermediate group, and 50% and 0% for the unfavorable group, respectively. Local recurrence, distant recurrence, and tumor-related deaths were also evaluated. Conclusion: The analysis of our experience singled out three novel prognostic classes and the assessment of risk identified treatment selection criteria.

  6. Radioprotection and Cell Cycle Arrest of Intestinal Epithelial Cells by Darinaparsin, a Tumor Radiosensitizer

    SciTech Connect

    Tian, Junqiang; Doi, Hiroshi; Saar, Matthias; Santos, Jennifer; Li, Xuejun; Peehl, Donna M.; Knox, Susan J.

    2013-12-01

    Purpose: It was recently reported that the organic arsenic compound darinaparsin (DPS) is a cytotoxin and radiosensitizer of tumor cells in vitro and in subcutaneous xenograft tumors. Surprisingly, it was also found that DPS protects normal intestinal crypt epithelial cells (CECs) from clonogenic death after ionizing radiation (IR). Here we tested the DPS radiosensitizing effect in a clinically relevant model of prostate cancer and explored the radioprotective effect and mechanism of DPS on CECs. Methods and Materials: The radiation modification effect of DPS was tested in a mouse model of orthotopic xenograft prostate cancer and of IR-induced acute gastrointestinal syndrome. The effect of DPS on CEC DNA damage and DNA damage responses was determined by immunohistochemistry. Results: In the mouse model of IR-induced gastrointestinal syndrome, DPS treatment before IR accelerated recovery from body weight loss and increased animal survival. DPS decreased post-IR DNA damage and cell death, suggesting that the radioprotective effect was mediated by enhanced DNA damage repair. Shortly after DPS injection, significant cell cycle arrest was observed in CECs at both G1/S and G2/M checkpoints, which was accompanied by the activation of cell cycle inhibitors p21 and growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A). Further investigation revealed that DPS activated ataxia telangiectasia mutated (ATM), an important inducer of DNA damage repair and cell cycle arrest. Conclusions: DPS selectively radioprotected normal intestinal CECs and sensitized prostate cancer cells in a clinically relevant model. This effect may be, at least in part, mediated by DNA damage response activation and has the potential to significantly increase the therapeutic index of radiation therapy.

  7. K-ras activation occurs frequently in mucinous adenocarcinomas and rarely in other common epithelial tumors of the human ovary.

    PubMed Central

    Enomoto, T.; Weghorst, C. M.; Inoue, M.; Tanizawa, O.; Rice, J. M.

    1991-01-01

    To explore the role of mutational activation of members of the ras family of cellular protooncogenes in the development of human ovarian neoplasms, a series of 37 ovarian tumors from Japanese patients was studied. These included 30 common epithelial tumors (1 mucinous tumor of borderline malignancy, 7 mucinous adenocarcinomas, and 22 nonmucinous carcinomas: 10 serous, 3 clear cell, 8 endometrioid, and 1 undifferentiated), 5 tumors of germ cell origin, and 2 sex cord/stromal cell tumors. Polymerase chain reaction was performed from selected areas of deparaffinized sections of formalin-fixed paraffin-embedded tissue, and the presence of activating point mutations in codons 12, 13, and 61 of the H-, N-, and K-ras genes was probed by dot-blot hybridization analysis with mutation specific oligonucleotides. Mutations in K-ras were also looked for by direct genomic sequencing. The overall frequency of ras gene mutations was 10/37 (27%). Mutations were detected only in K-ras, and were found in most of the mucinous tumors, including the one such tumor of borderline malignancy (6/8; 75%). In one mucinous adenocarcinoma, two mutations were detected in paraffin-embedded material that had not previously been found in high molecular weight DNA isolated from frozen tissue from the same case. K-ras mutations occurred significantly more frequently in mucinous tumors (6/8, 75%) than in serous carcinomas (2/10, 20%; P = 0.031) or in all nonmucinous types of epithelial ovarian tumors combined (3/22, 14%; P = 0.0031). Images Figure 1 Figure 2 PMID:1656759

  8. Methylseleninic acid, a potent growth inhibitor of synchronized mouse mammary epithelial tumor cells in vitro.

    PubMed

    Sinha, R; Unni, E; Ganther, H E; Medina, D

    2001-02-01

    Selenium compounds have been shown to be effective chemopreventive agents in several animal models and in cultured cells in vitro. It has been proposed that compounds able to generate monomethyl Se have an increased potential to inhibit cell growth. To test this hypothesis, methylseleninic acid (MSeA) and other compounds that could generate methylselenol rapidly were compared with Se compounds that do not generate monomethyl Se, using a well-characterized synchronized TM6 mouse mammary epithelial tumor model in vitro. MSeA at a low micromolar concentration inhibited TM6 growth after 10- to 15-min treatment times. Cells resumed growth after 24 hr but remained sensitive to the fresh addition of monomethyl Se-generators. Dimethyl selenide (DMSe), a putative metabolite of methylselenol, was inactive. Cells treated with 5 microM MSeA were arrested in G1. The effects of 5 microM MSeA on gene expression were evaluated using the Atlas mouse cDNA expression array. A 10-min exposure with MSeA caused a 2- to 3-fold change in the expression of three genes: laminin receptor 1 (decreased), integrin beta (decreased), and Egr-1 (increased). The results provide experimental support for the hypothesis that monomethylated forms of Se are the critical effector molecules in Se-mediated growth inhibition in vitro.

  9. Mouse mammary tumor virus suppresses apoptosis of mammary epithelial cells through ITAM-mediated signaling.

    PubMed

    Kim, Hyoung H; Grande, Shannon M; Monroe, John G; Ross, Susan R

    2012-12-01

    Many receptors in hematopoietic cells use a common signaling pathway that relies on a highly conserved immunoreceptor tyrosine-based activation motif (ITAM), which signals through Src family tyrosine kinases. ITAM-bearing proteins are also found in many oncogenic viruses, including the mouse mammary tumor virus (MMTV) envelope (Env). We previously showed that MMTV Env expression transformed normal mammary epithelial cells and that Src kinases were important mediators in this transformation. To study how ITAM signaling affects mammary cell transformation, we utilized mammary cell lines expressing two different ITAM-containing proteins, one encoding a MMTV provirus and the other a B cell receptor fusion protein. ITAM-expressing cells were resistant to both serum starvation- and chemotherapeutic drug-induced apoptosis, whereas cells transduced with these molecules bearing ITAM mutations were indistinguishable from untransduced cells in their sensitivity to these treatments. We also found that Src kinase was activated in the MMTV-expressing cells and that MMTV-induced apoptosis resistance was completely restored by the Src inhibitor PP2. In vivo, MMTV infection delayed involution-induced apoptosis in the mouse mammary gland. Our results show that MMTV suppresses apoptosis through ITAM-mediated Src tyrosine kinase signaling. These studies could lead to the development of effective treatment of nonhematopoietic cell cancers in which ITAM-mediated signaling plays a role.

  10. Chemo-mechanical modeling of tumor growth in elastic epithelial tissue

    NASA Astrophysics Data System (ADS)

    Bratsun, Dmitry A.; Zakharov, Andrey P.; Pismen, Len

    2016-08-01

    We propose a multiscale chemo-mechanical model of the cancer tumor development in the epithelial tissue. The epithelium is represented by an elastic 2D array of polygonal cells with its own gene regulation dynamics. The model allows the simulation of the evolution of multiple cells interacting via the chemical signaling or mechanically induced strain. The algorithm includes the division and intercalation of cells as well as the transformation of normal cells into a cancerous state triggered by a local failure of the spatial synchronization of the cellular rhythms driven by transcription/translation processes. Both deterministic and stochastic descriptions of the system are given for chemical signaling. The transformation of cells means the modification of their respective parameters responsible for chemo-mechanical interactions. The simulations reproduce a distinct behavior of invasive and localized carcinoma. Generally, the model is designed in such a way that it can be readily modified to take account of any newly understood gene regulation processes and feedback mechanisms affecting chemo-mechanical properties of cells.

  11. Chemo-mechanical modeling of tumor growth in elastic epithelial tissue

    SciTech Connect

    Bratsun, Dmitry A.; Zakharov, Andrey P.; Pismen, Len

    2016-08-02

    We propose a multiscale chemo-mechanical model of the cancer tumor development in the epithelial tissue. The epithelium is represented by an elastic 2D array of polygonal cells with its own gene regulation dynamics. The model allows the simulation of the evolution of multiple cells interacting via the chemical signaling or mechanically induced strain. The algorithm includes the division and intercalation of cells as well as the transformation of normal cells into a cancerous state triggered by a local failure of the spatial synchronization of the cellular rhythms driven by transcription/translation processes. Both deterministic and stochastic descriptions of the system are given for chemical signaling. The transformation of cells means the modification of their respective parameters responsible for chemo-mechanical interactions. The simulations reproduce a distinct behavior of invasive and localized carcinoma. Generally, the model is designed in such a way that it can be readily modified to take account of any newly understood gene regulation processes and feedback mechanisms affecting chemo-mechanical properties of cells.

  12. Tumor budding at the invasive front of colorectal cancer may not be associated with the epithelial-mesenchymal transition.

    PubMed

    Yamada, Noriyuki; Sugai, Tamotsu; Eizuka, Makoto; Tsuchida, Koudai; Sugimoto, Ryo; Mue, Yoshiharu; Suzuki, Masamichi; Osakabe, Mitsumasa; Uesugi, Noriyuki; Ishida, Kazuyuki; Otsuka, Kouki; Matsumoto, Takayuki

    2017-02-01

    Tumor budding is thought to reflect the epithelial-mesenchymal transition (EMT). However, the molecular mechanism linking tumor buds and the EMT remains unclear. Here, we examined the induction of tumor budding and EMT and their association with EMT-related proteins (ZEB1, TWIST, SNAIL, and SLUG) in colorectal cancer (CRC). Immunohistochemical expression of pan-cytokeratin was examined for identification of tumor budding in 101 CRCs. Grading of tumor budding was classified into low- and high-grade groups. Tissue microarray was conducted to identify tumor budding sites. The expression of E-cadherin, ZEB1, TWIST, SNAIL, and SLUG was examined in areas of tumor budding and the surrounding tumor stroma using a double-immunostaining method. Specifically, pan-cytokeratin and EMT-related proteins were assessed by double immunostaining. Low or no expression of E-cadherin was found in areas of tumor budding. Moreover, ZEB1, TWIST, SNAIL, and SLUG were not expressed in regions of tumor budding. However, the expression level of ZEB1 in the stromal cells surrounding tumor budding was significantly more frequent than that of TWIST, SNAI, and SLUG. In addition, the expression of EMT-related proteins in surrounding stromal cells was significantly greater in areas of high-grade tumor budding than in low-grade areas. Our present results suggest that EMT-related proteins play a minor role in forming tumor buds. In addition, our findings suggest the existence of subtypes of stromal cells in CRC with phenotypical and functional heterogeneity. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Ketones and lactate "fuel" tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism.

    PubMed

    Bonuccelli, Gloria; Tsirigos, Aristotelis; Whitaker-Menezes, Diana; Pavlides, Stephanos; Pestell, Richard G; Chiavarina, Barbara; Frank, Philippe G; Flomenberg, Neal; Howell, Anthony; Martinez-Outschoorn, Ubaldo E; Sotgia, Federica; Lisanti, Michael P

    2010-09-01

    Previously, we proposed a new model for understanding the "Warburg effect" in tumor metabolism. In this scheme, cancer-associated fibroblasts undergo aerobic glycolysis and the resulting energy-rich metabolites are then transferred to epithelial cancer cells, where they enter the TCA cycle, resulting in high ATP production via oxidative phosphorylation. We have termed this new paradigm "The Reverse Warburg Effect." Here, we directly evaluate whether the end-products of aerobic glycolysis (3-hydroxy-butyrate and L-lactate) can stimulate tumor growth and metastasis, using MDA-MB-231 breast cancer xenografts as a model system. More specifically, we show that administration of 3-hydroxy-butyrate (a ketone body) increases tumor growth by ∼2.5-fold, without any measurable increases in tumor vascularization/angiogenesis. Both 3-hydroxy-butyrate and L-lactate functioned as chemo-attractants, stimulating the migration of epithelial cancer cells. Although L-lactate did not increase primary tumor growth, it stimulated the formation of lung metastases by ∼10-fold. Thus, we conclude that ketones and lactate fuel tumor growth and metastasis, providing functional evidence to support the "Reverse Warburg Effect". Moreover, we discuss the possibility that it may be unwise to use lactate-containing i.v. solutions (such as Lactated Ringer's or Hartmann's solution) in cancer patients, given the dramatic metastasis-promoting properties of L-lactate. Also, we provide evidence for the up-regulation of oxidative mitochondrial metabolism and the TCA cycle in human breast cancer cells in vivo, via an informatics analysis of the existing raw transcriptional profiles of epithelial breast cancer cells and adjacent stromal cells. Lastly, our findings may explain why diabetic patients have an increased incidence of cancer, due to increased ketone production, and a tendency towards autophagy/mitophagy in their adipose tissue.

  14. Accumulation of FOXP3+T-cells in the tumor microenvironment is associated with an epithelial-mesenchymal-transition-type tumor budding phenotype and is an independent prognostic factor in surgically resected pancreatic ductal adenocarcinoma

    PubMed Central

    Wartenberg, Martin; Zlobec, Inti; Perren, Aurel; Koelzer, Viktor Hendrik; Gloor, Beat; Lugli, Alessandro; Eva, Karamitopoulou

    2015-01-01

    Here we explore the role of the interplay between host immune response and epithelial-mesenchymal-transition (EMT)-Type tumor-budding on the outcome of pancreatic adenocarcinoma (PDAC). CD4+, CD8+, and FOXP3+T-cells as well as iNOS+ (M1) and CD163+-macrophages (M2) were assessed on multipunch tissue-microarrays containing 120 well-characterized PDACs, precursor lesions (PanINs) and corresponding normal tissue. Counts were normalized for the percentage of tumor/spot and associated with the clinico-pathological features, including peritumoral (PTB) and intratumoral (ITB) EMT-Type tumor-budding and outcome. Increased FOXP3+T-cell-counts and CD163-macrophages and decreased CD8+T-cell-counts were observed in PDACs compared with normal tissues and PanINs (p < 0.0001). Increased peritumoral FOXP3+T-cell-counts correlated significantly with venous invasion, distant metastasis, R1-status, high-grade ITB, PTB and independently with reduced survival. Increased intratumoral FOXP3+T-cells correlated with lymphatic invasion, N1-stage, PTB and marginally with adverse outcome. High peritumoral CD163-counts correlated with venous invasion, PTB and ITB. High intratumoral CD163-counts correlated with higher T-stage and PTB. PDAC-microenvironment displays a tumor-favoring immune-cell composition especially in the immediate environment of the tumor-buds that promotes further growth and indicates a close interaction of the immune response with the EMT-process. Increased peritumoral FOXP3+T-cell density is identified as an independent adverse prognostic factor in PDAC. Patients with phenotypically aggressive PDACs may profit from targeted immunotherapy against FOXP3. PMID:25669968

  15. Cushing syndrome as presenting symptom of calcifying nested stromal-epithelial tumor of the liver in an adolescent boy: a case report.

    PubMed

    Weeda, V B; de Reuver, Ph R; Bras, H; Zsíros, J; Lamers, W H; Aronson, D C

    2016-06-16

    Ectopic adrenocorticotropic hormone-producing primary liver tumors are rare, especially in children. We report the case of an adolescent boy of mixed Dutch and Moroccan descent with an adrenocorticotropic hormone-producing calcifying nested stromal-epithelial tumor with long-term follow-up. Thus far, only two such cases have been reported. A 16-year-old boy of mixed Dutch and Moroccan descent presented with Cushing syndrome and a palpable abdominal mass. A calcifying nested stromal-epithelial tumor was diagnosed. Postoperatively, his plasma adrenocorticotropic hormone concentration normalized. He remains in complete remission 13 years after tumor resection. Calcifying nested stromal-epithelial tumor should be in the differential diagnosis of liver tumors, especially if associated with Cushing syndrome as significant morbidity and mortality may be associated. Literature on the topics involved is comprehensively reviewed.

  16. Coordinate expression of cytokeratins 7 and 14, vimentin, and Bcl-2 in canine cutaneous epithelial tumors and cysts.

    PubMed

    Pieper, Jason B; Stern, Adam W; LeClerc, Suzette M; Campbell, Karen L

    2015-07-01

    Forty-seven canine cutaneous epithelial tumors and cysts were examined to determine coordinate expression of cytokeratins 7 (CK7) and 14 (CK14), vimentin, and Bcl-2 using commercially available antibodies. Within non-affected normal skin adjacent to tumors or cysts, CK7 expression was observed in luminal cells in apocrine glands; CK14 expression was observed in the stratum basale, stratum spinosum, stratum granulosum, basal layer of outer root sheath, sebaceous glands, and myoepithelial cells of apocrine glands; vimentin expression was observed in dermal papilla and scattered non-epithelial cells within the epidermis; and Bcl-2 expression was observed in scattered non-epithelial cells in the epidermis and some apocrine glands. The pattern of expression of CK7 and CK14 in cases of adenocarcinoma of the apocrine gland of the anal sac (CK7+/CK14-) and hepatoid gland tumors (CK7-/CK14+) may prove useful for diagnostic purposes. Loss of expression of CK14 and vimentin, identifying myoepithelial cells, was observed in apocrine and ceruminous adenocarcinomas. Differences in patterns of expression of Bcl-2 were observed between infundibular keratinizing acanthomas compared to trichoepitheliomas.

  17. Enhanced expression and secretion of an epithelial membrane antigen (MA5) in a human mucinous breast tumor line (BT549).

    PubMed

    Williams, C J; Major, P P; Dion, A S

    1990-01-01

    The mouse monoclonal antibody MA5, generated versus a membrane-enriched extract of breast cancer metastatic to liver, detects one or two high molecular weight species (greater than 200 kD) in breast tumor membranes, human milk fat globule membranes, and various breast tumor cell lines. From comparative studies of five breast carcinoma lines (BT20, BT549, MCF-7, T47D, and ZR75-1), as well as an epithelial line established from milk (HBL-100), we report the stimulation of expression of MA5-reactive antigen in a mucinous breast tumor cell line (BT549) through the use of a culture medium supplemented with charcoal-absorbed fetal calf serum, insulin, and hydrocortisone. Large amounts of aggregated MA5-reactive antigen are secreted into the culture medium and can be recovered from the media for further purification by centrifugation. These findings suggest that BT549 cells, grown in the special nutritive medium, may be useful in providing an ample source of epithelial membrane antigen (also termed polymorphic epithelial mucin) for standardization of clinical assay protocols, as well as provide a model system for studies of the regulation of expression for this class of antigens in breast carcinoma.

  18. Inhibitor of Apoptosis Protein-1 Regulates Tumor Necrosis Factor-Mediated Destruction of Intestinal Epithelial Cells.

    PubMed

    Grabinger, Thomas; Bode, Konstantin J; Demgenski, Janine; Seitz, Carina; Delgado, M Eugenia; Kostadinova, Feodora; Reinhold, Cindy; Etemadi, Nima; Wilhelm, Sabine; Schweinlin, Matthias; Hänggi, Kay; Knop, Janin; Hauck, Christof; Walles, Heike; Silke, John; Wajant, Harald; Nachbur, Ueli; W Wei-Lynn, Wong; Brunner, Thomas

    2017-03-01

    Tumor necrosis factor (TNF) is a cytokine that promotes inflammation and contributes to pathogenesis of inflammatory bowel diseases. Unlike other cells and tissues, intestinal epithelial cells undergo rapid cell death upon exposure to TNF, by unclear mechanisms. We investigated the roles of inhibitor of apoptosis proteins (IAPs) in the regulation of TNF-induced cell death in the intestinal epithelium of mice and intestinal organoids. RNA from cell lines and tissues was analyzed by quantitative polymerase chain reaction, protein levels were analyzed by immunoblot assays. BIRC2 (also called cIAP1) was expressed upon induction from lentiviral vectors in young adult mouse colon (YAMC) cells. YAMC cells, the mouse colon carcinoma cell line MC38, the mouse macrophage cell line RAW 264.7, or mouse and human organoids were incubated with second mitochondrial activator of caspases (Smac)-mimetic compound LCL161 or recombinant TNF-like weak inducer of apoptosis (TNFSF12) along with TNF, and cell death was quantified. C57BL/6 mice with disruption of Xiap, Birc2 (encodes cIAP1), Birc3 (encodes cIAP2), Tnfrsf1a, or Tnfrsf1b (Tnfrsf1a and b encode TNF receptors) were injected with TNF or saline (control); liver and intestinal tissues were collected and analyzed for apoptosis induction by cleaved caspase 3 immunohistochemistry. We also measured levels of TNF and alanine aminotransferase in serum from mice. YAMC cells, and mouse and human intestinal organoids, died rapidly in response to TNF. YAMC and intestinal crypts expressed lower levels of XIAP, cIAP1, cIAP2, and cFLIP than liver tissue. Smac-mimetics reduced levels of cIAP1 and XIAP in MC38 and YAMC cells, and Smac-mimetics and TNF-related weak inducer of apoptosis increased TNF-induced cell death in YAMC cells and organoids-most likely by sequestering and degrading cIAP1. Injection of TNF greatly increased levels of cell death in intestinal tissue of cIAP1-null mice, compared with wild-type C57BL/6 mice, cIAP2-null mice, or

  19. The Non–Small Cell Lung Cancer Immune Contexture. A Major Determinant of Tumor Characteristics and Patient Outcome

    PubMed Central

    Remark, Romain; Becker, Christian; Gomez, Jorge E.; Damotte, Diane; Dieu-Nosjean, Marie-Caroline; Sautès-Fridman, Catherine; Fridman, Wolf-Herman; Powell, Charles A.; Altorki, Nasser K.; Merad, Miriam

    2015-01-01

    Solid tumors, beyond mere accumulation of cancer cells, form a complex ecosystem consisting of normal epithelial cells, fibroblasts, blood and lymphatic vessels, structural components, and infiltrating hematopoietic cells including myeloid and lymphoid elements that impact tumor growth, tumor spreading, and clinical outcome. The composition of the immune microenvironment is diverse, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, or macrophages. The immune contexture describes the density, location, and organization of these immune cells within solid tumors. In lung cancer, which is the deadliest type of cancer, and particularly in non–small cell lung cancer, its most prevalent form, reports have described some of the interactions between the tumor and the host. These data, in addition to articles on various types of tumors, provide a greater understanding of the tumor–host microenvironment interaction and stimulate the development of prognostic and predictive biomarkers, the identification of novel target antigens for therapeutic intervention, and the implementation of tools for long-term management of patients with cancer. PMID:25369536

  20. Photodynamic therapy induced production of cytokines by latent Epstein Barr virus infected epithelial tumor cells

    NASA Astrophysics Data System (ADS)

    Koon, H. K.; Lo, K. W.; Lung, M. L.; Chang, C. K. C.; Wong, R. N. S.; Mak, N. K.

    2007-02-01

    Photodynamic therapy (PDT) is a method to treat cancer or non-cancer diseases by activation of the light-sensitive photosensitizers. Epstein Barr virus (EBV) has been implicated in the development of certain cancers such as nasopharyngeal carcinoma and B cell lymphoma. This study aims to examine the effects of EBV infection on the production of pro-inflammatory cytokines and chemokines in cells after the photosensitizer Zn-BC-AM PDT treatment. Epithelial tumor cell lines HONE-1 and latent EBV-infected HONE-1 (EBV-HONE-1) cells were used in this study. Cells were treated with the photosensitizer Zn-BC-AM for 24 hours before light irradiation. RT-PCR and quantitative ELISA methods were used for the evaluation of mRNA expression and production of cytokines, respectively. Results show that Zn-BC-AM PDT increases the production of IL-1a and IL-1b in EBV-HONE-1. Over a 10-fold increase in the production of IL-6 was observed in the culture supernatant of Zn-BC-AM PDT-treated HONE-1 cells. PDT-induced IL-6 production was observed in HONE-1 cells. EBV-HONE-1 has a higher background level of IL-8 production than the HONE-1. The production of IL-8 was suppressed in EBV-HONE-1cells after Zn-BC-AM PDT. Our results indicate that the response of HONE-1 cells to Zn-BC-AM PDT depends on the presence of latent EBV infection. Since IL-8 is a cytokine with angiogenic activity, Zn-BC-AM PDT may exert an anti-angiogenic effect through the suppression of IL-8 production by the EBV-infected cells.

  1. Rare frequency of gene variation and survival analysis in thymic epithelial tumors

    PubMed Central

    Song, Zhengbo; Yu, Xinmin; Zhang, Yiping

    2016-01-01

    Objective Thymic epithelial tumor (TET) is a rare mediastinal neoplasm and little is known about its genetic variability and prognostic factors. This study investigated the genetic variability and prognostic factors of TET. Patients and methods We sequenced 22 cancer-related hotspot genes in TET tissues and matched normal tissues using Ampliseq Ion Torrent next-generation technology. Overall survival was evaluated using Kaplan–Meier methods and compared with log-rank tests. Results A histological analysis of 52 patients with a median age of 52 years showed 15 patients (28.8%) with thymic carcinoma, five with type A thymoma (9.6%), eight with type AB (15.4%), six with type B1 (11.5%), nine with type B2 (17.3%), and nine with type B3 thymoma (17.3%). Three gene mutations were identified, including two with PIK3CA mutation and one with EGFR mutation. The three patients with mutant genes included two cases of thymoma (one with EGFR and the other with PIK3CA mutation) in addition to a case of thymic carcinoma (PIK3CA mutation). The 5-year survival rates were 77.7% in all patients. The 5-year survival rates were 93.3%, 90.0%, 76.9%, and 22.9% corresponding to Masaoka stages I, II, III, and IV (P<0.001). The 5-year survival rates were 100%, 100%, 83.3%, 88.9%, 65.6%, and 60.9% in the histological subtypes of A, AB, B1, B2, and B3 thymomas, and thymic carcinoma, respectively (P=0.012). Conclusion Hotspot gene mutations are rare in TET. PIK3CA and EGFR mutations represent candidate driver genes and treatment targets in TET. Masaoka stage and histological subtypes predict the survival of TET. PMID:27789964

  2. Coexistence of borderline ovarian epithelial tumor, primary pelvic hydatid cyst, and lymphoepithelioma-like gastric carcinoma.

    PubMed

    Gungor, Tayfun; Altinkaya, Sunduz Ozlem; Sirvan, Levent; Lafuente, Roberto Alvarez; Ceylaner, Serdar

    2011-06-01

    Borderline ovarian tumors (BOTs) represent a heterogeneous group of ovarian epithelial neoplasms. Despite a favorable prognosis, 10-20% of BOTs exhibit progressively worsening clinic. Primary involvement of pelvic organs with echinococcus is very rare. Lymphoepithelioma-like gastric carcinoma is a rare neoplasm of the stomach. A 58-year-old woman referred with abdominal swelling and gastric complaints. Imaging studies revealed a huge cystic mass with multiple septations and solid component, another cystic mass with an appearance of cyst hydatid in the pelvis, and thickening of the small curvature of stomach. Gastroscopy revealed an ulcer with a suspicious malignant appearance, and histology of the endoscopic specimen showed severe chronic inflammation and lymphocytic infiltration. No other involvement of hydatid cyst was detected. In the exploration, there was a 25cm cystic lesion with solid components arising from right ovary, another 6cm cyst over the former, 7cm cystic lesion arising from left ovary, and 10cm mass near the small curvature of the stomach. Excision of the masses; total gastrectomy with esophagojejunal anastomosis; total abdominal hysterectomy; bilateral salpingo-oophorectomy; omentectomy; appendectomy; splenectomy; and pelvic, paraaortic, and coeliac lympadenectomy were performed. Final pathology revealed lymphoepithelioma-like gastric carcinoma, bilateral serous BOT, and hydatid cyst. Hydatid cyst should always be considered in the differential diagnosis of abdominopelvic masses in endemic regions of the world. Preoperative diagnosis of primary pelvic hydatid disease is difficult and awareness of its possibility is very important especially in patients residing in or coming from endemic areas. Copyright © 2011. Published by Elsevier B.V.

  3. Expression and Function of the Protein Tyrosine Phosphatase Receptor J (PTPRJ) in Normal Mammary Epithelial Cells and Breast Tumors

    PubMed Central

    Smart, Chanel E.; Askarian Amiri, Marjan E.; Wronski, Ania; Dinger, Marcel E.; Crawford, Joanna; Ovchinnikov, Dmitry A.; Vargas, Ana Cristina; Reid, Lynne; Simpson, Peter T.; Song, Sarah; Wiesner, Christiane; French, Juliet D.; Dave, Richa K.; da Silva, Leonard; Purdon, Amy; Andrew, Megan; Mattick, John S.; Lakhani, Sunil R.

    2012-01-01

    The protein tyrosine phosphatase receptor J, PTPRJ, is a tumor suppressor gene that has been implicated in a range of cancers, including breast cancer, yet little is known about its role in normal breast physiology or in mammary gland tumorigenesis. In this paper we show that PTPRJ mRNA is expressed in normal breast tissue and reduced in corresponding tumors. Meta-analysis revealed that the gene encoding PTPRJ is frequently lost in breast tumors and that low expression of the transcript associated with poorer overall survival at 20 years. Immunohistochemistry of PTPRJ protein in normal human breast tissue revealed a distinctive apical localisation in the luminal cells of alveoli and ducts. Qualitative analysis of a cohort of invasive ductal carcinomas revealed retention of normal apical PTPRJ localization where tubule formation was maintained but that tumors mostly exhibited diffuse cytoplasmic staining, indicating that dysregulation of localisation associated with loss of tissue architecture in tumorigenesis. The murine ortholog, Ptprj, exhibited a similar localisation in normal mammary gland, and was differentially regulated throughout lactational development, and in an in vitro model of mammary epithelial differentiation. Furthermore, ectopic expression of human PTPRJ in HC11 murine mammary epithelial cells inhibited dome formation. These data indicate that PTPRJ may regulate differentiation of normal mammary epithelia and that dysregulation of protein localisation may be associated with tumorigenesis. PMID:22815804

  4. Expression and function of the protein tyrosine phosphatase receptor J (PTPRJ) in normal mammary epithelial cells and breast tumors.

    PubMed

    Smart, Chanel E; Askarian Amiri, Marjan E; Wronski, Ania; Dinger, Marcel E; Crawford, Joanna; Ovchinnikov, Dmitry A; Vargas, Ana Cristina; Reid, Lynne; Simpson, Peter T; Song, Sarah; Wiesner, Christiane; French, Juliet D; Dave, Richa K; da Silva, Leonard; Purdon, Amy; Andrew, Megan; Mattick, John S; Lakhani, Sunil R; Brown, Melissa A; Kellie, Stuart

    2012-01-01

    The protein tyrosine phosphatase receptor J, PTPRJ, is a tumor suppressor gene that has been implicated in a range of cancers, including breast cancer, yet little is known about its role in normal breast physiology or in mammary gland tumorigenesis. In this paper we show that PTPRJ mRNA is expressed in normal breast tissue and reduced in corresponding tumors. Meta-analysis revealed that the gene encoding PTPRJ is frequently lost in breast tumors and that low expression of the transcript associated with poorer overall survival at 20 years. Immunohistochemistry of PTPRJ protein in normal human breast tissue revealed a distinctive apical localisation in the luminal cells of alveoli and ducts. Qualitative analysis of a cohort of invasive ductal carcinomas revealed retention of normal apical PTPRJ localization where tubule formation was maintained but that tumors mostly exhibited diffuse cytoplasmic staining, indicating that dysregulation of localisation associated with loss of tissue architecture in tumorigenesis. The murine ortholog, Ptprj, exhibited a similar localisation in normal mammary gland, and was differentially regulated throughout lactational development, and in an in vitro model of mammary epithelial differentiation. Furthermore, ectopic expression of human PTPRJ in HC11 murine mammary epithelial cells inhibited dome formation. These data indicate that PTPRJ may regulate differentiation of normal mammary epithelia and that dysregulation of protein localisation may be associated with tumorigenesis.

  5. HSP27 and 70 expression in thymic epithelial tumors and benign thymic alterations: diagnostic, prognostic and physiologic implications

    PubMed Central

    Janik, S.; Schiefer, A. I.; Bekos, C.; Hacker, P.; Haider, T.; Moser, J.; Klepetko, W.; Müllauer, L.; Ankersmit, H. J.; Moser, B.

    2016-01-01

    Thymic Epithelial Tumors (TETs), the most common tumors in the anterior mediastinum in adults, show a unique association with autoimmune Myasthenia Gravis (MG) and represent a multidisciplinary diagnostic and therapeutic challenge. Neither risk factors nor established biomarkers for TETs exist. Predictive and diagnostic markers are urgently needed. Heat shock proteins (HSPs) are upregulated in several malignancies promoting tumor cell survival and metastases. We performed immunohistochemical staining of HSP27 and 70 in patients with TETs (n = 101) and patients with benign thymic alterations (n = 24). Further, serum HSP27 and 70 concentrations were determined in patients with TETs (n = 46), patients with benign thymic alterations (n = 33) and volunteers (n = 49) by using ELISA. HSPs were differentially expressed in histologic types and pathological tumor stages of TETs. Weak HSP tumor expression correlated with worse freedom from recurrence. Serum HSP concentrations were elevated in TETs and MG, correlated with clinical tumor stage and histologic subtype and decreased significantly after complete tumor resection. To conclude, we found HSP expression in the vast majority of TETs, in physiologic thymus and staining intensities in patients with TETs have been associated with prognosis. However, although interesting and promising the role of HSPs in TETs as diagnostic and prognostic or even therapeutic markers need to be further evaluated. PMID:27097982

  6. HSP27 and 70 expression in thymic epithelial tumors and benign thymic alterations: diagnostic, prognostic and physiologic implications.

    PubMed

    Janik, S; Schiefer, A I; Bekos, C; Hacker, P; Haider, T; Moser, J; Klepetko, W; Müllauer, L; Ankersmit, H J; Moser, B

    2016-04-21

    Thymic Epithelial Tumors (TETs), the most common tumors in the anterior mediastinum in adults, show a unique association with autoimmune Myasthenia Gravis (MG) and represent a multidisciplinary diagnostic and therapeutic challenge. Neither risk factors nor established biomarkers for TETs exist. Predictive and diagnostic markers are urgently needed. Heat shock proteins (HSPs) are upregulated in several malignancies promoting tumor cell survival and metastases. We performed immunohistochemical staining of HSP27 and 70 in patients with TETs (n = 101) and patients with benign thymic alterations (n = 24). Further, serum HSP27 and 70 concentrations were determined in patients with TETs (n = 46), patients with benign thymic alterations (n = 33) and volunteers (n = 49) by using ELISA. HSPs were differentially expressed in histologic types and pathological tumor stages of TETs. Weak HSP tumor expression correlated with worse freedom from recurrence. Serum HSP concentrations were elevated in TETs and MG, correlated with clinical tumor stage and histologic subtype and decreased significantly after complete tumor resection. To conclude, we found HSP expression in the vast majority of TETs, in physiologic thymus and staining intensities in patients with TETs have been associated with prognosis. However, although interesting and promising the role of HSPs in TETs as diagnostic and prognostic or even therapeutic markers need to be further evaluated.

  7. 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.

  8. Carcinoma Initiation via Rb Tumor Suppressor Inactivation: A Versatile Approach to Epithelial Subtype-Dependent Cancer Initiation in Diverse Tissues

    PubMed Central

    Song, Yurong; Gilbert, Debra; O’Sullivan, T. Norene; Yang, Chunyu; Pan, Wenqi; Fathalizadeh, Alisan; Lu, Lucy; Haines, Diana C.; Martin, Philip L.; Van Dyke, Terry

    2013-01-01

    Carcinomas arise in a complex microenvironment consisting of multiple distinct epithelial lineages surrounded by a variety of stromal cell types. Understanding cancer etiologies requires evaluating the relationship among cell types during disease initiation and through progression. Genetically engineered mouse (GEM) models facilitate the prospective examination of early oncogenic events, which is not possible in humans. Since most solid tumors harbor aberrations in the RB network, we developed an inducible GEM approach for the establishment and assessment of carcinoma initiation in a diverse range of epithelial tissues and subtypes upon inactivation of RB-mediated tumor suppression (RB-TS). The system allows independent assessment of epithelial subtypes that express either cytokeratins (K) 18 or 19. By Cre-dependent expression of a protein that dominantly inactivates RB and functionally redundant proteins p107 and p130, neoplasia could be initiated in either K18 or K19 expressing cells of numerous tissues. By design, because only a single pathway aberration was engineered, carcinomas developed stochastically only after long latency. Hence, this system, which allows for directed cell type-specific carcinoma initiation, facilitates further definition of events that can progress neoplasms to aggressive cancers via engineered, carcinogen-induced and/or spontaneous evolution. PMID:24312475

  9. [Narrow band imaging for early diagnosis of epithelial dysplasias and microinvasive tumors in the upper aerodigestive tract].

    PubMed

    Arens, C; Betz, C; Kraft, M; Voigt-Zimmermann, S

    2016-01-01

    The various stages of tumor growth are characterized by typical epithelial, vascular, and secondary connective tissue changes. Narrow band imaging (NBI) endoscopy is a minimally invasive imaging technique that presents vascular structures in particular at a higher contrast than white light endoscopy alone. In combination with high-resolution image recording and reproduction (high-definition television, HDTV; ultra-high definition, 4K), progress has been made in otolaryngological differential diagnostics, both pre- and intraoperatively. This progress represents an important step towards a so-called optical biopsy. Flexible endoscopy in combination with NBI allows detailed assessment of areas of the upper aerodigestive tract which are difficult to assess by rigid endoscopy. Papillomas, precancerous, and cancerous lesions are characterized by epithelial and connective tissue changes, as well as by typical perpendicular vascular changes. Systematic use of NBI is recommended in the differential diagnosis of malignant lesions of the upper aerodigestive tract. NBI also convinces by a significant improvement in pre- and intraoperative assessment of superficial resection margins. In particular, the combination of NBI and contact endoscopy (compact endoscopy) permits excellent therapeutic decisions during tumor surgery. Intraoperative determination of resection margins at unprecedented precision is possible. In addition, assessment of the form and extent of the perpendicular vessel loops stimulated by epithelial signaling enables differential diagnostic decisions to be made, approximating our goal of an optical biopsy.

  10. Narrow band imaging for early diagnosis of epithelial dysplasia and microinvasive tumors in the upper aerodigestive tract.

    PubMed

    Arens, C; Betz, C; Kraft, M; Voigt-Zimmermann, S

    2017-01-01

    The various stages of tumor growth are characterized by typical epithelial, vascular, and secondary connective tissue changes. Narrow Band Imaging (NBI) endoscopy is a minimally invasive imaging technique that presents vascular structures in particular at a higher contrast than white light endoscopy alone. In combination with high-resolution image recording and reproduction (high-definition television, HDTV; ultra-high definition, 4K), progress has been made in otolaryngological differential diagnostics, both pre- and intraoperatively. This progress represents an important step toward a so-called optical biopsy. Flexible endoscopy in combination with NBI allows for a detailed assessment of areas of the upper aerodigestive tract that are difficult to assess by rigid endoscopy. Papillomas along with precancerous and cancerous lesions are characterized by epithelial and connective tissue changes as well as by typical perpendicular vascular changes. Systematic use of NBI is recommended in the differential diagnosis of malignant lesions of the upper aerodigestive tract. NBI also offers a significant improvement in the pre- and intraoperative assessment of superficial resection margins. In particular, the combination of NBI and contact endoscopy (compact endoscopy) facilitates excellent therapeutic decisions during tumor surgery. Intraoperative determination of resection margins at an unprecedented precision is possible. In addition, assessment of the form and extent of the perpendicular vessel loops stimulated by epithelial signaling enables differential diagnostic decisions to be made, approximating our goal of an optical biopsy.

  11. Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: evidence for stromal-epithelial metabolic coupling.

    PubMed

    Migneco, Gemma; Whitaker-Menezes, Diana; Chiavarina, Barbara; Castello-Cros, Remedios; Pavlides, Stephanos; Pestell, Richard G; Fatatis, Alessandro; Flomenberg, Neal; Tsirigos, Aristotelis; Howell, Anthony; Martinez-Outschoorn, Ubaldo E; Sotgia, Federica; Lisanti, Michael P

    2010-06-15

    Previously, we proposed a new model for understanding the Warburg effect in tumorigenesis and metastasis. In this model, the stromal fibroblasts would undergo aerobic glycolysis (a.k.a., the Warburg effect)--producing and secreting increased pyruvate/lactate that could then be used by adjacent epithelial cancer cells as "fuel" for the mitochondrial TCA cycle, oxidative phosphorylation, and ATP production. To test this model more directly, here we used a matched set of metabolically well-characterized immortalized fibroblasts that differ in a single gene. CL3 fibroblasts show a shift towards oxidative metabolism, and have an increased mitochondrial mass. In contrast, CL4 fibroblasts show a shift towards aerobic glycolysis, and have a reduced mitochondrial mass. We validated these differences in CL3 and CL4 fibroblasts by performing an unbiased proteomics analysis, showing the functional upregulation of 4 glycolytic enzymes, namely ENO1, ALDOA, LDHA and TPI1, in CL4 fibroblasts. Many of the proteins that were upregulated in CL4 fibroblasts, as seen by unbiased proteomics, were also transcriptionally upregulated in the stroma of human breast cancers, especially in the patients that were prone to metastasis. Importantly, when CL4 fibroblasts were co-injected with human breast cancer cells (MDA-MB-231) in a xenograft model, tumor growth was dramatically enhanced. CL4 fibroblasts induced a > 4-fold increase in tumor mass, and a near 8-fold increase in tumor volume, without any measurable increases in tumor angiogenesis. In parallel, CL3 and CL4 fibroblasts both failed to form tumors when they were injected alone, without epithelial cancer cells. Mechanistically, under co-culture conditions, CL4 glycolytic fibroblasts increased mitochondrial activity in adjacent breast cancer cells (relative to CL3 cells), consistent with the "Reverse Warburg Effect". Notably, Western blot analysis of CL4 fibroblasts revealed a significant reduction in caveolin-1 (Cav-1) protein levels

  12. TWIST1 and TWIST2 promoter methylation and protein expression in tumor stroma influence the epithelial-mesenchymal transition-like tumor budding phenotype in colorectal cancer.

    PubMed

    Galván, José A; Helbling, Melina; Koelzer, Viktor H; Tschan, Mario P; Berger, Martin D; Hädrich, Marion; Schnüriger, Beat; Karamitopoulou, Eva; Dawson, Heather; Inderbitzin, Daniel; Lugli, Alessandro; Zlobec, Inti

    2015-01-20

    Tumor budding in colorectal cancer is likened to an epithelial-mesenchymal transition (EMT) characterized predominantly by loss of E-cadherin and up-regulation of E-cadherin repressors like TWIST1 and TWIST2. Here we investigate a possible epigenetic link between TWIST proteins and the tumor budding phenotype. TWIST1 and TWIST2 promoter methylation and protein expression were investigated in six cell lines and further correlated with tumor budding in patient cohort 1 (n = 185). Patient cohort 2 (n = 112) was used to assess prognostic effects. Laser capture microdissection (LCM) of tumor epithelium and stroma from low- and high-grade budding cancers was performed. In colorectal cancers, TWIST1 and TWIST2 expression was essentially restricted to stromal cells. LCM results of a high-grade budding case show positive TWIST1 and TWIST2 stroma and no methylation, while the low-grade budding case was characterized by negative stroma and strong hypermethylation. TWIST1 stromal cell staining was associated with adverse features like more advanced pT (p = 0.0044), lymph node metastasis (p = 0.0301), lymphatic vessel invasion (p = 0.0373), perineural invasion (p = 0.0109) and worse overall survival time (p = 0.0226). Stromal cells may influence tumor budding in colorectal cancers through expression of TWIST1. Hypermethylation of the tumor stroma may represent an alternative mechanism for regulation of TWIST1.

  13. Assessing Tumor Oxygenation for Predicting Outcome in Radiation Oncology: A Review of Studies Correlating Tumor Hypoxic Status and Outcome in the Preclinical and Clinical Settings

    PubMed Central

    Colliez, Florence; Gallez, Bernard; Jordan, Bénédicte F.

    2017-01-01

    Tumor hypoxia is recognized as a limiting factor for the efficacy of radiotherapy, because it enhances tumor radioresistance. It is strongly suggested that assessing tumor oxygenation could help to predict the outcome of cancer patients undergoing radiation therapy. Strategies have also been developed to alleviate tumor hypoxia in order to radiosensitize tumors. In addition, oxygen mapping is critically needed for intensity modulated radiation therapy (IMRT), in which the most hypoxic regions require higher radiation doses and the most oxygenated regions require lower radiation doses. However, the assessment of tumor oxygenation is not yet included in day-to-day clinical practice. This is due to the lack of a method for the quantitative and non-invasive mapping of tumor oxygenation. To fully integrate tumor hypoxia parameters into effective improvements of the individually tailored radiation therapy protocols in cancer patients, methods allowing non-invasively repeated, safe, and robust mapping of changes in tissue oxygenation are required. In this review, non-invasive methods dedicated to assessing tumor oxygenation with the ultimate goal of predicting outcome in radiation oncology are presented, including positron emission tomography used with nitroimidazole tracers, magnetic resonance methods using endogenous contrasts (R1 and R2*-based methods), and electron paramagnetic resonance oximetry; the goal is to highlight results of studies establishing correlations between tumor hypoxic status and patients’ outcome in the preclinical and clinical settings. PMID:28180110

  14. Molecules involved in epithelial-mesenchymal transition and epithelial-stromal interaction in phyllodes tumors: implications for histologic grade and prognosis.

    PubMed

    Kwon, Ji Eun; Jung, Woo-Hee; Koo, Ja Seung

    2012-06-01

    The aim of this study was to investigate the expression of molecules associated with epithelial-mesenchymal transition (EMT) and epithelial-stromal interactions (ESI) and to evaluate their roles in phyllodes tumors (PTs). Tissue microarrays (TMAs) were constructed from 207 PT specimens (157 benign, 34 borderline and 16 malignant). The presence of EMT-related markers including N-cadherin, Twist, TGF-beta, HMGA2, S100A4 and Ezrin as well as ESI-related molecules such as SDF1 and CXCR4 among the TMAs was assessed immunohistochemically. Immunohistochemical results were analyzed in terms of clinicopathologic parameters. For higher grade PTs, expressions of Twist (p < 0.001), HMGA2 (p = 0.005), S100A4 (p < 0.001), CXCR4 (p < 0.001) and TGF-beta (p < 0.001) were higher. As PTs showed higher stromal cellularity, higher stromal mitosis, stromal overgrowth and infiltrative tumor margin, the expressions of Twist, HMGA2 and CXCR4 in the stromal component thereof were increased (p < 0.05). High Twist expression in the stromal component was associated with shorter disease-free survival (DFS) and overall survival (OS) (p < 0.001) as well as shorter OS in multivariate COX analysis (p = 0.031, odds ratio: 24.6). In conclusion, the expressions of Twist, HMGA2, TGF-beta and S100A4, which are EMT-associated molecules, and CXCR4, an ESI-associated molecule, were increased in the stromal component of advanced grade PTs. Further, high expression of Twist in the stromal component was correlated with poorer prognoses.

  15. 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.

  16. The multi-epitope approach for immunotherapy for cancer: identification of several CTL epitopes from various tumor-associated antigens expressed on solid epithelial tumors.

    PubMed

    Kawashima, I; Hudson, S J; Tsai, V; Southwood, S; Takesako, K; Appella, E; Sette, A; Celis, E

    1998-01-01

    One approach to development of specific cancer immunotherapy relies on the induction of cytotoxic T lymphocytes (CTL) specific for tumor-associated antigens (TAA). Induction of TAA-specific CTL could be used towards the eradication of established tumors, or to prevent their dissemination or recurrence after primary treatment. The present study identifies a set of CTL epitopes from TAA frequently found on solid epithelial tumors such as breast, lung and gastro-intestinal tumors. Specifically, HLA-A2.1 binding peptides from the MAGE2, MAGE3, HER-2/neu and CEA antigens were tested for their capacity to elicit in vitro anti-tumor CTL using lymphocytes from normal volunteers and autologous dendritic cells as antigen-presenting cells. A total of 6 new epitopes (MAGE2[10(157)], MAGE3[9(112)], CEA[9(691)], CEA[9(24)], HER2[9(435)] and HER2[9(5)]) were identified which were capable of specifically recognizing tumor cell lines lines expressing HLA-A2.1 and the corresponding TAA. In one case (CEA[9(24)]), induction of vigorous anti-tumor CTL responses required epitope engineering to increase HLA-A2.1 binding affinity. Finally, most of the newly identified epitopes (5 out of 6) were found to be highly crossreactive with other common HLA alleles of the A2 supertype (A2.2, A2.3, A2.6 and A6802), thus demonstrating their potential in providing broad and non-ethnically biased population coverage. The results are discussed in the context of the development of multi-epitope-based therapies with broad applicability for patients suffering from commonly found tumors.

  17. Differential distribution of tumor-associated macrophages and Treg/Th17 cells in the progression of malignant and benign epithelial ovarian tumors

    PubMed Central

    Zhu, Qinyi; Wu, Xiaoli; Wang, Xipeng

    2017-01-01

    Epithelial ovarian cancer (EOC) is one of the predominant causes of cancer-associated mortality in women with gynecological oncology. Tumor-associated macrophages (TAMs), regulatory T cells (Treg cells) and T helper cell 17 (Th17) cells have been hypothesized to be involved in the progression of EOC. However, the association between TAMs and T cells remains to be elucidated. The aim of the present study was to investigate the differential distribution of TAMs, Treg cells and Th17 cells in benign ovarian tumor tissues and in tissues from patients with EOC, and to examine their association with the clinical pathology of EOC. A total of 126 tissue samples from patients with EOC and 26 tissue samples from patients with benign ovarian tumors were analyzed, and it was identified that the distribution of TAMs, Treg cells, Th17 cells and the ratio of Treg/Th17 cells were higher in the patients with EOC using triple color immunofluorescence confocal microscopy. The high frequency of TAMs and ratio of Treg/Th17 cells in late tumor grades suggested that they may be significant in tumor progression. The frequency of TAMs was different between the histological types of EOC. Immunohistochemistry was used to investigate the microvessel density (MVD) in the EOC and benign ovarian tumor tissues. A higher MVD was observed in the EOC patient tissues, particularly, in the late tumor grade tissues. The present study provided clinical data demonstrating the high distribution of TAMs and T-cells in EOC, which may contribute to tumor progression through angiogenesis. The mechanisms by which TAMs are associated with Treg cells and Th17 cells requires further investigation as prognostic factors and therapeutic targets for EOC. PMID:28123537

  18. Clinical features and outcomes of neck lymphatic metastasis in ovarian epithelial carcinoma

    PubMed Central

    2013-01-01

    Background Neck lymph node metastasis (NLNM) in epithelial ovarian cancer (EOC) is rare and treated as advanced stage cancer. However, ovarian cancer with lymphatic metastasis may manifest a different clinical course from peritoneal carcinomatosis. Methods The authors retrospectively assessed 20 patients with EOC and pathologically diagnosed as NLNM between January 2001 and December 2010. The patients were divided into two groups according to the time of NLNM identification. Statistical methods included Kaplan-Meier, log-rank, and Cox regression analysis. Results Eleven patients were diagnosed with NLNM at the same time of surgical exploration of EOC (Group A) and nine patients at cancer recurrence 43.3 months after initial surgery (Group B). In Group A, patients with tumors confined to the pelvic cavity had no recurrence or had isolated lymph node recurrence (ILNR), and survived longer than patients with abdominal tumor spreading (P = 0.0007). In Group B, 2 patients showed ILNR. The median survival time after NLNM was 42 months in Group A and 6 months in Group B (P = 0.01). Cox model demonstrated that non-serous histology, brain metastasis, and NLNM identified at cancer recurrence were major predictors for poor overall survival (Hazard ratio [HR] = 18.67, 6.93, and 4.52; P = 0.01, 0.02, and 0.04, respectively). Conclusions A subgroup of EOC patients with NLNM who presented limited pelvic cancer had much better overall survival than patients who had cancer spreading beyond the pelvic cavity or were diagnosed with NLNM at cancer recurrence. PMID:24088247

  19. Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue.

    PubMed

    Whitaker-Menezes, Diana; Martinez-Outschoorn, Ubaldo E; Flomenberg, Neal; Birbe, Ruth C; Witkiewicz, Agnieszka K; Howell, Anthony; Pavlides, Stephanos; Tsirigos, Aristotelis; Ertel, Adam; Pestell, Richard G; Broda, Paolo; Minetti, Carlo; Lisanti, Michael P; Sotgia, Federica

    2011-12-01

    We have recently proposed a new mechanism for explaining energy transfer in cancer metabolism. In this scenario, cancer cells behave as metabolic parasites, by extracting nutrients from normal host cells, such as fibroblasts, via the secretion of hydrogen peroxide as the initial trigger. Oxidative stress in the tumor microenvironment then leads to autophagy-driven catabolism, mitochondrial dys-function, and aerobic glycolysis. This, in turn, produces high-energy nutrients (such as L-lactate, ketones, and glutamine) that drive the anabolic growth of tumor cells, via oxidative mitochondrial metabolism. A logical prediction of this new "parasitic" cancer model is that tumor-associated fibroblasts should show evidence of mitochondrial dys-function (mitophagy and aerobic glycolysis). In contrast, epithelial cancer cells should increase their oxidative mitochondrial capacity. To further test this hypothesis, here we subjected frozen sections from human breast tumors to a staining procedure that only detects functional mitochondria. This method detects the in situ enzymatic activity of cytochrome C oxidase (COX), also known as Complex IV. Remarkably, cancer cells show an over-abundance of COX activity, while adjacent stromal cells remain essentially negative. Adjacent normal ductal epithelial cells also show little or no COX activity, relative to epithelial cancer cells. Thus, oxidative mitochondrial activity is selectively amplified in cancer cells. Although COX activity staining has never been applied to cancer tissues, it could now be used routinely to distinguish cancer cells from normal cells, and to establish negative margins during cancer surgery. Similar results were obtained with NADH activity staining, which measures Complex I activity, and succinate dehydrogenase (SDH) activity staining, which measures Complex II activity. COX and NADH activities were blocked by electron transport inhibitors, such as Metformin. This has mechanistic and clinical implications for

  20. The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposals for the T Component for the forthcoming (8th) edition of the TNM classification of malignant tumors.

    PubMed

    Nicholson, Andrew G; Detterbeck, Frank C; Marino, Mirella; Kim, Jhingook; Stratton, Kelly; Giroux, Dorothy; Asamura, Hisao; Crowley, John; Falkson, Conrad; Filosso, Pier Luigi; Giaccone, Giuseppe; Huang, James; Kondo, Kazuya; Lucchi, Marco; Marom, Edith M; Okumura, Meinoshin; Ruffini, Enrico; Van Schil, Paul

    2014-09-01

    Despite longstanding recognition of thymic epithelial neoplasms, there is no official American Joint Committee on Cancer/Union for International Cancer Control stage classification. This article summarizes proposals for classification of the T component of stage classification for use in the 8th edition of the tumor, node, metastasis classification for malignant tumors. This represents the output of the International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group Staging and Prognostics Factor Committee, which assembled and analyzed a worldwide database of 10,808 patients with thymic malignancies from 105 sites. The committee proposes division of the T component into four categories, representing levels of invasion. T1 includes tumors localized to the thymus and anterior mediastinal fat, regardless of capsular invasion, up to and including infiltration through the mediastinal pleura. Invasion of the pericardium is designated as T2. T3 includes tumors with direct involvement of a group of mediastinal structures either singly or in combination: lung, brachiocephalic vein, superior vena cava, chest wall, and phrenic nerve. Invasion of more central structures constitutes T4: aorta and arch vessels, intrapericardial pulmonary artery, myocardium, trachea, and esophagus. Size did not emerge as a useful descriptor for stage classification. This classification of T categories, combined with a classification of N and M categories, provides a basis for a robust tumor, node, metastasis classification system for the 8th edition of American Joint Committee on Cancer/Union for International Cancer Control stage classification.

  1. Utility of Serum miR-125b as a Diagnostic and Prognostic Indicator and Its Alliance with a Panel of Tumor Suppressor Genes in Epithelial Ovarian Cancer

    PubMed Central

    Mir, Rashid; Gandhi, Gauri; Ray, Prakash Chandra

    2016-01-01

    MicroRNAs (miRNAs) have been found to be dysregulated in epithelial ovarian cancer (EOC) and may function as either tumor suppressor genes (TSGs) or as oncogenes. Hypermethylation of miRNA silences the tumour suppressive function of a miRNA or hypermethylation of a TSG regulating that miRNA (or vice versa) leads to its loss of function. The present study aims to evaluate the impact of aberrant microRNA-125b (miR-125b) expression on various clinicopathological features in epithelial ovarian cancer and its association with anomalous methylation of several TSGs. We enrolled 70 newly diagnosed cases of epithelial ovarian cancer, recorded their clinical history and 70 healthy female volunteers. Serum miR-125b levels were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and the methylation status of various TSGs was investigated by methylation specific PCR. ROC curves were constructed to estimate the diagnostic and prognostic usefulness of miR-125b. The Kaplan—Meier method was applied to compare survival curves. Expression of miR-125b was found to be significantly upregulated (p<0.0001) in comparison with healthy controls. The expression level of miR-125b was found to be significantly associated with FIGO stage, lymph node and distant metastasis. ROC curve for diagnostic potential yielded significant AUC with an equitable sensitivity and specificity. ROC curves for prognosis yielded significant AUCs for histological grade, distal metastasis, lymph node status and survival. The expression of miR-125b also correlated significantly with the hypermethylation of TSGs. Our results indicate that DNA hypermethylation may be involved in the inactivation of miR-125b and miR-125b may function as a potential independent biomarker for clinical outcome in EOC. PMID:27092777

  2. Utility of Serum miR-125b as a Diagnostic and Prognostic Indicator and Its Alliance with a Panel of Tumor Suppressor Genes in Epithelial Ovarian Cancer.

    PubMed

    Zuberi, Mariyam; Khan, Imran; Mir, Rashid; Gandhi, Gauri; Ray, Prakash Chandra; Saxena, Alpana

    2016-01-01

    MicroRNAs (miRNAs) have been found to be dysregulated in epithelial ovarian cancer (EOC) and may function as either tumor suppressor genes (TSGs) or as oncogenes. Hypermethylation of miRNA silences the tumour suppressive function of a miRNA or hypermethylation of a TSG regulating that miRNA (or vice versa) leads to its loss of function. The present study aims to evaluate the impact of aberrant microRNA-125b (miR-125b) expression on various clinicopathological features in epithelial ovarian cancer and its association with anomalous methylation of several TSGs. We enrolled 70 newly diagnosed cases of epithelial ovarian cancer, recorded their clinical history and 70 healthy female volunteers. Serum miR-125b levels were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and the methylation status of various TSGs was investigated by methylation specific PCR. ROC curves were constructed to estimate the diagnostic and prognostic usefulness of miR-125b. The Kaplan-Meier method was applied to compare survival curves. Expression of miR-125b was found to be significantly upregulated (p<0.0001) in comparison with healthy controls. The expression level of miR-125b was found to be significantly associated with FIGO stage, lymph node and distant metastasis. ROC curve for diagnostic potential yielded significant AUC with an equitable sensitivity and specificity. ROC curves for prognosis yielded significant AUCs for histological grade, distal metastasis, lymph node status and survival. The expression of miR-125b also correlated significantly with the hypermethylation of TSGs. Our results indicate that DNA hypermethylation may be involved in the inactivation of miR-125b and miR-125b may function as a potential independent biomarker for clinical outcome in EOC.

  3. The relationship between clinicopathological features and expression of epithelial and mesenchymal markers in spontaneous canine mammary gland tumors.

    PubMed

    Yoshida, Kota; Yoshida, Saori; Choisunirachon, Nan; Saito, Tomochika; Matsumoto, Kaori; Saeki, Kohei; Mochizuki, Manabu; Nishimura, Ryohei; Sasaki, Nobuo; Nakagawa, Takayuki

    2014-10-01

    It is known that epithelial mesenchymal transition (EMT) contributes to the acquisition of malignant property in human cancers. However, the role of EMT in canine tumors remains to be elucidated. To evaluate the correlation between expression levels of protein markers involved in EMT and clinicopathological characteristics in canine mammary gland tumors, immunohistochemistry using antibodies against ZO-1, E-cadherin, vimentin, N-cadherin and fibronectin was performed on 119 clinical tissue samples. Consequently, loss of ZO-1 and E-cadherin, and gain of vimentin and N-cadherin were more frequently observed in malignant tumors than in benign tumors. However, there was no correlation among expression of these molecules. Univariate and multivariate analysis identified that loss of E-cadherin independently had a low one-year survival rate (adjusted odds ratio: 2.3, P=0.02). These results suggested that EMT might relate to acquisition of malignancy, and additionally, E-cadherin was strongly correlated with malignant behavior in canine mammary gland tumors.

  4. Distinct Patterns of Stromal and Tumor Expression of ROR1 and ROR2 in Histological Subtypes of Epithelial Ovarian Cancer.

    PubMed

    Henry, C E; Emmanuel, C; Lambie, N; Loo, C; Kan, B; Kennedy, C J; de Fazio, A; Hacker, N F; Ford, C E

    2017-06-01

    The ROR1 and ROR2 receptor tyrosine kinases have both been implicated in ovarian cancer progression and have been shown to drive migration and invasion. There is an increasing importance of the role of stroma in ovarian cancer metastasis; however, neither ROR1 nor ROR2 expression in tumor or stromal cells has been analyzed in the same clinical cohort. To determine ROR1 and ROR2 expression in ovarian cancer and surrounding microenvironment and examine associations with clinicopathological characteristics. Immunohistochemistry for ROR1 and ROR2 was used to assess receptor expression in a cohort of epithelial ovarian cancer patients (n=178). Results were analyzed in relation to clinical and histopathological characteristics and survival. Matched patient sample case studies of normal, primary, and metastatic lesions were used to examine ROR expression in relation to ovarian cancer progression. ROR1 and ROR2 are abnormally expressed in malignant ovarian epithelium and stroma. Higher ROR2 tumor expression was found in early-stage, low-grade endometrioid carcinomas. ROR2 stromal expression was highest in the serous subtype. In matched patient case studies, metastatic samples had higher expression of ROR2 in the stroma, and a recurrent sample had the highest expression of ROR2 in both tumor and stroma. ROR1 and ROR2 are expressed in tumor-associated stroma in all histological subtypes of ovarian cancer and hold potential as therapeutic targets which may disrupt tumor and stroma interactions. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Enhanced detection and comprehensive in situ phenotypic characterization of circulating and disseminated heteroploid epithelial and glioma tumor cells

    PubMed Central

    Wang, Daisy Dandan; Li, Linda; Lin, Peter Ping

    2015-01-01

    Conventional strategy of anti-EpCAM capture and immunostaining of cytokeratins (CKs) to detect circulating tumor cells (CTCs) is limited by highly heterogeneous and dynamic expression or absence of EpCAM and/or CKs in CTCs. In this study, a novel integrated cellular and molecular approach of subtraction enrichment (SE) and immunostaining-FISH (iFISH) was successfully developed. Both large or small size CTCs and circulating tumor microemboli (CTM) in various biofluid samples including cerebrospinal fluid (CSF) of cancer patients and patient-derived-xenograft (PDX) mouse models were efficiently enriched and comprehensively identified and characterized by SE-iFISH. Non-hematopoietic CTCs with heteroploid chromosome 8 were detected in 87–92% of lung, esophageal and gastric cancer patients. Characterization of CTCs performed by CK18-iFISH showed that CK18, the dual epithelial marker and tumor biomarker, was strong positive in only 14% of lung and 24% of esophageal CTCs, respectively. Unlike conventional methodologies restricted only to the large and/or both EpCAM and CK positive CTCs, SE-iFISH enables efficient enrichment and performing in situ phenotypic and karyotypic identification and characterization of the highly heterogeneous CTC subtypes classified by both chromosome ploidy and the expression of various tumor biomarkers. Each CTC subtype may possess distinct clinical significance relative to tumor metastasis, relapse, therapeutic drug sensitivity or resistance, etc. PMID:26267323

  6. LINE1 and Alu repetitive element DNA methylation in tumors and white blood cells from epithelial ovarian cancer patients

    PubMed Central

    Akers, Stacey N.; Moysich, Kirsten; Zhang, Wa; Lai, Golda Collamat; Miller, Austin; Lele, Shashikant; Odunsi, Kunle; Karpf, Adam R.

    2014-01-01

    Objective We determined whether DNA methylation of repetitive elements (RE) is altered in epithelial ovarian cancer (EOC) patient tumors and white blood cells (WBC), compared to normal tissue controls. Methods Two different quantitative measures of RE methylation (LINE1 and Alu bisulfite pyrosequencing) were used in normal and tumor tissues from EOC cases and controls. Tissues analyzed included: i) EOC, ii) normal ovarian surface epithelia (OSE), iii) normal fallopian tube surface epithelia (FTE), iv) WBC from EOC patients, obtained before and after treatment, and v) WBC from demographically-matched controls. Results REs were significantly hypomethylated in EOC compared to OSE and FTE, and LINE1 and Alu methylation showed a significant direct association in these tissues. In contrast, WBC RE methylation was significantly higher in EOC cases compared to controls. RE methylation in patient-matched EOC tumors and pre-treatment WBC did not correlate. Conclusions EOC shows robust RE hypomethylation compared to normal tissues from which the disease arises. In contrast, RE are generally hypermethylated in EOC patient WBC compared to controls. EOC tumor and WBC methylation did not correlate in matched patients, suggesting that RE methylation is independently controlled in tumor and normal tissues. Despite the significant differences observed over the population, the range of RE methylation in patient and control WBC overlapped, limiting their specific utility as an EOC biomarker. However, our data demonstrate that DNA methylation is deranged in normal tissues from EOC patients, supporting further investigation of WBC DNA methylation biomarkers suitable for EOC risk assessment. PMID:24374023

  7. Treatment Outcomes of Epithelial Ovarian Cancers Following Maximum Cytoreduction and Adjuvant Paclitaxel-Carboplatin Chemotherapy: Egyptian NCI Experience.

    PubMed

    Nassar, Hanan Ramadan; Zeeneldin, Ahmed A; Helal, Amany Mohamed; Ismail, Yahia Mahmoud; Elsayed, Abeer Mohamed; Elbassuiony, Mohamed A; Moneer, Manar M

    2015-01-01

    Epithelial ovarian cancer (EOC) is the commonest malignancy involving the ovaries. Maximum surgical cytoreduction (MCR) followed by adjuvant taxane-platinum chemotherapy are the standard of care treatments. To study treatment outcomes of EOC patients that were maximally cyto-reduced and received adjuvant paclitaxel-carboplatin (PC) chemotherapy. This retrospective cohort study included 174 patients with EOC treated at the Egyptian National Cancer Institute between 2006 and 2010. For inclusion, they should have had undergone MCR with no-gross residual followed by adjuvant PC chemotherapy. MCR was total abdominal hysterectomy/bilateral salpingo-oophorectomy [TAH/BSO] or unilateral salpingo- oophorectomy [USO] plus comprehensive staging. The median age was 50 years. Most patients were married (97.1%), had offspring (92.5%), were postmenopausal (53.4%), presented with abdominal/pelvic pain and swelling (93.7%), had tumors involving both ovaries (45.4%) without extra-ovarian extension i.e. stage I (55.2%) of serous histology (79.9%) and grade II (87.4%). TAH/BSO was performed in 97.7% of cases. A total of 1,014 PC chemotherapy cycles were administered and were generally tolerable with 93.7% completing 6 cycles. Alopecia and numbness were the commonest adverse events. The median follow up period was 42 months. The 2-year rates for disease free survival (DFS) and overall survival (OS) were 70.7% and 94.8%, respectively. The respective 5-year rates were 52.6% and 81.3%. Advanced stage and high-grade were significantly associated with poor DFS and OS (p<0.001). Age >65 years was associated with poor OS (p =0.008). Using Cox-regression, stage was independent predictor of poor DFS and OS. Age was an independent predictor of poor OS.

  8. Imatinib Spares cKit-Expressing Prostate Neuroendocrine Tumors, whereas Kills Seminal Vesicle Epithelial-Stromal Tumors by Targeting PDGFR-β.

    PubMed

    Jachetti, Elena; Rigoni, Alice; Bongiovanni, Lucia; Arioli, Ivano; Botti, Laura; Parenza, Mariella; Cancila, Valeria; Chiodoni, Claudia; Festinese, Fabrizio; Bellone, Matteo; Tardanico, Regina; Tripodo, Claudio; Colombo, Mario P

    2017-02-01

    Prostate cancer is a leading cause of cancer-related death in males worldwide. Indeed, advanced and metastatic disease characterized by androgen resistance and often associated with neuroendocrine (NE) differentiation remains incurable. Using the spontaneous prostate cancer TRAMP model, we have shown that mast cells (MCs) support in vivo the growth of prostate adenocarcinoma, whereas their genetic or pharmacologic targeting favors prostate NE cancer arousal. Aiming at simultaneously targeting prostate NE tumor cells and MCs, both expressing the cKit tyrosine kinase receptor, we have tested the therapeutic effect of imatinib in TRAMP mice. Imatinib-treated TRAMP mice experience a partial benefit against prostate adenocarcinoma, because of inhibition of supportive MCs. However, they show an unexpected outgrowth of prostate NE tumors, likely because of defective signaling pathway downstream of cKit receptor. Also unexpected but very effective was the inhibition of epithelial-stromal tumors of the seminal vesicles achieved by imatinib treatment. These tumors normally arise in the seminal vesicles of TRAMP mice, independently of the degree of prostatic glandular lesions, and resemble phyllodes tumors found in human prostate and seminal vesicles, and in breast. In both mice and in patients, these tumors are negative for cKit but express PDGFR-β, another tyrosine kinase receptor specifically inhibited by imatinib. Our results imply a possible detrimental effect of imatinib in prostate cancer patients but suggest a promising therapeutic application of imatinib in the treatment of recurrent or metastatic phyllodes tumors. Mol Cancer Ther; 16(2); 365-75. ©2016 AACR. ©2016 American Association for Cancer Research.

  9. Two-dimensional electrophoretic comparison of metastatic and non-metastatic human breast tumors using in vitro cultured epithelial cells derived from the cancer tissues

    PubMed Central

    Vydra, Jan; Selicharová, Irena; Smutná, Kateřina; Šanda, Miloslav; Matoušková, Eva; Buršíková, Eva; Prchalová, Markéta; Velenská, Zuzana; Coufal, David; Jiráček, Jiří

    2008-01-01

    Background Breast carcinomas represent a heterogeneous group of tumors diverse in behavior, outcome, and response to therapy. Identification of proteins resembling the tumor biology can improve the diagnosis, prediction, treatment selection, and targeting of therapy. Since the beginning of the post-genomic era, the focus of molecular biology gradually moved from genomes to proteins and proteomes and to their functionality. Proteomics can potentially capture dynamic changes in protein expression integrating both genetic and epigenetic influences. Methods We prepared primary cultures of epithelial cells from 23 breast cancer tissue samples and performed comparative proteomic analysis. Seven patients developed distant metastases within three-year follow-up. These samples were included into a metastase-positive group, the others formed a metastase-negative group. Two-dimensional electrophoretical (2-DE) gels in pH range 4–7 were prepared. Spot densities in 2-DE protein maps were subjected to statistical analyses (R/maanova package) and data-mining analysis (GUHA). For identification of proteins in selected spots, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed. Results Three protein spots were significantly altered between the metastatic and non-metastatic groups. The correlations were proven at the 0.05 significance level. Nucleophosmin was increased in the group with metastases. The levels of 2,3-trans-enoyl-CoA isomerase and glutathione peroxidase 1 were decreased. Conclusion We have performed an extensive proteomic study of mammary epithelial cells from breast cancer patients. We have found differentially expressed proteins between the samples from metastase-positive and metastase-negative patient groups. PMID:18416831

  10. Renal functional outcomes after surgery for renal cortical tumors

    PubMed Central

    Finkelstein, Julia B.; DeCastro, G. Joel; McKiernan, James M.

    2015-01-01

    Historically, radical nephrectomy represented the gold standard for the treatment of small (≤ 4cm) as well as larger renal masses. Recently, for small renal masses, the risk of ensuing chronic kidney disease and end stage renal disease has largely favored nephron-sparing surgical techniques, mainly partial nephrectomy. In this review, we surveyed the literature on renal functional outcomes after partial nephrectomy for renal tumors. The largest randomized control trial comparing radical and partial nephrectomy failed to show a survival benefit for partial nephrectomy. With regards to overall survival, surgically induced chronic kidney disease (GFR < 60 ml/min/ 1.73m2) caused by nephrectomy might not be as deleterious as medically induced chronic kidney disease. In evaluating patients who underwent donor nephrectomy, transplant literature further validates that surgically induced reductions in GFR may not affect patient survival, unlike medically induced GFR declines. Yet, because patients who present with a renal mass tend to be elderly with multiple comorbidities, many develop a mixed picture of medically, and surgically-induced renal disease after extirpative renal surgery. In this population, we believe that nephron sparing surgery optimizes oncological control while protecting renal function.

  11. Prognostic significance of TRAIL-R3 and CCR-2 expression in tumor epithelial cells of patients with early breast cancer.

    PubMed

    Labovsky, Vivian; Martinez, Leandro Marcelo; Davies, Kevin Mauro; de Luján Calcagno, María; García-Rivello, Hernán; Wernicke, Alejandra; Feldman, Leonardo; Matas, Ayelén; Giorello, María Belén; Borzone, Francisco Raúl; Choi, Hosoon; Howard, Scott C; Chasseing, Norma Alejandra

    2017-04-18

    Tumor epithelial cells (TEpCs) and spindle-shaped stromal cells, not associated with the vasculature, of patients with early breast cancer express osteoprotegerin (OPG), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), receptor activator of nuclear factor kappa B ligand, stromal cell derived factor-1, interleukin-6, macrophage colony stimulating factor, chemokine (C-C motif) ligand-2 (CCL-2) and their receptors at significantly higher levels compared with non-neoplastic breast tissues. We evaluated the clinicopathological significance of these ligands and receptors in TEpC and spindle-shaped stromal cells, not associated with the vasculature, to determine their impact on prognosis of patients with early-stage breast cancer. We conducted immunohistochemical analyses of protein expression in primary tumors of patients with early breast cancer and analyzed their association with standard prognostic parameters and clinical outcomes, including local relapse, metastatic recurrence, disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS). Elevated levels of TRAIL-R3 and chemokine (C-C motif) receptor 2 (CCR-2) in TEpCs and OPG and CCL-2 in stromal cells were significantly associated with a higher risk of metastasis (p = 0.032, p = 0.003, p = 0.038, and p = 0.049; respectively). Moreover, high expression of TRAIL-R3 and CCR-2 in TEpCs was associated with shorter DFS, MFS, and OS. High TRAIL-R3 expression in TEpCs was an independent prognostic factor for DFS and OS, and high CCR-2 expression in these cells was an independent prognostic factor for MFS. High levels of TRAIL-R3 and CCR-2 expression in TEpCs identified patients with early breast cancer with poor outcomes.

  12. Novel Therapies Against Aggressive and Recurrent Epithelial Cancers by Molecular Targeting Tumor- and Metastasis-Initiating Cells and Their Progenies

    PubMed Central

    Mimeault, Murielle; Batra, Surinder K.

    2010-01-01

    A growing body of experimental evidence has revealed that the highly tumorigenic cancer stem/progenitor cells endowed with stem cell-like properties might be responsible for initiation and progression of numerous aggressive epithelial cancers into locally invasive, metastatic and incurable disease states. The malignant transformation of tissue-resident adult stem/progenitor cells or their progenies into tumorigenic and migrating cancer stem/progenitor cells and their resistance to current cancer therapies have been associated with their high expression levels of specific oncogenic products and drug resistance-associated molecules. In this regard, we describe the tumorigenic cascades that are frequently activated in cancer stem/progenitor cells versus their differentiated progenies during the early and late stages of the epithelial cancer progression. The emphasis is on the growth factor signaling pathways involved in the malignant behavior of prostate and pancreatic cancer stem/progenitor cells and their progenies. Of clinical interest, the potential molecular therapeutic targets to eradicate the tumor- and metastasis-initiating cells and their progenies and develop new effective combination therapies against locally advanced and metastatic epithelial cancers are also described. PMID:20184544

  13. Markers of fibrosis and epithelial to mesenchymal transition demonstrate field cancerization in histologically normal tissue adjacent to breast tumors

    PubMed Central

    Trujillo, Kristina A.; Heaphy, Christopher M.; Mai, Minh; Vargas, Keith M.; Jones, Anna C.; Vo, Phung; Butler, Kimberly S.; Joste, Nancy E.; Bisoffi, Marco; Griffith, Jeffrey K

    2011-01-01

    Previous studies have shown that a field of genetically altered but histologically normal tissue extends 1 cm or more from the margins of human breast tumors. The extent, composition and biological significance of this field are only partially understood, but the molecular alterations in affected cells could provide mechanisms for limitless replicative capacity, genomic instability and a microenvironment that supports tumor initiation and progression. We demonstrate by microarray, qRT-PCR and immunohistochemistry a signature of differential gene expression that discriminates between patient-matched, tumor-adjacent histologically normal breast tissues located 1 cm and 5 cm from the margins of breast adenocarcinomas (TAHN-1 and TAHN-5, respectively). The signature includes genes involved in extracellular matrix remodeling, wound healing, fibrosis and epithelial to mesenchymal transition (EMT). Myofibroblasts, which are mediators of wound healing and fibrosis, and intra-lobular fibroblasts expressing MMP2, SPARC, TGF-β3, which are inducers of EMT, were both prevalent in TAHN-1 tissues, sparse in TAHN-5 tissues, and absent in normal tissues from reduction mammoplasty. Accordingly, EMT markers S100A4 and vimentin were elevated in both luminal and myoepithelial cells, and EMT markers α-smooth muscle actin and SNAIL were elevated in luminal epithelial cells of TAHN-1 tissues. These results identify cellular processes that are differentially activated between TAHN-1 and TAHN-5 breast tissues, implicate myofibroblasts as likely mediators of these processes, provide evidence that EMT is occurring in histologically normal tissues within the affected field and identify candidate biomarkers to investigate whether or how field cancerization contributes to the development of primary or recurrent breast tumors. PMID:21105047

  14. A promoter polymorphism in human interleukin-32 modulates its expression and influences the risk and the outcome of epithelial cell-derived thyroid carcinoma.

    PubMed

    Plantinga, Theo S; Costantini, Irene; Heinhuis, Bas; Huijbers, Angelique; Semango, George; Kusters, Benno; Netea, Mihai G; Hermus, Ad R M M; Smit, Jan W A; Dinarello, Charles A; Joosten, Leo A B; Netea-Maier, Romana T

    2013-07-01

    Interleukin (IL)-32 is an intracellular proinflammatory mediator that strongly modulates the inflammatory reaction. Recent studies have suggested the involvement of IL-32 in the pathogenesis of malignancies. We aimed to assess whether a known germ-line polymorphism in the IL32 promoter modulates IL-32 expression, and whether it influences susceptibility and/or outcome of epithelial cell-derived thyroid carcinoma (TC). In this study, IL32 genotype was assessed in 139 TC patients and 138 healthy controls and was correlated with TC susceptibility and clinical outcome. Furthermore, IL-32 messenger RNA expression and protein were assessed in TC tissues and functional consequences of genetic variants of IL32 were studied in a model of human primary immune cells. Results demonstrate substantial IL-32 expression in TC tumor tissue. Lipopolysaccharide (LPS) stimulation of primary immune cells revealed 2-fold higher expression of IL-32γ, but not IL-32β, in cells homozygous for the ancient T allele. Furthermore, production of LPS-induced cytokines was increased in cells bearing this T allele. Genetic analysis revealed that the ancient T allele was overrepresented in TC patients with odds ratio (95% confidence interval) = 1.71 (1.06-2.75). In addition, the cumulative radioactive iodine (RAI) dose received after total thyroidectomy was significantly higher in TC patients bearing the ancient T allele. In conclusion, individuals bearing genetic variants of IL32 that lead to an increased IL-32γ gene expression and higher production of proinflammatory cytokines have higher risk for developing epithelial cell-derived TC. Subsequently, they require higher dosages of RAI to achieve successful tumor remission. These data suggest an important role of IL-32 in the pathogenesis of TC.

  15. SIRT1 induces tumor invasion by targeting epithelial mesenchymal transition-related pathway and is a prognostic marker in triple negative breast cancer.

    PubMed

    Jin, Min-Sun; Hyun, Chang Lim; Park, In Ae; Kim, Ji Young; Chung, Yul Ri; Im, Seock-Ah; Lee, Kyung-Hun; Moon, Hyeong-Gon; Ryu, Han Suk

    2016-04-01

    Absence of therapeutic targets poses a critical hurdle in improving prognosis for patients with triple negative breast cancer (TNBC). We evaluated interaction between SIRT1 and epithelial mesenchymal transition (EMT)-associated proteins as well as the role of combined protein expression as a predictor of lymph node metastasis and clinical outcome in TNBC through in vivo and vitro studies. Three hundred nineteen patients diagnosed with TNBC were chosen, immunohistochemical staining for SIRT1 and EMT-related markers' expression was performed on tissue microarrays, and in vitro experiments with each of the three human TNBC cell lines were carried out. The cohort was reclassified according to the use of adjuvant chemotherapy, tumor size, and AJCC stage to analyze the prognostic role of SIRT1 and EMT-related proteins' expression considering different therapeutic modalities and AJCC stages. Combination of four proteins including SIRT1 and three EMT-related proteins was revealed to be a statistically significant independent predictor of lymph node metastasis in the tumor size cohort as well as in the total patient population. Upon Cox regression analysis, increased expression level of the combined proteins correlated with decreased disease-free survival in the total patients as well as those who received adjuvant chemotherapy and those who had early stage breast cancer. In additional in vitro experiments, inhibition of SIRT1 expression with small interfering RNA (siRNA) suppressed tumor invasion in three different TNBC cell lines, and altered expression levels of EMT-related proteins following SIRT1 gene inhibition were identified on western blotting and fluorescence activated cell sorting (FACS) analysis; on the other hand, no change in expression levels of the cell cycle-related factors was observed. Our analysis showed the potential role of SIRT1 in association with EMT-related factors on tumor invasion, metastasis, and disease-free survival in TNBC, SIRT1, and

  16. Adoptive Immunotherapy for Epithelial Ovarian Cancer Using T Cells Simultaneously Targeted to Tumor and Tumor-Associated Macrophages

    DTIC Science & Technology

    2011-07-01

    will be delivered to separate T-cell populations using the SFG retroviral vector and retronectin - coated tissue culture dishes: (i) HOX – targets MUC1 and...cancer. Patient derived T-cells were activated with CSD3+CD28- coated beads and transduced with retroviral expression vectors. A representative example for...cells from ascites and tumor tissue stained from a patient with ovarian cancer. Tumor cells were separated using magnetic beads coated with antibodies

  17. Immunohistochemical expression of WNT5A and MMPs in odontogenic epithelial tumors and cysts.

    PubMed

    Guimarães, Douglas Magno; Antunes, Daniella Moraes; Saturno, Juvani Lago; Massuda, Fabiola; Paiva, Katiúcia Batista da Silva; Nunes, Fabio Daumas

    2015-10-01

    The aim of this study was compare the expression of WNT5A and MMP2, 7 and 20, in frequent benign odontogenic tumors and odontogenic cysts, since these lesions have a different biological behavior. Eighty-one paraffin-embedded specimens of odontogenic tumors, including ameloblastoma and keratocystic odontogenic tumor, and thirty-two odontogenic cysts were used for immunohistochemical analysis. The expression of WNT5A in odontogenic tumors and inflammatory cyst was higher than in developmental odontogenic cyst. There was no statistical difference (p<0.05) in the expression of WNT5A when comparing the analyzed tumors. The expression of MMP7 was lower in RC with a statistical difference when compared with all tumors and cysts. Statistical differences also occurred when comparing glandular odontogenic cyst (GOC) to keratocyst odontogenic tumor (KOT) and calcifying cystic odontogenic tumor (CCOT). MMP20 expression was higher in ameloblastoma when compared to adenomatoid odontogenic tumor (AOT), DC and GOC. The expression of MMP20 was lower in CCOT when compared to all tumors and cysts. The expression of WNT5A in a group of odontogenic lesions suggests the participation of a non-canonical WNT signaling pathway in the progression and maintenance of these lesions. These molecules are possibly involved in the biological differences between odontogenic tumors and cysts. Considering previous studies, WNT5A may help promote the calcification seen in AOT, CCOT and CEOT by activating MMP7. Copyright © 2015 Elsevier GmbH. All rights reserved.

  18. The accuracy of frozen section by tumor weight for ovarian epithelial neoplasms.

    PubMed

    Puls, L; Heidtman, E; Hunter, J E; Crane, M; Stafford, J

    1997-10-01

    This study evaluated the effect ovarian weight has on the accuracy of frozen sections in serous and mucinous ovarian tumors. The study group included 294 patients who had an initial frozen section (189 serous and 105 mucinous tumors) at surgery. The pathology reports were separated into subgroups (benign, borderline, or malignant). Tumors were broken down into three weight categories: < or = 450 g, > 450 to < or = 1360 g, and > 1360 g. In each weight category, accuracy, sensitivity, specificity, and positive and negative predicative values were calculated on frozen sections. The mean weight of the ovarian tumors was 1042 g. As the weight increased in serous tumors, the sensitivity fell from 96.2 to 93.8 to 75%, respectively, in each weight category. The same trend was noted with mucinous tumors as sensitivity fell from 91.7 to 87.5 to 66.7%, respectively. With an increase in the size of ovarian tumors, a decrease in the sensitivity of frozen section was observed. With tumors greater than 1360 g, sensitivity was only 69%. Twenty-three percent of ovarian tumors revealing borderline diagnosis at frozen section were malignant on the final pathology report, with the greatest misclassification in > 1360-g mucinous tumors (50%). For patients with large ovarian tumors, consideration should be given to performing staging at the time of the initial laparotomy.

  19. Tumor Suppressor Maspin as a Rheostat in HDAC Regulation to Achieve the Fine-Tuning of Epithelial Homeostasis

    PubMed Central

    Kaplun, Alexander; Dzinic, Sijana; Bernardo, M. Margarida; Sheng, Shijie

    2013-01-01

    Maspin, a class II tumor suppressor, is often downregulated during tumor progression and its depletion from the nucleus is associated with poor prognosis. Recently, we reported that reintroduction of maspin is sufficient for redifferentiation of prostate cancer cells to epithelial phenotype, a reversal of epithelial-to-mesenchymal transition. We have linked this effect of maspin with its ability to directly inhibit HDAC1, thereby influencing the acetylation state of transcription factors and other proteins. Maspin overexpression leads to changes in the expression level of a large number of proteins and these changes are often microenvironment specific. In this review, we summarize the epigenetic effects of maspin and provide comprehensive bioinformatic analysis of microarray-derived gene expression changes caused by maspin in different microenvironments. The analysis was performed on multiple levels, including identification of statistically enriched gene ontology groups, detection of overreprepresented transcription factors binding sites in promoters of differentially expressed genes, followed by searching for key nodes of regulatory networks controlling these transcription factors. The results are consistent with our hypothesis that maspin serves as an endogenous regulator of HDAC activity and suggest that the effect of maspin is primarily mediated by TGFβ, β-catenin/E-cadherin pathways, and network key nodes such as Abl kinase, p62, IL1, and caspases 6 and 8. PMID:23140166

  20. Canine mammary tumors: a review and consensus of standard guidelines on epithelial and myoepithelial phenotype markers, HER2, and hormone receptor assessment using immunohistochemistry.

    PubMed

    Peña, L; Gama, A; Goldschmidt, M H; Abadie, J; Benazzi, C; Castagnaro, M; Díez, L; Gärtner, F; Hellmén, E; Kiupel, M; Millán, Y; Miller, M A; Nguyen, F; Poli, A; Sarli, G; Zappulli, V; de las Mulas, J Martín

    2014-01-01

    Although there have been several studies on the use of immunohistochemical biomarkers of canine mammary tumors (CMTs), the results are difficult to compare. This article provides guidelines on the most useful immunohistochemical markers to standardize their use and understand how outcomes are measured, thus ensuring reproducibility of results. We have reviewed the biomarkers of canine mammary epithelial and myoepithelial cells and identified those biomarkers that are most useful and those biomarkers for invasion and lymph node micrometastatic disease. A 10% threshold for positive reaction for most of these markers is recommended. Guidelines on immunolabeling for HER2, estrogen receptors (ERs), and progesterone receptors (PRs) are provided along with the specific recommendations for interpretation of the results for each of these biomarkers in CMTs. Only 3+ HER2-positive tumors should be considered positive, as found in human breast cancer. The lack of any known response to adjuvant endocrine therapy of ER- and PR-positive CMTs prevents the use of the biological positive/negative threshold used in human breast cancer. Immunohistochemistry results of ER and PR in CMTs should be reported as the sum of the percentage of positive cells and the intensity of immunolabeling (Allred score). Incorporation of these recommendations in future studies, either prospective or retrospective, will provide a mechanism for the direct comparison of studies and will help to determine whether these biomarkers have prognostic significance. Finally, these biomarkers may ascertain the most appropriate treatment(s) for canine malignant mammary neoplasms.

  1. Infection of Human Fallopian Tube Epithelial Cells with Neisseria gonorrhoeae Protects Cells from Tumor Necrosis Factor Alpha-Induced Apoptosis

    PubMed Central

    Morales, Priscilla; Reyes, Paz; Vargas, Macarena; Rios, Miguel; Imarai, Mónica; Cardenas, Hugo; Croxatto, Horacio; Orihuela, Pedro; Vargas, Renato; Fuhrer, Juan; Heckels, John E.; Christodoulides, Myron; Velasquez, Luis

    2006-01-01

    Following infection with Neisseria gonorrhoeae, bacteria may ascend into the Fallopian tubes (FT) and induce salpingitis, a major cause of infertility. In the FT, interactions between mucosal epithelial cells and gonococci are pivotal events in the pathogen's infection cycle and the inflammatory response. In the current study, primary FT epithelial cells were infected in vitro with different multiplicities of infection (MOI) of Pil+ Opa+ gonococci. Bacteria showed a dose-dependent association with cells and induced the secretion of tumor necrosis factor alpha (TNF-α). A significant finding was that gonococcal infection (MOI = 1) induced apoptosis in approximately 30% of cells, whereas increasing numbers of bacteria (MOI = 10 to 100) did not induce apoptosis. Apoptosis was observed in only 11% of cells with associated bacteria, whereas >84% of cells with no adherent bacteria were apoptotic. TNF-α was a key contributor to apoptosis, since (i) culture supernatants from cells infected with gonococci (MOI = 1) induced apoptosis in naïve cultures, suggesting that a soluble factor was responsible; (ii) gonococcal infection-induced apoptosis was inhibited with anti-TNF-α antibodies; and (iii) the addition of exogenous TNF-α induced apoptosis, which was inhibited by the presence of increasing numbers of bacteria (MOI = 10 to 100). These data suggest that TNF-α-mediated apoptosis of FT epithelial cells is likely a primary host defense mechanism to prevent pathogen colonization. However, epithelial cell-associated gonococci have evolved a mechanism to protect the cells from undergoing TNF-α-mediated apoptosis, and this modulation of the host innate response may contribute to establishment of infection. Understanding the antiapoptotic mechanisms used by Neisseria gonorrhoeae will inform the pathogenesis of salpingitis and could suggest new intervention strategies for prevention and treatment of the disease. PMID:16714596

  2. ADP-ribosylation factor 1 expression regulates epithelial-mesenchymal transition and predicts poor clinical outcome in triple-negative breast cancer

    PubMed Central

    Schlienger, Sabrina; Campbell, Shirley; Pasquin, Sarah; Gaboury, Louis; Claing, Audrey

    2016-01-01

    Metastatic capacities are fundamental features of tumor malignancy. ADP-ribosylation factor (ARF) 1 has emerged as a key regulator of invasion in breast cancer cells. However, the importance of this GTPase, in vivo, remains to be demonstrated. We report that ARF1 is highly expressed in breast tumors of the most aggressive and advanced subtypes. Furthermore, we show that lowered expression of ARF1 impairs growth of primary tumors and inhibits lung metastasis in a murine xenograft model. To understand how ARF1 contributes to invasiveness, we used a poorly invasive breast cancer cell line, MCF7 (ER+), and examined the effects of overexpressing ARF1 to levels similar to that found in invasive cell lines. We demonstrate that ARF1 overexpression leads to the epithelial-mesenchymal transition (EMT). Mechanistically, ARF1 controls cell–cell adhesion through ß-catenin and E-cadherin, oncogenic Ras activation and expression of EMT inducers. We further show that ARF1 overexpression enhances invasion, proliferation and resistance to a chemotherapeutic agent. In vivo, ARF1 overexpressing MCF7 cells are able to form more metastases to the lung. Overall, our findings demonstrate that ARF1 is a molecular switch for cancer progression and thus suggest that limiting the expression/activation of this GTPase could help improve outcome for breast cancer patients. PMID:26908458

  3. Influence of large peritumoral vessels on outcome of radiofrequency ablation of liver tumors.

    PubMed

    Lu, David S K; Raman, Steven S; Limanond, Piyaporn; Aziz, Donya; Economou, James; Busuttil, Ronald; Sayre, James

    2003-10-01

    The effect of large vessels (>/=3 mm) contiguous to hepatic tumors was evaluated with respect to clinical tumor recurrence rates after radiofrequency (RF) ablation. The first 105 malignant liver tumors treated by RF ablation therapy at our institution with pathologic analysis or a minimum of 6 months of clinical follow-up were reviewed. The original pretreatment imaging studies were reviewed by a radiologist who was blinded to the cases, and, based on lesion contiguity to vessels of at least 3 mm, the lesions were categorized as perivascular or nonperivascular. Treatment outcomes with respect to local tumor recurrence between these two groups were then compared. Logistic regression analysis was performed to take into account other variables and to determine whether this categorization was an independent predictor of treatment outcome. There were 74 nonperivascular tumors and 31 perivascular tumors. Mean tumor size was 2.4 cm and mean follow-up was 11.3 months. Residual or locally recurrent tumors were documented in 20 of 105 cases (19%). In the nonperivascular group, five of 74 (7%) had either incompletely treated tumor (manifested within 6 months) or local recurrence beyond 6 months. In the perivascular group, 15 of 31 (48%) had incompletely treated or locally recurrent tumor (P <.001). Subanalysis of lesion size (61 tumors tumors 2.6-4 cm, and 11 tumors >4 cm), tumor type (40 hepatocellular carcinomas, 48 colorectal metastases, and 17 other metastases), access (53 intraoperative, 52 percutaneous), and RF device (45 Radiotherapeutics electrodes, 18 Rita electrodes, and 42 Radionics electrodes) showed similar results. Multivariate logistic regression analysis showed that presence or absence of a large peritumoral vessel is an independent, and the dominant, predictor of treatment outcome. The presence of vessels at least 3 mm in size contiguous to hepatic tumors is a strong independent predictor of incomplete tumor destruction by RF ablation. Modified

  4. Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines

    SciTech Connect

    Gu Yongpeng; Li Hongzhen; Miki, Jun; Kim, Kee-Hong; Furusato, Bungo; Sesterhenn, Isabell A.; Chu, Wei-Sing; McLeod, David G.; Srivastava, Shiv; Ewing, Charles M.; Isaacs, William B.; Rhim, Johng S. . E-mail: jrhim@cpdr.org

    2006-04-01

    In vitro human prostate cell culture models are critical for clarifying the mechanism of prostate cancer progression and for testing preventive and therapeutic agents. Cell lines ideal for the study of human primary prostate tumors would be those derived from spontaneously immortalized tumor cells; unfortunately, explanted primary prostate cells survive only short-term in culture, and rarely immortalize spontaneously. Therefore, we recently have generated five immortal human prostate epithelial cell cultures derived from both the benign and malignant tissues of prostate cancer patients with telomerase, a gene that prevents cellular senescence. Examination of these cell lines for their morphologies and proliferative capacities, their abilities to grow in low serum, to respond to androgen stimulation, to grow above the agar layer, to form tumors in SCID mice, suggests that they may serve as valid, useful tools for the elucidation of early events in prostate tumorigenesis. Furthermore, the chromosome alterations observed in these immortalized cell lines expressing aspects of the malignant phenotypes imply that these cell lines accurately recapitulate the genetic composition of primary tumors. These novel in vitro models may offer unique models for the study of prostate carcinogenesis and also provide the means for testing both chemopreventive and chemotherapeutic agents.

  5. Appalachian mountaintop mining particulate matter induces neoplastic transformation of human bronchial epithelial cells and promotes tumor formation.

    PubMed

    Luanpitpong, Sudjit; Chen, Michael; Knuckles, Travis; Wen, Sijin; Luo, Juhua; Ellis, Emily; Hendryx, Michael; Rojanasakul, Yon

    2014-11-04

    Epidemiological studies suggest that living near mountaintop coal mining (MTM) activities is one of the contributing factors for high lung cancer incidence. The purpose of this study was to investigate the long-term carcinogenic potential of MTM particulate matter (PMMTM) exposure on human bronchial epithelial cells. Our results show that chronic exposure (3 months) to noncytotoxic, physiological relevant concentration (1 μg/mL) of PMMTM, but not control particle PMCON, induced neoplastic transformation, accelerated cell proliferation, and enhanced cell migration of the exposed lung cells. Xenograft transplantation of the PMMTM-exposed cells in mice caused no apparent tumor formation, but promoted tumor growth of human lung carcinoma H460 cells, suggesting the tumor-promoting effect of PMMTM. Chronic exposure to the main inorganic chemical constituent of PMMTM, molybdenum but not silica, similarly induced cell transformation and tumor promotion, suggesting the contribution of molybdenum, at least in part, in the PMMTM effects. These results provide new evidence for the carcinogenic potential of PMMTM and support further risk assessment and implementation of exposure control for PMMTM.

  6. Epithelial ovarian cancer-secreted exosomal miR-222-3p induces polarization of tumor-associated macrophages.

    PubMed

    Ying, Xiang; Wu, Quanfeng; Wu, Xiaoli; Zhu, Qinyi; Wang, Xinjing; Jiang, Lu; Chen, Xin; Wang, Xipeng

    2016-07-12

    Cancer secreted exosomal miRNAs are emerging as mediators between tumor-stoma crosstalk. Here, we show epithelial ovarian cancer (EOC)-derived exosomes activated macrophages to a tumor-associated macrophage (TAM)-like phenotype with SOCS3/STAT3 pathway involvement, which could facilitate the progression of cancer. MiR-222-3p was enrichment in exosomes released from EOC cells and it could be transferred to macrophages. Overexpression of miR-222-3p in macrophages induced polarization of the M2 phenotype. Luciferase assay verified miR-222-3p targeted SOCS3 genes and expression of SOCS3 was decreased after transfection with a miR-222-3p mimic. Down-regulation of SOCS3 correlated with an increased expression of STAT3 activation. MiR-222-3p could be detected in the exosomes from serum and its levels were related to EOC. These observations propose tumor-derived exosomal miR-222-3p is an effective regulator in the polarization of tumor-promoting M2 macrophages and may be a biomarker of EOC.

  7. Linking of mPGES-1 and iNOS activates stem-like phenotype in EGFR-driven epithelial tumor cells.

    PubMed

    Terzuoli, Erika; Finetti, Federica; Costanza, Filomena; Giachetti, Antonio; Ziche, Marina; Donnini, Sandra

    2017-03-01

    Inflammatory prostaglandin E-2 (PGE-2) favors cancer progression in epithelial tumors characterized by persistent oncogene input. However, its effects on tumor cell stemness are poorly understood at molecular level. Here we describe two epithelial tumor cells A431 and A459, originating from human lung and skin tumors, in which epithelial growth factor (EGF) induces sequential up-regulation of mPGES-1 and iNOS enzymes, producing an inflammatory intracellular milieu. We demonstrated that concerted action of EGF, mPGES-1 and iNOS causes sharp changes in cell phenotype demonstrated by acquisition of stem-cell features and activation of the epithelial-mesenchymal transition (EMT). When primed with EGF, epithelial tumor cells transfected with mPGES-1 or iNOS to ensure steady enzyme levels display major stem-like and EMT markers, such as reduction in E-cadherin with a concomitant rise in vimentin, ALDH-1, CD133 and ALDH activity. Tumorsphere studies with these cells show increased sphere number and size, enhanced migratory and clonogenic capacity and sharp changes in EMT markers, indicating activation of this process. The concerted action of the enzymes forms a well-orchestrated cascade where expression of iNOS depends on overexpression of mPGES-1. Indeed, we show that through its downstream effectors (PGE-2, PKA, PI3K/Akt), mPGES-1 recruits non-canonical transcription factors, thus facilitating iNOS production. In conclusion, we propose that the initial event leading to tumor stem-cell activation may be a leveraged intrinsic mechanism in which all players are either inherent constituents (EGF) or highly inducible proteins (mPGES-1, iNOS) of tumor cells. We suggest that incipient tumor aggressiveness may be moderated by reducing pivotal input of mPGES-1.

  8. Anti-Epithelial Cell Adhesion Molecule Antibodies and the Detection of Circulating Normal-Like Breast Tumor Cells

    PubMed Central

    Kraan, Jaco; Bolt, Joan; van der Spoel, Petra; Elstrodt, Fons; Schutte, Mieke; Martens, John W. M.; Gratama, Jan-Willem; Sleijfer, Stefan; Foekens, John A.

    2009-01-01

    Identification of specific subtypes of circulating tumor cells in peripheral blood of cancer patients can provide information about the biology of metastasis and improve patient management. However, to be effective, the method used to identify circulating tumor cells must detect all tumor cell types. We investigated whether the five subtypes of human breast cancer cells that have been defined by global gene expression profiling—normal-like, basal, HER2-positive, and luminal A and B—were identified by CellSearch, a US Food and Drug Administration–approved test that uses antibodies against the cell surface–expressed epithelial cell adhesion molecule (EpCAM) to isolate circulating tumor cells. We used global gene expression profiling to determine the subtypes of a well-defined panel of 34 human breast cancer cell lines (15 luminal, nine normal-like, five basal-like, and five Her2-positive). We mixed 50-150 cells from 10 of these cell lines with 7.5 mL of blood from a single healthy human donor, and the mixtures were subjected to the CellSearch test to isolate the breast cancer cells. We found that the CellSearch isolation method, which uses EpCAM on the surface of circulating tumor cells for cell isolation, did not recognize, in particular, normal-like breast cancer cells, which in general have aggressive features. New tests that include antibodies that specifically recognize normal-like breast tumor cells but not cells of hematopoietic origin are needed. PMID:19116383

  9. Expression of preoperative KISS1 gene in tumor tissue with epithelial ovarian cancer and its prognostic value.

    PubMed

    Cao, Fang; Chen, Liping; Liu, Manhua; Lin, Weiwei; Ji, Jinlong; You, Jun; Qiao, Fenghai; Liu, Hongbin

    2016-11-01

    Our study aimed to elucidate the role of Kisspeptin (KISS1) in tumor tissues of patients with epithelial ovarian cancer (EOC) and investigate the prognostic value of this biomarker.Forty EOC patients and 20 uterine fibroids female patients with healthy ovaries undergoing cytoreductive surgery between January 2010 and January 2014 in our hospital were enrolled in this study. KISS1 expression in tumor and normal tissues was detected. Correlations between clinic-pathologic variables and KISS1 expression in EOC tissues and the prognostic value of KISS1 for overall survival were evaluated.During the follow-up of 11.2 to 62.1 months, the overall survival rate and mean survival time were 28.9% (11/38) and 38.35 ± 2.84 months. Preoperative KISS1 mRNA was higher in tumor tissue than in normal tissue (P <0.001), and it was associated with histologic grade of tumor, surgical FIGO stage, metastasis, and residual tumor size (all P <0.05). Multivariate survival analysis indicated significant influence of residual tumor size (HR = 2.357, P = 0.039) and preoperative KISS1 mRNA (HR = 0.0001, P <0.001) on mean survival time. Patients with low KISS1 mRNA expression had shorter survival time than those with high expression (P = 0.001).Preoperative KISS1 mRNA was a potential prognostic biomarker for EOC, and high preoperative KISS1 expression indicated a favorable prognosis.

  10. Expression of preoperative KISS1 gene in tumor tissue with epithelial ovarian cancer and its prognostic value

    PubMed Central

    Cao, Fang; Chen, Liping; Liu, Manhua; Lin, Weiwei; Ji, Jinlong; You, Jun; Qiao, Fenghai; Liu, Hongbin

    2016-01-01

    Abstract Our study aimed to elucidate the role of Kisspeptin (KISS1) in tumor tissues of patients with epithelial ovarian cancer (EOC) and investigate the prognostic value of this biomarker. Forty EOC patients and 20 uterine fibroids female patients with healthy ovaries undergoing cytoreductive surgery between January 2010 and January 2014 in our hospital were enrolled in this study. KISS1 expression in tumor and normal tissues was detected. Correlations between clinic-pathologic variables and KISS1 expression in EOC tissues and the prognostic value of KISS1 for overall survival were evaluated. During the follow-up of 11.2 to 62.1 months, the overall survival rate and mean survival time were 28.9% (11/38) and 38.35 ± 2.84 months. Preoperative KISS1 mRNA was higher in tumor tissue than in normal tissue (P <0.001), and it was associated with histologic grade of tumor, surgical FIGO stage, metastasis, and residual tumor size (all P <0.05). Multivariate survival analysis indicated significant influence of residual tumor size (HR = 2.357, P = 0.039) and preoperative KISS1 mRNA (HR = 0.0001, P <0.001) on mean survival time. Patients with low KISS1 mRNA expression had shorter survival time than those with high expression (P = 0.001). Preoperative KISS1 mRNA was a potential prognostic biomarker for EOC, and high preoperative KISS1 expression indicated a favorable prognosis. PMID:27861355

  11. Berberine reverses epithelial-to-mesenchymal transition and inhibits metastasis and tumor-induced angiogenesis in human cervical cancer cells.

    PubMed

    Chu, Shu-Chen; Yu, Cheng-Chia; Hsu, Li-Sung; Chen, Kuo-Shuen; Su, Mei-Yu; Chen, Pei-Ni

    2014-12-01

    Metastasis is the most common cause of cancer-related death in patients, and epithelial-to-mesenchymal transition (EMT) is essential for cancer metastasis, which is a multistep complicated process that includes local invasion, intravasation, extravasation, and proliferation at distant sites. When cancer cells metastasize, angiogenesis is also required for metastatic dissemination, given that an increase in vascular density will allow easier access of tumor cells to circulation, and represents a rational target for therapeutic intervention. Berberine has several anti-inflammation and anticancer biologic effects. In this study, we provided molecular evidence that is associated with the antimetastatic effect of berberine by showing a nearly complete inhibition on invasion (P < 0.001) of highly metastatic SiHa cells via reduced transcriptional activities of matrix metalloproteinase-2 and urokinase-type plasminogen activator. Berberine reversed transforming growth factor-β1-induced EMT and caused upregulation of epithelial markers such as E-cadherin and inhibited mesenchymal markers such as N-cadherin and snail-1. Selective snail-1 inhibition by snail-1-specific small interfering RNA also showed increased E-cadherin expression in SiHa cells. Berberine also reduced tumor-induced angiogenesis in vitro and in vivo. Importantly, an in vivo BALB/c nude mice xenograft model and tail vein injection model showed that berberine treatment reduced tumor growth and lung metastasis by oral gavage, respectively. Taken together, these findings suggested that berberine could reduce metastasis and angiogenesis of cervical cancer cells, thereby constituting an adjuvant treatment of metastasis control.

  12. Adoptive Immunotherapy for Epithelial Ovarian Cancer Using T-cells Simultaneously Targeted to Tumor and Tumor-Associated Macrophages

    DTIC Science & Technology

    2013-12-01

    Figure   10   that   demonstrate   ring   enhancement   around   the   viable   circumference   of   the   tumor.   When...in head and neck cancer. Taken together, it is logical to build on this experience by developing the use of TiN-4+ T-cell immunotherapy for the

  13. Outcomes of dogs with grade 3 mast cell tumors: 43 cases (1997-2007).

    PubMed

    Hume, Carrie Tupper; Kiupel, Matti; Rigatti, Lora; Shofer, Frances S; Skorupski, Katherine A; Sorenmo, Karin U

    2011-01-01

    This study reports the outcomes of dogs with grade 3 mast cell tumors (MCTs). Clinical and histopathological data were available for 43 dogs. Median progression-free survival (PFS) and overall survival (OS) were 133 and 257 days, respectively. Tumor size, lymph node (LN) status, and mitotic index (MI) significantly influenced PFS in univariate analysis. Tumor size and LN status remained significant in the multivariate analysis. Lymph node status, local tumor control, LN treatment, and MI significantly influenced OS in univariate analysis but only LN status remained significant in multivariate analysis. These results confirm that locoregional control improves outcomes in patients with grade 3 MCTs.

  14. The Inflammatory Cytokine Tumor Necrosis Factor-α Generates an Autocrine Tumor-Promoting Network in Epithelial Ovarian Cancer Cells

    PubMed Central

    Kulbe, Hagen; Thompson, Richard; Wilson, Julia L.; Robinson, Stephen; Hagemann, Thorsten; Fatah, Rewas; Gould, David; Ayhan, Ayse; Balkwill, Frances

    2009-01-01

    Constitutive expression of the inflammatory cytokine tumor necrosis factor-α (TNF-α) is characteristic of malignant ovarian surface epithelium. We investigated the hypothesis that this autocrine action of TNF-α generates and sustains a network of other mediators that promote peritoneal cancer growth and spread. When compared with two ovarian cancer cell lines that did not make TNF-α, constitutive production of TNF-α was associated with greater release of the chemokines CCL2 and CXCL12, the cytokines interleukin-6 (IL-6) and macrophage migration-inhibitory factor (MIF), and the angiogenic factor vascular endothelial growth factor (VEGF). TNF-α production was associated also with increased peritoneal dissemination when the ovarian cancer cells were xenografted. We next used RNA interference to generate stable knockdown of TNF-α in ovarian cancer cells. Production of CCL2, CXCL12, VEGF, IL-6, and MIF was decreased significantly in these cells compared with wild-type or mock-transfected cells, but in vitro growth rates were unaltered. Tumor growth and dissemination in vivo were significantly reduced when stable knockdown of TNF-α was achieved. Tumors derived from TNF-α knockdown cells were noninvasive and well circumscribed and showed high levels of apoptosis, even in the smallest deposits. This was reflected in reduced vascularization of TNF-α knockdown tumors. Furthermore, culture supernatants from such cells failed to stimulate endothelial cell growth in vitro. We conclude that autocrine production of TNF-α by ovarian cancer cells stimulates a constitutive network of other cytokines, angiogenic factors, and chemokines that may act in an autocrine/paracrine manner to promote colonization of the peritoneum and neovascularization of developing tumor deposits. PMID:17234767

  15. Brown tumor of secondary hyperparathyroidism: surgical approach and clinical outcome.

    PubMed

    Queiroz, Isaac Vieira; Queiroz, Samara Pereira; Medeiros, Rui; Ribeiro, Rodolfo Bonfim; Crusoé-Rebello, Iêda Margarida; Leão, Jair Carneiro

    2016-12-01

    Secondary hyperparathyroidism is a frequent complication of chronic renal failure. The brown tumor is an unusual presentation of fibrous osteitis that represents a serious complication of renal osteodystrophy, affecting predominantly the hands, feet, skull, and facial bones. The aim of this paper is to describe the case of a 53-year-old female patient, with renal failure who has been on dialysis for 6 years and developed severe secondary hyperparathyroidism and brown tumor of the maxilla and mandible, confirmed by incisional biopsy. Parathyroidectomy was indicated as a result of rapid growth of the tumor and the maintenance of laboratory findings. Despite the normalization of serum parathyroid hormone and alkaline phosphatase, tumor regression was slow and patient's important functional and esthetic deficits persisted. Excision of the mandible tumor was conservative. Osteoplasty was recommended because during a 5-year follow-up there was regression of the lesion, decreased pain, bleeding, and tooth mobility.

  16. Transformation of epithelial cells through recruitment leads to polyclonal intestinal tumors

    PubMed Central

    Thliveris, Andrew T.; Schwefel, Brittany; Clipson, Linda; Plesh, Lauren; Zahm, Christopher D.; Leystra, Alyssa A.; Washington, Mary Kay; Sullivan, Ruth; Deming, Dustin A.; Newton, Michael A.; Halberg, Richard B.

    2013-01-01

    Intestinal tumors from mice and humans can have a polyclonal origin. Statistical analyses indicate that the best explanation for this source of intratumoral heterogeneity is the presence of interactions among multiple progenitors. We sought to better understand the nature of these interactions. An initial progenitor could recruit others by facilitating the transformation of one or more neighboring cells. Alternatively, two progenitors that are independently initiated could simply cooperate to form a single tumor. These possibilities were tested by analyzing tumors from aggregation chimeras that were generated by fusing together embryos with unequal predispositions to tumor development. Strikingly, numerous polyclonal tumors were observed even when one genetic component was highly, if not completely, resistant to spontaneous tumorigenesis in the intestine. Moreover, the observed number of polyclonal tumors could be explained by the facilitated transformation of a single neighbor within 144 μm of an initial progenitor. These findings strongly support recruitment instead of cooperation. Thus, it is conceivable that these interactions are necessary for tumors to thrive, so blocking them might be a highly effective method for preventing the formation of tumors in the intestine and other tissues. PMID:23798428

  17. GLUT3 is induced during epithelial-mesenchymal transition and promotes tumor cell proliferation in non-small cell lung cancer

    PubMed Central

    2014-01-01

    Background Alterations in glucose metabolism and epithelial-mesenchymal transition (EMT) constitute two important characteristics of carcinoma progression toward invasive cancer. Despite an extensive characterization of each of them separately, the links between EMT and glucose metabolism of tumor cells remain elusive. Here we show that the neuronal glucose transporter GLUT3 contributes to glucose uptake and proliferation of lung tumor cells that have undergone an EMT. Results Using a panel of human non-small cell lung cancer (NSCLC) cell lines, we demonstrate that GLUT3 is strongly expressed in mesenchymal, but not epithelial cells, a finding corroborated in hepatoma cells. Furthermore, we identify that ZEB1 binds to the GLUT3 gene to activate transcription. Importantly, inhibiting GLUT3 expression reduces glucose import and the proliferation of mesenchymal lung tumor cells, whereas ectopic expression in epithelial cells sustains proliferation in low glucose. Using a large microarray data collection of human NSCLCs, we determine that GLUT3 expression correlates with EMT markers and is prognostic of poor overall survival. Conclusions Altogether, our results reveal that GLUT3 is a transcriptional target of ZEB1 and that this glucose transporter plays an important role in lung cancer, when tumor cells loose their epithelial characteristics to become more invasive. Moreover, these findings emphasize the development of GLUT3 inhibitory drugs as a targeted therapy for the treatment of patients with poorly differentiated tumors. PMID:25097756

  18. Clinical superficial Raman probe aimed for epithelial tumor detection: Phantom model results

    PubMed Central

    Agenant, Michelle; Grimbergen, Matthijs; Draga, Ronald; Marple, Eric; Bosch, Ruud; van Swol, Christiaan

    2014-01-01

    Abstract: A novel clinical Raman probe for sampling superficial tissue to improve in vivo detection of epithelial malignancies is compared to a non-superficial probe regarding depth response function and signal-to-noise ratio. Depth response measurements were performed in a phantom tissue model consisting of a polyethylene terephthalate disc in an 20%-Intralipid® solution. Sampling ranges of 0-200 and 0-300 μm were obtained for the superficial and non-superficial probe, respectively. The mean signal-to-noise ratio of the superficial probe increased by a factor of 2 compared with the non-superficial probe. This newly developed superficial Raman probe is expected to improve epithelial cancer detection in vivo. PMID:24761301

  19. Outcomes of surgical management of bowel obstruction in relapsed epithelial ovarian cancer (EOC).

    PubMed

    Kolomainen, D F; Daponte, A; Barton, D P J; Pennert, K; Ind, T E J; Bridges, J E; Shepherd, J H; Gore, M E; Kaye, S B; Riley, J

    2012-04-01

    To describe the outcomes of surgical management of bowel obstruction in relapsed epithelial ovarian cancer (EOC) so as to define the criteria for patient selection for palliative surgery. 90 women with relapsed EOC underwent palliative surgery for bowel obstruction between 1992 and 2008. Median age at time of surgery for bowel obstruction was 57 years (range, 26 to 85 years). All patients had received at least one line of platinum-based chemotherapy. Median time from diagnosis of primary disease to documented bowel obstruction requiring surgery was 19.5 months (range, 29 days-14 years). Median interval from date of completed course of chemotherapy preceding surgery for bowel obstruction was 3.8 months (range, 5 days-14 years). Ascites was present in 38/90(42%). 49/90(54%) underwent emergency surgery for bowel obstruction. The operative mortality and morbidity rates were 18% and 27%, respectively. Successful palliation, defined as adequate oral intake at least 60 days postoperative, was achieved in 59/90(66%). Only the absence of ascites was identified as a predictor for successful palliation (p=0.049). The median overall survival (OS) was 90.5 days (range, <1 day-6 years). Optimal debulking, treatment-free interval (TFI) and elective versus emergency surgery did not predict survival or successful palliation from surgery for bowel obstruction (p>0.05). Surgery for bowel obstruction in relapsed EOC is associated with a high morbidity and mortality rate especially in emergency cases when compared to other gynaecological oncological procedures. Palliation can be achieved in almost two thirds of cases, is equally likely in elective and emergency cases but is less likely in those with ascites. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Perioperative fluid status and surgical outcomes in patients undergoing cytoreductive surgery for advanced epithelial ovarian cancer.

    PubMed

    Desale, M G; Tanner, E J; Sinno, A K; Angarita, A Africano; Fader, A N; Stone, R L; Levinson, K L; Bristow, R E; Roche, K Long

    2016-10-28

    The objective of this study is to investigate the impact of fluid status on perioperative outcomes of patients undergoing cytoreductive surgery (CRS) for advanced epithelial ovarian cancer (EOC). Patients undergoing CRS for stage III or IV EOC at a comprehensive cancer center from 12/2010 to 05/2015 were identified. Those who underwent upper abdominal procedures or colon resections were included. Demographic, perioperative, and 30-day complication data were collected. Perioperative weight change was utilized as a surrogate for fluid status. The time to diuresis (tD) was defined as the postoperative day the patient's weight began to downtrend. One hundred ten patients were included. Median age was 62years and median BMI 25.8kg/m(2). The majority (74.5%) were stage IIIC. At least 1 bowel resection was performed in 60 cases (54.5%). A median of 5381mL of crystalloid (range 1000-17,550mL) and 500mL of colloids (range 0-2783mL) was given intraoperatively. The median perioperative weight change was +7.3kg (range-0.9kg to +35.7kg). The median tD was 3days (range 1-17days). On univariate analysis, net positive fluid status was associated with unscheduled reoperation, anastomotic leak, surgical site infections (SSI), and length of stay >5days. On multivariate analysis, fluid status was independently associated with SSI (p=0.01). Perioperative fluid excess is common in patients undergoing CRS for EOC and is independently associated with SSI. Copyright © 2016. Published by Elsevier Inc.

  1. The Impact of Ethnicity-Dependent Differences in Breast Epithelial Hierarchy on Tumor Incidence and Characteristics

    DTIC Science & Technology

    2016-10-01

    discovered unique normal breast epithelial population in AA women determines the phenotype of breast cancer in this ethnic group. Keywords...generation. P a g e | 4 PROCR+/EpCAM- phenotype, which represents a unique population of cells enriched in African American women and displays...mCherry within cells by fluorescence imaging indicated the integration of mutated genes into the genome (Fig. 2). GFP, YFP or mCherry populations were

  2. Intramedullary Spinal Cord Tumors: Part II—Management Options and Outcomes

    PubMed Central

    Samartzis, Dino; Gillis, Christopher C.; Shih, Patrick; O'Toole, John E.; Fessler, Richard G.

    2015-01-01

    Study Design Broad narrative review. Objectives Intramedullary spinal cord tumors (IMSCT) are uncommon lesions that can affect any age group or sex. However, numerous IMSCT exist and the clinical course of each tumor varies. The following article addresses the various management options and outcomes in patients with IMSCT. Methods An extensive review of the peer-reviewed literature was performed, addressing management options and clinical outcomes of patients with IMSCT. Results Early diagnosis and intervention are essential to obtain optimal functional outcome. Each IMSCT have specific imaging characteristics, which help in the clinical decision-making and prognostication. A comprehension of the tumor pathology and the clinical course associated with each tumor can allow for the proper surgical and nonsurgical management of these tumors, and reduce any associated morbidity and mortality. Recent advances in the operative management of such lesions have increased the success rate of tumor removal while minimizing iatrogenic-related trauma to the patient and, in tandem, improving patient outcomes. Conclusions Awareness and understanding of IMSCT is imperative to design proper management and obtain optimal patient outcomes. Meticulous operative technique and the use of surgical adjuncts are essential to accomplish proper tumor removal, diminish the risk of recurrence, and preserve neurologic function. Operative management of IMSCT should be individualized and based on tumor type, location, and dimensional extensions. To assist with preoperative and intraoperative decision-making, a general algorithm is provided. PMID:26933620

  3. The gene expression landscape of breast cancer is shaped by tumor protein p53 status and epithelial-mesenchymal transition

    PubMed Central

    2012-01-01

    Introduction Gene expression data derived from clinical cancer specimens provide an opportunity to characterize cancer-specific transcriptional programs. Here, we present an analysis delineating a correlation-based gene expression landscape of breast cancer that identifies modules with strong associations to breast cancer-specific and general tumor biology. Methods Modules of highly connected genes were extracted from a gene co-expression network that was constructed based on Pearson correlation, and module activities were then calculated using a pathway activity score. Functional annotations of modules were experimentally validated with an siRNA cell spot microarray system using the KPL-4 breast cancer cell line, and by using gene expression data from functional studies. Modules were derived using gene expression data representing 1,608 breast cancer samples and validated in data sets representing 971 independent breast cancer samples as well as 1,231 samples from other cancer forms. Results The initial co-expression network analysis resulted in the characterization of eight tightly regulated gene modules. Cell cycle genes were divided into two transcriptional programs, and experimental validation using an siRNA screen showed different functional roles for these programs during proliferation. The division of the two programs was found to act as a marker for tumor protein p53 (TP53) gene status in luminal breast cancer, with the two programs being separated only in luminal tumors with functional p53 (encoded by TP53). Moreover, a module containing fibroblast and stroma-related genes was highly expressed in fibroblasts, but was also up-regulated by overexpression of epithelial-mesenchymal transition factors such as transforming growth factor beta 1 (TGF-beta1) and Snail in immortalized human mammary epithelial cells. Strikingly, the stroma transcriptional program related to less malignant tumors for luminal disease and aggressive lymph node positive disease among

  4. Comprehensive proteome quantification reveals NgBR as a new regulator for epithelial-mesenchymal transition of breast tumor cells.

    PubMed

    Zhao, Baofeng; Xu, Bo; Hu, Wenquan; Song, Chunxia; Wang, Fangjun; Liu, Zhong; Ye, Mingliang; Zou, Hanfa; Miao, Qing R

    2015-01-01

    Nogo-B receptor (NgBR) is a type I receptor and specifically binds to ligand Nogo-B. Our previous work has shown that NgBR is highly expressed in human breast invasive ductal carcinoma. Here, comprehensive proteome quantification was performed to examine the alteration of protein expression profile in MDA-MB-231 breast tumor cells after knocking down NgBR using lentivirus-mediated shRNA approach. Among a total of 1771 proteins feasibly quantified, 994 proteins were quantified in two biological replicates with RSD <50%. There are 122 proteins significantly down-regulated in NgBR knockdown MDA-MB-231 breast tumor cells, such as vimentin and S100A4, well-known markers for mesenchymal cells, and CD44, a stemness indicator. The decrease of vimentin, S100A4 and CD44 protein expression levels was further confirmed by Western blot analysis. MDA-MB-231 cells are typical breast invasive ductal carcinoma cells showing mesenchymal phenotype. Cell morphology analysis demonstrates NgBR knockdown in MDA-MB-231 cells results in reversibility of epithelial-mesenchymal transition (EMT), which is one of the major mechanisms involved in breast cancer metastasis. Furthermore, we demonstrated that NgBR knockdown in MCF-7 cells significantly prevented the TGF-β-induced EMT process as determined by the morphology change, and staining of E-cadherin intercellular junction as well as the decreased expression of vimentin. Our previous publication showed that NgBR is highly expressed in human breast invasive ductal carcinoma. However, the roles of NgBR and NgBR-mediated signaling pathway in breast tumor cells are still unclear. Here, we not only demonstrated that the quantitative proteomics analysis is a powerful tool to investigate the global biological function of NgBR, but also revealed that NgBR is involved in the transition of breast epithelial cells to mesenchymal stem cells, which is one of the major mechanisms involved in breast cancer metastasis. These findings provide new insights

  5. Outcome of allo simple limbal epithelial transplantation (alloSLET) in the early stage of ocular chemical injury.

    PubMed

    Iyer, Geetha; Srinivasan, Bhaskar; Agarwal, Shweta; Tarigopula, Anil

    2017-06-01

    To analyse the outcome of allo simple limbal epithelial transplantation (alloSLET) in eyes in the early stage following ocular chemical injury to achieve rapid epithelialisation. Records of 18 eyes of 17 patients who underwent alloSLET between April 2013 and Jan 2016 were analysed retrospectively. Patients with grade 4 or worse Dua's classification for chemical injury, who presented within a month of the injury or with a non-healing epithelial defect since the injury despite earlier medical or surgical interventions, were included in the study. The time to epithelialisation was the primary outcome measure and the best corrected visual acuity, the clinically assessed epithelial phenotype and symblepharon formation were the secondary outcome measures. The mean time to epithelialisation was noted to be 22.5±9.14 days. A best corrected visual acuity of better than 20/120 was achieved in 13 eyes in a mean duration of 33.06+10.73 days following alloSLET. Corneal phenotype with complete epithelialisation was achieved in the immediate postoperative period in 17 of the 18 eyes (94.11%). Seven eyes had a gradual failure of the allograft and 5 eyes underwent subsequent limbal autograft. Symblepharon formation involving one to two quadrants was noted in 3 eyes (16.7%). AlloSLET seems to be a useful technique to achieve rapid epithelialisation in severe chemical injuries thereby preventing the adverse effects of delayed epithelial healing. Visual rehabilitative procedures in the chronic phase of chemical injury, in most instances following an alloSLET in the acute stage, did not require keratoplasty, either lamellar or penetrating. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  6. SPARC (osteonectin) in breast tumors of different histologic types and its role in the outcome of invasive ductal carcinoma.

    PubMed

    Hsiao, Yi-Hsuan; Lien, Huang-Chun; Hwa, Hsiao-Lin; Kuo, Wen-Hung; Chang, King-Jen; Hsieh, Fon-Jou

    2010-01-01

    The purpose of this study was to characterize the immunohistochemical distribution of secreted protein acidic and rich in cystein (SPARC) in benign and malignant breast tumors of different histologic types and define its association with the outcome of invasive ductal carcinoma (IDC) patients. A total of 286 samples of benign and malignant breast lesions between 1994 and 2005 were retrieved from National Taiwan University Hospital. Up to 11 years clinical follow-up data were available for 185 patients with IDC. Immunohistochemistry staining with SPARC was performed in tissue microarray or whole section. The association of expression of SPARC and cumulative overall survival of IDC patients were analyzed using Kaplan-Meier survival analysis and Cox regression analysis. Secreted protein acidic and rich in cystein was not expressed in benign breast phylloides and all benign breast tumors, while expressed in 17.2% of IDC, 85% of metaplastic carcinoma of the breast (MCB), and all malignant breast phylloides. Secreted protein acidic and rich in cystein was strongly expressed in mesenchymal components of MCB and expression levels in epithelial components were variable. The correlation of positive expression of SPARC and poor long-term survival in IDC is significant (p = 0.004). Individuals with positive SPARC expression had 2.34 times higher hazard of death compared with those with negative SPARC expression after adjusting for factors including positive lymph node, TNM tumor stage, estrogen receptor, and progesterone receptor. Secreted protein acidic and rich in cystein may be useful as a prognostic indicator for IDC.

  7. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer.

    PubMed

    Stevanović, Sanja; Pasetto, Anna; Helman, Sarah R; Gartner, Jared J; Prickett, Todd D; Howie, Bryan; Robins, Harlan S; Robbins, Paul F; Klebanoff, Christopher A; Rosenberg, Steven A; Hinrichs, Christian S

    2017-04-14

    Immunotherapy has clinical activity in certain virally associated cancers. However, the tumor antigens targeted in successful treatments remain poorly defined. We used a personalized immunogenomic approach to elucidate the global landscape of antitumor T cell responses in complete regression of human papillomavirus-associated metastatic cervical cancer after tumor-infiltrating adoptive T cell therapy. Remarkably, immunodominant T cell reactivities were directed against mutated neoantigens or a cancer germline antigen, rather than canonical viral antigens. T cells targeting viral tumor antigens did not display preferential in vivo expansion. Both viral and nonviral tumor antigen-specific T cells resided predominantly in the programmed cell death 1 (PD-1)-expressing T cell compartment, which suggests that PD-1 blockade may unleash diverse antitumor T cell reactivities. These findings suggest a new paradigm of targeting nonviral antigens in immunotherapy of virally associated cancers. Copyright © 2017, American Association for the Advancement of Science.

  8. Nanoelectromechanical Chip (NELMEC) Combination of Nanoelectronics and Microfluidics to Diagnose Epithelial and Mesenchymal Circulating Tumor Cells from Leukocytes.

    PubMed

    Hosseini, Seied Ali; Abdolahad, Mohammad; Zanganeh, Somayeh; Dahmardeh, Mahyar; Gharooni, Milad; Abiri, Hamed; Alikhani, Alireza; Mohajerzadeh, Shams; Mashinchian, Omid

    2016-02-17

    An integrated nano-electromechanical chip (NELMEC) has been developed for the label-free distinguishing of both epithelial and mesenchymal circulating tumor cells (ECTCs and MCTCs, respectively) from white blood cells (WBCs). This nanoelectronic microfluidic chip fabricated by silicon micromachining can trap large single cells (>12 µm) at the opening of the analysis microchannel arrays. The nature of the captured cells is detected using silicon nanograss (SiNG) electrodes patterned at the entrance of the channels. There is an observable difference between the membrane capacitance of the ECTCs and MCTCs and that of WBCs (measured using SiNG electrodes), which is the key indication for our diagnosis. The NELMEC chip not only solves the problem of the size overlap between CTCs and WBCs but also detects MCTCs without the need for any markers or tagging processes, which has been an important problem in previously reported CTC detection systems. The great conductivity of the gold-coated SiNG nanocontacts as well as their safe penetration into the membrane of captured cells, facilitate a precise and direct signal extraction to distinguish the type of captured cell. The results achieved from epithelial (MCF-7) and mesenchymal (MDA-MB231) breast cancer cells circulated in unprocessed blood suggest the significant applications for these diagnostic abilities of NELMEC. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in normal prostate epithelial cells.

    PubMed

    Nesterov, Alexandre; Ivashchenko, Yuri; Kraft, Andrew S

    2002-02-07

    TRAIL is a pro-apoptotic cytokine believed to selectively kill cancer cells without harming normal ones. However, we found that in normal human prostate epithelial cells (PrEC) TRAIL is capable of inducing apoptosis as efficiently as in some tumor cell lines. At the same time, TRAIL did not cause apoptosis in several other human primary cell lines: aorta smooth muscle cells, foreskin fibroblasts, and umbilical vein endothelial cells. Compared to these primary cells, PrEC were found to contain significantly fewer TRAIL receptors DcR1 and DcR2 which are not capable of conducting the apoptotic signal. This result suggests that the unusual sensitivity of PrEC to TRAIL may result from their deficiency in anti-apoptotic decoy receptors. The protein synthesis inhibitor cycloheximide significantly enhanced TRAIL toxicity toward PrEC as measured by tetrazolium conversion but had little or no effect on other TRAIL-induced apoptotic responses. Although cycloheximide did not further accelerate the processing of caspases 3 and 8, it significantly enhanced cleavage of the caspase 3 substrate gelsolin, indicating that in PrEC a protein(s) with a short half-life may inhibit the activity of the executioner caspases toward specific substrates. As the majority of prostate cancers are derived from epithelial cells, our data suggest the possibility that TRAIL could be a useful treatment for the early stages of prostate cancer.

  10. Induction of duodenal mucosal tumors of intestinal epithelial cell origin showing frequent nuclear β-catenin accumulation similar to the concurrently induced colorectal tumors in rats after treatment with azoxymethane.

    PubMed

    Kikuchihara, Yoh; Onda, Nobuhiko; Kimura, Masayuki; Kangawa, Yumi; Mizukami, Sayaka; Yoshida, Toshinori; Shibutani, Makoto

    2015-01-01

    Azoxymethane (AOM) is a potent carcinogen used for induction of colon tumors in rats and mice. It is also known that AOM treatment induces small bowel tumors in addition to colorectal tumors in rats. The present study examined the histogenesis of AOM-induced rat duodenal tumors in comparison with concurrently induced colorectal tumors by histochemical and immunohistochemical approaches. Duodenal and colorectal tumors were positive for both periodic acid-Schiff reaction and Alcian blue staining. Immunohistochemically, duodenal tumors were positive for intestinal epithelial markers such as cytokeratin (CK) 20 (100%) and mucin (MUC) 2 (91.7%) but negative for pancreaticobiliary markers such as CK7 (100%) and MUC1 (100%). All colorectal tumors were also negative for CK7 and MUC1 but positive for CK20. Eighty percent of colorectal tumors were positive for MUC2. In addition, nuclear accumulation of β-catenin was found in duodenal tumors (70.8%), which was similar to colorectal tumors (90.0%). These results indicate that duodenal tumors induced by AOM treatment of rats were derived from intestinal epithelium. Similar to colorectal tumors, nuclear accumulation of β-catenin indicates activation of Wnt signaling as a driving force for tumor progression in AOM-induced duodenal tumors.

  11. Antibody-independent capture of circulating tumor cells of non-epithelial origin with the ApoStream® system.

    PubMed

    Balasubramanian, Priya; Kinders, Robert J; Kummar, Shivaani; Gupta, Vishal; Hasegawa, David; Menachery, Anoop; Lawrence, Scott M; Wang, Lihua; Ferry-Galow, Katherine; Davis, Darren; Parchment, Ralph E; Tomaszewski, Joseph E; Doroshow, James H

    2017-01-01

    Circulating tumor cells (CTCs) are increasingly employed for research and clinical monitoring of cancer, though most current methods do not permit the isolation of non-epithelial tumor cells. Furthermore, CTCs isolated with antibody-dependent methods are not suitable for downstream experimental uses, including in vitro culturing and implantation in vivo. In the present study, we describe the development, validation, and transfer across laboratories of a new antibody-independent device for the enrichment of CTCs from blood samples of patients with various cancer diagnoses. The ApoStream® device uses dielectrophoresis (DEP) field-flow assist to separate non-hematopoietic cells from the peripheral blood mononuclear fraction by exposing cells in a laminar flow stream to a critical alternating current frequency. The ApoStream® device was calibrated and validated in a formal cross-laboratory protocol using 3 different cancer cell lines spanning a range of distinct phenotypes (A549, MDA-MB-231, and ASPS-1). In spike-recovery experiments, cancer cell recovery efficiencies appeared independent of spiking level and averaged between 68% and 55%, depending on the cell line. No inter-run carryover was detected in control samples. Moreover, the clinical-readiness of the device in the context of non-epithelial cancers was evaluated with blood specimens from fifteen patients with metastatic sarcoma. The ApoStream® device successfully isolated CTCs from all patients with sarcomas examined, and the phenotypic heterogeneity of the enriched cells was demonstrated by fluorescence in situ hybridization or with multiplex immunophenotyping panels. Therefore, the ApoStream® technology expands the clinical utility of CTC evaluation to mesenchymal cancers.

  12. Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin

    PubMed Central

    Eswaraiah, Anand; Crombet, Tania; Piedra, Patricia; Saurez, Giselle; Iyer, Harish; Arvind, AS

    2009-01-01

    Nimotuzumab is a humanized therapeutic monoclonal antibody against epidermal growth factor receptor (EGFR). Clinical trials are ongoing globally to evaluate nimotuzumab in different indications. Nimotuzumab has been granted approval for use in squamous cell carcinoma of head and neck (SCCHN), glioma and nasopharyngeal cancer in different countries. This review focuses on the unique functional characteristics of nimotuzumab. Also, it discusses the safety and efficacy data obtained from the Phase IIb clinical trial conducted in India in SCCHN. Post marketing surveillance data from Cuba for the use of nimotuzumab in pediatric and adult glioma is also discussed. Overall, nimotuzumab has immense therapeutic potential in cancers of epithelial origin. PMID:20046573

  13. Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin.

    PubMed

    Ramakrishnan, Melarkode S; Eswaraiah, Anand; Crombet, Tania; Piedra, Patricia; Saurez, Giselle; Iyer, Harish; Arvind, A S

    2009-01-01

    Nimotuzumab is a humanized therapeutic monoclonal antibody against epidermal growth factor receptor (EGFR). Clinical trials are ongoing globally to evaluate nimotuzumab in different indications. Nimotuzumab has been granted approval for use in squamous cell carcinoma of head and neck (SCCHN), glioma and nasopharyngeal cancer in different countries. This review focuses on the unique functional characteristics of nimotuzumab. Also, it discusses the safety and efficacy data obtained from the Phase IIb clinical trial conducted in India in SCCHN. Post marketing surveillance data from Cuba for the use of nimotuzumab in pediatric and adult glioma is also discussed. Overall, nimotuzumab has immense therapeutic potential in cancers of epithelial origin.

  14. Mixed epithelial and stromal tumor of the kidney (MEST) simulating an upper tract TCC.

    PubMed

    Sountoulides, Petros; Koptsis, Michail; Metaxa, Linda; Theodosiou, Alexandros; Kikidakis, Dimitrios; Filintatzi, Chrysa; Paschalidis, Konstantinos

    2012-02-01

    We present a rare and interesting case of a mixed epithelial and stromal tumour (MEST) of the kidney. The case is unique as it involves a male patient with no history of hormonal therapy presenting with a filling defect in the renal collecting system and positive urine cytology. The patient was diagnosed with transitional cell carcinoma of the renal pelvis and subjected to nephroureterectomy, which revealed a solid tumour arising from the lower calyces and extending into the renal pelvis and upper ureter. Pathology revealed a MEST. The patient was disease-free at the 6-month follow-up.

  15. Treatment and outcome of giant cell tumors of the pelvis

    PubMed Central

    2009-01-01

    Background and purpose Giant cell tumors (GCTs) of bone rarely affect the pelvis. We report on 20 cases that have been treated at our institution during the last 20 years. Methods 20 patients with histologically benign GCT of the pelvis were included in this study. 9 tumors were primarily located in the iliosacral area, 6 in the acetabular area, and 5 in the ischiopubic area. 8 patients were treated by intralesional curettage and 6 by intralesional resection with additional curettage of the margins. 3 patients with iliacal tumors were treated by wide resection. 2 patients were treated by a combination of external beam irradiation and surgery, and 1 patient solely by irradiation. In addition, 9 patients received selective arterial embolization one day before surgery. Of the 6 patients with acetabular tumors, 1 secondarily received an endoprosthesis and 1 was primarily treated by hip transposition. The patients were followed for a median time of 3 (1–11) years. Results 1 patient with a pubic tumor developed a local recurrence 1 year after intralesional resection and additional curettage of the margins. The recurrence presented as a small soft tissue mass within the scar tissue of the gluteal muscles and was treated by resection. No secondary sarcoma was detected and none of the patients developed pulmonary metastases or multicentricity. No major complication occurred during surgery. Interpretation We conclude that most GCTs of the pelvis can be treated by intralesional procedures. For tumors of the iliac wing, wide resection can be an alternative. Surgical treatment of tumors affecting the acetabular region often results in functional impairment. Pre-surgical selective arterial embolization appears to be a safe procedure that may reduce the risk of local recurrence. PMID:19916695

  16. Functional and neuropsychological late outcomes in posterior fossa tumors in children.

    PubMed

    Lassaletta, Alvaro; Bouffet, Eric; Mabbott, Donald; Kulkarni, Abhaya V

    2015-10-01

    Tumors of the posterior fossa (PF) account for up to 60 % of all childhood intracranial tumors. Over the last decades, the mortality rate of children with posterior fossa tumors has gradually decreased. While survival has been the primary objective in most reports, quality of survival increasingly appears to be an important indicator of a successful outcome. Children with a PF tumor can sustain damage to the cerebellum and other brain structures from the tumor itself, concomitant hydrocephalus, the consequences of treatment (surgery, chemotherapy, radiotherapy), or a combination of these factors. Together, these contribute to long-term sequelae in physical functioning, neuropsychological late outcomes (including academic outcome, working memory, perception and estimation of time, and selective attention, long-term neuromotor speech deficits, and executive functioning). Long-term quality of life can also be affected by endocrinological complication or the occurrence of secondary tumors. A significant proportion of survivors of PF tumors require long-term special education services and have reduced rates of high school graduation and employment. Interventions to improve neuropsychological functioning in childhood PF tumor survivors include (1) pharmacological interventions (such as methylphenidate, modafinil, or donepezil), (2) cognitive remediation, and (3) home-based computerized cognitive training. In order to achieve the best possible outcome for survivors, and ultimately minimize long-term complications, new interventions must be developed to prevent and ameliorate the neuro-toxic effects experienced by these children.

  17. Assessment of the argyrophilic nucleolar organizer region area/nucleus ratio in ovarian serous epithelial adenomas, borderline tumors and cancers

    PubMed Central

    Danilewicz, Marian; Suzin, Jacek; Wagrowska-Danilewicz, Malgorzata; Spych, Michal; Tylinski, Wieslaw; Topczewska-Tylinska, Katarzyna; Piekarski, Janusz; Kazmierczak-Lukaszewicz, Sylwia; Cialkowska-Rysz, Aleksandra

    2013-01-01

    Introduction There is a need to assess the value of the novel potentially useful biomarkers in ovarian tumors. The aim of study was to assess the value of sAgNOR analysis in ovarian serous epithelial tumors. Material and methods The analysis was performed in ovaries from 113 patients treated operatively due to serous ovarian tumors (30 adenomas, 14 borderline tumors and 69 cancers). After silver staining of paraffin specimens from surgery, sAgNOR in tumor cells was analyzed. Additionally, the value of the argyrophilic nucleolar organizer region area/nucleus ratio (sAgNOR) in the prediction of disease-free survival (DFS) and overall survival (OS) in 52 patients with serous ovarian cancer with complete follow-ups in November 2009 was evaluated. Age, grading, radicality of surgery and FIGO staging were analyzed as additional factors. Results sAgNOR in adenomas, borderline tumors and cancers was in the following ranges: (0.73 ±0.23) × 106, (0.81 ±0.18) × 106 and (0.96 ±0.33) × 106 [AgNOR/cm2] respectively. In cancers from G1 to G3 sAgNOR was (1.02 ±0.32) × 106 (G1), (0.98 ±0.37) × 106 (G2) and (0.82 ±0.24) × 106 (G3) [AgNOR/cm2] respectively. In univariate analysis, but not in multivariate analysis, staging negatively correlated with better DFS and OS. sAgNOR, age of patients, grading and radicality of surgery were not associated with DFS or OS in either univariate or multivariate analysis. Conclusions sAgNOR analysis is not sufficient to precisely characterize cellular kinetics in serous ovarian tumors, and the analysis of sAgNOR, mAgNOR and pAgNOR should be performed commonly. The prognostic significance of sAgNOR in patients with serous ovarian cancer was not proven. PMID:23515230

  18. Myosin Light Chain Kinase Expression Induced via Tumor Necrosis Factor Receptor 2 Signaling in the Epithelial Cells Regulates the Development of Colitis-Associated Carcinogenesis

    PubMed Central

    Yamazaki, Motomi; Onizawa, Michio; Watabe, Taro; Sakamaki, Yuriko; Ichinose, Shizuko; Totsuka, Mamoru; Oshima, Shigeru; Okamoto, Ryuichi; Shimonaka, Motoyuki; Yagita, Hideo; Nakamura, Tetsuya; Watanabe, Mamoru

    2014-01-01

    It has been suggested that prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). We previously observed that the NF-κB activation in colonic epithelial cells is associated with increased tumor necrosis factor receptor 2 (TNFR2) expression in CAC development. However, the mechanism by which epithelial NF-κB activation leading to CAC is still unclear. Myosin light chain kinase (MLCK) has been reported to be responsible for the epithelial permeability associated with TNF signaling. Therefore we focused on the role of MLCK expression via TNFR2 signaling on CAC development. Pro-tumorigenic cytokines such as IL-1β, IL-6 and MIP-2 production as well as INF-γ and TNF production at the lamina propria were increased in the setting of colitis, and further in tumor tissues in associations with up-regulated TNFR2 and MLCK expressions in the epithelial cells of a CAC model. The up-regulated MLCK expression was observed in TNF-stimulated colonic epithelial cells in a dose-dependent fashion in association with up-regulation of TNFR2. Silencing TNFR2, but not TNFR1, resulted in restoration of epithelial tight junction (TJ) associated with decreased MLCK expression. Antibody-mediated blockade of TNF signaling also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results were observed with suppressing TNFR2 and MLCK expressions by inhibiting MLCK in the epithelial cells. Silencing of MLCK also resulted in suppressed TNFR2, but not TNFR1, expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in restored TJ, decreased pro-tumorigenic cytokines and reduced CAC development. These results suggest that MLCK may be a potential target for the prevention of IBD-associated tumor development. PMID:24520376

  19. Eudaimonic Well-Being and Tumor Norepinephrine in Epithelial Ovarian Cancer Patients

    PubMed Central

    Davis, Lauren Z.; Slavich, George M.; Thaker, Premal H.; Goodheart, Michael J.; Bender, David; Dahmoush, Laila; Farley, Donna; Markon, Kristian; Penedo, Frank J.; Lubaroff, David M.; Cole, Steve W.; Sood, Anil K.; Lutgendorf, Susan K.

    2015-01-01

    Background The impact of psychological well-being on physiologic processes involved in cancer progression remains unclear. Prior research has implicated adrenergic signaling in tumor growth and metastasis. Given that adrenergic signaling is influenced by both positive and negative factors, we examined how two different aspects of well-being (eudaimonic and positive affect) and psychological distress were associated with tumor norepinephrine (NE) in ovarian cancer patients. Methods Women with suspected ovarian cancer (N=365) completed psychosocial assessments pre-surgery and clinical information was obtained from medical records. Study inclusion was confirmed following histological diagnosis. Tumor NE was measured in frozen tissue samples using HPLC with electrochemical detection. We employed confirmatory factor analysis to model eudaimonic well-being, positive affect, and psychological distress, and structural equation modeling (SEM) to examine associations between these factors and tumor NE. Results Eudaimonic well-being, positive affect, and psychological distress, modeled as distinct but correlated constructs, best fit the data (i.e., compared to unitary or 2-factor models) (RMSEA=.048, CFI=.982, SRMR=.035). SEM analyses that included physical well-being, stage, histology, psychological treatment history, beta-blocker use, and caffeine use as covariates had good model fit (RMSEA=.052, CFI=.955, SRMR=.036) and showed that eudaimonic well-being was related to lower tumor NE (β=−.24, p=.045). In contrast, we found no effects for positive affect or psychological distress. Conclusion Eudaimonic well-being is associated with lower tumor NE, independent of positive affect and psychological distress. Because adrenergic signaling is implicated in tumor progression, increasing eudaimonic well-being may improve both psychological and physiologic resilience in ovarian cancer patients. PMID:26096769

  20. Glutamine fuels a vicious cycle of autophagy in the tumor stroma and oxidative mitochondrial metabolism in epithelial cancer cells

    PubMed Central

    Ko, Ying-Hui; Lin, Zhao; Flomenberg, Neal; Pestell, Richard G; Howell, Anthony; Sotgia, Federica

    2011-01-01

    Glutamine metabolism is crucial for cancer cell growth via the generation of intermediate molecules in the tricarboxylic acid (TCA) cycle, antioxidants and ammonia. The goal of the current study was to evaluate the effects of glutamine on metabolism in the breast cancer tumor microenvironment, with a focus on autophagy and cell death in both epithelial and stromal compartments. For this purpose, MCF7 breast cancer cells were cultured alone or co-cultured with nontransformed fibroblasts in media containing high glutamine and low glucose (glutamine +) or under control conditions, with no glutamine and high glucose (glutamine −). Here, we show that MCF7 cells maintained in co-culture with glutamine display increased mitochondrial mass, as compared with control conditions. Importantly, treatment with the autophagy inhibitor chloroquine abolishes the glutamine-induced augmentation of mitochondrial mass. It is known that loss of caveolin-1 (Cav-1) expression in fibroblasts is associated with increased autophagy and an aggressive tumor microenvironment. Here, we show that Cav-1 downregulation which occurs in fibroblasts maintained in co-culture specifically requires glutamine. Interestingly, glutamine increases the expression of autophagy markers in fibroblasts, but decreases expression of autophagy markers in MCF7 cells, indicating that glutamine regulates the autophagy program in a compartment-specific manner. Functionally, glutamine protects MCF7 cells against apoptosis, via the upregulation of the anti-apoptotic and anti-autophagic protein TIGAR. Also, we show that glutamine cooperates with stromal fibroblasts to confer tamoxifen-resistance in MCF7 cancer cells. Finally, we provide evidence that co-culture with fibroblasts (1) promotes glutamine catabolism, and (2) decreases glutamine synthesis in MCF7 cancer cells. Taken together, our findings suggest that autophagic fibroblasts may serve as a key source of energy-rich glutamine to fuel cancer cell mitochondrial

  1. KLF4 and PCNA identify stages of tumor initiation in a conditional model of cutaneous squamous epithelial neoplasia

    PubMed Central

    Huang MD, Conway C.; Liu, Zhaoli; Li, Xingnan; Bailey, Sarah K.; Nail, Clinton D.; Foster, K. Wade; Frost, Andra R.; Ruppert, J. Michael; Lobo-Ruppert, Susan M.

    2006-01-01

    KLF4 is induced upon growth-arrest in vitro and during epithelial maturation in vivo, and is essential for proper cell fate specification of post-mitotic cells. In spite of a normal role in post-mitotic cells, expression is upregulated and constitutive in certain tumor types. KLF4 functions as an oncogene in vitro, and enforced expression in basal cells of mouse skin rapidly induces lesions similar to hyperplasia, dysplasia and squamous cell carcinoma (SCC). Here we used conditional expression to characterize early steps in KLF4-mediated tumor initiation. In contrast to SCC-like lesions that result when using a conditional, keratin 14 promoter-dependent strategy, lower conditional expression achieved using a MMTV promoter induced only epidermal cycling within morphologically normal skin, a process we termed occult cell turnover. Surprisingly, KLF4-induced hyperplastic lesions showed increased transgene-derived mRNA and protein in maturing, PCNA-negative cells, a property of endogenous KLF4. In contrast, hyperplastic lesions induced by GLI1, a control, showed uniform transgene expression. In KLF4-induced dysplasia and SCC the complementarity of KLF4 and PCNA was replaced by concordance of the two proteins. These studies show that KLF4 transcripts are normally suppressed in cycling cells in a promoter-independent fashion, consistent with a post-transcriptional control, and reveal loss of this control in the transition from hyperplasia to dysplasia. Like the mouse tumors, human cutaneous SCCs and adjacent dysplasias frequently showed maturation-independence of KLF4, with co-expression of KLF4 and PCNA. A smaller subset of human SCCs showed complementarity of KLF4 and PCNA, similar to hyperplastic mouse skin. The results identify parallels between a mouse model and human primary tumors, and show that successive increases of KLF4 in the nuclei of basal keratinocytes leads to occult cell turnover followed by hyperplasia, dysplasia, and invasive SCC. PMID:16357510

  2. Peroxisome Proliferator Activated Receptor-γ Activation Inhibits Tumor Metastasis by Antagonizing Smad3 Mediated Epithelial Mesenchymal Transition

    PubMed Central

    Reka, Ajaya Kumar; Kurapati, Himabindu; Narala, Venkata R; Bommer, Guido; Chen, Jun; Standiford, Theodore J.; Keshamouni, Venkateshwar G.

    2011-01-01

    Epithelial-mesenchymal transition (EMT) was shown to confer tumor cells with abilities essential for metastasis, including migratory phenotype, invasiveness, and resistance to apoptosis, evading immune surveillance and tumor stem cell traits. Therefore, inhibition of EMT can be an important therapeutic strategy to inhibit tumor metastasis. Here we demonstrate that activation of peroxisome proliferator activated receptor (PPAR) -γ inhibits TGF-β-induced EMT in lung cancer cells and prevents metastasis by antagonizing Smad3 function. Activation of PPAR-γ by synthetic ligands (Troglitazone and Rosiglitazone) or by a constitutively-active form of PPAR-γ prevents TGF-β-induced loss of E-cadherin expression and inhibited the induction of mesenchymal markers (vimentin, N-cadherin, fibronectin) and MMPs. Consistently, activation of PPAR-γ also inhibited EMT-induced migration and invasion of lung cancer cells. Furthermore, effects of PPAR-γ ligands were attenuated by siRNA mediated knockdown of PPAR-γ, indicating that the ligand induced responses are PPAR-γ dependent. Selective knockdown of Smad2 and Smad3 by siRNA demonstrated that TGF-β-induced EMT is Smad3 dependent in lung cancer cells. Activation of PPAR-γ inhibits TGF-β-induced Smad transcriptional activity but had no effect on the phosphorylation or nuclear translocation of Smads. Consistently PPAR-γ activation prevented TGF-ß-induced transcriptional repression of E-cadherin promoter and inhibited transcriptional activation of N-cadherin promoter. Finally, treatment of mice with troglitazone or knockdown of Smad3 in tumor cells both significantly inhibited TGF-β-induced experimental metastasis in Scid-Beige mice. Together, with the low toxicity profile of PPAR-γ ligands, our data demonstrates that these ligands may serve as potential therapeutic agents to inhibit metastasis. PMID:21159608

  3. KLF4 and PCNA identify stages of tumor initiation in a conditional model of cutaneous squamous epithelial neoplasia.

    PubMed

    Huang, Conway C; Liu, Zhaoli; Li, Xingnan; Bailey, Sarah K; Nail, Clinton D; Foster, K Wade; Frost, Andra R; Ruppert, J Michael; Lobo-Ruppert, Susan M

    2005-12-01

    KLF4 is induced upon growth-arrest in vitro and during epithelial maturation in vivo, and is essential for proper cell fate specification of post-mitotic cells. In spite of a normal role in post-mitotic cells, expression is upregulated and constitutive in certain tumor types. KLF4 functions as an oncogene in vitro, and enforced expression in basal cells of mouse skin rapidly induces lesions similar to hyperplasia, dysplasia and squamous cell carcinoma (SCC). Here we used conditional expression to characterize early steps in KLF4-mediated tumor initiation. In contrast to SCC-like lesions that result when using a conditional, keratin 14 promoter-dependent strategy, lower conditional expression achieved using a MMTV promoter induced only epidermal cycling within morphologically normal skin, a process we termed occult cell turnover. Surprisingly, KLF4-induced hyperplastic lesions showed increased transgene-derived mRNA and protein in maturing, PCNA-negative cells, a property of endogenous KLF4. In contrast, hyperplastic lesions induced by GLI1, a control, showed uniform transgene expression. In KLF4-induced dysplasia and SCC the complementarity of KLF4 and PCNA was replaced by concordance of the two proteins. These studies show that KLF4 transcripts are normally suppressed in cycling cells in a promoter-independent fashion, consistent with a post-transcriptional control, and reveal loss of this control in the transition from hyperplasia to dysplasia. Like the mouse tumors, human cutaneous SCCs and adjacent dysplasias frequently showed maturation-independence of KLF4, with co-expression of KLF4 and PCNA. A smaller subset of human SCCs showed complementarity of KLF4 and PCNA, similar to hyperplastic mouse skin. The results identify parallels between a mouse model and human primary tumors, and show that successive increases of KLF4 in the nuclei of basal keratinocytes leads to occult cell turnover followed by hyperplasia, dysplasia, and invasive SCC.

  4. Establishment of Primary Cell Culture From Ascitic Fluid and Solid Tumor Obtained From Epithelial Ovarian Carcinoma Patients.

    PubMed

    Kar, Rajarshi; Chawla, Diwesh; Gupta, Bindiya; Mehndiratta, Mohit; Wadhwa, Neelam; Agarwal, Rachna

    2017-08-16

    Ovarian cancer is the seventh leading cause of cancer death worldwide. This is mainly due to late diagnosis and high rate of relapse and resistance following chemotherapy. In the present study, we describe simple and cost-effective method to establish primary culture from ascitic fluid and solid tumor obtained from epithelial ovarian carcinoma patient, which may provide a better tool for in vitro testing of drug sensitivity and designing individualized treatment protocol. Complete Dulbecco modified Eagle medium (DMEM) was prepared by supplementing DMEM with 10% fetal bovine serum and antibiotics (ciprofloxacin and amphotericin B). Establishment of primary culture of ovarian cancer cells from ascites fluid and solid tumor was done by using complete DMEM media. Primary cultures of ovarian cancer cells were established from ascitic fluid and solid tumor tissue. Of the 7 ascitic fluid samples, we were able to establish 5 primary cultures of ovarian cancer cells. All the 7 samples were diagnosed as serous papillary adenocarcinoma. Some fibroblasts were also attached to culture flask on day 4; they were removed by exposing them to trypsin for a brief period. On day 7, grape-like clusters were visualized under inverted microscope. The cells became confluent on the 10th and 11th day and showed cobblestone appearance, which is a hallmark of ovarian cancer cells. Senescent irregularly shaped cells that have ceased dividing were seen after 8 to 10 passages. This study highlights the fact that establishing primary cultures from ascitic fluid or solid tumor tissue may help us to understand the molecular profile of the cancer cells, which allow us to select the best chemotherapeutic agent for ovarian cancer patients and thus take a step toward patient-tailored therapy so that patients are not exposed to drugs to which they are not likely to respond.

  5. Keratin 17 promotes epithelial proliferation and tumor growth by polarizing the immune response in skin

    PubMed Central

    DePianto, Daryle; Kerns, Michelle; Dlugosz, Andrzej A.; Coulombe, Pierre A.

    2010-01-01

    Basaloid skin tumors, including basal cell carcinoma (BCC) and basaloid follicular hamartoma (BFH), are associated with aberrant Hedgehog (Hh) signaling1 and, in the case of BCC, an expanding set of genetic variants including keratin 5 (K5)2, an intermediate filament-forming protein. We show that genetic ablation of keratin 17 (K17) protein, which is induced in basaloid skin tumors3,4 and co-polymerizes with K5 in vivo5, delays BFH tumor initiation and growth in mice with constitutive Hh signaling in epidermis6,7. The delay is preceded by reduced inflammation and a polarization of inflammatory cytokines from a Th1/Th17- to a Th2-dominated profile. Absence of K17 also attenuates hyperplasia and inflammation in a model of acute dermatitis. Re-expression of K17 in Gli2tg K17−/− keratinocytes induces select Th1 chemokines with established roles in BCC. Our findings establish a novel immunomodulatory role for K17 in Hh-driven basaloid skin tumors that could impact additional tumor settings, psoriasis, and wound repair. PMID:20871598

  6. Plasma membrane reorganization induced by tumor promoters in an epithelial cell line

    SciTech Connect

    PACKARD, BEVERLY S.; SAXTON, MICHAEL J.; BISSELL, MINA J.; KLEIN, MELVIN P.

    1984-01-01

    The effects of phorbol ester tumor promoters on the lateral diffusion in plasma membrane lipid environments were examined by the technique of fluorescence recovery after photobleaching. To this end, the probe collarein, a fluorescent lipid analog that has the property of exclusive localization in the plasma membrane, was synthesized. Measured decreases in three parameters [percentage of fluorescence bleached (30%), percentage of recovery (52%), and half-time for recovery (52%)] connoted the appearance of an immobile fraction upon exposure to tumor promoters. These data are consistent with lipid reorganization in response to a reorganization of the intra- and perimembranous macromolecular scaffolding upon the interaction of cells with tumor promoters. The idea of induced reorganization is supported by experiments in which cell shape change, brought about by either exposure to cytochalasin B or growth on matrices of collagen, fibronectin, or laminin, resulted in values in the fluorescence recovery after photobleaching technique similar to those with active phorbol esters.

  7. Plasma membrane reorganization induced by tumor promoters in an epithelial cell line

    SciTech Connect

    Packard, B.S.; Saxton, M.J.; Bissell, M.J.; Klein, M.P.

    1984-01-01

    The effects of phorbol ester tumor promoters on the lateral diffusion in plasma membrane lipid environments were examined by the technique of fluorescence recovery after photobleaching. To this end, the probe collarein, a fluorescent lipid analog that has the property of exclusive localization in the plasma membrane, was synthesized. Measured decreases in three parameters (percentage of fluorescence bleached (30%), percentage of recovery (52%), and half-time for recovery (52%)) connoted the appearance of an immobile fraction upon exposure to tumor promoters. These data are consistent with lipid reorganization in response to a reorganization of the intra- and perimembranous macromolecular scaffolding upon the interaction of cells with tumor promoters. The idea of induced reorganization is supported by experiments in which cell shape change, brought about by either exposure to cytochalasin B or growth on matrices of collagen, fibronectin, or laminin, resulted in values in the fluorescence recovery after photobleaching technique similar to those with active phorbol esters. 35 references, 3 figures, 1 table.

  8. Malignant transformation of breast fibroadenoma to malignant phyllodes tumor: long-term outcome of 36 malignant phyllodes tumors.

    PubMed

    Abe, Makoto; Miyata, Satoshi; Nishimura, Seiichiro; Iijima, Kotaro; Makita, Masujiro; Akiyama, Futoshi; Iwase, Takuji

    2011-10-01

    Malignant phyllodes tumor of the breast is a rare neoplasm for which clinical findings remain insufficient for determination of optimal management. We examined the clinical behavior of these lesions in an attempt to determine appropriate management. We evaluated long-term outcome and clinical characteristics of malignant phyllodes tumors arising from fibroadenomas of the breast. A total of 173 patients were given a diagnosis of phyllodes tumor and underwent surgery at the Cancer Institute Hospital in Japan between January 1980 and December 1999. Of these patients, 39 (22.5%) were given a diagnosis of malignant phyllodes tumor; in three of these cases, detailed medical records were lost. Malignant phyllodes tumors were classified into two groups based on history of malignant transformation. Of the 36 malignant cases, 11 (30.6%) were primary and were given a diagnosis of fibroadenoma, experienced recurrence during the follow-up period, and were diagnosed with malignant phyllodes tumor (cases with a history of fibroadenoma). The other group was defined as cases without history of fibroadenoma and in whom lesions initially occurred as malignant phyllodes tumors. Based on differences between the two groups, overall survival curves were plotted using the Kaplan–Meier method, and statistical comparisons were performed using the log-rank test and Peto and Peto’s test. The outcome of cases with history of fibroadenoma was significantly better than that of cases without history of fibroadenoma. Patients with malignant phyllodes tumors but without prior history of malignant transformation who exhibit rapid growth within 6 months require aggressive treatment.

  9. Brain tumors in the mesial temporal lobe: long-term oncological outcome.

    PubMed

    Phi, Ji Hoon; Chung, Chun Kee

    2009-08-01

    Surgical treatment of brain tumors in the mesial temporal lobe (MTL) is a highly demanding procedure. Only a few studies describing the surgery of MTL tumors have been reported, and they have been focused on the operative techniques and immediate results of the surgery. The authors have analyzed the long-term oncological outcome in patients with MTL tumors. Thirty-six patients with an MTL tumor were studied. The mean patient age at surgery was 32 years (range 13-62 years). The tumors were confined to the MTL (Schramm Type A) in 25 patients (69%). Extension of the tumor into the fusiform gyrus (Schramm Type C) and temporal stem (Schramm Type D) was observed in 4 and 7 patients (11 and 19%), respectively. There was a significant difference in the tumor size according to Schramm types (p = 0.001). Complete tumor resection was achieved in 26 patients (72%). All tumors were low-grade lesions except for 1 anaplastic astrocytoma. After a median follow-up period of 50.5 months, 7 patients showed progression of the disease. The actuarial progression-free survival rates were 97% in the 1st year, 84% in the 2nd year, and 80% in the 5th year. The degree of tumor resection was significantly related to the tumor control failure (p < 0.001) and malignant transformation of a low-grade tumor (p < 0.001). Univariate analyses using a Cox proportional hazards model showed that the following factors were significantly associated with a failure to control the tumor: 1) extent of the tumor (Schramm Type D; p = 0.003, relative risk [RR] 12.04); 2) size of the tumor (p = 0.033, RR 1.052/mm); 3) patient age at surgery >or= 50 years (p = 0.007, RR 8.312); and 4) short duration of epilepsy (< 6 months; p = 0.001, RR 21.54). Surgery is the principal treatment for MTL tumors, despite its technical difficulty. Complete tumor resection is strongly recommended for long-term tumor control. The MTL tumors are heterogeneous in their prognosis. Older age, short duration of epilepsy, and tumor size are

  10. Absence of the Epithelial Glycocalyx As Potential Tumor Marker for the Early Detection of Colorectal Cancer

    PubMed Central

    Ramaker, Katrin; Bade, Steffen; Röckendorf, Niels; Meckelein, Barbara; Vollmer, Ekkehard; Schultz, Holger; Fröschle, Günter-Willi; Frey, Andreas

    2016-01-01

    Detection of cancer at an early stage is pivotal for successful treatment and long term survival, yet early diagnosis requires sensitive and specific markers that can be easily detected by screening procedures. Differences in the surface structure of tumor and healthy cells, if sufficiently pronounced and discernible, may serve that purpose. We analyzed the luminal surface of healthy and neoplastic human colorectal tissues for the presence and architecture of the glycocalyx—a dense network of highly glycosylated proteins—using transmission electron microscopy. The ultrastructural analyses showed that 93% of healthy mucosae were covered by an intact glycocalyx. Contrarily, on over 90% of the surface of neoplastic cells the glycocalyx was absent. The sensitivity and specificity of our marker “absence of a glycocalyx” are excellent, being 91% (83–96%) and 96% (89–99%) for adenocarcinomas and 94% (73–100%) and 92% (85–97%) for precancerous polyps (means and 95% confidence intervals). Using a cell culture model we could demonstrate that a particulate probe targeting a cell surface receptor usually concealed beneath the glycocalyx can bind selectively to glycocalyx-free areas of a tumor cell layer. We propose that the absence of a glycocalyx may serve as novel type of tumor marker. If the absence of the glycocalyx can be detected e.g. via binding of imaging probes to non-shielded surface receptors of anomalously differentiated cells, this tumor marker could be used to enable early diagnosis of colorectal cancer. PMID:28033349

  11. In Vivo Tagging of Lung Epithelial Cells to Define the Early Steps of Tumor Cell Dissemination

    DTIC Science & Technology

    2014-10-01

    Tatalovich Z, Cho H, Mariotto A, Lewis DR, Chen HS, Feuer EJ, and Cronin KA (eds). PDF Version - SEER Cancer Statistics Review ( CSR ), 1975-2010 http...seer.cancer.gov/ csr /1975_2010/sections.html (accessed Dec 11, 2013). 4. Quail DF and Joyce J. Microenvironmental regulation of tumor progression and

  12. TGF-β signal rewiring sustains epithelial-mesenchymal transition of circulating tumor cells in prostate cancer xenograft hosts

    PubMed Central

    Huang, Guangcun; Osmulski, Pawel A.; Bouamar, Hakim; Mahalingam, Devalingam; Lin, Chun-Lin; Liss, Michael A.; Kumar, Addanki Pratap; Chen, Chun-Liang; Thompson, Ian M.; Sun, Lu-Zhe; Gaczynska, Maria E.; Huang, Tim H.-M.

    2016-01-01

    Activation of TGF-β signaling is known to promote epithelial-mesenchymal transition (EMT) for the development of metastatic castration-resistant prostate cancer (mCRPC). To determine whether targeting TGF-β signaling alone is sufficient to mitigate mCRPC, we used the CRISPR/Cas9 genome-editing approach to generate a dominant-negative mutation of the cognate receptor TGFBRII that attenuated TGF-β signaling in mCRPC cells. As a result, the delicate balance of oncogenic homeostasis is perturbed, profoundly uncoupling proliferative and metastatic potential of TGFBRII-edited tumor xenografts. This signaling disturbance triggered feedback rewiring by enhancing ERK signaling known to promote EMT-driven metastasis. Circulating tumor cells displaying upregulated EMT genes had elevated biophysical deformity and an increase in interactions with chaperone macrophages for facilitating metastatic extravasation. Treatment with an ERK inhibitor resulted in decreased aggressive features of CRPC cells in vitro. Therefore, combined targeting of TGF-β and its backup partner ERK represents an attractive strategy for treating mCRPC patients. PMID:27780930

  13. CONVERGENCE OF P53 AND TGFβ SIGNALING ON ACTIVATING EXPRESSION OF THE TUMOR SUPPRESSOR GENE MASPIN IN MAMMARY EPITHELIAL CELLS

    PubMed Central

    Wang, Shizhen Emily; Narasanna, Archana; Whitell, Corbin W.; Wu, Frederick Y.; Friedman, David B.; Arteaga, Carlos L.

    2014-01-01

    Using two-dimensional difference gel electrophoresis, we identified the tumor suppressor gene maspin as a TGFβ target gene in human mammary epithelial cells. TGFβ upregulates maspin expression both at the RNA and protein levels. This upregulation required Smad2/3 function and intact p53 binding elements in the maspin promoter. DNA affinity immunoblot and chromatin immunoprecipitation (ChIP) revealed the presence of both Smads and p53 at the maspin promoter in TGFβ-treated cells, suggesting that both transcription factors cooperate to induce maspin transcription. TGFβ did not activate maspin-luciferase reporter in p53-mutant MDA-MB-231 breast cancer cells, which exhibit methylation of the endogenous maspin promoter. Expression of ectopic p53, however, restored ligand-induced association of Smad2/3 with a transfected maspin promoter. Stable transfection of maspin inhibited basal and TGFβ-stimulated MDA-MB-231 cell motility. Finally, knockdown of endogenous maspin in p53 wild-type MCF10A/HER2 cells enhanced basal and TGFβ-stimulated motility. Taken together, these data support cooperation between the p53 and TGFβ tumor suppressor pathways in the induction of maspin expression, thus leading to inhibition of cell migration. PMID:17204482

  14. YThe BigH3 Tumor Suppressor Gene in Radiation-Induced Malignant Transformation of Human Bronchial Epithelial Cells

    NASA Astrophysics Data System (ADS)

    Zhao, Y.; Shao, G.; Piao, C.; Hei, T.

    Carcinogenesis is a multi-stage process with sequences of genetic events governing the phenotypic expression of a series of transformation steps leading to the development of metastatic cancer Previous studies from this laboratory have identified a 7 fold down- regulation of the novel tumor suppressor Big-h3 among radiation induced tumorigenic BEP2D cells Furthermore ectopic re-expression of this gene suppresses tumorigenic phenotype and promotes the sensitivity of these tumor cells to etoposide-induced apoptosis To extend these studies using a genomically more stable bronchial cell line we ectopically expresses the catalytic subunit of telomerase hTERT in primary human small airway epithelial SAE cells and generated several clonal cell lines that have been continuously in culture for more than 250 population doublings and are considered immortal Comparably-treated control SAE cells infected with only the viral vector senesced after less than 10 population doublings The immortalized clones demonstrated anchorage dependent growth and are non-tumorigenic in nude mice These cells show no alteration in the p53 gene but a decrease in p16 expression Exponentially growing SAEh cells were exposed to graded doses of 1 GeV nucleon of 56 Fe ions accelerated at the Brookhaven National Laboratory Irradiated cells underwent gradual phenotypic alterations after extensive in vitro cultivation Transformed cells developed through a series of successive steps before becoming anchorage independent in semisolid medium These findings indicate

  15. Eudaimonic well-being and tumor norepinephrine in patients with epithelial ovarian cancer.

    PubMed

    Davis, Lauren Z; Slavich, George M; Thaker, Premal H; Goodheart, Michael J; Bender, David P; Dahmoush, Laila; Farley, Donna M; Markon, Kristian E; Penedo, Frank J; Lubaroff, David M; Cole, Steve W; Sood, Anil K; Lutgendorf, Susan K

    2015-10-01

    The impact of psychological well-being on the physiologic processes involved in cancer progression remains unclear. Prior research has implicated adrenergic signaling in tumor growth and metastasis. Given that adrenergic signaling is influenced by both positive and negative factors, the authors examined how 2 different aspects of well-being (eudaimonic and positive affect) and psychological distress were associated with tumor norepinephrine (NE) in patients with ovarian cancer. A total of 365 women with suspected ovarian cancer completed psychosocial assessments before surgery and clinical information was obtained from medical records. Study inclusion was confirmed after histological diagnosis. Tumor NE was measured in frozen tissue samples using high-performance liquid chromatography with electrochemical detection. Confirmatory factor analysis was used to model eudaimonic well-being, positive affect, and psychological distress, and structural equation modeling was used to examine associations between these factors and tumor NE. Eudaimonic well-being, positive affect, and psychological distress, modeled as distinct but correlated constructs, best fit the data (ie, compared with unitary or 2-factor models) (root mean square error of approximation, 0.048; comparative fit index, 0.982; and standardized root-mean-squared residual, 0.035). Structural equation modeling analysis that included physical well-being, stage of disease, histology, psychological treatment history, beta-blocker use, and caffeine use as covariates was found to have good model fit (root mean square error of approximation, 0.052; comparative fit index, 0.955; and standardized root-mean-squared residual, 0.036) and demonstrated that eudaimonic well-being was related to lower tumor NE (β = -.24 [P = .045]). In contrast, no effects were found for positive affect or psychological distress. Eudaimonic well-being was found to be associated with lower tumor NE, independent of positive affect and

  16. Deguelin Suppresses Pancreatic Tumor Growth and Metastasis by Inhibiting Epithelial to Mesenchymal Transition in an Orthotopic Model1

    PubMed Central

    Boreddy, Srinivas Reddy; Srivastava, Sanjay K.

    2012-01-01

    Deguelin is known to suppress the growth of cancer cells; however, its anti-metastatic effects have not been studied so far in any cancer model. In the present study, we aimed to evaluate the anti-metastatic potential of deguelin in vivo and in TGFβ1-stimulated cells. Our results demonstrate that tumor growth, peritoneal-dissemination and liver/lung metastasis of orthotopically implanted PanC-1-luc cells were significantly reduced in deguelin-treated mice along with the induction of apoptosis. Furthermore, deguelin-treated tumors showed increased epithelial signature such as increased expression of E-Cadherin and cytokeratin-18 and decreased expression of Snail. Similar observations were made when PanC-1, COLO-357 and L3.6pl cells were treated in vitro with deguelin. Moreover, E-cadherin was transcriptionally up-regulated and accumulated in the membrane fraction of deguelin-treated cells as indicated by increased interaction of E-Cadherin with β-catenin. TGFβ1-induced down-regulation of E-Cadherin and up-regulation of Snail were abrogated by deguelin treatment. In addition, deguelin inhibited TGFβ1-induced Smad3 phosphorylation and Smad4 nuclear translocation in PanC-1 cells. Furthermore, when TGFβ1-induced NFkB activation was inhibited, TGFβ1-induced Snail up-regulation or E-Cadherin down-regulation was blocked. Deguelin also significantly down regulated the constitutive phosphorylation and DNA binding of NFkB in a dose dependent manner. Interestingly, overexpression of either NFkB or Snail completely abrogated deguelin-mediated EMT inhibition, whereas overexpression of NFkB but not Snail rescued cells from deguelin-induced apoptosis. Hence, deguelin targets NFkB to induce reversal of EMT and apoptosis but downstream effectors might be different for both processes. Taken together, our results suggest that deguelin suppresses both pancreatic tumor growth and metastasis by inducing apoptosis and inhibiting epithelial to mesenchymal transition. PMID:22986522

  17. NF-κB Expression and Outcomes in Solid Tumors

    PubMed Central

    Wu, Dang; Wu, Pin; Zhao, Lufeng; Huang, Lijian; Zhang, Zhigang; Zhao, Shuai; Huang, Jian

    2015-01-01

    Abstract Nuclear factor-kappaB (NF-κB) is a key inflammatory transcription factor expressed frequently in tumors. Numerous studies have investigated the correlation between NF-κB expression and prognosis in solid tumors, but the conclusions are still in contradiction. Here, we conduct a meta-analysis to explore the overall association of NF-κB overexpression and survival in human solid tumors. Pubmed and EBSCO databases were searched for studies evaluating expression of NF-κB (as measured by immunohistochemistry) and overall survival (OS) and disease-free survival (DFS) in solid tumors. Published data were extracted and computed into odds ratios (ORs) for death at 3, 5, and 10 years. Data were pooled using the Mantel–Haenszel random-effect model. All statistical tests were two-sided. Forty-four studies with a total of 4418 patients were included in this meta-analysis. NF-κB overexpression was associated with worse OS at 3 years (OR = 3.40, 95% confidence interval [CI] = 2.41–4.79, P < 0.00001), 5 years (OR = 2.72, 95% CI = 1.92–3.85, P < 0.00001), and 10 years (OR = 2.63, 95% CI = 1.34–5.16, P = 0.005) of solid tumors. Results for 3- and 5-year DFS were similar. NF-κB expression was associated with poor 3-year OS in both Tumor, Lymph Node, Metastasis stage I-II (OR = 9.11, 95% CI = 2.90–28.68, P = 0.0002) and III-IV (OR = 2.59, 95% CI = 1.61–4.15, P < 0.0001). There is no correlation between cellular localization of NF-kB overexpression and OS of solid tumors. Among the tumor types, NF-κB was associated with worse 3 year-OS of colorectal cancer (OR = 2.70, 95% CI = 1.64–4.46, P < 0.0001), esophageal carcinoma (OR = 6.00, 95% CI = 3.29–10.94, P < 0.0001) and worse 5 year-OS of colorectal cancer (OR = 2.72, 95% CI = 1.92–3.85, P < 0.00001), esophageal carcinoma (OR = 5.96, 95% CI = 3.48–10.18, P = 0.03), and nonsmall cell lung cancer

  18. Gene Expression in Wilms’ Tumor Mimics the Earliest Committed Stage in the Metanephric Mesenchymal-Epithelial Transition

    PubMed Central

    Li, Chi-Ming; Guo, Meirong; Borczuk, Alain; Powell, Charles A.; Wei, Michelle; Thaker, Harshwardhan M.; Friedman, Richard; Klein, Ulf; Tycko, Benjamin

    2002-01-01

    Wilms’ tumor (WT) has been considered a prototype for arrested cellular differentiation in cancer, but previous studies have relied on selected markers. We have now performed an unbiased survey of gene expression in WTs using oligonucleotide microarrays. Statistical criteria identified 357 genes as differentially expressed between WTs and fetal kidneys. This set contained 124 matches to genes on a microarray used by Stuart and colleagues (Stuart RO, Bush KT, Nigam SK: Changes in global gene expression patterns during development and maturation of the rat kidney. Proc Natl Acad Sci USA 2001, 98:5649–5654) to establish genes with stage-specific expression in the developing rat kidney. Mapping between the two data sets showed that WTs systematically overexpressed genes corresponding to the earliest stage of metanephric development, and underexpressed genes corresponding to later stages. Automated clustering identified a smaller group of 27 genes that were highly expressed in WTs compared to fetal kidney and heterologous tumor and normal tissues. This signature set was enriched in genes encoding transcription factors. Four of these, PAX2, EYA1, HBF2, and HOXA11, are essential for cell survival and proliferation in early metanephric development, whereas others, including SIX1, MOX1, and SALL2, are predicted to act at this stage. SIX1 and SALL2 proteins were expressed in the condensing mesenchyme in normal human fetal kidneys, but were absent (SIX1) or reduced (SALL2) in cells at other developmental stages. These data imply that the blastema in WTs has progressed to the committed stage in the mesenchymal-epithelial transition, where it is partially arrested in differentiation. The WT-signature set also contained the Wnt receptor FZD7, the tumor antigen PRAME, the imprinted gene NNAT and the metastasis-associated transcription factor E1AF. PMID:12057921

  19. Chronic cadmium exposure in vitro causes acquisition of multiple tumor cell characteristics in human pancreatic epithelial cells.

    PubMed

    Qu, Wei; Tokar, Erik J; Kim, Andrew J; Bell, Matthew W; Waalkes, Michael P

    2012-09-01

    Cancer may be a stem cell (SC)-based disease involving formation of cancer SCs (CSCs) potentially arising from transformation of normal SCs. Cadmium has been linked to human pancreatic cancer. We studied cadmium exposure of human pancreatic ductal epithelial (HPDE) cells and whether SCs may be targeted in this process. We chronically exposed HPDE cells to low level cadmium (1 μM) for ≤ 29 weeks. Nonadherent spheroid formation was used to indicate CSC-like cell production, and we assessed tumor cell characteristics in such spheres. Assessed tumor cell characteristics including secretion of matrix metalloproteinase-9 (MMP-9), invasion, and colony formation were fortified by evaluating expression of relevant genes by real-time reverse transcription polymerase chain reaction and by Western blot. Increased MMP-9 secretion and overexpression of the pancreatic cancer marker S100P occurred in chronic (29 weeks of exposure) cadmium-exposed (CCE) cells. CCE cells also showed markedly higher colony formation and invasion, typical of cancer cells. Floating "spheres" of viable cells, known to contain an abundance of normal SCs or CSCs, form in vitro with many cell types. CCE cells produced 3-fold more spheres than control cells and were more invasive, secreted more MMP-9, and overexpressed markers for pancreatic SCs/CSCs (i.e., CXCR4, OCT4, CD44) and S100P, a marker for pancreatic cancer. CCE-derived spheres rapidly produced aggressive, highly branched, and poorly differentiated glandular-like structures in Matrigel. Chronic cadmium exposure produced multiple tumor cell characteristics in HPDE cells and CCE cell-derived spheres. These data support the plausibility of cadmium as a human pancreatic carcinogen.

  20. ERK and PI3K regulate different aspects of the epithelial to mesenchymal transition of mammary tumor cells induced by truncated MUC1

    SciTech Connect

    Horn, Galit; Gaziel, Avital; Wreschner, Daniel H.; Smorodinsky, Nechama I.; Ehrlich, Marcelo

    2009-05-01

    Epithelial to mesenchymal transition (EMT) integrates changes to cell morphology and signaling pathways resulting from modifications to the cell's transcriptional response. Different combinations of stimuli ignite this process in the contexts of development or tumor progression. The human MUC1 gene encodes multiple alternatively spliced forms of a polymorphic oncoprotein that is aberrantly expressed in epithelial malignancies. MUC1 is endowed with various signaling modules and has the potential to mediate proliferative and morphological changes characteristic of the progression of epithelial tumors. The tyrosine-rich cytoplasmic domain and the heavily glycosylated extracellular domain both play a role in MUC1-mediated signal transduction. However, the attribution of function to specific domains of MUC1 is difficult due to the concomitant presence of multiple forms of the protein, which stem from alternative splicing and proteolytic cleavage. Here we show that DA3 mouse mammary tumor cells stably transfected with a truncated genomic fragment of human MUC1 undergo EMT. In their EMT, these cells demonstrate altered [i] morphology, [ii] signaling pathways and [iii] expression of epithelial and mesenchymal markers. Similarly to well characterized human breast cancer cell lines, cells transfected with truncated MUC1 show an ERK-dependent increased spreading on fibronectin, and a PI3K-dependent enhancement of their proliferative rate.

  1. Primitive neuroectodermal tumor of adrenal: clinical presentation and outcomes.

    PubMed

    Dutta, Deep; Shivaprasad, K S; Das, Ram Narayan; Ghosh, Sujoy; Chowdhury, Subhankar

    2013-01-01

    Primitive neuroectodermal tumor (PNET) of adrenal is an extremely rare tumor of neural crest origin. A nonfunctional left adrenal mass (14.6 × 10.5 × 10.0 cm) on computed tomography (CT) was detected in a 40-year-old lady with abdominal pain, swelling, and left pleural effusion. She underwent left adrenalectomy and left nephrectomy with retroperitoneal resection. Histopathology revealed sheets and nest of oval tumor cells with hyperchromatic nuclei, prominent nucleoli, scanty cytoplasm, brisk mitotic activity, necrosis, lymphovascular invasion, capsular invasion, and extension to the surrounding muscles; staining positive for Mic-2 (CD-99 antigen), vimentin, synaptophysin, and Melan-A. Thoracocentesis, pleural fluid study, and pleural biopsy did not show metastasis. She responded well to vincristine, adriamycin, and cyclophosphamide followed by ifosfamide and etoposide (IE). This is the first report of adrenal peripheral PNET (pPNET) from India. This report intends to highlight that pPNET should be suspected in a patient presenting with huge nonfunctional adrenal mass which may be confused with adrenocortical carcinoma.

  2. Phyllodes tumor with osteosarcomatous differentiation: a comparative immunohistochemical study between epithelial and mesenchymal cells.

    PubMed

    Ribeiro-Silva, Alfredo; Zambelli Ramalho, Leandra Náira; Zucoloto, Sérgio

    2006-01-01

    Phyllodes tumor of the breast with osteosarcomatous differentiation is rare and very little is known about its molecular profile. An immunohistochemical panel with 37 primary antibodies including cytokeratins, mesenchymal markers, key regulators of the cell cycle, oncogenes, apoptosis-related proteins, metalloproteinases and their inhibitors was performed on a formalin-fixed paraffin-embedded sample of phyllodes tumor with osteosarcomatous differentiation in a 49-year-old woman. Antiapoptotic stimuli (survivin) predominated in sarcomatous cells. Antiproteolytic stimuli (TIMP-1, TIMP-2 and PAI) were preponderant in all cells, a surprising fact in view of the aggressiveness of the neoplasm. The immunoprofile of the osteoblastic and stromal cells was quite similar, except for c-erbB-3, c-myc, cyclin D1 and p21. Both exhibited positive cells for actin, MyoD1 and GFAP. Our results suggest that this osteosarcoma may have originated from metaplasia of stromal cells that underwent a malignant change.

  3. Mechanism of Ovarian Epithelial Tumor Predisposition in Individuals Carrying Germline BRCA1 Mutations

    DTIC Science & Technology

    2006-01-01

    gene knockout developed ovarian/ tubal tumors morphologically very similar to human ovarian serous cystadenomas in strong support of our hypothesis. We...proliferation activity in the uterus of 5 wild type and 5 mutant mice at the diestrus ad estrus phases of the estrus cycle. Histological cross- sections were...zygous knockout restricted to granulosa cells. One ovary was removed from each of 30 Brca1 flox/flox; Fshr-Cre mice at 2 months of age. Histological

  4. Dub3 expression correlates with tumor progression and poor prognosis in human epithelial ovarian cancer.

    PubMed

    Zhou, Bo; Shu, Bin; Xi, Tao; Su, Ning; Liu, Jing

    2015-03-01

    Dub3 is a deubiquitinating enzyme. It is highly expressed in tumor-derived cell lines and has an established role in tumor proliferation. However, the role of Dub3 in human ovarian cancer remains unclear. Expression of Dub3 was evaluated in ovarian cancer tissues and cell lines by immunohistochemistry and Western blot analysis. The relationship between Dub3 expression and clinicopathological characteristics was analyzed. Using RNA interference, the effects of Dub3 on cell proliferation and apoptosis were investigated in ovarian cancer cell line. All normal ovary tissues exhibited very little or no Dub3 immunoreactivity. High levels of Dub3 expression were examined by immunohistochemical analysis in 13.3% of cystadenomas, in 30.0% of borderline tumors, and in 58.9% of ovarian carcinomas, respectively. Dub3 expression was significantly associated with lymph node metastasis and clinical staging (P<0.05). Multivariate survival analysis indicated that Dub3 expression was an independent prognostic indicator of the survival of patients with ovarian cancer. Furthermore, the expression of Cdc25A was closely correlated with that of Dub3 in cancer cells and tissues. Knockdown of Dub3 could inhibit the proliferation of ovarian cancer cells and increase cell apoptosis. These data indicate that the Dub3 might be a valuable biomarker for the prediction of ovarian cancer prognosis and Dub3 inhibition might be a potential strategy for ovarian cancer treatment.

  5. Relevance of MicroRNA200 Family and MicroRNA205 for Epithelial to Mesenchymal Transition and Clinical Outcome in Biliary Tract Cancer Patients

    PubMed Central

    Urbas, Romana; Mayr, Christian; Klieser, Eckhard; Fuereder, Julia; Bach, Doris; Stättner, Stefan; Primavesi, Florian; Jaeger, Tarkan; Stanzer, Stefanie; Ress, Anna Lena; Löffelberger, Magdalena; Wagner, Andrej; Berr, Frieder; Ritter, Markus; Pichler, Martin; Neureiter, Daniel; Kiesslich, Tobias

    2016-01-01

    Extensive stromal interaction is one reason for the dismal outcome of biliary tract cancer (BTC) patients. Epithelial to mesenchymal transition (EMT) is involved in tumor invasion and metastasis and is partly regulated by microRNAs (miRs). This study explores the expression of anti-EMT miR200 family (miR141, −200a/b/c, −429) and miR205 as well as the EMT-related proteins E-cadherin and vimentin in a panel of BTC cell lines and clinical specimens by quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry, respectively. MicroRNA expression was correlated to (i) the expression patterns of E-cadherin and vimentin; (ii) clinicopathological characteristics; and (iii) survival data. MicroRNA-200 family and miR205 were expressed in all BTC cells and clinical specimens. E-cadherin and vimentin showed a mutually exclusive expression pattern in both, in vitro and in vivo. Expression of miR200 family members positively correlated with E-cadherin and negatively with vimentin expression in BTC cells and specimens. High expression of miR200 family members (but not miR205) and E-cadherin was associated with longer survival, while low miR200 family and high vimentin expression was a predictor of unfavorable survival. Overall, the current study demonstrates the relevance of the miR200 family in EMT of BTC tumors and suggests these miRs as predictors for positive outcome. PMID:27941621

  6. Tumor necrosis factor (TNF)-neuropeptide Y (NPY) crosstalk regulates inflammation, epithelial barrier functions and colonic motility

    PubMed Central

    Chandrasekharan, Bindu; Jeppsson, Sabrina; Pienkowski, Stefan; Belsham, Denise D; Sitaraman, Shanthi V.; Merlin, Didier; Kokkotou, Efi; Nusrat, Asma; Tansey, Malu G.; Srinivasan, Shanthi

    2014-01-01

    Background Neuro-immune interactions play a significant role in regulating the severity of inflammation. Our previous work demonstrated that neuropeptide Y (NPY) is up regulated in the enteric nervous system (ENS) during murine colitis, and that NPY knockout mice exhibit reduced inflammation. Here we investigated if NPY expression during inflammation is induced by tumor necrosis factor (TNF), the main pro-inflammatory cytokine. Methods Utilizing primary enteric neurons and colon explant cultures from WT and NPY knockout (NPY−/−) mice, we determined if NPY knockdown modulates TNF release and epithelial permeability. Further we assessed if NPY expression is inducible by TNF in enteric neuronal cells and mouse model of experimental colitis, utilizing the TNF inhibitors-etanercept (blocks transmembrane and soluble TNF) and XPro1595 (blocks soluble TNF only). Results We found that enteric neurons express TNF receptors (TNFR1 and R2). Primary enteric neurons from NPY−/− mice produced less TNF compared to WT. Further, TNF activated NPY promoter in enteric neurons via phospho-c-jun. NPY−/− mice had decreased intestinal permeability. In vitro, NPY increased epithelial permeability via phosphatidyl inositol-3-kinase (PI3-K)-induced pore-forming claudin-2. TNF inhibitors attenuated NPY expression in vitro and in vivo. TNF-inhibitor-treated colitic mice exhibited reduced NPY expression and inflammation, reduced oxidative stress, enhanced neuronal survival and improved colonic motility. XPro1595 had more protective effects on neuronal survival and motility compared to etanercept. Conclusions We demonstrate a novel TNF-NPY cross talk that modulates inflammation, barrier functions and colonic motility during inflammation. It is also suggested that selective blocking of soluble TNF maybe a better therapeutic option than using anti-TNF antibodies. PMID:24108115

  7. Tumor budding is an independent predictor of outcome in AJCC/UICC stage II colorectal cancer.

    PubMed

    Betge, Johannes; Kornprat, Peter; Pollheimer, Marion J; Lindtner, Richard A; Schlemmer, Andrea; Rehak, Peter; Vieth, Michael; Langner, Cord

    2012-11-01

    In colorectal cancer, the morphology of the invasive tumor margin may reflect aggressiveness of tumor growth, thus providing important prognostic information. The tumor growth pattern according to Jass and the extent of tumor budding were analyzed in patients with American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) stage II disease. Tumors of 120 randomly selected patients with AJCC/UICC stage II disease were retrospectively reviewed for tumor growth pattern (expanding vs. infiltrating) and the extent of tumor budding, with high-grade budding reflecting presence of 10 or more budding foci scattered at the invasive tumor margin. Progression-free and cancer-specific survivals were determined by the Kaplan-Meier method. For multivariable analysis, Cox's proportional hazards regression models were performed. The infiltrating growth pattern was significantly associated with histological subtype and lymphovascular invasion, while high-grade budding was significantly associated with tumor grade and lymphovascular invasion. High-grade budding, but not the infiltrating growth pattern, was significantly associated with outcome in univariable analysis. Cox's proportional hazards regression models proved tumor budding to be an independent predictor of disease progression (hazard ratio 3.91, 95 % confidence interval 1.3-11.77; P = 0.02) and cancer-related death (hazard ratio 5.90, 95 % confidence interval 1.62-21.51; P = 0.007). The combination of infiltrating growth pattern and high-grade budding did not have a stronger prognostic significance than tumor budding alone. Tumor budding independently predicted patient outcome in patients with AJCC/UICC stage II colorectal cancer and may therefore be used for accurate prognostication, patient counseling, and design of clinical trials by using integrated multimodal therapy.

  8. MiR-143 targets CTGF and exerts tumor-suppressing functions in epithelial ovarian cancer

    PubMed Central

    Wang, Lufei; He, Jin; Xu, Hongmei; Xu, Longjie; Li, Na

    2016-01-01

    A series of recent studies suggested that miR-143 might involve in the tumorigenesis and metastasis of various cancer types. However, the biological function and underlying mechanisms of miR-143 in human epithelial ovarian carcinoma (EOC) remain unknown. Therefore, this study aimed to investigate the miR-143 expression and its clinical diagnosis significance in patients suffering EOC and to analyze its role and underlying molecular mechanism in EOC. Our result showed that the expression levels of miR-143 were downregulated in EOC tissues and cell lines, was associated with International Federation of Gynaecology and Obstetrics (FIGO) stage, pathological grade and lymph node metastasis (all P < 0.01) . Overexpression of miR-143 significantly inhibited EOC cell proliferation, migration, and invasion. Furthermore, computational algorithm combined with luciferase reporter assays identified connective tissue growth factor (CTGF) as the direct target of miR-143 in EOC cells. The expression level of CTGF was significantly increased in EOC tissues, was inversely correlated with miR-143 expression in clinical EOC tissues. Knockdown of CTGF mimicked the suppression effect induced by miR-143 overexpression. Restoration of CTGF expression partially reversed the suppression effect induced by miR-143 overexpression. These results suggested that miR-143 inhibited EOC cell proliferation, migration, and invasion, at least in part, via suppressing CTGF expression. PMID:27398154

  9. The effects of selenium on tumor growth in epithelial ovarian carcinoma.

    PubMed

    Park, Jin Sun; Ryu, Ji Yoon; Jeon, Hye-Kyung; Cho, Young Jae; Park, Young Ae; Choi, Jung-Joo; Lee, Jeong-Won; Kim, Byoung-Gie; Bae, Duk-Soo

    2012-07-01

    Epidemiological studies suggest that selenium protects against the development of several cancers. Selenium (sodium selenite) has been reported to interfere with cell growth and proliferation, and to induce cell death. In this study, we tested whether selenium could have growth-inhibiting effect in ovarian cancer cells and an orthotopic animal model. Cell growth in selenium-treated cells was determined in human ovarian cancer cells, A2780, HeyA8, and SKOV3ip1 using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay. Animal experiment of selenium with paclitaxel was performed using SKOV3ip1 cells in nude mice to evaluate their inhibiting effect for tumor growth. In addition, another animal experiment of paclitaxel with or without selenium was performed to assess the effect of survival and food intake in mice. The in vitro growth of selenium-treated cells was significantly decreased dose-dependently in A2780, HeyA8, and SKOV3ip1 cells. Therapy experiment in mice was started 1 week after injection of the SKOV3ip1 cells. Treatment with selenium (1.5 mg/kg, 3 times/week) and paclitaxel injection showed no addictive effect of the inhibition of tumor growth. However, combination of selenium and paclitaxel showed the slightly increased food intake compared with paclitaxel alone. Although selenium has growth-inhibiting effect in ovarian carcinoma cells in vitro, there is no additive effect on tumor growth in mice treated with combination of paclitaxel and selenium. However, food intake is slightly higher in selenium-treated mice during chemotherapy.

  10. Imaging and surgical outcomes of spinal tumors in 18 dogs and one cat

    PubMed Central

    Caliskan, Murat; Can, Pinar; Vural, Sevil Atalay; Algin, Oktay; Ahlat, Ozan

    2016-01-01

    Clinical and magnetic resonance imaging (MRI) findings, histological appearances and surgical outcomes of 18 dogs and one cat with spinal tumors are presented. Medical records of the cases admitted for spinal disorders were reviewed, and cases of spinal tumors that were diagnosed by MRI and confirmed by histological examination were included in this study. T1 weighted, T2 weighted and contrast enhanced T1 weighted images were taken and interpreted to evaluate the spinal tumors. The tumors were diagnosed as: meningioma (n = 6), ependymoma (n = 1), nerve sheath tumor (n = 4), metastatic spinal tumor (n = 3), osteosarcoma (n = 2), osteoma (n = 1), rhabdomyosarcoma (n = 1), and nephroblastoma (n = 1). Thirteen cases underwent surgical operation and the remaining six cases were euthanized at the request of the owners. The neurological status of the surgical cases did not deteriorate, except for one dog that showed ependymoma in the early period after the operation. These results indicate the potential for surgical gross total tumor removal of vertebral tumors to provide better quality of life and surgical collection of histological specimens for definitive diagnosis. For effective case management, dedicated MRI examination is important to accurate evaluation of the spinal tumors, and surgical treatment is useful for extradural and intradural-extramedullary spinal tumors. PMID:26645333

  11. Nuclear location of tumor suppressor protein maspin inhibits proliferation of breast cancer cells without affecting proliferation of normal epithelial cells

    PubMed Central

    2014-01-01

    Background Maspin, which is classified as a tumor suppressor protein, is downregulated in many types of cancer. Several studies have suggested potential anti-proliferative activity of maspin as well as sensitizing activity of maspin for therapeutic cytotoxic agents in breast cancer tissue culture and animal models. All of the experimental data gathered so far have been based on studies with maspin localized cytoplasmically, while maspin in breast cancer tumor cells may be located in the cytoplasm, nucleus or both. In this study, the effect of maspin cytoplasmic and nuclear location and expression level on breast cancer proliferation and patient survival was studied. Methods Tissue sections from 166 patients with invasive ductal breast cancer were stained by immunohistochemistry for maspin and Ki-67 protein. The localization and expression level of maspin were correlated with estimated patient overall survival and percent of Ki-67-positive cells. In further studies, we created constructs for transient transfection of maspin into breast cancer cells with targeted cytoplasmic and nuclear location. We analyzed the effect of maspin location in normal epithelial cell line MCF10A and three breast cancer cell lines - MCF-7, MDA-MB-231 and SKBR-3 - by immunofluorescence and proliferation assay. Results We observed a strong positive correlation between moderate and high nuclear maspin level and survival of patients. Moreover, a statistically significant negative relationship was observed between nuclear maspin and Ki-67 expression in patients with invasive ductal breast cancer. Spearman’s correlation analysis showed a negative correlation between level of maspin localized in nucleus and percentage of Ki-67 positive cells. No such differences were observed in cells with cytoplasmic maspin. We found a strong correlation between nuclear maspin and loss of Ki-67 protein in breast cancer cell lines, while there was no effect in normal epithelial cells from breast. The anti

  12. Epithelial-mesenchymal transition (EMT) phenotype at invasion front of squamous cell carcinoma of the penis influences oncological outcomes.

    PubMed

    da Cunha, Isabela Werneck; Souza, Maria José L; da Costa, Walter Henriques; Amâncio, Alice M; Fonseca, Francisco Paulo; Zequi, Stenio de Cassio; Lopes, Ademar; Guimarães, Gustavo Cardoso; Soares, Fernando

    2016-10-01

    Our aims were to evaluate epithelial-mesenchymal transition (EMT) as a useful prognostic marker in penile carcinoma (PC), and establish an objective criterion to define EMT in PC specimens. A total of 149 consecutive cases surgically treated for PC were retrospectively selected. E-cadherin (E-CAD) and vimentin immunohistochemical expressions were evaluated. A combined analysis was performed using both markers to determine EMT status. To establish a normal control to E-CAD expression, we included 14 cases from circumcisions from patients without any neoplastic disease and 77 cases of tumor-free margins. The analyses of tumor samples were evaluated in 2 different areas of the tumor. The first one was in the tumor core. The second analyses were performed on the deepest infiltrative edge of the tumor, nominated invasion front. Cases were classified into EMT absent group, partial EMT group and complete EMT group. Overall survival (OS) and cancer-specific survival (CSS) were analyzed. Kaplan-Meier curves and the log-rank test were used. Cox proportional hazards model was used to determine which variables influenced survival. Tumor specimens presented a significant loss of expression of E-CAD when compared with normal epithelium. Vimentin expression in more than 10% of tumor cells was observed in 50 cases. EMT status was associated with histologic grade, pattern of invasion, lymph node metastasis, and perineural and vascular invasion. Further, 10-year OS and CSS rates in patients with presence and absence of complete EMT status were 38.0% and 55.6%; and 48.0% and 91.9%, respectively. EMT status significantly affected CSS and OS rates even after patients were grouped based on lymph node involvement status. The presence of complete EMT status was associated with both CSS and OS rates. Patients in the complete EMT group had a higher risk of death from cancer (hazard ratio = 7.6, P<0.001) and overall death (hazard ratio = 3.0, P<0.001). Our study represents an evidence of the

  13. Urokinase Receptor Promotes Skin Tumor Formation by Preventing Epithelial Cell Activation of Notch1.

    PubMed

    Mazzieri, Roberta; Pietrogrande, Giovanni; Gerasi, Laura; Gandelli, Alessandro; Colombo, Piergiuseppe; Moi, Davide; Brombin, Chiara; Ambrosi, Alessandro; Danese, Silvio; Mignatti, Paolo; Blasi, Francesco; D'Alessio, Silvia

    2015-11-15

    The urokinase-type plasminogen activator receptor (uPAR) has a well-established role in cancer progression, but it has been little studied at earlier stages of cancer initiation. Here, we show that uPAR deficiency in the mouse dramatically reduces susceptibility to the classical two-stage protocol of inflammatory skin carcinogenesis. uPAR genetic deficiency decreased papilloma formation and accelerated keratinocyte differentiation, effects mediated by Notch1 hyperactivation. Notably, Notch1 inhibition in uPAR-deficient mice rescued their susceptibility to skin carcinogenesis. Clinically, we found that human differentiated keratoacanthomas expressed low levels of uPAR and high levels of activated Notch1, with opposite effects in proliferating tumors, confirming the relevance of the observations in mice. Furthermore, we found that TACE-dependent activation of Notch1 in basal kerantinocytes was modulated by uPAR. Mechanistically, uPAR sequestered TACE within lipid rafts to prevent Notch1 activation, thereby promoting cell proliferation and tumor formation. Given that uPAR signaling is nonessential for normal epidermal homeostasis, our results argue that uPAR may present a promising disease-specific target for preventing skin cancer development.

  14. EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes.

    PubMed

    Hernando, Henar; Gelato, Kathy A; Lesche, Ralf; Beckmann, Georg; Koehr, Silke; Otto, Saskia; Steigemann, Patrick; Stresemann, Carlo

    2016-02-01

    Multiple myeloma is a plasma cell malignancy characterized by marked heterogeneous genomic instability including frequent genetic alterations in epigenetic enzymes. In particular, the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) is overexpressed in multiple myeloma. EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), a master transcriptional regulator of differentiation. EZH2 catalyzes methylation of lysine 27 on histone H3 and its deregulation in cancer has been reported to contribute to silencing of tumor suppressor genes, resulting in a more undifferentiated state, and thereby contributing to the multiple myeloma phenotype. In this study, we propose the use of EZH2 inhibitors as a new therapeutic approach for the treatment of multiple myeloma. We demonstrate that EZH2 inhibition causes a global reduction of H3K27me3 in multiple myeloma cells, promoting reexpression of EZH2-repressed tumor suppressor genes in a subset of cell lines. As a result of this transcriptional activation, multiple myeloma cells treated with EZH2 inhibitors become more adherent and less proliferative compared with untreated cells. The antitumor efficacy of EZH2 inhibitors is also confirmed in vivo in a multiple myeloma xenograft model in mice. Together, our data suggest that EZH2 inhibition may provide a new therapy for multiple myeloma treatment and a promising addition to current treatment options. Mol Cancer Ther; 15(2); 287-98. ©2015 AACR.

  15. Occasional detection of thymic epithelial tumor 4 years after diagnosis of adult onset Still disease

    PubMed Central

    Lococo, Filippo; Bajocchi, Gianluigi; Caruso, Andrea; Valli, Riccardo; Ricchetti, Tommaso; Sgarbi, Giorgio; Salvarani, Carlo

    2016-01-01

    Abstract Background: Thymoma is a T cell neoplasm arising from the thymic epithelium that due to its immunological role, frequently undercover derangements of immunity such a tumors and autoimmune diseases. Methods: Herein, we report, to the best of our knowledge, the first description of an association between thymoma and adult onset Still disease (AOSD) in a 47-year-old man. The first one was occasionally detected 4 years later the diagnosis of AOSD, and surgically removed via right lateral thoracotomy. Histology confirmed an encapsulated thymic tumor (type AB sec. WHO-classification). Results: The AOSD was particularly resistant to the therapy, requiring a combination of immunosuppressant followed by anti-IL1R, that was the only steroids-sparing treatment capable to induce and maintain the remission. The differential diagnosis was particularly challenging because of the severe myasthenic-like symptoms that, with normal laboratory tests, were initially misinterpreted as fibromyalgia. The pathogenic link of this association could be a thymus escape of autoreactive T lymphocytes causing autoimmunity. Conclusion: Clinicians should be always include the possibility of a thymoma in the differential diagnosis of an unusual new onset of weakness and normal laboratories data, in particular once autoimmune disease is present in the medical history. PMID:27603335

  16. Tissue Reactivity of the 14F7 Mab Raised against N-Glycolyl GM3 Ganglioside in Tumors of Neuroectodermal, Mesodermal, and Epithelial Origin

    PubMed Central

    Blanco, Rancés; Quintana, Yisel; Blanco, Damián; Cedeño, Mercedes; Rengifo, Charles E.; Frómeta, Milagros; Ríos, Martha; Rengifo, Enrique; Carr, Adriana

    2013-01-01

    The expression of N-glycolylneuraminic acid forming the structure of gangliosides and/or other glycoconjugates (Hanganutziu-Deicher antigen) in human has been considered as a tumor-associated antigen. Specifically, some reports of 14F7 Mab (a highly specific Mab raised against N-glycolyl GM3 ganglioside) reactivity in human tumors have been recently published. Nevertheless, tumors of epithelial origin have been mostly evaluated. The goal of the present paper was to evaluate the immunohistochemical recognition of 14F7 Mab in different human tumors of neuroectodermal, mesodermal, and epithelial origins using an immunoperoxidase staining method. Samples of fetal, normal, and reactive astrocytosis of the brain were also included in the study. In general, nontumoral tissues, as well as, low-grade brain tumors showed no or a limited immunoreaction with 14F7 Mab. Nevertheless, high-grade astrocytomas (III-IV) and neuroblastomas, as well as, sarcomas and thyroid carcinomas were mostly reactive with 14F7. No reaction was evidenced in medulloblastomas and ependymoblastomas. Our data suggest that the expression of N-glycolyl GM3 ganglioside could be related to the aggressive behavior of malignant cells, without depending on the tumor origin. Our data could also support the possible use of N-glycolyl GM3 as a target for both active and passive immunotherapies of malignancies expressing this molecule. PMID:26317019

  17. Tissue Reactivity of the 14F7 Mab Raised against N-Glycolyl GM3 Ganglioside in Tumors of Neuroectodermal, Mesodermal, and Epithelial Origin.

    PubMed

    Blanco, Rancés; Quintana, Yisel; Blanco, Damián; Cedeño, Mercedes; Rengifo, Charles E; Frómeta, Milagros; Ríos, Martha; Rengifo, Enrique; Carr, Adriana

    2013-01-01

    The expression of N-glycolylneuraminic acid forming the structure of gangliosides and/or other glycoconjugates (Hanganutziu-Deicher antigen) in human has been considered as a tumor-associated antigen. Specifically, some reports of 14F7 Mab (a highly specific Mab raised against N-glycolyl GM3 ganglioside) reactivity in human tumors have been recently published. Nevertheless, tumors of epithelial origin have been mostly evaluated. The goal of the present paper was to evaluate the immunohistochemical recognition of 14F7 Mab in different human tumors of neuroectodermal, mesodermal, and epithelial origins using an immunoperoxidase staining method. Samples of fetal, normal, and reactive astrocytosis of the brain were also included in the study. In general, nontumoral tissues, as well as, low-grade brain tumors showed no or a limited immunoreaction with 14F7 Mab. Nevertheless, high-grade astrocytomas (III-IV) and neuroblastomas, as well as, sarcomas and thyroid carcinomas were mostly reactive with 14F7. No reaction was evidenced in medulloblastomas and ependymoblastomas. Our data suggest that the expression of N-glycolyl GM3 ganglioside could be related to the aggressive behavior of malignant cells, without depending on the tumor origin. Our data could also support the possible use of N-glycolyl GM3 as a target for both active and passive immunotherapies of malignancies expressing this molecule.

  18. Association of tumor location, extent of resection, and neurofibromatosis status with clinical outcomes for 221 spinal nerve sheath tumors.

    PubMed

    Safaee, Michael; Parsa, Andrew T; Barbaro, Nicholas M; Chou, Dean; Mummaneni, Praveen V; Weinstein, Philip R; Tihan, Tarik; Ames, Christopher P

    2015-08-01

    OBJECT Intradural extramedullary spine tumors represent two-thirds of all primary spine neoplasms. Approximately half of these are peripheral nerve sheath tumors, mainly neurofibromas and schwannomas. Given the rarity of this disease and, thus, the limited analyses of clinical outcomes, the authors examined the association of tumor location, extent of resection, and neurofibromatosis (NF) status with clinical outcomes. METHODS Patients were identified through a search of the University of California, San Francisco, neuropathology database and a separate review of current procedural terminology codes. Data recorded included patient age, patient sex, clinical presentation, presence of NF, tumor type, tumor location, extent of resection (gross-total resection [GTR] or subtotal resection [STR]), and clinical follow-up. RESULTS Of 221 tumors in 199 patients (mean age 45 years), 53 were neurofibromas, 163 were schwannomas, and 5 were malignant peripheral nerve sheath tumors. The most common presenting symptom was spinal pain (76%), followed by weakness (36%) and sensory abnormalities (34%). Mean symptom duration was 16 months. In terms of spinal location, neurofibromas were more common in the cervical spine (74% vs 27%, p < 0.001), and schwannomas were more common in the thoracic and lumbosacral spine (73% vs 26%, p < 0.001). Rates of GTR were lower for neurofibromas than schwannomas (51% vs 83%, p < 0.001), regardless of location. Rates of GTR were lower for cervical (54%) than thoracic (90%) and lumbosacral (86%) lesions (p < 0.001). NF was associated with lower rates of GTR among all tumors (43% vs 86%, p < 0.001). The mean follow-up time was 32 months. Recurrence/progression was more common for neurofibromas than schwannomas (17% vs 7%, p = 0.03), although the mean time to recurrence/progression did not differ according to tumor type (45 vs 53 months, p = 0.63). As expected, GTR was associated with lower recurrence rates (4% vs 22%, p < 0.001). According to

  19. Targeting tumor perfusion and oxygenation to improve the outcome of anticancer therapy.

    PubMed

    Jordan, Bénédicte F; Sonveaux, Pierre

    2012-01-01

    Radiotherapy and chemotherapy are widespread clinical modalities for cancer treatment. Among other biological influences, hypoxia is a main factor limiting the efficacy of radiotherapy, primarily because oxygen is involved in the stabilization of the DNA damage caused by ionizing radiations. Radiobiological hypoxia is found in regions of rodent and human tumors with a tissue oxygenation level below 10 mmHg at which tumor cells become increasingly resistant to radiation damage. Since hypoxic tumor cells remain clonogenic, their resistance to the treatment strongly influences the therapeutic outcome of radiotherapy. There is therefore an urgent need to identify adjuvant treatment modalities aimed to increase tumor pO(2) at the time of radiotherapy. Since tumor hypoxia fundamentally results from an imbalance between oxygen delivery by poorly efficient blood vessels and oxygen consumption by tumor cells with high metabolic activities, two promising approaches are those targeting vascular reactivity and tumor cell respiration. This review summarizes the current knowledge about the development and use of tumor-selective vasodilators, inhibitors of tumor cell respiration, and drugs and treatments combining both activities in the context of tumor sensitization to X-ray radiotherapy. Tumor-selective vasodilation may also be used to improve the delivery of circulating anticancer agents to tumors. Imaging tumor perfusion and oxygenation is of importance not only for the development and validation of such combination treatments, but also to determine which patients could benefit from the therapy. Numerous techniques have been developed in the preclinical setting. Hence, this review also briefly describes both magnetic resonance and non-magnetic resonance in vivo methods and compares them in terms of sensitivity, quantitative or semi-quantitative properties, temporal, and spatial resolutions, as well as translational aspects.

  20. "Nonfunctional" Adrenal Tumors and the Risk for Incident Diabetes and Cardiovascular Outcomes: A Cohort Study.

    PubMed

    Lopez, Diana; Luque-Fernandez, Miguel Angel; Steele, Amy; Adler, Gail K; Turchin, Alexander; Vaidya, Anand

    2016-10-18

    Benign adrenal tumors are commonly discovered on abdominal imaging. Most are classified as nonfunctional and are considered to pose no health risk, but some are considered functional because they secrete hormones that increase risk for metabolic and cardiovascular diseases. To evaluate the hypothesis that nonfunctional adrenal tumors (NFATs) increase risk for cardiometabolic outcomes compared with absence of adrenal tumors. Cohort study. Integrated hospital system. Participants with benign NFATs ("exposed"; n = 166) and those with no adrenal tumor ("unexposed"; n = 740), with at least 3 years of follow-up. Medical records were reviewed from the time of abdominal imaging for development of incident outcomes (hypertension, composite diabetes [prediabetes or type 2 diabetes], hyperlipidemia, cardiovascular events, and chronic kidney disease) (mean, 7.7 years). Primary analyses evaluated independent associations between exposure status and incident outcomes by using adjusted generalized linear models. Secondary analyses evaluated relationships between NFATs and cortisol physiology. Participants with NFATs had significantly higher risk for incident composite diabetes than those without adrenal tumors (30 of 110 [27.3%] vs. 72 of 615 [11.7%] participants; absolute risk, 15.6% [95% CI, 6.9% to 24.3%]; adjusted risk ratio, 1.87 [CI, 1.17 to 2.98]). No significant associations between NFATs and other outcomes were observed. Higher "normal" postdexamethasone cortisol levels (≤50 nmol/L) were associated with larger NFAT size and higher prevalence of type 2 diabetes. Potential bias in the selection of participants and ascertainment of outcomes. Participants with NFATs had a significantly higher risk for diabetes than those without adrenal tumors. These results should prompt a reassessment of whether the classification of benign adrenal tumors as "nonfunctional" adequately reflects the continuum of hormone secretion and metabolic risk they may harbor. National Institutes of

  1. Targeting Epithelial-Mesenchymal Transition for Identification of Inhibitors for Pancreatic Cancer Cell Invasion and Tumor Spheres Formation

    PubMed Central

    Polireddy, Kishore; Dong, Ruochen; McDonald, Peter R.; Wang, Tao; Luke, Brendan; Chen, Ping; Broward, Melinda; Roy, Anuradha; Chen, Qi

    2016-01-01

    Background Pancreatic cancer has an enrichment of stem-like cancer cells (CSCs) that contribute to chemoresistant tumors prone to metastasis and recurrence. Drug screening assays based on cytotoxicity cannot identify specific CSC inhibitors, because CSCs comprise only a small portion of cancer cell population, and it is difficult to propagate stable CSC populations in vitro for high-throughput screening (HTS) assays. Based on the important role of cancer cell epithelial-to-mesenchymal transition (EMT) in promoting CSCs, we hypothesized that inhibition of EMT can be a useful strategy for inhibiting CSCs, and therefore a feasible approach for HTS can be built for identification of CSC inhibitors, based on assays detecting EMT inhibition. Methods An immunofluorescent assay was established and optimized for HTS to identify compounds that enhance E-cadherin expression, as a hallmark of inhibition of EMT. Four chemical libraries containing 41,472 compounds were screened in PANC-1 pancreatic cancer cell line. Positive hits were validated for EMT and CSC inhibition in vitro using sphere formation assay, western blotting, immune fluorescence, and scratch assay. Results Initial hits were refined to 73 compounds with a secondary screening, among which 17 exhibited concentration dependent induction of E-cadherin expression. Six compounds were selected for further study which belonged to 2 different chemical structural clusters. A novel compound 1-(benzylsulfonyl) indoline (BSI, Compound #38) significantly inhibited pancreatic cancer cell migration and invasion. BSI inhibited histone deacetylase, increased histone 4 acetylation preferably, resulting in E-cadherin up-regulation. BSI effectively inhibited tumor spheres formation. Six more analogues of BSI were tested for anti-migration and anti-CSC activities. Conclusion This study demonstrated a feasible approach for discovery of agents targeting EMT and CSCs using HTS, and identified a class of novel chemicals that could be

  2. CD133/Src Axis Mediates Tumor Initiating Property and Epithelial-Mesenchymal Transition of Head and Neck Cancer

    PubMed Central

    Chen, Yu-Syuan; Wu, Meng-Ju; Huang, Chih-Yang; Lin, Shu-Chun; Chuang, Tsung-Hsien; Yu, Cheng-Chia; Lo, Jeng-Fan

    2011-01-01

    Background Head and Neck squamous cell carcinoma (HNSCC) is a human lethal cancer with clinical, pathological, phenotypical and biological heterogeneity. Caner initiating cells (CICs), which are responsible for tumor growth and coupled with gain of epithelial-mesenchymal transition (EMT), have been identified. Previously, we enriched a subpopulation of head and neck cancer initiating cells (HN-CICs) with up-regulation of CD133 and enhancement of EMT. Others demonstrate that Src kinase interacts with and phosphorylates the cytoplasmic domain of CD133. However, the physiological function of CD133/Src signaling in HNSCCs has not been uncovered. Methodology/Principal Finding Herein, we determined the critical role of CD133/Src axis modulating stemness, EMT and tumorigenicity of HNSCC and HN-CICs. Initially, down-regulation of CD133 significantly reduced the self-renewal ability and expression of stemness genes, and promoted the differentiation and apoptotic capability of HN-CICs. Additionally, knockdown of CD133 in HN-CICs also lessened both in vitro malignant properties including cell migration/cell invasiveness/anchorage independent growth, and in vivo tumor growth by nude mice xenotransplantation assay. In opposite, overexpression of CD133 enhanced the stemness properties and tumorigenic ability of HNSCCs. Lastly, up-regulation of CD133 increased phosphorylation of Src coupled with EMT transformation in HNSCCs, on the contrary, silence of CD133 or treatment of Src inhibitor inversely abrogated above phenotypic effects, which were induced by CD133 up-regulation in HNSCCs or HN-CICs. Conclusion/Significance Our results suggested that CD133/Src signaling is a regulatory switch to gain of EMT and of stemness properties in HNSCC. Finally, CD133/Src axis might be a potential therapeutic target for HNSCC by eliminating HN-CICs. PMID:22140506

  3. Robust feature selection to predict tumor treatment outcome.

    PubMed

    Mi, Hongmei; Petitjean, Caroline; Dubray, Bernard; Vera, Pierre; Ruan, Su

    2015-07-01

    Recurrence of cancer after treatment increases the risk of death. The ability to predict the treatment outcome can help to design the treatment planning and can thus be beneficial to the patient. We aim to select predictive features from clinical and PET (positron emission tomography) based features, in order to provide doctors with informative factors so as to anticipate the outcome of the patient treatment. In order to overcome the small sample size problem of datasets usually met in the medical domain, we propose a novel wrapper feature selection algorithm, named HFS (hierarchical forward selection), which searches forward in a hierarchical feature subset space. Feature subsets are iteratively evaluated with the prediction performance using SVM (support vector machine). All feature subsets performing better than those at the preceding iteration are retained. Moreover, as SUV (standardized uptake value) based features have been recognized as significant predictive factors for a patient outcome, we propose to incorporate this prior knowledge into the selection procedure to improve its robustness and reduce its computational cost. Two real-world datasets from cancer patients are included in the evaluation. We extract dozens of clinical and PET-based features to characterize the patient's state, including SUV parameters and texture features. We use leave-one-out cross-validation to evaluate the prediction performance, in terms of prediction accuracy and robustness. Using SVM as the classifier, our HFS method produces accuracy values of 100% and 94% on the two datasets, respectively, and robustness values of 89% and 96%. Without accuracy loss, the prior-based version (pHFS) improves the robustness up to 100% and 98% on the two datasets, respectively. Compared with other feature selection methods, the proposed HFS and pHFS provide the most promising results. For our HFS method, we have empirically shown that the addition of prior knowledge improves the robustness and

  4. Suprasellar granular cell tumor of the neurohypophysis: surgical outcome of a very rare tumor.

    PubMed

    Gagliardi, Filippo; Spina, Alfio; Barzaghi, Lina Raffaella; Bailo, Michele; Losa, Marco; Terreni, Maria Rosa; Mortini, Pietro

    2016-06-01

    Granular cell tumors of the neurohypophysis are rare, solitary lesions, mostly presenting in the adult age. They rarely grow to a sufficient size to cause mass effect related symptoms and they may be found in most cases incidentally at autopsy. Because of their rarity as of now they have been described only as case reports or included in small clinical series. We report a series of 11 patients, who underwent surgery for granular cell tumors of the neurohypophysis between 1996 and 2013 in a single center. Mean follow-up time after treatment was 92.2 months (range 9-231 months). Mean age at surgery was 40.7 years (range 12-66 years). There were 7 males (63.6 %) and 4 females (36.4 %). Main symptoms at presentation were: hyperprolactinemia (72.7 %), visual impairment (45.5 %) and headache (36 %). Except for 2 patients, all the others underwent surgery as primary treatment at our Institution, through a transsphenoidal (54.5 %) or a transcranial approach (45.5 %). Overall- and progression-free survival times for the entire series (calculated from the time of diagnosis) were 112.9 and 100.5 months respectively. There was one case of perioperative death in a patient who had undergone repeat transcranial surgery for residual tumor. Although extremely rare, granular cell tumors of the neurohypophysis have to be considered in the differential diagnosis of suprasellar masses, to avoid misleading interpretation and consequent wrong therapeutic management. Early diagnosis, extensive tumor removal, opportune indication of adjuvant radiotherapy are the keys to manage these cases.

  5. Detailed analysis of epithelial-mesenchymal transition and tumor budding identifies predictors of long-term survival in pancreatic ductal adenocarcinoma.

    PubMed

    Kohler, Ilona; Bronsert, Peter; Timme, Sylvia; Werner, Martin; Brabletz, Thomas; Hopt, Ulrich Theodor; Schilling, Oliver; Bausch, Dirk; Keck, Tobias; Wellner, Ulrich Friedrich

    2015-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive biology and poor prognosis even after resection. Long-term survival is very rare and cannot be reliably predicted. Experimental data suggest an important role of epithelial-mesenchymal transition (EMT) in invasion and metastasis of PDAC. Tumor budding is regarded as the morphological correlate of local invasion and cancer cell dissemination. The aim of this study was to evaluate the biological and prognostic implications of EMT and tumor budding in PDAC of the pancreatic head. Patients were identified from a prospectively maintained database, and baseline, operative, histopathological, and follow-up data were extracted. Serial tissue slices stained for Pan-Cytokeratin served for analysis of tumor budding, and E-Cadherin, Beta-Catenin, and Vimentin staining for analysis of EMT. Baseline, operative, standard pathology, and immunohistochemical parameters were evaluated for prediction of long-term survival (≥ 30 months) in uni- and multivariate analysis. Intra- and intertumoral patterns of EMT marker expression and tumor budding provide evidence of partial EMT induction at the tumor-host interface. Lymph node ratio and E-Cadherin expression in tumor buds were independent predictors of long-term survival in multivariate analysis. Detailed immunohistochemical assessment confirms a relationship between EMT and tumor budding at the tumor-host interface. A small group of patients with favorable prognosis can be identified by combined assessment of lymph node ratio and EMT in tumor buds. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  6. Downregulation of FBP1 Promotes Tumor Metastasis and Indicates Poor Prognosis in Gastric Cancer via Regulating Epithelial-Mesenchymal Transition.

    PubMed

    Li, Jing; Wang, Ying; Li, Qing-Guo; Xue, Jin-Jun; Wang, Zhu; Yuan, Xin; Tong, Jian-Dong; Xu, Li-Chun

    2016-01-01

    Recent studies indicated that some glycolytic enzymes are complicated, multifaceted proteins rather than simple components of the glycolytic pathway. FBP1 plays a vital role in glucose metabolism, but its role in gastric cancer tumorigenesis and metastasis has not been fully understood. The prognostic value of FBP1 was first studied in The Cancer Genome Atlas (TCGA) database and validated in in-house database. The effect of FBP1 on cell proliferation and metastasis was examined in vitro. Nonparametric test and Log-rank test were used to evaluate the clinical significance of FBP1 expression. In the TCGA cohort, FBP1 mRNA level were shown to be predictive of overall survival in gastric cancer (P = 0.029). In the validation cohort, FBP1 expression were inversely correlated with advanced N stage (P = 0.021) and lymphovascular invasion (P = 0.011). Multivariate Cox regression analysis demonstrated that FBP1 was an independent predictor for both overall survival (P = 0.004) and disease free survival (P<0.001). Functional studies demonstrated that ectopic FBP1 expression inhibited proliferation and invasion in gastric cancer cells, while silencing FBP1 expression had opposite effects (P<0.05). Mechanically, FBP1 serves as a tumor suppressor by inhibiting epithelial-mesenchymal transition (EMT). Downregulation of FBP1 promotes gastric cancer metastasis by facilitating EMT and acts as a potential prognostic factor and therapeutic target in gastric cancer.

  7. Methylation decreases the Bin1 tumor suppressor in ESCC and restoration by decitabine inhibits the epithelial mesenchymal transition.

    PubMed

    Wang, Xuexiao; Wang, Jiali; Jia, Yunlong; Wang, Yu; Han, Xiaonan; Duan, Yuqing; Lv, Wei; Ma, Ming; Liu, Lihua

    2017-01-31

    Bridging integrator-1 (Bin1), as a tumor suppressor, is frequently attenuated or even abolished in multiple primary cancers. A reduced expression of Bin1 caused by DNA methylation, has been reported in breast and prostate cancers. However, the methylation status of Bin1 and potent biological functions in esophageal squamous cell carcinoma (ESCC) remain unclear. In a previous study, we showed that the Bin1 expression was low in ESCC tissues. Herein, we further characterized this mechanism, confirming that gene hypermethylation was significantly correlated with the aberrant attenuation of Bin1. In addition, the Bin1 hypermethylation was associated with the poorer clinical parameters and shorter survival times of ESCC patients. Methylation-specific reverse transcription-polymerase chain reaction (MS-RT-PCR) showed that Bin1 was hypermethylated in several ESCC cell lines, which might be the main cause of reduced Bin1 expression. In addition, treatment with the de-methylation agent Decitabine (DAC) could restore Bin1 expression and evidently restrained ESCC cell malignant behaviors, particularly the epithelial mesenchymal transition (EMT) via reactivating the PTEN/AKT signaling pathway to inhibit matrix metalloproteinase (MMP)-2 and MMP-9 expression in vitro and in vivo. In conclusion, these results demonstrated that Bin1 methylation could augment the malignant biological behaviors of ESCC and predict the poor prognosis for ESCC patients, thus indicating the potential clinical application value of DAC-based de-methylation therapy in ESCC.

  8. Downregulation of FBP1 Promotes Tumor Metastasis and Indicates Poor Prognosis in Gastric Cancer via Regulating Epithelial-Mesenchymal Transition

    PubMed Central

    Li, Qing-Guo; Xue, Jin-Jun; Wang, Zhu; Yuan, Xin; Tong, Jian-Dong; Xu, Li-Chun

    2016-01-01

    Background Recent studies indicated that some glycolytic enzymes are complicated, multifaceted proteins rather than simple components of the glycolytic pathway. FBP1 plays a vital role in glucose metabolism, but its role in gastric cancer tumorigenesis and metastasis has not been fully understood. Methods The prognostic value of FBP1 was first studied in The Cancer Genome Atlas (TCGA) database and validated in in-house database. The effect of FBP1 on cell proliferation and metastasis was examined in vitro. Nonparametric test and Log-rank test were used to evaluate the clinical significance of FBP1 expression. Results In the TCGA cohort, FBP1 mRNA level were shown to be predictive of overall survival in gastric cancer (P = 0.029). In the validation cohort, FBP1 expression were inversely correlated with advanced N stage (P = 0.021) and lymphovascular invasion (P = 0.011). Multivariate Cox regression analysis demonstrated that FBP1 was an independent predictor for both overall survival (P = 0.004) and disease free survival (P<0.001). Functional studies demonstrated that ectopic FBP1 expression inhibited proliferation and invasion in gastric cancer cells, while silencing FBP1 expression had opposite effects (P<0.05). Mechanically, FBP1 serves as a tumor suppressor by inhibiting epithelial-mesenchymal transition (EMT). Conclusions Downregulation of FBP1 promotes gastric cancer metastasis by facilitating EMT and acts as a potential prognostic factor and therapeutic target in gastric cancer. PMID:27978536

  9. Aberrant high expression of immunoglobulin G in epithelial stem/progenitor-like cells contributes to tumor initiation and metastasis.

    PubMed

    Liao, Qinyuan; Liu, Wei; Liu, Yang; Wang, Fulin; Wang, Chong; Zhang, Jingxuan; Chu, Ming; Jiang, Dongyang; Xiao, Lin; Shao, Wenwei; Sheng, Zhengzuo; Tao, Xia; Huo, Lei; Yin, C Cameron; Zhang, Youhui; Lee, Gregory; Huang, Jing; Li, Zihai; Qiu, Xiaoyan

    2015-11-24

    High expression of immunoglobulin G (IgG) in many non-B cell malignancies and its non-conventional roles in promoting proliferation and survival of cancer cells have been demonstrated. However, the precise function of non-B IgG remains incompletely understood. Here we define the antigen specificity of RP215, a monoclonal antibody that specifically recognizes the IgG in cancer cells. Using RP215, our study shows that IgG is overexpressed in cancer cells of epithelial lineage, especially cells with cancer stem/progenitor cell-like features. The RP215-recognized IgG is primarily localized on the cell surface, particularly lamellipodia-like structures. Cells with high IgG display higher migration, increased invasiveness and metastasis, and enhanced self-renewal and tumorgenecity ability in vitro and in vivo. Importantly, depletion of IgG in breast cancer leads to reduced adhesion, invasion and self-renewal and increased apoptosis of cancer cells. We conclude that high expression of IgG is a novel biomarker of tumor progression, metastasis and cancer stem cell maintenance and demonstrate the potential therapeutic benefits of RP215-recognized IgG targeted strategy.

  10. Perioperative problems in patients with brainstem tumors and their influence on patient outcome

    PubMed Central

    Bharati, Sachidanand J; Pandia, Mihir Prakash; Rath, Girija Prasad; Bithal, Parmod Kumar; Dash, Hari Hara; Dube, Surya K

    2016-01-01

    Background and Aims: Patients with brainstem tumors have many associated systemic abnormalities and are prone to develop perioperative complications. We studied the problems associated with brainstem tumors and their influence on the postoperative neurological outcome. Material and Methods: Retrospective review of records of patients who underwent surgery for brainstem tumors over a period of 8 years was done. Preoperative variables, perioperative complications and neurological outcome as assessed by Glasgow Outcome Scale at the time of hospital discharge were noted. Association between perioperative factors and the unfavorable neurological outcome was evaluated. Results: Data of 70 patients were retrieved, 7 patients were excluded from the study because of incomplete data and data analysis was carried out for 63 patients. We found that lower cranial nerve palsies (32%) and hydrocephalus (43%) were common preoperatively. Various intraoperative problems encountered were hemodynamic instability (56%), major blood loss requiring blood transfusion (40%) and venous air embolism (11%), and postoperative problems were meningitis (51%), hypokalemia (38%), chest infection (21%), seizure (11%), deterioration of Glasgow Coma Scale (GCS, 11%), hyponatremia (8%), hydrocephalus (6%), respiratory distress (3%) and operatives site hematoma (3%). Fifty-six (89%) patients had favorable outcome at hospital discharge whereas, 7 (11%) had an unfavorable outcome. There was no association between pre- and intra-operative factors and the neurological outcome. Deterioration of GCS, chest infection, and the need for reintubation and tracheostomy were associated with unfavorable neurological outcome. Conclusion: Patients of brainstem tumors are at increased risk of perioperative complications. Some of the postoperative complications were associated with unfavorable neurological outcome. PMID:27275044

  11. Early detection of poor outcome in patients with metastatic colorectal cancer: tumor kinetics evaluated by circulating tumor cells

    PubMed Central

    Souza e Silva, Virgílio; Chinen, Ludmilla Thomé Domingos; Abdallah, Emne A; Damascena, Aline; Paludo, Jociana; Chojniak, Rubens; Dettino, Aldo Lourenço Abbade; de Mello, Celso Abdon Lopes; Alves, Vanessa S; Fanelli, Marcello F

    2016-01-01

    Background Colorectal cancer (CRC) is the third most prevalent cancer worldwide. New prognostic markers are needed to identify patients with poorer prognosis, and circulating tumor cells (CTCs) seem to be promising to accomplish this. Patients and methods A prospective study was conducted by blood collection from patients with metastatic CRC (mCRC), three times, every 2 months in conjunction with image examinations for evaluation of therapeutic response. CTC isolation and counting were performed by Isolation by Size of Epithelial Tumor Cells (ISET). Results A total of 54 patients with mCRC with a mean age of 57.3 years (31–82 years) were included. Among all patients, 60% (n=32) were carriers of wild-type KRAS (WT KRAS) tumors and 90% of them (n=29) were exposed to monoclonal antibodies along with systemic treatment. Evaluating CTC kinetics, when we compared the baseline (pretreatment) CTC level (CTC1) with the level at first follow-up (CTC2), we observed that CTC1-positive patients (CTCs above the median), who became negative (CTCs below the median) had a favorable evolution (n=14), with a median progression-free survival (PFS) of 14.7 months. This was higher than that for patients with an unfavorable evolution (CTC1− that became CTC2+; n=13, 6.9 months; P=0.06). Patients with WT KRAS with favorable kinetics had higher PFS (14.7 months) in comparison to those with WT KRAS with unfavorable kinetics (9.4 months; P=0.02). Moreover, patients whose imaging studies showed radiological progression had an increased quantification of CTCs at CTC2 compared to those without progression (P=0.04). Conclusion This study made possible the presentation of ISET as a feasible tool for evaluating CTC kinetics in patients with mCRC, which can be promising in their clinical evaluation. PMID:28008271

  12. Comparison of plasma amino acid profile-based index and CA125 in the diagnosis of epithelial ovarian cancers and borderline malignant tumors.

    PubMed

    Miyagi, Etsuko; Maruyama, Yasuyo; Mogami, Tae; Numazaki, Reiko; Ikeda, Atsuko; Yamamoto, Hiroshi; Hirahara, Fumiki

    2017-02-01

    We previously developed a new plasma amino acid profile-based index (API) to detect ovarian, cervical, and endometrial cancers. Here, we compared API to serum cancer antigen 125 (CA125) for distinguishing epithelial ovarian malignant tumors from benign growths. API and CA125 were measured preoperatively in patients with ovarian tumors, which were later classified into 59 epithelial ovarian cancers, 21 epithelial borderline malignant tumors, and 97 benign tumors including 40 endometriotic cysts. The diagnostic accuracy and cutoff points of API were evaluated using receiver operating characteristic (ROC) curves. The area under the ROC curves showed the equivalent performance of API and CA125 to discriminate between malignant/borderline malignant and benign tumors (both 0.77), and API was superior to CA125 for discrimination between malignant/borderline malignant lesions and endometriotic cysts (API, 0.75 vs. CA125, 0.59; p < 0.05). At the API cutoff level of 6.0, API and CA125 had equal positive rates of detecting cancers and borderline malignancies (API, 0.71 vs. CA125, 0.74; p = 0.84) or cancers alone (API, 0.73 vs. CA125, 0.85; p = 0.12). However, API had a significantly lower detection rate of benign endometriotic cysts (0.35; 95 % CI, 0.21-0.52) compared with that of CA125 (0.65; 95 % CI, 0.48-0.79) (p < 0.05). API is an effective new tumor marker to detect ovarian cancers and borderline malignancies with a low false-positive rate for endometriosis. A large-scale prospective clinical study using the cutoff value of API determined in this study is warranted to validate API for practical clinical use.

  13. Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2.

    PubMed

    Yan, Chunli; Grimm, Wesley A; Garner, Warren L; Qin, Lan; Travis, Taryn; Tan, Neiman; Han, Yuan-Ping

    2010-05-01

    Epithelial-mesenchymal transition (EMT), characterized by loss of epithelial adhesion and gain of mesenchymal features, is an important mechanism to empower epithelial cells into the motility that occurs during embryonic development and recurs in cancer and fibrosis. Whether and how EMT occurs in wound healing and fibrosis in human skin remains unknown. In this study we found that migrating epithelial cells in wound margins and deep epithelial ridges had gained mesenchymal features such as vimentin and FSP1 expression. In hypertrophic scars, EMT-related genes were elevated along with inflammatory cytokines, indicating a causal relationship. To reconstitute EMT in vitro, normal human skin and primary keratinocytes were exposed to cytokines such as tumor necrosis factor-alpha (TNF-alpha), resulting in expression of vimentin, FSP1, and matrix metalloproteinases. Moreover, TNF-alpha-induced EMT was impaired by antagonists against bone morphogen proteins (BMP) 2/4, suggesting that BMP mediates the TNF-alpha-induced EMT in human skin. Indeed, TNF-alpha could induce BMP-2 and its receptor (BMPR1A) in human skin and primary keratinocytes, and BMP2 could induce EMT features in skin explants and primary keratinocytes. In summary, we uncovered EMT features in both acute and fibrotic cutaneous wound healing of human skin. Moreover, we propose that the mesenchymal induction in wound healing is motivated by TNF-alpha, in part, through induction of BMP.

  14. Association Between Patient and Tumor Characteristics With Clinical Outcomes in Women With Ductal Carcinoma In Situ

    PubMed Central

    Wang, Shi-Yi; Virnig, Beth A.; Tuttle, Todd M.; Kane, Robert L.

    2010-01-01

    We synthesized the evidence of the association between patient and tumor characteristics with clinical outcomes in women with ductal carcinoma in situ of the breast. We identified five randomized controlled clinical trials and 64 observational studies that were published in English from January 1970 to January 2009. Younger women with clinically presented ductal carcinoma in situ had higher risk of ipsilateral recurrent cancer. African Americans had higher mortality and greater rates of advanced recurrent cancer. Women with larger tumor size, comedo necrosis, worse pathological grading, positive surgical margins, and at a higher risk category, using a composite prognostic index, had worse outcomes. Inconsistent evidence suggested that positive HER2 receptor and negative estrogen receptor status were associated with worse outcomes. Synthesis of evidence was hampered by low statistical power to detect significant differences in predictor categories and inconsistent adjustment practices across the studies. Future research should address composite prediction indices among race groups for all outcomes. PMID:20956815

  15. Optical Imaging of Mesenchymal Epithelial Transition Factor (MET) for Enhanced Detection and Characterization of Primary and Metastatic Hepatic Tumors

    PubMed Central

    Esfahani, Shadi A.; Heidari, Pedram; Kim, Sun A.; Ogino, Shuji; Mahmood, Umar

    2016-01-01

    Purpose: To assess optical imaging of Mesenchymal-Epithelial Transition factor (MET) for delineation and characterization of intrahepatic models of human hepatocellular carcinoma (HCC) and metastatic colorectal cancer (CRC), and thereby demonstrate its potential use in precision oncology. Materials and Methods: MET expression in human CRC and HCC was assessed in tissue microarrays. We used GE-137, a modified cyanine 5-tagged peptide for MET targeting. HepG2 and Huh-7 (HCC) and HT-29 (CRC) cells with MET overexpression, and LNCaP cells (negative control) with minimal MET expression were incubated with the probe. Correlation between the relative fluorescence signal intensity and cellular MET expression level was assessed. Flow cytometry was used to assess probe specific binding and dissociation constant (Kd). Orthotopic xenograft models of human HCC and metastatic CRC were generated in nu/nu mice by subcapsular implantation of cells. Epifluorescence imaging was performed to capture the changes in deferential probe accumulation at different time points after injection. Target-to-liver background ratio (TBR) was calculated and the probe biodistribution within different organs was assessed. Histopathologic analysis of extracted xenografts was performed to correlate the tumors MET expression with probe uptake by cancer cells. Results: Approximately 91.5% of HCC and 81% of CRC microarray cores showed MET expression. HCC and CRC cells incubated with the probe showed substantial fluorescence compared to control LNCaP, with strong correlation between fluorescence signal and MET expression (R2 = 0.99, p < 0.001). Probe binding affinity to MET (Kd) was measured to be 2.9 ± 0.36 nM. Epifluorescence imaging showed intense uptake in subcapsular tumors with peak TBR of 5.46 ± 0.46 in Huh-7, 3.55 ± 0.38 in HepG2, and 15.93 ± 0.61 in HT-29 orthotopic xenografts at 4 hours post-injection (mean ± standard deviation). We demonstrated that in vivo probe uptake in xenografts is

  16. Expression of tumor necrosis factor-alpha-induced protein 8 in pancreas tissues and its correlation with epithelial growth factor receptor levels.

    PubMed

    Liu, Ke; Qin, Cheng-Kun; Wang, Zhi-Yi; Liu, Su-Xia; Cui, Xian-Ping; Zhang, Dong-Yuan

    2012-01-01

    Tumor necrosis factor (TNF)-alpha-induced protein 8 (TNFAIP8 or TIPE) is a recently identified protein considered to be associated with carcinogenesis. To investigate its expression pattern in pancreatic cancer patients and to analyse its correlation with clinicopathological significance and the expression levels of epithelial growth factor receptor (EGFR), immunohistochemistry was performed to detect the TNFAIP8 and EGFR proteins in pancreatic cancers, pancreatitis tissues, and healthy controls. The results showed stronger staining of TNFAIP8 protein in pancreatic cancer tissues compared with normal pancreas tissue. Furthermore, in 56 patients with pancreatic cancer, the expression levels of TNFAIP8 in patients with low tumor stage was higher than that with high tumor stage, and correlated with tumor staging and lymph node metastasis (P<0.05). Furthermore, TNFAIP8 expression positively correlated with EGFR levels (r=0.671135, P<0.05). These results indicate that TNFAIP8 may play important roles in the progression of pancreatic cancer.

  17. Comparison between immunohistochemical expression of Ki-67 and MCM-3 in major salivary gland epithelial tumors in children and adolescents. Preliminary study.

    PubMed

    Zieliński, Rafał; Kobos, Jozef; Zakrzewska, Anna

    While Ki-67 expression is frequently used as an indicator of tumor cell proliferation, alternative markers have also been proposed. Possible alternative indicators of proliferation are the minichromosome maintenance (MCM) proteins, whose levels are inversely associated with tumor cell differentiation. The aim of this preliminary study was to compare the levels of Ki-67 and MCM-3 expression in major salivary gland epithelial tumors in all children and adolescents who underwent surgery in our department in the years 2009-2014. The histopathological diagnosis of the subjects was reviewed, as well as the expression of Ki-67 and MCM-3 in post-op specimens of the tumors. The normality of data was checked with the Shapiro-Wilk test. The t test for independent variables or the U test was used as appropriate to determine statistically significant differences in the expression of Ki-67 and MCM-3. Five cases of pleomorphic adenoma, one of myoepithelioma, one of basal cell adenoma and one of mucoepidermoid carcinoma were identified. Significantly greater MCM-3 than Ki-67 expression was observed in every case. The results of our preliminary study emphasize the need for future research on MCM-3 as a sensitive proliferation marker, providing an alternative to Ki-67, in cases of various major salivary gland epithelial tumors in children and adolescents.

  18. Pediatric brain tumors in Nigeria: clinical profile, management strategies, and outcome.

    PubMed

    Uche, E O; Shokunbi, M T; Malomo, A O; Akang, E E U; Lagunju, I; Amanor-Boadu, S D

    2013-07-01

    Although modern neuroimaging has facilitated early care of brain tumors in children worldwide, there are, however, few published reports on clinical profile, treatment, and outcome of brain tumors in children from our subregion. We aimed to retrospectively study the clinical profile and outcome of pediatric brain tumors in a tertiary referral center from a developing country. Forty pediatric patients with histologically verified brain tumors managed by the authors over a 13-year period (May 1994-April 2006) were studied. Patients' data from clinical, radiological, and pathology records were analyzed using the statistical package for social sciences version 16. The mean age was 9.75 years (range 1-15 years). Twenty-two males, 18 females. Common presenting symptoms were headaches (23 patients, 57.5%) and seizures (15 patients, 37.5%). Hyperreflexia (72.5%) and focal motor deficits (62.5%) were the most common neurologic signs. The mean interval from onset of symptoms to neurosurgical diagnosis was 13.4 months (95% CI). All patients had tumor resection, while 11 (27.5%) patients received adjuvant radiotherapy. Hydrocephalus occurred in 19 (47.5%) patients and was associated with early presentation (X2 = 10.65, p < 0.01). Low-grade astrocytoma (25%) and medulloblastoma (25%) were the most common tumors. Survival at 1 and 5 years were 56 and 47%, respectively. Focal motor signs and elevated intracranial pressure are the salient presenting features of brain tumors in children seen in Nigeria. Those of them with hydrocephalus are likely to present early. The outcome for pediatric brain tumors remains poor.

  19. Molecular sub-classification of renal epithelial tumors using meta-analysis of gene expression microarrays.

    PubMed

    Sanford, Thomas; Chung, Paul H; Reinish, Ariel; Valera, Vladimir; Srinivasan, Ramaprasad; Linehan, W Marston; Bratslavsky, Gennady

    2011-01-01

    To evaluate the accuracy of the sub-classification of renal cortical neoplasms using molecular signatures. A search of publicly available databases was performed to identify microarray datasets with multiple histologic sub-types of renal cortical neoplasms. Meta-analytic techniques were utilized to identify differentially expressed genes for each histologic subtype. The lists of genes obtained from the meta-analysis were used to create predictive signatures through the use of a pair-based method. These signatures were organized into an algorithm to sub-classify renal neoplasms. The use of these signatures according to our algorithm was validated on several independent datasets. We identified three Gene Expression Omnibus datasets that fit our criteria to develop a training set. All of the datasets in our study utilized the Affymetrix platform. The final training dataset included 149 samples represented by the four most common histologic subtypes of renal cortical neoplasms: 69 clear cell, 41 papillary, 16 chromophobe, and 23 oncocytomas. When validation of our signatures was performed on external datasets, we were able to correctly classify 68 of the 72 samples (94%). The correct classification by subtype was 19/20 (95%) for clear cell, 14/14 (100%) for papillary, 17/19 (89%) for chromophobe, 18/19 (95%) for oncocytomas. Through the use of meta-analytic techniques, we were able to create an algorithm that sub-classified renal neoplasms on a molecular level with 94% accuracy across multiple independent datasets. This algorithm may aid in selecting molecular therapies and may improve the accuracy of subtyping of renal cortical tumors.

  20. Expectant management of vestibular schwannoma: a retrospective multivariate analysis of tumor growth and outcome.

    PubMed

    Hughes, Mark; Skilbeck, Christopher; Saeed, Shakeel; Bradford, Robert

    2011-09-01

    We conducted a retrospective observational study to assess the consequences of conservative management of vestibular schwannoma (VS). Data were collected from tertiary neuro-otological referral units in United Kingdom. The study included 59 patients who were managed conservatively with radiological diagnosis of VS. The main outcome measures were growth rate and rate of failure of conservative management. Multivariate analysis sought correlation between tumor growth and (i) demographic features, (ii) tumor characteristics. The mean tumor growth was 0.66 mm/y. 11 patients (19%) required intervention. Mean time to intervention was 37 months with two notable late "failures" occurring at 75 and 84 months. Tumors extending into the cerebellopontine angle (CPA) grew significantly faster than intracanalicular tumors (p = 0.0045). No association was found between growth rate and age, sex, tumor laterality, facial nerve function, and grade of hearing loss. Conservative management is acceptable for a subset of patients. Tumors extending into the CPA at diagnosis grow significantly faster than intracanalicular tumors. No growth within 5 years of surveillance does not guarantee a continued indolent growth pattern; surveillance must therefore continue.

  1. Outcomes of corneal collagen crosslinking using a customized epithelial debridement technique in keratoconic eyes with thin corneas.

    PubMed

    Cagil, Nurullah; Sarac, Ozge; Can, Gamze Dereli; Akcay, Emine; Can, Mehmet Erol

    2017-02-01

    The purpose of the study was to evaluate the outcomes and possible complications of CXL performed with customized epithelial debridement technique to keratoconic corneas with the thinnest pachymetry values less than 400 µm. Nineteen eyes of 19 patients were included. The uncorrected (UCVA) and best corrected visual acuity (BCVA), flattest and steepest keratometric (K) readings, central corneal thickness at the thinnest point (t-CCT), endothelial cell density (ECD) were assessed before and 12 months after CXL. The mean UCVA was increased (p = 0.001), while the mean BCVA did not show any difference (p > 0.05). The mean flattest and steepest K readings were decreased (p = 0.001). No change was observed in the mean t-CCT (p > 0.05). The mean ECD was decreased (p = 0.001). The mean pre-CXL and post-CXL percentages of polymegathism and pleomorphism did not show any significant difference (p > 0.05). CXL performed with customized epithelial debridement technique is successful in halting the progression of keratoconus in corneas thinner than 400 µm after 12 months of treatment. However, significant endothelial cell loss can occur after this procedure.

  2. Determinants of outcome of solitary fibrous tumors of the pleura: an observational cohort study

    PubMed Central

    2014-01-01

    Background Solitary fibrous tumors of the pleura (SFTP) are rare and their long-term outcome is difficult to predict, as there are insufficient data which allow accurate characterization of the malignant variant. Thus the aim of this study was to describe the outcome and possible determinants of malignant behavior of SFTPs. Methods Data were collected retrospectively from medical records of patients treated at the University Hospital Zurich from 1992 to 2012. Kaplan-Meier and Cox regression analysis were performed to define disease-free survival time (defined as survival without tumor-recurrence or tumor-related death) using the classical histo-morphological criteria (tumor size, localization, pedunculation, tumor necrosis or hemorrhage, mitotic activity and nuclear pleomorphism) and immunohistochemical parameters. Results 42 patients (20 males) with SFTP (median (IQR) age 62 (56–71) years) could be identified. SFTP were associated with symptoms in 50% of all cases. Complete resection was achieved by video-assisted thoracic surgery or thoracotomy in 20 and 22 patients, respectively. Three SFTP-related deaths (7.1%) and four tumor recurrences (9.5%) were observed. Mean disease-free survival time was 136.2 (±13.1) months, and 2-, 5- and 10-year disease-free survival was 91%, 84%, and 67%, respectively. Mean disease-free survival inversely correlated with the mean tumor diameter, number of mitotic figures and proliferation rate (Ki-67 expression). Other criteria (tumor necrosis, atypical localization, sessile tumor, and pleomorphism) were not statistically significant prognostic parameters. Conclusions Patients with large SFTP with a high mitotic index and high proliferation rate should be followed-up closely and over a prolonged time period in order to recognize recurrence of the SFTP early and at a treatable stage. Future research on this topic should focus on the prognostic role of immunohistochemistry including Ki-67 expression and molecular parameters. PMID

  3. Molecular genetic analysis of VRK1 in mammary epithelial cells: depletion slows proliferation in vitro and tumor growth and metastasis in vivo

    PubMed Central

    Molitor, T P; Traktman, P

    2013-01-01

    The vaccinia-related kinases (VRKs) comprise a branch of the casein kinase family. VRK1, a ser/thr kinase with a nuclear localization, is the most well-studied paralog and has been described as a proproliferative protein. In lower eukaryotes, a loss of VRK1 activity is associated with severe mitotic and meiotic defects. Mice that are hypomorphic for VRK1 expression are infertile, and depletion of VRK1 in tissue culture cells can impair cell proliferation and alter several signaling pathways. VRK1 has been implicated as part of a ‘gene-expression signature' whose overexpression correlates with poor clinical outcome in breast cancer patients. We present here our investigation of the role of VRK1 in the growth of normal (MCF10) and malignant (MDA-MB-231) human mammary epithelial cells, and demonstrate that shRNA-mediated depletion of VRK1 slows their proliferation significantly. Conversely, stable overexpression of a FLAG-tagged VRK1 transgene imparts a survival advantage to highly malignant MDA-MB-231 cells under conditions of nutrient and growth factor deprivation. Moreover, in a murine orthotopic xenograft model of breast cancer, we demonstrate that tumors depleted of VRK1 show a 50% reduction in size from 4–13 weeks postengraftment. The incidence and burden of distal metastases in the lungs and brain was also significantly reduced in mice engrafted with VRK1-depleted cells. These studies demonstrate that VRK1 depletion or overexpression has an impact on the proliferation and survival of cell lines derived from normal or malignant mammary tissue, and moreover show that depletion of VRK1 in MDA-MB-231 cells reduces their oncogenic and metastatic properties in vivo. PMID:23732708

  4. Diffuse optical measurements of head and neck tumor hemodynamics for early prediction of chemoradiation therapy outcomes

    NASA Astrophysics Data System (ADS)

    Dong, Lixin; Kudrimoti, Mahesh; Irwin, Daniel; Chen, Li; Kumar, Sameera; Shang, Yu; Huang, Chong; Johnson, Ellis L.; Stevens, Scott D.; Shelton, Brent J.; Yu, Guoqiang

    2016-08-01

    This study used a hybrid near-infrared diffuse optical instrument to monitor tumor hemodynamic responses to chemoradiation therapy for early prediction of treatment outcomes in patients with head and neck cancer. Forty-seven patients were measured once per week to evaluate the hemodynamic status of clinically involved cervical lymph nodes as surrogates for the primary tumor response. Patients were classified into two groups: complete response (CR) (n=29) and incomplete response (IR) (n=18). Tumor hemodynamic responses were found to be associated with clinical outcomes (CR/IR), wherein the associations differed depending on human papillomavirus (HPV-16) status. In HPV-16 positive patients, significantly lower levels in tumor oxygenated hemoglobin concentration ([HbO2]) at weeks 1 to 3, total hemoglobin concentration at week 3, and blood oxygen saturation (StO2) at week 3 were found in the IR group. In HPV-16 negative patients, significantly higher levels in tumor blood flow index and reduced scattering coefficient (μs‧) at week 3 were observed in the IR group. These hemodynamic parameters exhibited significantly high accuracy for early prediction of clinical outcomes, within the first three weeks of therapy, with the areas under the receiver operating characteristic curves (AUCs) ranging from 0.83 to 0.96.

  5. Outcomes of sprayed cultured epithelial autografts for full-thickness wounds: a single-centre experience.

    PubMed

    Lee, Haguen

    2012-09-01

    The lack of autograft donor sites with major burns provides the impetus to develop innovative solutions due to the difficulty of wound closure. Autograft donor sites are particularly limited in patients with burns involving over 50% total body surface area (TBSA). The introduction of cultured epithelial cell autografts offers a potential solution to assist in wound closure. The objective of this study was the assessment of clinical results after sprayed application of the cultured epithelial autograft (CEA, Keraheal™, Seoul, Korea, MCTT) suspension onto the wounds of extensively burned patients. This retrospective clinical audit of major burn patients (n=16) describes the use of CEA which was combined with 6:1 meshed expansion grafts in those with the burn over 40% TBSA in our hospital between the period of August 2007 and January 2010. The burn patients included 12 males and 4 females with a mean age 41.5 and a burn area of 51.3 ± 3.1% TBSA (30-70%; median: 50.5%) and a mean third burn area of 32.5 ± 3.0% TBSA (median 34.0%). The take rates were 37.6%, 68.0% and 90.0% on average at 2, 4 and 8 weeks after treatment with the suspension, respectively, and the transplantation of the cultured cells was applied to full-thickness burns, with the coverage of a skin area of 497.5 cm(2) per 1 ml of the cultured cells. For clinical follow-up, 12 patients were observed for 21.5 months on average, with a maximum follow-up period of 39 months. Six patients were excluded from the surveillance because two died during hospitalisation and the other four were impossible to trace. The use of a sprayed cultured epithelial cell autograft (Keraheal™) in treating a full-thickness skin wound in severely burned patients results in favourable quality of scars and also good potential to save lives by providing epidermal cover. Copyright © 2012 Elsevier Ltd and ISBI. All rights reserved.

  6. Treatment with the vascular disruptive agent OXi4503 induces an immediate and widespread epithelial to mesenchymal transition in the surviving tumor.

    PubMed

    Fifis, Theodora; Nguyen, Linh; Malcontenti-Wilson, Cathy; Chan, Lie Sam; Nunes Costa, Patricia Luiza; Daruwalla, Jurstine; Nikfarjam, Mehrdad; Muralidharan, Vijayaragavan; Waltham, Mark; Thompson, Erik W; Christophi, Christopher

    2013-10-01

    Epithelial to mesenchymal transition (EMT) is considered an important mechanism in tumor resistance to drug treatments; however, in vivo observation of this process has been limited. In this study we demonstrated an immediate and widespread EMT involving all surviving tumor cells following treatment of a mouse model of colorectal liver metastases with the vascular disruptive agent OXi4503. EMT was characterized by significant downregulation of E-cadherin, relocation and nuclear accumulation of β-catenin as well as significant upregulation of ZEB1 and vimentin. Concomitantly, significant temporal upregulation in hypoxia and the pro-angiogenic growth factors hypoxia-inducible factor 1-alpha, hepatocyte growth factor, vascular endothelial growth factor and transforming growth factor-beta were seen within the surviving tumor. The process of EMT was transient and by 5 days after treatment tumor cell reversion to epithelial morphology was evident. This reversal, termed mesenchymal to epithelial transition (MET) is a process implicated in the development of new metastases but has not been observed in vivo histologically. Similar EMT changes were observed in response to other antitumor treatments including chemotherapy, thermal ablation, and antiangiogenic treatments in our mouse colorectal metastasis model and in a murine orthotopic breast cancer model after OXi4503 treatment. These results suggest that EMT may be an early mechanism adopted by tumors in response to injury and hypoxic stress, such that inhibition of EMT in combination with other therapies could play a significant role in future cancer therapy. © 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  7. Cooperation of c-raf-1 and c-myc protooncogenes in the neoplastic transformation of simian virus 40 large tumor antigen-immortalized human bronchial epithelial cells.

    PubMed Central

    Pfeifer, A M; Mark, G E; Malan-Shibley, L; Graziano, S; Amstad, P; Harris, C C

    1989-01-01

    Overexpression of c-raf-1 and the myc family of protooncogenes is primarily associated with small cell carcinoma, which accounts for approximately 25% of human lung cancer. To determine the functional significance of the c-raf-1 and/or c-myc gene expression in lung carcinogenesis and to delineate the relationship between protooncogene expression and tumor phenotype, we introduced both protooncogenes, alone or in combination, into human bronchial epithelial cells. Two retroviral recombinants, pZip-raf and pZip-myc, containing the complete coding sequences of the human c-raf-1 and murine c-myc genes, respectively, were constructed and transfected into simian virus 40 large tumor antigen-immortalized bronchial epithelial cells (BEAS-2B); this was followed by selection for G418 resistance. BEAS-2B cells expressing both the transfected c-raf-1 and c-myc sequences formed large cell carcinomas in athymic nude mice with a latency of 4-21 weeks, whereas either pZip-raf- or pZip-myc-transfected cells were nontumorigenic after 12 months. Cell lines established from tumors (designated RMT) revealed the presence of the cotransfected c-raf-1 and c-myc sequences and expressed morphological, chromosomal, and isoenzyme markers, which identified BEAS-2B cells as the progenitor line of the tumors. A significant increase in the mRNA levels of neuron-specific enolase was detected in BEAS-2B cells containing both the c-raf-1 and c-myc genes and derived tumor cell lines. The data demonstrate that the concomitant expression of the c-raf and c-myc protooncogenes causes neoplastic transformation of human bronchial epithelial cells resulting in large cell carcinomas with certain neuroendocrine markers. The presented model system should be useful in studies of molecular events involved in multistage lung carcinogenesis. Images PMID:2557616

  8. The Effect of Inflammatory Status on Butyrate and Folate Uptake by Tumoral (Caco-2) and Non-Tumoral (IEC-6) Intestinal Epithelial Cells.

    PubMed

    Couto, Mafalda R; Gonçalves, Pedro; Catarino, Telmo A; Martel, Fátima

    2017-01-01

    Colorectal cancer (CRC) is the second leading cause of cancer death in occidental countries. Chronic inflammatory bowel disease (crohn's disease and ulcerative colitis) is associated with an increased risk for CRC development. The aim of this work was to investigate the relationship between inflammatory status and absorption of nutrients with a role in CRC pathogenesis. In this experimental study, we evaluated the in vitro effect of tumour necrosis factor-alpha (TNF-α), interferon-γ (IF-γ), and acetylsalicylic acid on 14C-butyrate (14C- BT), 3H-folic acid (3H-FA) uptake, and on proliferation, viability and differentiation of Caco-2 and IEC-6 cells in culture. The proinflammatory cytokines TNF-α and INF-γ were found to decrease uptake of a low concentration of 14C-BT (10 µM) by Caco-2 (tumoral) and IEC-6 (normal) intestinal epithelial cell lines. However, the effect of TNF-α and INF-γ in IEC-6 cells is most probably related to a cytotoxic and antiproliferative impact. In contrast, INF-γ increases uptake of a high concentration (10 mM) of 14C-BT in Caco-2 cells. The anticarcinogenic effect of BT (10 mM) in these cells is not affected by the presence of this cytokine. On the other hand, acetylsalicylic acid stimulates 14C-BT uptake by Caco-2 cells and potentiates its antiproliferative effect. Finally, both TNF-α and INF-γ cause a significant decrease in 3H-FA uptake by Caco-2 cells. The inflammatory status has an impact upon cellular uptake of BT and FA, two nutrients with a role in CRC pathogenesis. Moreover, the anti-inflammatory acetylsalicylic acid potentiates the anticarcinogenic effect of BT in Caco-2 cells by increasing its cellular uptake.

  9. Transanal Endoscopic Operation for Rectal Tumor: Short-term Outcomes and Learning Curve Analysis.

    PubMed

    Hur, Hyuk; Bae, Sung Uk; Han, Yoon Dae; Kang, Jeonghyun; Min, Byung Soh; Baik, Seung Hyuk; Lee, Kang Young; Kim, Nam Kyu

    2016-06-01

    We aim to report outcomes and learning curve of transanal endoscopic operation (TEO) for rectal tumors, using standard laparoscopic instruments under a magnifying laparoscopic monitor view. From January 2012 to July 2014, local excision was performed using a TEO system in 46 consecutive patients with rectal tumors. Patient and tumor characteristics and perioperative outcomes were prospectively assessed. The median patient age was 56 years for 15 women and 31 men. The mean tumor size was 1.8 cm, and the mean distance from the anal verge was 7.8 cm. The mean operative time was 85 minutes, and the mean postoperative hospital stay was 4.5 days. The postoperative pathologic diagnosis was adenocarcinoma for 17 patients (37%), adenoma for 4 patients (9%), carcinoid tumor for 23 patients (50%), and leiomyoma and lipoma for the 2 remaining patients (2%). A positive resection margin was documented for 4 patients (9%). No mortality was associated with the procedure although postoperative bleeding, leakage, perianal fistula, fecal incontinence, and voiding difficulty developed in 8 patients. According to the cumulative sum (CUSUM) analysis, the operation time and hospital stay significantly decreased after 17 case experiences. TEO is a feasible and safe treatment option for local excision of rectal tumors. TEO has the advantage of being a precise surgical procedure with a stable and magnifying endoscopic view. However, TEO requires a learning period and a careful selection of patients through proper indications and preoperative diagnostics.

  10. Immunostimulatory early phenotype of tumor-associated macrophages does not predict tumor growth outcome in an HLA-DR mouse model of prostate cancer.

    PubMed

    Riabov, Vladimir; Kim, David; Chhina, Surmeet; Alexander, Richard B; Klyushnenkova, Elena N

    2015-07-01

    Tumor-associated macrophages (TAM) were shown to support the progression of many solid tumors. However, anti-tumor properties of TAM were also reported in several types of cancer. Here, we investigated the phenotype and functions of TAM in two transgenic mouse models of prostate cancer that display striking differences in tumor growth outcome. Mice expressing prostate-specific antigen (PSA) as a self-antigen specifically in prostate (PSAtg mice) rejected PSA-expressing transgenic adenocarcinoma of mouse prostate (TRAMP) tumors. However, the introduction of HLA-DRB1*1501 (DR2b) transgene presenting PSA-derived peptides in a MHC class II-restricted manner exacerbated the growth of TRAMP-PSA tumors in DR2bxPSA F 1 mice. Despite the difference in tumor growth outcome, tumors in both strains were equally and intensively infiltrated by macrophages on the first week after tumor challenge. TAM exhibited mixed M1/M2 polarization and simultaneously produced pro-inflammatory (TNFα, IL1β) and anti-inflammatory (IL10) cytokines. TAM from both mouse strains demonstrated antigen-presenting potential and pronounced immunostimulatory activity. Moreover, they equally induced apoptosis of tumor cells. In vivo depletion of macrophages in DR2bxPSA F 1 but not PSAtg mice aggravated tumor growth suggesting that macrophages more strongly contribute to anti-tumor immunity when specific presentation of PSA to CD4+ T cells is possible. In summary, we conclude that in the early stages of tumor progression, the phenotype and functional properties of TAM did not predict tumor growth outcome in two transgenic prostate cancer models. Furthermore, we demonstrated that during the initial stage of prostate cancer development, TAM have the potential to activate T cell immunity and mediate anti-tumor effects.

  11. Perioperative Mortality and Long-Term Survival in 80 Dogs and 32 Cats Undergoing Excision of Thymic Epithelial Tumors.

    PubMed

    Garneau, Mark S; Price, Lori Lyn; Withrow, Stephen J; Boston, Sarah E; Ewing, Patty J; McClaran, Janet Kovak; Liptak, Julius M; Berg, John

    2015-07-01

    To examine perioperative mortality, long-term survival, causes of death, and prognostic factors for dogs and cats undergoing surgical excision of thymic epithelial tumors (TETs). Multi-institutional case series. Eighty dogs and 32 cats. Follow-up information was obtained for dogs and cats that underwent surgical excision of a TET between 2001 and 2012. Perioperative mortality was 20% in dogs and 22% in cats. No independent risk factors for perioperative mortality were identified. The estimated median survival time for all dogs was 1.69 years (95% CI 0.56-4.32) and the 1- and 4-year survival rates were 55% (95% CI 44-67) and 44% (95% CI 32-56). The estimated median survival time for all cats was 3.71 years (95% CI 0.56-unestimatable) and the 1- and 4-year survival rates were 70% (95% CI 53-87) and 47% (95% CI 0-100). Of animals that survived to discharge, 42% of dogs and 20% of cats eventually died of TET-related causes. The presence of paraneoplastic syndromes (hazard ratio [HR] 5.78, 95% CI 1.64-20.45, P = .007) or incomplete histologic margins (HR 6.09, 95% CI 1.50-24.72, P = .01) were independently associated with decreased survival in dogs. No significant predictors of survival were identified in cats. Conclusions regarding the effect of chemotherapy or radiation therapy could not be made. While there is substantial risk of perioperative death in dogs and cats undergoing surgery for TETs, many animals that survive to discharge have prolonged survival. Survival is significantly decreased in dogs with paraneoplastic syndromes or incomplete histologic margins. © Copyright 2014 by The American College of Veterinary Surgeons.

  12. Abnormal Localization and Tumor Suppressor Function of Epithelial Tissue-Specific Transcription Factor ESE3 in Esophageal Squamous Cell Carcinoma.

    PubMed

    Wang, Li; Xing, Jie; Cheng, Rui; Shao, Ying; Li, Peng; Zhu, Shengtao; Zhang, Shutian

    2015-01-01

    Esophageal cancer is one of the most common malignant cancers worldwide. The molecular mechanism of esophageal squamous cell carcinoma (ESCC) is still poorly understood. ESE3 is a member of the Ets transcription family, which is only expressed in epithelial tissues and acts as a tumor suppressor gene in prostate cancer. Our study aim was to confirm whether ESE3 is involved in the carcinogenesis of ESCC. Immunohistochemical analysis revealed that ESE3 was mainly located in cell nuclei of normal tissues and the cytoplasm in ESCC tissues. Immunofluorescence and western blot analyses of the normal esophageal cell line HEEpiC and ESCC cell lines EC9706 TE-1, KYSE150, and KYSE410 confirmed these results. pEGFP-ESE3 and pcDNA3.1-V5/HisA-ESE3 plasmids were constructed for overexpression of ESE3 in EC9706 and KYSE150 cells. The stably transfected cells showed restoration of the nuclear localization of ESE3. EC9706 cells with re-localization of ESE3 to the nucleus showed inhibition of proliferation, colony formation, migration, and invasion. To explore the possible mechanism of the differences in localization of ESE3 in normal esophageal cells and ESCC cells, ESCC cell lines were treated with the nuclear export inhibitor leptomycin B, transcription inhibitor actinomycin D, PKC inhibitor sphinganine, P38 MAPK inhibitor SB202190, and CK II inhibitor TBCA. These reagents were chosen according to the well-known mechanisms of protein translocation. However, the localization of ESE3 was unchanged after these treatments. The sequence of ESE3 cDNA in ESCC cells was identical to the standard sequence of ESE3 in the NCBI Genebank database, indicating that there was no mutation in the coding region of ESE3 in ESCC. Taken together, our study suggests that ESE3 plays an important role in the carcinogenesis of ESCC through changes in subcellular localization and may act as a tumor suppressor gene in ESCC, although the mechanisms require further study.

  13. Prognostic Value of Metabolic Tumor Volume and Velocity in Predicting Head-and-Neck Cancer Outcomes

    SciTech Connect

    Chu, Karen P.; Murphy, James D.; La, Trang H.; Krakow, Trevor E.; Iagaru, Andrei; Graves, Edward E.; Hsu, Annie; Maxim, Peter G.; Loo, Billy; Chang, Daniel T.; Le, Quynh-Thu

    2012-08-01

    Purpose: We previously showed that metabolic tumor volume (MTV) on positron emission tomography-computed tomography (PET-CT) predicts for disease recurrence and death in head-and-neck cancer (HNC). We hypothesized that increases in MTV over time would correlate with tumor growth and biology, and would predict outcome. We sought to examine tumor growth over time in serial pretreatment PET-CT scans. Methods and Materials: From 2006 to 2009, 51 patients had two PET-CT scans before receiving HNC treatment. MTV was defined as the tumor volume {>=}50% of maximum SUV (SUV{sub max}). MTV was calculated for the primary tumor, nodal disease, and composite (primary tumor + nodes). MTV and SUV velocity were defined as the change in MTV or SUV{sub max} over time, respectively. Cox regression analyses were used to examine correlations between SUV, MTV velocity, and outcome (disease progression and overall survival). Results: The median follow-up time was 17.5 months. The median time between PET-CT scans was 3 weeks. Unexpectedly, 51% of cases demonstrated a decrease in SUV{sub max} (average, -0.1 cc/week) and MTV (average, -0.3 cc/week) over time. Despite the variability in MTV, primary tumor MTV velocity predicted disease progression (hazard ratio 2.94; p = 0.01) and overall survival (hazard ratio 1.85; p = 0.03). Conclusions: Primary tumor MTV velocity appears to be a better prognostic indicator of disease progression and survival in comparison to nodal MTV velocity. However, substantial variability was found in PET-CT biomarkers between serial scans. Caution should be used when PET-CT biomarkers are integrated into clinical protocols for HNC.

  14. Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition

    SciTech Connect

    Gudjonsson, Thorarinn; Ronnov-Jessen, Lone; Villadsen, Rene; Rank, Fritz; Bissell, Mina J.; Petersen, Ole William

    2001-10-04

    The signals that determine the correct polarity of breast epithelial structures in vivo are not understood. We have shown previously that luminal epithelial cells can be polarized when cultured within a reconstituted basement membrane gel. We reasoned that such cues in vivo may be given by myoepithelial cells. Accordingly, we used an assay where luminal epithelial cells are incorrectly polarized to test this hypothesis. We show that culturing human primary luminal epithelial cells within collagen-I gels leads to formation of structures with no lumina and with reverse polarity as judged by dual stainings for sialomucin, epithelial specific antigen or occludin. No basement membrane is deposited, and {beta}4-integrin staining is negative. Addition of purified human myoepithelial cells isolated from normal glands corrects the inverse polarity, and leads to formation of double-layered acini with central lumina. Among the laminins present in the human breast basement membrane (laminin-1, -5 and -10/11), laminin-1 was unique in its ability to substitute for myoepithelial cells in polarity reversal. Myoepithelial cells were purified also from four different breast cancer sources including a biphasic cell line. Three out of four samples either totally lacked the ability to interact with luminal epithelial cells, or conveyed only correction of polarity in a fraction of acini. This behavior was directly related to the ability of the tumor myoepithelial cells to produce {alpha}-1 chain of laminin. In vivo, breast carcinomas were either negative for laminin-1 (7/12 biopsies) or showed a focal, fragmented deposition of a less intensely stained basement membrane (5/12 biopsies). Dual staining with myoepithelial markers revealed that tumorassociated myoepithelial cells were either negative or weakly positive for expression of laminin-1, establishing a strong correlation between loss of laminin-1 and breast cancer. We conclude that the double-layered breast acinus may be

  15. Key participants of the tumor microenvironment of the prostate: an approach of the structural dynamic of cellular elements and extracellular matrix components during epithelial-stromal transition.

    PubMed

    Gonçalves, Bianca F; Campos, Silvana G P de; Costa, Carolina F P; Scarano, Wellerson R; Góes, Rejane M; Taboga, Sebastião R

    2015-01-01

    Cancer is a multistep process that begins with the transformation of normal epithelial cells and continues with tumor growth, stromal invasion and metastasis. The remodeling of the peritumoral environment is decisive for the onset of tumor invasiveness. This event is dependent on epithelial-stromal interactions, degradation of extracellular matrix components and reorganization of fibrillar components. Our research group has studied in a new proposed rodent model the participation of cellular and molecular components in the prostate microenvironment that contributes to cancer progression. Our group adopted the gerbil Meriones unguiculatus as an alternative experimental model for prostate cancer study. This model has presented significant responses to hormonal treatments and to development of spontaneous and induced neoplasias. The data obtained indicate reorganization of type I collagen fibers and reticular fibers, synthesis of new components such as tenascin and proteoglycans, degradation of basement membrane components and elastic fibers and increased expression of metalloproteinases. Fibroblasts that border the region, apparently participate in the stromal reaction. The roles of each of these events, as well as some signaling molecules, participants of neoplastic progression and factors that promote genetic reprogramming during epithelial-stromal transition are also discussed. Copyright © 2014 Elsevier GmbH. All rights reserved.

  16. p53 directly activates cystatin D/CST5 to mediate mesenchymal-epithelial transition: a possible link to tumor suppression by vitamin D3

    PubMed Central

    Hünten, Sabine; Hermeking, Heiko

    2015-01-01

    Cystatin D (CST5) encodes an inhibitor of cysteine proteases of the cathepsin family and is directly induced by the vitamin D receptor (VDR). Interestingly, vitamin D3 exerts tumor suppressive effects in a variety of tumor types. In colorectal cancer (CRC) cells CST5 was shown to mediate mesenchymal-epithelial transition (MET). We recently performed an integrated genomic and proteomic screen to identify targets of the p53 tumor suppressor in CRC cells. Thereby, we identified CST5 as a putative p53 target gene. Here, we validated and characterized CST5 as a direct p53 target gene. After activation of a conditional p53 allele, CST5 was upregulated on mRNA and protein levels. Treatment with nutlin-3a or etoposide induced CST5 in a p53-dependent manner. These regulations were direct, since ectopic and endogenous p53 occupied a conserved binding site in the CST5 promoter region. In addition, treatment with calcitriol, the active vitamin D3 metabolite, and simultaneous activation of p53 resulted in enhanced CST5 induction and increased repression of SNAIL, an epithelial-mesenchymal transition (EMT) inducing transcription factor. Furthermore, CST5 inactivation decreased p53-induced mesenchymal-epithelial transition (MET) as evidenced by decreased inhibition of SNAIL and of migration by p53. Furthermore, CST5 expression was directly repressed by SNAIL. In summary, these results imply CST5 as an important mediator of tumor suppression by p53 in colorectal cancer. In addition, they suggest that a combined treatment activating p53 and the vitamin D3 pathway may function via induction of CST5. PMID:26158294

  17. Comparing oncologic outcomes after minimally invasive and open surgery for pediatric neuroblastoma and Wilms tumor.

    PubMed

    Ezekian, Brian; Englum, Brian R; Gulack, Brian C; Rialon, Kristy L; Kim, Jina; Talbot, Lindsay J; Adibe, Obinna O; Routh, Jonathan C; Tracy, Elisabeth T; Rice, Henry E

    2017-08-09

    Minimally invasive surgery (MIS) has been widely adopted for common operations in pediatric surgery; however, its role in childhood tumors is limited by concerns about oncologic outcomes. We compared open and MIS approaches for pediatric neuroblastoma and Wilms tumor (WT) using a national database. The National Cancer Data Base from 2010 to 2012 was queried for cases of neuroblastoma and WT in children ≤21 years old. Children were classified as receiving open or MIS surgery for definitive resection, with clinical outcomes compared using a propensity matching methodology (two open:one MIS). For children with neuroblastoma, 17% (98 of 579) underwent MIS, while only 5% of children with WT (35 of 695) had an MIS approach for tumor resection. After propensity matching, there was no difference between open and MIS surgery for either tumor for 30-day mortality, readmissions, surgical margin status, and 1- and 3-year survival. However, in both tumors, open surgery more often evaluated lymph nodes and had larger lymph node harvest. Our retrospective review suggests that the use of MIS appears to be a safe method of oncologic resection for select children with neuroblastoma and WT. Further research should clarify which children are the optimal candidates for this approach. © 2017 Wiley Periodicals, Inc.

  18. Factors Associated With Outcomes in Endoscopic Submucosal Dissection of Gastric Cardia Tumors: A Retrospective Observational Study.

    PubMed

    Jang, Yae Su; Lee, Bong Eun; Kim, Gwang Ha; Park, Do Youn; Jeon, Hye Kyung; Baek, Dong Hoon; Kim, Dong Uk; Song, Geun Am

    2015-08-01

    Tumors of the gastric cardia are among the most technically difficult lesions to remove by endoscopic submucosal dissection (ESD). This study aimed to evaluate the therapeutic outcomes of ESD in gastric cardia tumors according to clinicopathologic characteristics, and to assess the predictive factors for incomplete resection.We conducted a retrospective observational study of 82 patients with adenomas and early cancers of the gastric cardia who underwent ESD between January 2006 and December 2013 at the Pusan National University Hospital. Therapeutic outcomes of ESD and procedure-related complications were analyzed.En bloc resection, complete resection, and curative resection rates were 87%, 79%, and 66%, respectively. Deep submucosal invasion was the most common cause of noncurative resection in the cases in which complete resection was achieved. On multivariate analyses, hemispheric distribution (anterior hemisphere; odds ratio [OR] 4.808) and depth of tumor invasion (submucosal cancer; OR 22.056) were independent factors associated with incomplete resection. The rates of procedure-related bleeding, perforation, and stenosis were 6%, 1%, and 0%, respectively; none of the complications required surgical intervention.In conclusion, ESD is a safe, effective, and feasible treatment for gastric cardia tumors. However, the complete resection rate decreases for tumors that are located in the anterior hemisphere or have deep submucosal invasion.

  19. Factors Associated With Outcomes in Endoscopic Submucosal Dissection of Gastric Cardia Tumors

    PubMed Central

    Jang, Yae Su; Lee, Bong Eun; Kim, Gwang Ha; Park, Do Youn; Jeon, Hye Kyung; Baek, Dong Hoon; Kim, Dong Uk; Song, Geun Am

    2015-01-01

    Abstract Tumors of the gastric cardia are among the most technically difficult lesions to remove by endoscopic submucosal dissection (ESD). This study aimed to evaluate the therapeutic outcomes of ESD in gastric cardia tumors according to clinicopathologic characteristics, and to assess the predictive factors for incomplete resection. We conducted a retrospective observational study of 82 patients with adenomas and early cancers of the gastric cardia who underwent ESD between January 2006 and December 2013 at the Pusan National University Hospital. Therapeutic outcomes of ESD and procedure-related complications were analyzed. En bloc resection, complete resection, and curative resection rates were 87%, 79%, and 66%, respectively. Deep submucosal invasion was the most common cause of noncurative resection in the cases in which complete resection was achieved. On multivariate analyses, hemispheric distribution (anterior hemisphere; odds ratio [OR] 4.808) and depth of tumor invasion (submucosal cancer; OR 22.056) were independent factors associated with incomplete resection. The rates of procedure-related bleeding, perforation, and stenosis were 6%, 1%, and 0%, respectively; none of the complications required surgical intervention. In conclusion, ESD is a safe, effective, and feasible treatment for gastric cardia tumors. However, the complete resection rate decreases for tumors that are located in the anterior hemisphere or have deep submucosal invasion. PMID:26252277

  20. Association of tumor growth on nude mice and poor clinical outcome in soft tissue sarcoma patients.

    PubMed

    Budach, W; Budach, V

    2001-09-01

    Permanent growth in nude mice (PGNM) may be associated with poor clinical outcome. We tested this hypothesis in a group of soft tissue sarcoma (STS) patients. Small chunks from fresh tumor biopsies of 81 patients with STS were transplanted subcutaneously into NMRI-nu/nu nude mice. Tumor cell lines exhibiting growth in nude mice for more than three tumor passages were considered as permanently established. Clinical outcome of all patients was monitored with a median follow-up of 38 months. 39/81 (48%) STSs exhibited PGNM. High grade, high S-phase proportion, and aneuploidy were significant predictors of PGNM. Overall survival (OS) at 3 years was 21% (+7% standard error of median) for STS patients with PGNM and 53% (+/-8%) for patients without PGNM (P<0.01). Considering only patients without distant metastasis at the time of biopsy (n = 49), 3-year-OS was 25% (+/-10%) and 71% (+/-9%) for STS with PGNM and without PGNM, respectively (P<0.01). In the univariate analysis, PGNM, aneuploidy high S-phase proportion, tumor location at the trunk, high tumor grade, and non-liposarcoma histology were associated with reduced survival time. In the multivariate analysis, aneuploidy and tumor location at the trunk were the only independent predictors of overall survival. Permanent growth of STS on nude mice is associated with poor clinical outcome in the univariate analysis, but is not an independent predictor of survival in the multivariate analysis due to a strong co-correlation to other known adverse prognostic factors.

  1. Clinical characteristics and outcomes of uterine tumors resembling ovarian sex-cord tumors (UTROSCT): a systematic review of literature.

    PubMed

    Blake, Erin A; Sheridan, Todd B; Wang, Karen L; Takiuchi, Tsuyoshi; Kodama, Michiko; Sawada, Kenjiro; Matsuo, Koji

    2014-10-01

    with less aggressive tumor behavior when compared to Type I disease: extra-uterine spread (Type I versus II, 40% versus 5.9%, p=0.007) and lymphovascular space invasion (50% versus 6.7%, p=0.012). Among 17 cases of Type II disease, disease recurrence was reported in 1 (5.9%) case at 3 years after the initial treatment. In conclusion, our study showed that UTROSCT was often not subcategorized. Because classic UTROSCT has a distinct clinical outcome and characteristic histological patterns when compared to ESTSCLE, distinguishing UTROSCT from ESTSCLE is an integral component of the diagnosis. While classic UTROSCT typically has a favorable prognosis, it has been known to develop a late recurrence. If risk factors for recurrence are absent, both hysterectomy and mass resection alone are possible options for management.

  2. Prostate tumor DNA methylation is associated with cigarette smoking and adverse prostate cancer outcomes

    PubMed Central

    Shui, Irene M; Wong, Chao-Jen; Zhao, Shanshan; Kolb, Suzanne; Ebot, Ericka M; Geybels, Milan; Rubicz, Rohina; Wright, Jonathan L.; Lin, Daniel W.; Klotzle, Brandy; Bibikova, Marina; Fan, Jian-Bing; Ostrander, Elaine A.; Feng, Ziding; Stanford, Janet L.

    2016-01-01

    Background DNA methylation has been hypothesized as a mechanism to explain the association between smoking and adverse prostate cancer (PCa) outcomes. We aimed to assess whether smoking was associated with prostate tumor DNA methylation and whether these alterations may explain, in part, the association of smoking with PCa recurrence and mortality. Methods A total of 523 men had radical prostatectomy as primary treatment, detailed smoking history data, long-term follow-up for PCa outcomes and tumor tissue profiled for DNA methylation. Ninety percent of men also had matched tumor gene expression data. We conducted a methylome-wide analysis to identify differentially methylated regions (DMRs) by smoking status. To select potential functionally relevant DMRs, we evaluated their correlation with mRNA expression of corresponding genes. Finally, a smoking-related methylation score based on the top-ranked DMRs was created to assess its association with PCa outcomes. Results Forty DMRs were associated with smoking status, and ten of these were strongly correlated with mRNA expression (AOX1, CLDN5, EBF1, HOXA7, LGALS3, MAPT, PCDHGA/PCDHGB, PON3, SYCP2L, and ZSCAN12). Men who were in the highest tertile of the smoking-methylation score derived from these DMRs had a higher risk of recurrence (OR: 2.29; 95% CI: 1.42-3.72) and lethal disease (OR: 4.21; 95% CI: 1.65-11.78) compared to men in the lower two tertiles. Conclusions This integrative molecular epidemiology study supports the hypothesis that smoking-associated tumor DNA methylation changes may explain, at least a portion of the association between smoking and adverse PCa outcomes. Future studies are warranted to confirm these findings and understand the implications for improving patient outcomes. PMID:27142338

  3. Comparison of c-met Expression in Ovarian Epithelial Tumors and Normal Epithelia of the Female Reproductive Tract by Quantitative Laser Scan Microscopy

    PubMed Central

    Huntsman, David; Resau, James H.; Klineberg, Eric; Auersperg, Nelly

    1999-01-01

    The transmembrane tyrosine kinase receptor c-met with its ligand, hepatocyte growth factor/scatter factor (HGF/SF), acts as a mitogen, motogen, and morphogen in many normal epithelia. HGF/SF-met signaling has also been implicated in neoplastic progression and metastasis. In this study, immunofluorescence staining and quantitative laser scanning confocal microscopy were used to measure c-met expression in ovarian surface epithelial tumors from 17 oophorectomy specimens. These specimens were from patients aged 25 to 81 (mean age, 52) and included 10 malignant tumors, 4 borderline tumors, and five benign tumors including a Brenner tumor. For comparison, c-met expression was measured in normal tissues from the same patients, including 4 ovarian surface epithelia, 4 fallopian tube epithelia, 2 endometria, and 3 endocervical epithelia, as well as 3 cases of endometriosis. Relative pixel intensity values of c-met expression ranged from 0.4 in a normal ovarian surface epithelium to 22.3 in a borderline serous tumor. Malignant tumors (mean, 9.6) and borderline tumors (mean, 12.9) had higher average c-met expression levels than normal tissues (mean, 3.6) and endometriosis (mean, 1.8). The expression levels of benign tumors were intermediate (mean, 7.9). Among the normal tissues, c-met expression in fallopian tubes (mean, 8.2; range, 3.4–12.9) was higher than that of the other normal epithelia (mean, 1.6; range, 0.4–4.3). In eight cases where both normal and malignant tissues were sampled, c-met expression was significantly greater in malignant than in normal epithelia (P = 0.01). These findings indicate that c-met plays a role in the biology of the normal tissues examined. They confirm that its expression increases in the malignant progression of ovarian surface epithelial tumors, and suggest that increases comparable to those in frankly malignant carcinomas have already been reached in borderline lesions, ie, early in the neoplastic process. PMID:10433927

  4. Promoter methylation and expression of SOCS-1 affect clinical outcome and epithelial-mesenchymal transition in colorectal cancer.

    PubMed

    Kang, Xiao-Chun; Chen, Mei-Ling; Yang, Fang; Gao, Bao-Qin; Yang, Qing-Hui; Zheng, Wei-Wei; Hao, Sha

    2016-05-01

    Abnormal DNA methylation can cause gene silencing in colorectal cancer (CRC) patients. A gene that is suspected to have a crucial role in various types of cancers is the suppressor of cytokine signaling 1 (SOCS-1). Thus, this study will analyze the ramifications of SOCS-1 promoter methylation in CRC patients. This study will also test the therapeutic effects of hypomethylation as a possible CRC therapy. First, 97CRC patients' tumor and adjacent normal tissues were collected. Next, the methylation status of the SOCS-1 promoter region was assessed by methylation-specific polymerase chain reaction (MS-PCR); SOCS-1 protein and mRNA expression were also measured. A 48-month median follow-up period was used for the survival analysis of research participants. Lastly, to analyze the changes in cell invasion and migration in conjunction with protein and mRNA expression, the demethylating agent 5-azacytidine was applied in vitro to human CRC cells. The results showed increased SOCS-1 hypermethylation in CRC samples compared to controls. Methylated SOCS-1 was associated with significant suppression of SOCS-1 expression in tumors. Additionally, SOCS-1 hypermethylation was significantly correlated with lymph node metastasis and TNM stage. The study also found a poor overall survival rate to be significantly correlated with reduced expression of SOCS-1. After 5-azacytidine treatment, reduced in vitro DNA methylation and increased SOCS-1 expression were observed, and decreased cell migration and epithelial-mesenchymal transition biomarker expression alteration were further confirmed. In colorectal cancer tissues, the rate of methylation in the SOCS-1 promoter region is high. Through promoter hypermethylation, the SOCS-1 gene was severely down-regulated in the CRC tissue samples, thereby revealing a plausible therapeutic target for CRC therapy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  5. Dying cell clearance and its impact on the outcome of tumor radiotherapy

    PubMed Central

    Lauber, Kirsten; Ernst, Anne; Orth, Michael; Herrmann, Martin; Belka, Claus

    2012-01-01

    The induction of tumor cell death is one of the major goals of radiotherapy and has been considered to be the central determinant of its therapeutic outcome for a long time. However, accumulating evidence suggests that the success of radiotherapy does not only derive from direct cytotoxic effects on the tumor cells alone, but instead might also depend – at least in part – on innate as well as adaptive immune responses, which can particularly target tumor cells that survive local irradiation. The clearance of dying tumor cells by phagocytic cells of the innate immune system represents a crucial step in this scenario. Dendritic cells and macrophages, which engulf, process and present dying tumor cell material to adaptive immune cells, can trigger, skew, or inhibit adaptive immune responses, respectively. In this review we summarize the current knowledge of different forms of cell death induced by ionizing radiation, the multi-step process of dying cell clearance, and its immunological consequences with special regard toward the potential exploitation of these mechanisms for the improvement of tumor radiotherapy. PMID:22973558

  6. The p16-cyclin D1/CDK4-pRb pathway and clinical outcome in epithelial ovarian cancer.

    PubMed

    Kusume, T; Tsuda, H; Kawabata, M; Inoue, T; Umesaki, N; Suzuki, T; Yamamoto, K

    1999-12-01

    A significant positive association has been reported between p16 expression and clinical outcome for epithelial ovarian cancer patients. However, there is a reciprocal correlation between genetic alterations of single members of the p16-cyclin D1/CDK4-pRb pathway (G1 pathway). Simultaneous evaluation of these four elements may produce a better prognostic factor than p16 alone. We studied the prognostic significance of the G1 pathway in 59 epithelial ovarian cancer patients undergoing surgery and platinum-based chemotherapy by immunohistochemical technique. Abnormal expression of p16 or pRb was defined by negative nuclei staining, and that of CDK4 and cyclin D1 was defined by 50% nuclear staining. An abnormal G1 pathway was indicated in cases that have at least one abnormality among these four elements. Abnormal expression of p16, pRb, and cyclin D1/CDK4 was observed in 33.9, 3.4, and 15.3% of studied cases, respectively. Abnormal G1 pathway was detected in 49.2% (29 of 59) of all cases. The patients with normal G1 pathway tended to achieve a higher complete response rate (81.0%) to chemotherapy, compared with patients with abnormal G1 pathway (55.0%); however, there was no significant difference (P = 0.1001) between the two groups. Univariate analyses identified advanced stage [hazards ratio (HR), 3.665; P = 0.0218], histological low grade (HR, 3.625; P = 0.0066), and abnormal G1 pathway (HR, 2.935; P = 0.03) as prognostic factors for overall survival. The G1 pathway might help as a prognostic factor to select high-risk patients.

  7. Analysis of the hormone receptor status of circulating tumor cell subpopulations based on epithelial-mesenchymal transition: a proof-of-principle study on the heterogeneity of circulating tumor cells

    PubMed Central

    Guan, Xiuwen; Ma, Fei; Liu, Suyan; Wu, Shiyang; Xiao, Rong; Yuan, Lifang; Sun, Xiaoying; Yi, Zongbi; Yang, Huiyi; Xu, Binghe

    2016-01-01

    Although the enumeration of circulating tumor cells (CTCs) has been demonstrated to be a prognostic indicator in metastatic breast cancer, the heterogeneous characteristics of CTCs, such as variations in the epithelial-mesenchymal transition (EMT), may limit its broad clinical application. To investigate an uncomplicated and practicable detection approach based on the potential utility of the heterogeneity of CTCs from the standpoint of the EMT phenotype and ER/PR status of CTCs, an analysis was conducted using peripheral blood samples obtained from 28 metastatic breast cancer patients. The CanPatrol CTC enrichment technique was used to identify different CTC subpopulations, including epithelial-dominated CTCs, biophenotypic epithelial/mesenchymal CTCs, and mesenchymal-dominated CTCs, according to epithelial and mesenchymal markers. Furthermore, the hormone receptor (HR) status of each CTC was determined based on the expression levels of three reference genes and was characterized by four levels, which ranged from high-level expression to non-expression. We subsequently concluded that based on EMT phenotypes, the order of different CTC subgroups differed according to the HR expression status of the primary tumor. With respect to the HR status between tissues and CTCs, the variation tendency from high-level expression to non-expression of HR in CTCs was significantly correlated with the HR status of the primary tumor. The findings could provide evidence for the potential application of this uncomplicated and practicable detection approach for prognostic analysis and individualized endocrine therapeutic direction in a real-time manner via confirmation in further large-scale trials. PMID:27602758

  8. Comparison of total plasma lysophosphatidic acid and serum CA-125 as a tumor marker in the diagnosis and follow-up of patients with epithelial ovarian cancer

    PubMed Central

    Barbaros, Merve; Baykara, Elif; Guralp, Onur; Cengiz, Salih; Demirkiran, Fuat; Sanioglu, Cevdet; Arvas, Macit

    2010-01-01

    Objective To evaluate the role of lysophosphatidic acid (LPA) as a tumor marker in diagnosis and follow-up of patients with epithelial ovarian cancer. Methods Eighty-seven epithelial ovarian cancer patients, 74 benign ovarian tumor patients, and 50 healthy women were enrolled in the study. Twenty-nine of 87 epithelial ovarian cancer patients were followed up for 6 cycles of paclitaxel-carboplatin chemotherapy. CA-125 and total plasma LPA levels were measured preoperatively and before each chemotherapy cycle. Results Preoperative total plasma LPA and serum CA-125 levels were significantly higher in patients with epithelial ovarian cancer compared to patients with benign ovarian tumors and healthy women. Cut-off value for LPA was determined as 1.3 µmol/L and sensitivity, specificity, positive predictive value and negative predictive value were 95%, 92%, 95% and 92%, respectively. Mean total plasma LPA level of 29 patients who received chemotherapy was 7.21±6.63 µmol/L preoperatively and 6.84±6.34 µmol/L, 6.34±5.92 µmol/L, 6.14±5.79 µmol/L, 5.86±5.68 µmol/L, 5.23±5.11 µmol/L and 5.21±5.32 µmol/L in measurements held just before the 1st, 2nd, 3rd, 4th, 5th and 6th chemotherapy cycles, respectively (ANOVA, p=0.832). Total plasma LPA levels decreased slightly with chemotherapy administration and there was a weak negative correlation (Spearman, rs=-0.151, p=0.034), compared to a significant negative correlation in CA-125 (Spearman, rs=-0.596, p<0.001). Conclusion LPA is a better biomarker for diagnosis of epithelial ovarian cancer compared to CA-125. However, measurement of total plasma LPA levels during chemotherapy administration have no superiority to the serum CA-125 levels. PMID:21278887

  9. Features and Outcome of Surgical Management of Spinal Tumors in a Cohort of Nigerian Patients.

    PubMed

    Adeolu, Augustine A; Oyemolade, Toyin A; Salami, A A; Adigun, T A; Malomo, A O; Akang, E A; Shokunbi, M T

    2015-10-01

    There is a dearth of information on operated cases of spinal tumors in patients in sub-Saharan Africa. The objective of this study was to evaluate the histologic pattern, anatomic distribution, and extent and outcome of surgery of Nigerian patients with spinal tumors. This retrospective study comprised a cohort of Nigerians who underwent surgery for spinal tumors. Data obtained included patient demographics, duration of symptoms, anatomic location, imaging findings, Frankel grading before and after surgery, and type and outcome of surgery. Univariate analysis was performed, and results were compared with results from other parts of the world. There were 59 patients (male-to-female ratio 1:1.1) with a bimodal age distribution. The highest (20.34%) incidence was seen in the 20-29 age group. More than half (58.06%) of the patients presented with a duration of symptoms of at least 6 months (duration of symptoms was >12 months in 35.48%). Motor deficit was present in 97.73% of patients at presentation. Functional grading was Frankel A in 38.10% of patients, Frankel C in 26.19%, Frankel B in 16.67%, Frankel D in 16.67%, and Frankel E in 2.38%. The tumors were mostly in the thoracic region (65.45%), and 58% were extradural in location. Gross total tumor excision was performed in 50.88% of the cases, and subtotal resection was performed in 24.56%. Spinal stabilization was performed in 17.86% with spinous process wiring and vertical strut being the most common method of stabilization (80%) among this group. Metastasis was the most common histologic tumor type (23.21%). Meningioma accounted for 12.50% of tumors, and ependymoma, astrocytoma, and hemangioma each accounted for 7.14%. The most common source of metastasis was the prostate (38.46%). Postoperatively, 45% of patients improved neurologically, 52.5% remained the same, and 2.5% deteriorated. There was no perioperative mortality. Metastasis was the most common histologic type of spinal tumor in this study, and the most

  10. Validation that Metabolic Tumor Volume Predicts Outcome in Head and Neck Cancer

    PubMed Central

    Tang, Chad; Murphy, James D.; Khong, Brian; La, Trang H.; Kong, Christina; Fischbein, Nancy J.; Colevas, A. Dimitrios; Iagaru, Andrei H.; Graves, Edward E.; Loo, Billy W.; Le, Quynh-Thu

    2011-01-01

    Purpose We have previously reported that metabolic tumor volume (MTV) obtained from pre-treatment FDG PET/CT predicted outcome in patients with head-and-neck cancer (HNC). The purpose of this study is to validate these results on an independent dataset, determine if the primary tumor or nodal MTV drives this correlation, and explore the interaction with p16INK4a status as a surrogate marker for HPV. Methods and Materials The validation dataset in this study included 83 patients with squamous cell HNC who had a FDG PET/CT scan prior to definitive radiotherapy. MTV and SUVmax were calculated for the primary tumor, involved nodes, and the combination of both. The primary endpoint was to validate that MTV predicted progression-free survival and overall survival. Secondary analyses included determining the prognostic utility of primary tumor versus nodal MTV. Results Similar to our prior findings, an increase in total MTV of 17 cm3 (difference between 75th and 25th percentile) was associated with a 2.1 fold increase in the risk of disease progression (p=0.0002), and a 2.0 fold increase in the risk of death (p=0.0048). SUVmax was not associated with either outcome. Primary tumor MTV predicted progression-free (HR=1.94; p<0.0001) and overall (HR=1.57; p<0.0001) survival, whereas nodal MTV did not. In addition, MTV predicted progression-free (HR=4.23; p<0.0001) and overall (HR=3.21; p=0.0029) survival in patients with p16INK4a positive oropharyngeal cancer. Conclusions This study validates our previous findings that MTV independently predicts outcomes in HNC. MTV should be considered as a potential risk stratifying biomarker in future studies of HNC. PMID:22270174

  11. Early Cognitive Outcomes Following Proton Radiation in Pediatric Patients With Brain and Central Nervous System Tumors

    SciTech Connect

    Pulsifer, Margaret B.; Sethi, Roshan V.; Kuhlthau, Karen A.; MacDonald, Shannon M.; Tarbell, Nancy J.; Yock, Torunn I.

    2015-10-01

    Purpose: To report, from a longitudinal study, cognitive outcome in pediatric patients treated with proton radiation therapy (PRT) for central nervous system (CNS) tumors. Methods and Materials: Sixty patients receiving PRT for medulloblastoma (38.3%), gliomas (18.3%), craniopharyngioma (15.0%), ependymoma (11.7%), and other CNS tumors (16.7%) were administered age-appropriate measures of cognitive abilities at or near PRT initiation (baseline) and afterward (follow-up). Patients were aged ≥6 years at baseline to ensure consistency in neurocognitive measures. Results: Mean age was 12.3 years at baseline; mean follow-up interval was 2.5 years. Treatment included prior surgical resection (76.7%) and chemotherapy (61.7%). Proton radiation therapy included craniospinal irradiation (46.7%) and partial brain radiation (53.3%). At baseline, mean Wechsler Full Scale IQ was 104.6; means of all 4 Index scores were also in the average range. At follow-up, no significant change was observed in mean Wechsler Full Scale IQ, Verbal Comprehension, Perceptual Reasoning/Organization, or Working Memory. However, Processing Speed scores declined significantly (mean 5.2 points), with a significantly greater decline for subjects aged <12 years at baseline and those with the highest baseline scores. Cognitive outcome was not significantly related to gender, extent of radiation, radiation dose, tumor location, histology, socioeconomic status, chemotherapy, or history of surgical resection. Conclusions: Early cognitive outcomes after PRT for pediatric CNS tumors are encouraging, compared with published outcomes from photon radiation therapy.

  12. A Predictive Model of Unfavorable Outcomes After Benign Intracranial Tumor Resection.

    PubMed

    Bekelis, Kimon; Kalakoti, Piyush; Nanda, Anil; Missios, Symeon

    2015-07-01

    Benchmarking of outcomes and individualized risk prediction are central in patient-oriented shared decision making. We attempted to create a predictive model of complications in patients undergoing benign intracranial tumor resection. We performed a retrospective cohort study involving patients who underwent craniotomies for benign intracranial tumor resection during the period 2005-2011 and were registered in the National (Nationwide) Inpatient Sample database. A model for outcome prediction based on individual patient characteristics was developed. There were 19,894 patients who underwent benign tumor resection. The respective inpatient postoperative incidences were 1.3% for death, 22.7% for unfavorable discharge, 4.2% for treated hydrocephalus, 1.1% for cardiac complications, 0.9% for respiratory complications, 0.5% for wound infection, 0.5% for deep venous thrombosis, 2.3% for pulmonary embolus, and 1.5% for acute renal failure. Multivariable analysis identified risk factors independently associated with the above-mentioned outcomes. A model for outcome prediction based on patient and hospital characteristics was developed and subsequently validated in a bootstrap sample. The models demonstrated good discrimination with areas under the curve of 0.85, 0.76, 0.72, 0.74, 0.72, 0.74, 0.76, 0.68, and 0.86 for postoperative risk of death, unfavorable discharge, hydrocephalus, cardiac complications, respiratory complications, wound infection, deep venous thrombosis, pulmonary embolus, and acute renal failure. The models also had good calibration, as assessed by the Hosmer-Lemeshow test. Our models can provide individualized estimates of the risks of postoperative complications based on preoperative conditions and potentially can be used as an adjunct for decision making in benign intracranial tumor surgery. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Predicting outcomes in glioblastoma patients using computerized analysis of tumor shape: preliminary data

    NASA Astrophysics Data System (ADS)

    Mazurowski, Maciej A.; Czarnek, Nicholas M.; Collins, Leslie M.; Peters, Katherine B.; Clark, Kal

    2016-03-01

    Glioblastoma (GBM) is the most common primary brain tumor characterized by very poor survival. However, while some patients survive only a few months, some might live for multiple years. Accurate prognosis of survival and stratification of patients allows for making more personalized treatment decisions and moves treatment of GBM one step closer toward the paradigm of precision medicine. While some molecular biomarkers are being investigated, medical imaging remains significantly underutilized for prognostication in GBM. In this study, we investigated whether computer analysis of tumor shape can contribute toward accurate prognosis of outcomes. Specifically, we implemented applied computer algorithms to extract 5 shape features from magnetic resonance imaging (MRI) for 22 GBM patients. Then, we determined whether each one of the features can accurately distinguish between patients with good and poor outcomes. We found that that one of the 5 analyzed features showed prognostic value of survival. The prognostic feature describes how well the 3D tumor shape fills its minimum bounding ellipsoid. Specifically, for low values (less or equal than the median) the proportion of patients that survived more than a year was 27% while for high values (higher than median) the proportion of patients with survival of more than 1 year was 82%. The difference was statistically significant (p < 0.05) even though the number of patients analyzed in this pilot study was low. We concluded that computerized, 3D analysis of tumor shape in MRI may strongly contribute to accurate prognostication and stratification of patients for therapy in GBM.

  14. Evidence for a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts.

    PubMed

    Whitaker-Menezes, Diana; Martinez-Outschoorn, Ubaldo E; Lin, Zhao; Ertel, Adam; Flomenberg, Neal; Witkiewicz, Agnieszka K; Birbe, Ruth C; Howell, Anthony; Pavlides, Stephanos; Gandara, Ricardo; Pestell, Richard G; Sotgia, Federica; Philp, Nancy J; Lisanti, Michael P

    2011-06-01

    Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. In this new paradigm, cancer-associated fibroblasts undergo aerobic glycolysis, and extrude lactate to "feed" adjacent cancer cells, which then drives mitochondrial biogenesis and oxidative mitochondrial metabolism in cancer cells. Thus, there is vectorial transport of energy-rich substrates from the fibroblastic tumor stroma to anabolic cancer cells. A prediction of this hypothesis is that cancer-associated fibroblasts should express MCT4, a mono-carboxylate transporter that has been implicated in lactate efflux from glycolytic muscle fibers and astrocytes in the brain. To address this issue, we co-cultured MCF7 breast cancer cells with normal fibroblasts. Interestingly, our results directly show that breast cancer cells specifically induce the expression of MCT4 in cancer-associated fibroblasts; MCF7 cells alone and fibroblasts alone, both failed to express MCT4. We also show that the expression of MCT4 in cancer-associated fibroblasts is due to oxidative stress, and can be prevented by pre-treatment with the anti-oxidant N-acetyl-cysteine. In contrast to our results with MCT4, we see that MCT1, a transporter involved in lactate uptake, is specifically upregulated in MCF7 breast cancer cells when co-cultured with fibroblasts. Virtually identical results were also obtained with primary human breast cancer samples. In human breast cancers, MCT4 selectively labels the tumor stroma, e.g., the cancer-associated fibroblast compartment. Conversely, MCT1 was selectively expressed in the epithelial cancer cells within the same tumors. Functionally, we show that overexpression of MCT4 in fibroblasts protects both MCF7 cancer cells and fibroblasts against cell death, under co-culture conditions. Thus, we provide the first evidence for the existence of a stromal-epithelial lactate shuttle in human tumors, analogous to the lactate shuttles that are essential for the normal

  15. Outcomes analysis of an alternative formulation of PEGylated liposomal doxorubicin in recurrent epithelial ovarian carcinoma during the drug shortage era.

    PubMed

    Berger, Jessica L; Smith, Ashlee; Zorn, Kristin K; Sukumvanich, Paniti; Olawaiye, Alexander B; Kelley, Joseph; Krivak, Thomas C

    2014-01-01

    In response to the critical shortage of Doxil(®), the US Food and Drug Administration (FDA) allowed temporary importation of non-FDA-approved second-generation liposomal doxorubicin, Lipo-Dox(®). Lipo-Dox utilizes a different liposomal particle than Doxil and demonstrates different pharmacokinetic properties. Its use has never been evaluated in a North American population. The objective of this study was to evaluate the efficacy and tolerability of Lipo-Dox at Magee-Womens Hospital, University of Pittsburgh Medical Center, for patients with recurrent epithelial ovarian cancer who were treated during the Doxil shortage. Patients treated with Lipo-Dox from January 2012 to December 2012 were identified retrospectively. Disease response was defined radiographically by RECIST (Response Evaluation Criteria in Solid Tumors) or biochemically by CA-125 level if measurable disease was not present. Survival was defined from the start date of Lipo-Dox until the date of progression or death. Toxicity was assessed by the Gynecologic Oncology Group common toxicity criteria. Eighteen patients with recurrent epithelial ovarian cancer who received Lipo-Dox were identified. These patients had a median of three prior treatment regimens. The median number of Lipo-Dox cycles given was 3.5 (range 1-8). No patients had a complete or partial response. Two patients had stable disease over a mean follow-up of 144.5 days. Fourteen patients had progressive disease, with a median time to progression of 82 days. Progression was based on CA-125 in four patients and RECIST in the remainder. Nine patients died from the disease. Although this represents a small, pretreated population, there were no clinical responses to Lipo-Dox, raising the question as to whether it is an equivalent substitute for Doxil. Further evaluation is needed, but if confirmed, these findings raise concerns regarding the use of current stocks of Lipo-Dox, as well as the prudence of managing future drug shortages with

  16. Robot-Assisted Partial Nephrectomy for T1b Tumors: Strict Trifecta Outcomes

    PubMed Central

    Tufek, Ilter; Doganca, Tunkut; Obek, Can; Argun, Omer Burak; Tuna, Mustafa Bilal; Keskin, Mehmet Selcuk; Kural, Ali Rıza

    2017-01-01

    Background and Objectives: “Trifecta” in partial nephrectomy consists of negative surgical margins, minimal renal function decrease and absence of complications. In the present article, our single-center robot-assisted partial nephrectomy (RAPN) experience in T1b renal masses is reported in terms of strict Trifecta outcomes. Methods: This is a retrospective analysis of patients with a tumor diameter between 4 and 7 cm (stage T1b), who underwent RAPN by a single surgeon. Preoperative, intraoperative, and postoperative data were recorded and analyzed to evaluate short-term functional and oncologic outcomes. Patients with absence of grade ≥ 2 Clavien-Dindo complications, warm ischemia time (WIT) ≤25 minutes, ≤15% postoperative estimated glomerular filtration rate (eGFR) decrease and negative surgical margins were reported to achieve strict Trifecta outcomes. P < .05 was indicated statistically significant. Results: A total of 150 patients underwent RAPN, and 50 patients were identified with tumor size between 4 and 7 cm. Mean WIT was 20.8 ± 6.2 minutes and mean estimated blood loss (EBL) was 269 ± 191 mL. Surgical margins were negative in all patients. Eleven patients (22%) had a >15% eGFR decrease after surgery. Nine patients (18%) had WIT longer than 25 minutes. Four patients (8%) had grade ≥2 Clavien-Dindo complications. Twenty-nine (58%) patients had strict Trifecta outcomes. Mean follow-up was 44.2 ± 27.2 months. Tumor recurrence was not observed in any patient. Conclusions: Robot-assisted laparoscopic partial nephrectomy for T1b renal masses can be safely performed in experienced hands. Optimal strict Trifecta outcomes and recurrence rates can be achieved. PMID:28352149

  17. Maternal and neonatal outcomes in pregnancies complicated by bone and soft-tissue tumors.

    PubMed

    Maxwell, Cynthia; Barzilay, Bernard; Shah, Vibhuti; Wunder, Jay S; Bell, Robert; Farine, Dan

    2004-08-01

    Primary bone and soft-tissue tumors occur rarely in pregnancy. The objective of this study was to describe the outcome of a large cohort of pregnant patients with these rare tumors. Pregnant women diagnosed with bone or soft-tissue tumors during pregnancy or within 3 months after delivery were identified retrospectively for the years 1983-2003 in the University Health Network database, University of Toronto. Relevant maternal and neonatal data were collected on a standardized data form. In more than 60,000 deliveries during the study period, 17 patients were identified. Gestational age at diagnosis ranged from 11 weeks to 2 months postpartum. Eight cases involved the lower extremity and 6 involved the upper extremity. Osteosarcoma, chondrosarcoma, and giant-cell tumors were the most common histological types. Metastases occurred in 7 cases. Nine cases were treated surgically during the course of pregnancy. The majority of patients were delivered at term. Chemotherapy was deferred until the postpartum period. One patient elected for early termination of pregnancy. Three patients were delivered before 37 weeks of gestation to proceed with therapy. One neonate delivered at 34 weeks developed respiratory distress syndrome and required intubation. Three patients died, all as the result of metastatic disease. There were no perinatal or infant deaths. Most cases of soft-tissue and bone tumors during pregnancy can be successfully managed with surgery during gestation. Therapies with fetal toxicity were more likely to be deferred to the postpartum period.

  18. Syndecan-4 Promotes Epithelial Tumor Cells Spreading and Regulates the Turnover of PKCα Activity under Mechanical Stimulation on the Elastomeric Substrates.

    PubMed

    2015-01-01

    Heparan sulfate proteoglycans (HSPGs) at the cell surface play an important role in cell adhesion, spreading, formation of focal adhesion complexes (FACs), and sensing mechanical stress. Syndecans are members of the HSPGs family and are highly expressed in various tumor cells. Syndecan-4 (SDC4) is a unique member of syndecans that activates protein kinase C alpha (PKCα). However, syndecan-4 in tumor cells development is not clear when receiving mechanical stress. Aims: Here we investigate the role of syndecan-4 in tumor cells spreading and its downstream kinases under mechanical stimulation. Epithelial tumor cells were seeded onto elastomeric polydimethylsiloxane (PDMS) membranes coated with poly-L-lysine (Pl), fibronectin (Fn), or anti-SDC4 antibody and stretched with a modified pressure-driven cell-stretching (PreCS) device. When cells received mechanical stimulation, engagement of syndecan-4 promoted the phosphorylation of focal adhesion kinase (FAK) at tyrosine 397 and PKCα at serine 657. Furthermore, we analyzed the cell contractility marker-myosin light chain 2 (MLC2) in 30 min time courses. The levels of phosphorylated MLC2 at serine19 were augmented through ligations of syndecan-4 but not integrin binding motif (RGD) at 10 min mechanical stimulation and were suppressed at 30 min and this phenomenon was associated with the activity of PKCα. Our data demonstrate that syndecan-4 is essential for transmitting the mechanotransduction signals via activation of PKCα and is important for tumor cells spreading, assembly of actin cytoskeleton and cell contractility. © 2015 S. Karger AG, Basel.

  19. Heterozygosity for p53 (Trp53+/-) accelerates epithelial tumor formation in fanconi anemia complementation group D2 (Fancd2) knockout mice.

    PubMed

    Houghtaling, Scott; Granville, Laura; Akkari, Yassmine; Torimaru, Yumi; Olson, Susan; Finegold, Milton; Grompe, Markus

    2005-01-01

    Fanconi anemia (FA) is an autosomal recessive disease characterized by progressive bone marrow failure and an increased susceptibility to cancer. FA is genetically heterogeneous, consisting of at least 11 complementation groups, FA-A through L, including FA-D1 (BRCA2) and D2. We have previously reported an increased incidence of epithelial tumors in Fancd2 knockout mice. To further investigate the role of the FA pathway in tumor prevention, Fancd2 mutant mice were crossed to mice with a null mutation in the tumor suppressor gene, Trp53. The tumor spectrum in Fancd2(-/-)/Trp53(+/-) mice included sarcomas expected in Trp53 heterozygotes, as well as mammary and lung adenocarcinomas that occur rarely in Trp53 heterozygotes. These tumors occurred earlier than in Fancd2(-/-) control mice. Therefore, the Fancd2(-/-)/Trp53(+/-) mice represent an improved model for the study of adenocarcinoma in FA. In addition, it was found that Fancd2(-/-) mouse embryonic fibroblasts but not Fancd2(-/-)/Trp53(-/-) mouse embryonic fibroblasts arrest following DNA damage. Therefore, Trp53 is required for the S phase checkpoint activation observed in Fancd2 mutant cells. Fancd2(-/-)/Trp53(-/-) cells showed an increase in aneuploidy and had multiple gross chromosomal rearrangements.

  20. Distinct subpopulations of epithelial ovarian cancer cells can differentially induce macrophages and T regulatory cells toward a pro-tumor phenotype.

    PubMed

    Alvero, Ayesha B; Montagna, Michele K; Craveiro, Vinicius; Liu, Lanzhen; Mor, Gil

    2012-03-01

    Presence of immune infiltrates in the tumor does not always correlate with an anti-tumoral immune response. We previously identified two subpopulations of epithelial ovarian cancer (EOC) cells with differential cytokine profile. We hypothesize that these two subpopulations of EOC cells may differentially regulate the immune phenotype in the tumor microenvironment and therefore affect the immune response. Macrophages derived from CD14+ monocytes and naive CD4+T cells were treated with conditioned media from two subpopulations of EOC cells. Differentiation markers and phagocytic activity were measured by western blot analysis and flow cytometry. Cytokine levels were quantified using xMAP technology. Type I EOC cells are able to enhance macrophages' capacity for tumor repair and renewal by enhancing expression of scavenger receptors and by promoting the secretion of cytokines associated with tissue repair. On the other hand, type II EOC cells are able to create a tolerant microenvironment and prevent an immune response by inducing macrophages' to secrete IL-10 and by promoting the generation of T regs. We demonstrate that each ovarian cancer cell subpopulation can induce a unique phenotype of macrophages and T cells, both associated with tumor-supportive function. © 2011 John Wiley & Sons A/S.

  1. Differentiation of MCF-7 tumor cells from leukocytes and fibroblast cells using epithelial cell adhesion molecule targeted multicore surface-enhanced Raman spectroscopy labels

    NASA Astrophysics Data System (ADS)

    Freitag, Isabel; Matthäus, Christian; Csaki, Andrea; Clement, Joachim H.; Cialla-May, Dana; Weber, Karina; Krafft, Christoph; Popp, Jürgen

    2015-05-01

    Identification of tumor and normal cells is a promising application of Raman spectroscopy. The throughput of Raman-assisted cell sorting is limited by low sensitivity. Surface-enhanced Raman spectroscopy (SERS) is a well-recognized candidate to increase the intensity of Raman signals of cells. First, different strategies are summarized to detect tumor cells using targeted SERS probes. Then, a protocol is described to prepare multicore-SERS-labels (MSLs) by aggregating gold nanoparticles, coating with a reporter molecule and a thin silver shell to further boost enhancement, encapsulating with a stable silica layer, and functionalizing by epithelial cell adhesion molecule (EpCAM) antibodies. Raman, dark field and fluorescence microscopy proved the specific and nonspecific binding of functionalized and nonfunctionalized MSLs to MCF-7 tumor cells, leukocytes from blood, and nontransformed human foreskin fibroblasts. Raman imaging and dark field microscopy indicated no uptake of MSLs, yet binding to the cellular membrane. Viability tests were performed with living tumor cells to demonstrate the low toxicity of MSL-EpCAM. The SERS signatures were detected from cells with exposure times down to 25 ms at 785-nm laser excitation. The prospects of these MSLs in multiplex assays, for enumeration and sorting of circulating tumor cells in microfluidic chips, are discussed.

  2. Differentiation of MCF-7 tumor cells from leukocytes and fibroblast cells using epithelial cell adhesion molecule targeted multicore surface-enhanced Raman spectroscopy labels.

    PubMed

    Freitag, Isabel; Matthäus, Christian; Csaki, Andrea; Clement, Joachim H; Cialla-May, Dana; Weber, Karina; Krafft, Christoph; Popp, Jürgen

    2015-05-01

    Identification of tumor and normal cells is a promising application of Raman spectroscopy. The throughput of Raman-assisted cell sorting is limited by low sensitivity. Surface-enhanced Raman spectroscopy (SERS) is a well-recognized candidate to increase the intensity of Raman signals of cells. First, different strategies are summarized to detect tumor cells using targeted SERS probes. Then, a protocol is described to prepare multicore-SERS-labels (MSLs) by aggregating gold nanoparticles, coating with a reporter molecule and a thin silver shell to further boost enhancement, encapsulating with a stable silica layer, and functionalizing by epithelial cell adhesion molecule (EpCAM) antibodies. Raman, dark field and fluorescence microscopy proved the specific and nonspecific binding of functionalized and nonfunctionalized MSLs to MCF-7 tumor cells, leukocytes from blood, and nontransformed human foreskin fibroblasts. Raman imaging and dark field microscopy indicated no uptake of MSLs, yet binding to the cellular membrane. Viability tests were performed with living tumor cells to demonstrate the low toxicity of MSL-EpCAM. The SERS signatures were detected from cells with exposure times down to 25 ms at 785-nm laser excitation. The prospects of these MSLs in multiplex assays, for enumeration and sorting of circulating tumor cells in microfluidic chips, are discussed.

  3. Long-term outcome of gamma knife radiosurgery for metastatic brain tumors originating from lung cancer

    PubMed Central

    Bir, Shyamal C.; Ambekar, Sudheer; Bollam, Papireddy; Nanda, Anil

    2014-01-01

    Background: Gamma knife radiosurgery (GKRS) has emerged as an important treatment option for metastasis brain tumors (MBTs). However, the long-term outcome of GKRS on MBTs originating from lung carcinoma is not well understood. The treatment of MBTs derived from lung cancer with GKRS at our institution is reviewed. Methods: We performed a retrospective review (2000-2013) of 173 patients with MBTs from lung cancer who received GKRS. Out of 173 patients, 38 patients had recurrent tumors after microsurgical resection and whole brain radiotherapy (WBT). Results: GKRS in MBTs metastasized from lung carcinoma showed significant variations in tumor growth control (decreased in 79 [45.7%] patients, arrested growth in 54 [31.2%] patients, and increased tumor size in 40 [23.1%] patients). The median survival in the study population was 14 months. Overall survival after 3 years was 25%, whereas progression-free survival after 3 years was 45%. The predictive factors for improving survival in the patients with MBTs were recursive partitioning analysis (RPA) class I (P = 0.005), absence of hydrocephalus (P = 0.001), Karnofsky performance scale (KPS) >70 (P = 0.007), age ≤65 (P = 0.041), tumor size ≤3 cm (P = 0.023), controlled primary tumor (P = 0.049), and single number of MBTS (P = 0.044). Conclusion: Long-term follow-up revealed that GKRS offers a high rate of tumor control and good overall survival period in both new and recurrent patients with MBTs originating from lung carcinoma. Thus, GKRS is an effective treatment option for new patients with MBTs from lung cancer, as well as an adjuvant therapy in patients with recurrent MBTs derived from lung cancer. PMID:25289169

  4. Gamma knife radiosurgery of radiation-induced intracranial tumors: Local control, outcomes, and complications

    SciTech Connect

    Jensen, Ashley W.; Brown, Paul D.; Pollock, Bruce E.; Stafford, Scott L.; Link, Michael J.; Garces, Yolanda I.; Foote, Robert L.; Gorman, Deborah A.; Schomberg, Paula J.

    2005-05-01

    Purpose: To determine local control (LC) and complication rates for patients who underwent radiosurgery for radiation-induced intracranial tumors. Methods and Materials: Review of a prospectively maintained database (2,714 patients) identified 16 patients (20 tumors) with radiation-induced tumors treated with radiosurgery between 1990 and 2004. Tumor types included typical meningioma (n = 17), atypical meningioma (n = 2), and schwannoma (n 1). Median patient age at radiosurgery was 47.5 years (range, 27-70 years). The median tumor margin dose was 16 Gy (range, 12-20 Gy). Median follow-up was 40.2 months (range, 10.8-146.2 months). Time-to-event outcomes were calculated with Kaplan-Meier estimates. Results: Three-year and 5-year LC rates were 100%. Three-year and 5-year overall survival rates were 92% and 80%, respectively. Cause-specific survival rates at 3 and 5 years were 100%. Three patients died: 1 had in-field progression 65.1 months after radiosurgery and later died of the tumor, 1 died of progression of a preexisting brain malignancy, and 1 died of an unrelated cause. One patient had increased seizure activity that correlated with development of edema seen on neuroimaging. Conclusions: LC, survival, and complication rates in our series are comparable to those in previous reports of radiosurgery for intracranial meningiomas. Also, LC rates with radiosurgery are at least comparable to those of surgical series for radiation-induced meningiomas. Radiosurgery is a safe and effective treatment option for radiation-induced intracranial tumors, most of which are typical meningiomas.

  5. The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors.

    PubMed

    Detterbeck, Frank C; Stratton, Kelly; Giroux, Dorothy; Asamura, Hisao; Crowley, John; Falkson, Conrad; Filosso, Pier Luigi; Frazier, Aletta A; Giaccone, Giuseppe; Huang, James; Kim, Jhingook; Kondo, Kazuya; Lucchi, Marco; Marino, Mirella; Marom, Edith M; Nicholson, Andrew G; Okumura, Meinoshin; Ruffini, Enrico; Van Schil, Paul

    2014-09-01

    A universal and consistent stage classification system, which describes the anatomic extent of a cancer, provides a foundation for communication and collaboration. Thymic epithelial malignancies have seen little progress, in part because of the lack of an official system. The International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group assembled a large retrospective database, a multispecialty international committee and carried out extensive analysis to develop proposals for the 8th edition of the stage classification manuals. This tumor, node, metastasis (TNM)-based system is applicable to all types of thymic epithelial malignancies. This article summarizes the proposed definitions of the T, N, and M components and describes how these are combined into stage groups. This represents a major step forward for thymic malignancies.

  6. Seizure outcomes of lesionectomy in pediatric lesional epilepsy with brain tumor -- single institute experience.

    PubMed

    Jo, Kyung Il; Shin, Hyung Jin; Hong, Seung-Chyul

    2013-09-01

    To determine the clinical characteristics, surgical strategy, and outcome in pediatric lesional epilepsy patients younger than 5years of age undergoing surgery in a single institute. Retrospective data were collected and analyzed on patients younger than 5years of age who underwent lesionectomy for lesional epilepsy at single institute from January 2001 to August 2010. Fourteen pediatric lesional epilepsy patients were enrolled in this study. Engel classification was used to classify seizure outcome. Median preoperative seizure period was 1month (range, 1-21). Median post-operative follow up period was 35months (range 13-84). Ten patients who underwent gross total resection of tumor showed Engel class Ia seizure outcome without any antiepileptic drug (AED). Subtotal resection was performed in four patients to avoid eloquent area injury. Two of these four patients with subtotal removal became seizure-free (Engel class Ia) without AED, while two were in Engel class Ib with AED medication. There was no significant surgical morbidity or mortality. Lesionectomy in children younger than 5years of age is relatively safe and effective in controlling seizures. Short preoperative seizure periods and total removal of tumor might be associated with good outcome. Therefore, early and complete lesionectomy alone may help allow for seizure freedom and optimal brain development in pediatric patients. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  7. Using tumor registry resources in analyzing concordance with guidelines and outcomes.

    PubMed

    Bookman, M A

    2000-11-01

    Collection and analysis of standardized multi-institutional outcomes data is a labor-intensive process. As the National Comprehensive Cancer Network (NCCN) seeks to expand its Outcomes Database to include multiple primary tumor types, the amount of time and effort required for detailed data abstraction and transmission will become an obstacle for many primary institutions. In addition, as the NCCN Guidelines become more widely distributed and adopted in the oncology community, it would be appealing to evaluate guideline concordance and quality of care in community hospitals and community-based physician practices vs major cancer centers. However, methods for case finding and collection of detailed outcomes data in the community setting are not well established. Most cancer centers and community hospitals have already set aside resources for maintaining a local tumor registry that includes limited information on demographics, diagnosis, staging, treatment, and survival for all new cancer patients treated at the specific institution. One strategy that can be used to facilitate a global outcomes program within the NCCN community calls for capitalizing on existing local database resources and experienced coding and data management staff.

  8. Tumor stem cells (CD271, c-kit, SOX10) in Melanomas: prognostic and outcome implications.

    PubMed

    Mohamed, Amr; Gonzalez, Raul S; Lawson, Diane; Wang, Jason; Cohen, Cynthia

    2014-01-01

    Melanoma cells that express stem cell marker CD271 are shown to form tumors when transplanted into nude or immunodeficient mice. These tumors have a higher metastatic potential and worse prognosis than melanomas resulting from transplantation of CD271-negative cells. We studied stem cell markers (CD271, c-kit, SOX1O) in melanomas, correlating their presence with prognostic factors and outcome. A total of 82 melanomas in tissue microarrays were immunostained for CD271, c-kit, and SOX10. Results were correlated with clinicopathologic prognostic parameters (Breslow depth of invasion, Clark level, sentinel lymph node status, and pathologic stage) and outcome (recurrence, metastases, and death). Of the 82 melanomas, CD271 was expressed in 18 (21%), c-kit in 47 (57%), and SOX10 in all (100%). CD271 does show correlation with metastases (P=0.05). c-kit is associated with favorable prognostic parameters [Breslow depth (P<0.001) and pathologic stage (P=0.02)] and with improved outcome [recurrence (P=0.03) and metastases (P=0.004)]. Although SOX10 is a good diagnostic marker, it cannot be used for prognosis because it is expressed in all the melanomas studied. In conclusion, CD271 expression in melanomas is associated with increased frequency of metastases, and c-kit immunoreactivity is associated with favorable prognostic parameters and improved outcome.

  9. Comparison of survival outcomes after recurrence detected by cancer antigen 125 elevation versus imaging study in epithelial ovarian cancer.

    PubMed

    Paik, E Sun; Kim, Tae Joong; Lee, Yoo Young; Choi, Chel Hun; Lee, Jeong Won; Kim, Byoung Gie; Bae, Duk Soo

    2016-09-01

    The aim of this study was to compare survival outcomes in two groups of patients with recurrent epithelial ovarian cancer (EOC) with initial recurrence detection by cancer antigen 125 (CA-125) elevation or imaging, and underwent secondary cytoreductive surgery (SCS). A retrospective review of the medical records was performed on 99 recurrent EOC patients who underwent SCS at the Samsung Medical Center between January 2002 and December 2013. For follow-up after primary treatment, patients were routinely assessed by CA-125 levels every 3 months and computed tomography (CT) scan (or magnetic resonance imaging [MRI]) every 6 months for first 3 years, and by CA-125 every 6 months and CT scan (or MRI) every 12 months thereafter. The first recurrence was initially identified by either CA-125 elevation (n=41, 41.4%) or by imaging study (n=58, 58.6%). None of the patients showed the symptoms as initial sign of recurrence. There were higher percentages of extra-pelvic recurrence (87.8%) and multiple recurrences (78.0%) in the group diagnosed by CA-125 elevation. The proportion of no residual disease after SCS was comparably lower in the CA-125 group (22.0% vs. 72.4%). There were 19 cancer-associated deaths (19.2%) within a median follow-up period of 67 months. The group diagnosed by imaging had better overall survival from initial diagnosis (OS1), overall survival after SCS (OS2), progression-free survival after the initial treatment (PFS1) and progression-free survival after SCS compared to those of the CA-125 group (PFS2). EOC patients with recurrence initially detected by imaging study showed better survival outcomes than patients diagnosed by CA-125 elevation.

  10. Tumor necrosis factor-alpha increases reactive oxygen species by inducing spermine oxidase in human lung epithelial cells: a potential mechanism for inflammation-induced carcinogenesis.

    PubMed

    Babbar, Naveen; Casero, Robert A

    2006-12-01

    Inflammation has been implicated in the development of many human epithelial cancers, including those of the stomach, lung, colon, and prostate. Tumor necrosis factor-alpha (TNF-alpha) is a potent pleiotropic, proinflammatory cytokine produced by many cells in response to injury and inflammation. Here, we show that TNF-alpha exposure results in increased production of reactive oxygen species (ROS), with a concomitant increase in the production of 8-oxo-deoxyguanosine, a marker for oxidative DNA damage, in human lung bronchial epithelial cells. The source of the ROS in TNF-alpha-treated cells was determined by both pharmacologic and small interfering RNA (siRNA) strategies to be spermine oxidase (SMO/PAOh1). SMO/PAOh1 oxidizes spermine into spermidine, 3-aminopropanal, and H(2)O(2). Inhibition of TNF-alpha-induced SMO/PAOh1 activity with MDL 72,527 or with a targeted siRNA prevented ROS production and oxidative DNA damage. Further, similar induction in SMO/PAOh1 is observed with treatment of another inflammatory cytokine, interleukin-6. The data are consistent with a model that directly links inflammation and DNA damage through the production of H(2)O(2) by SMO/PAOh1. Further, these results suggest a common mechanism by which inflammation from multiple sources can lead to the mutagenic changes necessary for the development and progression of epithelial cancers.

  11. Pindborg tumor

    PubMed Central

    Caliaperoumal, Santhosh Kumar; Gowri, S.; Dinakar, J.

    2016-01-01

    Calcifying epithelial odontogenic tumor (CEOT), also known as Pindborg tumor, is a rare odontogenic epithelial neoplasm. So far, nearly 200 cases have been reported in the literature. We are reporting a case of CEOT in a 42-year-old male patient with painless bony swelling in the mandible. The clinical, radiographic, and histopathologic features are discussed with relevant references. PMID:27041911

  12. The role of mirror focus in the surgical outcome of patients with indolent temporal lobe tumors.

    PubMed

    Sampaio, Leticia; Yacubian, Elza Marcia; Manreza, Maria Luiza

    2004-03-01

    To review the clinical and neurophysiological data of 21 patients with epilepsy due to temporal lobe tumors and who had undergone evaluation and surgery at the Hospital das Clínicas da Universidade de São Paulo. The aim of this study was to investigate whether the occurrence of a mirror focus was influenced either by certain clinical factors or if the surgical outcome was influenced by the presence of a mirror focus. We included these 21 patients who had undergone at least one interictal electroencephalogram in the pre- and post-surgical periods. They had had a minimum follow-up of one year. Eight patients had mirror focus (Group 1) and 13 did not (Group 2). The mean age at seizure onset, duration of epilepsy disorder and total number of seizures did not vary statistically between the two groups of patients. Generalized tonic-clonic seizures occurred more frequently in the mirror focus group. All, but one patient, with a mirror focus were seizure free at follow- up. The mirror focus disappeared in all eight patients in the post-surgical electroencephalogram. In this group, the patient who was not seizure - free had a seizure recorded in his post-surgical electroencephalogram with seizure onset ipsilateral to the resected tumor. The patients who were not seizure-free had either been submitted to an incomplete resection of the tumor or showed evidence of associated cortical dysplasia. The occurrence of mirror focus is not a contraindication to surgery even when interictal epileptiform activity predominates contralaterally to the tumor and neither when seizures appear to arise from the mirror focus on scalp EEG. Good surgical outcome is expected despite EEG findings that may conflict with tumor location.

  13. Effects of curcumin in pediatric epithelial liver tumors: inhibition of tumor growth and alpha-fetoprotein in vitro and in vivo involving the NFkappaB- and the beta-catenin pathways

    PubMed Central

    Bortel, Nicola; Armeanu-Ebinger, Sorin; Schmid, Evi; Kirchner, Bettina; Frank, Jan; Kocher, Alexa; Schiborr, Christina; Warmann, Steven; Fuchs, Jörg; Ellerkamp, Verena

    2015-01-01

    In children with hepatocellular carcinoma (pHCC) the 5-year overall survival rate is poor. Effects of cytostatic therapies such as cisplatin and doxorubicin are limited due to chemoresistance and tumor relapse. In adult HCC, several antitumor properties are described for the use of curcumin. Curcumin is one of the best-investigated phytochemicals in complementary oncology without relevant side effects. Its use is limited by low bioavailability. Little is known about the influence of curcumin on pediatric epithelial hepatic malignancies. We investigated the effects of curcumin in combination with cisplatin on two pediatric epithelial liver tumor cell lines. As mechanisms of action inhibition of NFkappaB, beta-catenin, and decrease of cyclin D were identified. Using a mouse xenograft model we could show a significant decrease of alpha-fetoprotein after combination therapy of oral micellar curcumin and cisplatin. Significant concentrations of curcuminoids were found in blood samples, organ lysates, and tumor tissue after oral micellar curcumin administration. Micellar curcumin in combination with cisplatin can be a promising strategy for treatment of pediatric HCC. PMID:26515460

  14. The O-Linked Glycome and Blood Group Antigens ABO on Mucin-Type Glycoproteins in Mucinous and Serous Epithelial Ovarian Tumors

    PubMed Central

    Vitiazeva, Varvara; Kattla, Jayesh J.; Flowers, Sarah A.; Lindén, Sara K.; Premaratne, Pushpa; Weijdegård, Birgitta; Sundfeldt, Karin; Karlsson, Niclas G.

    2015-01-01

    Background Mucins are heavily O-glycosylated proteins where the glycosylation has been shown to play an important role in cancer. Normal epithelial ovarian cells do not express secreted mucins, but their abnormal expression has previously been described in epithelial ovarian cancer and may relate to tumor formation and progression. The cyst fluids were shown to be a rich source for acidic glycoproteins. The study of these proteins can potentially lead to the identification of more effective biomarkers for ovarian cancer. Methods In this study, we analyzed the expression of the MUC5AC and the O-glycosylation of acidic glycoproteins secreted into ovarian cyst fluids. The samples were obtained from patients with serous and mucinous ovarian tumors of different stages (benign, borderline, malignant) and grades. The O-linked oligosaccharides were released and analyzed by negative-ion graphitized carbon Liquid Chromatography (LC) coupled to Electrospray Ionization tandem Mass Spectrometry (ESI-MSn). The LC-ESI-MSn of the oligosaccharides from ovarian cyst fluids displayed differences in expression of fucose containing structures such as blood group ABO antigens and Lewis-type epitopes. Results The obtained data showed that serous and mucinous benign adenomas, mucinous low malignant potential carcinomas (LMPs, borderline) and mucinous low-grade carcinomas have a high level of blood groups and Lewis type epitopes. In contrast, this type of fucosylated structures were low abundant in the high-grade mucinous carcinomas or in serous carcinomas. In addition, the ovarian tumors that showed a high level of expression of blood group antigens also revealed a strong reactivity towards the MUC5AC antibody. To visualize the differences between serous and mucinous ovarian tumors based on the O-glycosylation, a hierarchical cluster analysis was performed using mass spectrometry average compositions (MSAC). Conclusion Mucinous benign and LMPs along with mucinous low-grade carcinomas

  15. Dynamics of melanoma tumor therapy with vesicular stomatitis virus: explaining the variability in outcomes using mathematical modeling.

    PubMed

    Rommelfanger, D M; Offord, C P; Dev, J; Bajzer, Z; Vile, R G; Dingli, D

    2012-05-01

    Tumor selective, replication competent viruses are being tested for cancer gene therapy. This approach introduces a new therapeutic paradigm due to potential replication of the therapeutic agent and induction of a tumor-specific immune response. However, the experimental outcomes are quite variable, even when studies utilize highly inbred strains of mice and the same cell line and virus. Recognizing that virotherapy is an exercise in population dynamics, we utilize mathematical modeling to understand the variable outcomes observed when B16ova malignant melanoma tumors are treated with vesicular stomatitis virus in syngeneic, fully immunocompetent mice. We show how variability in the initial tumor size and the actual amount of virus delivered to the tumor have critical roles on the outcome of therapy. Virotherapy works best when tumors are small, and a robust innate immune response can lead to superior tumor control. Strategies that reduce tumor burden without suppressing the immune response and methods that maximize the amount of virus delivered to the tumor should optimize tumor control in this model system.

  16. Circulating miR-21-5p and miR-148a-3p as emerging non-invasive biomarkers in thymic epithelial tumors

    PubMed Central

    Bellissimo, Teresa; Russo, Emanuele; Ganci, Federica; Vico, Carmen; Sacconi, Andrea; Longo, Flavia; Vitolo, Domenico; Anile, Marco; Disio, Daniele; Marino, Mirella; Blandino, Giovanni; Venuta, Federico; Fazi, Francesco

    2016-01-01

    ABSTRACT Thymic epithelial cells give rise to both thymoma and thymic carcinoma. A crucial advance in thymic epithelial tumors (TET) management may derive from the identification of novel molecular biomarkers able to improve diagnosis, prognosis and treatment planning.In a previous study, we identified microRNAs that were differentially expressed in tumor vs normal thymic tissues. Among the microRNAs resulted up-regulated in TET tissues, we evaluated miR-21-5p, miR-148a-3p, miR-141-3p, miR-34b-5p, miR-34c-5p, miR-455-5p as blood plasma circulating non-invasive biomarkers for TET management.We firstly report that the expression levels of specific onco-miRNAs, that we found upregulated in the blood plasma collected from TET patients at surgery, resulted significantly reduced in follow-up samples.This pilot study suggests that circulating miR-21-5p and miR-148a-3p could represent novel non-invasive biomarkers to evaluate the efficacy of therapy and the prognosis of TET. PMID:26575977

  17. Postpubertal Persistent Hyperestrogenemia in McCune-Albright Syndrome: Unilateral Oophorectomy Improved Fertility but Detected an Unexpected Borderline Epithelial Ovarian Tumor.

    PubMed

    Chevalier, Nicolas; Paris, Françoise; Fontana, Sylvie; Delotte, Jérôme; Gaspari, Laura; Ferrari, Patricia; Sultan, Charles; Fénichel, Patrick

    2015-12-01

    McCune-Albright syndrome (MAS), due to a somatic mutation of the GNAS1 gene, begins usually in girls with peripheral precocious puberty. Ovarian autonomy may persist in adulthood with acyclic hyperestrogenemia, infertility, and a potential risk of estrogen-dependent cancer. A 22-year-old woman, with MAS, was referred for infertility with left macropolycystic ovary, hyperestrogenemia, and chronic anovulation unsuccessfully treated by controlled hyperstimulation. Once ovarian cyst punctures and cDNA analysis verified that GNAS1 mutation was restricted to the left ovary, unilateral ovariectomy was performed. It improved right ovarian function, allowed an in vitro fertilization-induced pregnancy, but revealed an unexpected borderline epithelial ovarian tumor. Several breast cancers have already been reported in young MAS patients but not a borderline epithelial ovarian tumor. In this context, we would recommend that persistent hyperestrogenemia in an adult be corrected and gynecological follow-up of the breasts, ovaries, and endometrium be implemented. Copyright © 2015 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

  18. Clinicopathological features and microsurgical outcomes for giant pediatric intracranial tumor in 60 consecutive cases.

    PubMed

    Guo, Ailing; Suresh, Vigneyshwar; Liu, Xianzhi; Guo, Fuyou

    2017-03-01

    Giant pediatric intracranial tumor (GPIT) remains to be a challenging disease with high morbidity and mortality. The clinical data of 60 patients under 18 years of age operated on with GPIT (≥5 cm in diameter) were retrospectively analyzed. Gross total resection was achieved in 46 cases (77%) and subtotal resection was obtained in 14 cases (23%). Ninety percent (47/52) of the cases with obstructive hydrocephalus were resolved remarkably and only 10% (5/52) of the patients needed a ventriculoperitoneal shunt after tumor resection. Postoperative histopathological type revealed malignant brain tumors in 51 cases (85%). The most common neoplasm was medulloblastoma; other types include the following: ependymoma, pilocytic astrocytoma, mixed glioma, primitive neuroectoderm tumor (PNET), subependymal giant cell astrocytoma, gangliocytoma, gliosarcoma, choroid plexus carcinoma, and atypical teratoid rhabdoid tumor (AT/RT). Benign histopathological categories include the following: craniopharyngioma, choroid plexus papilloma, and meningioma. No death or serious complications occurred after the operation. However, transient subcutaneous effusion occurred in 14 patients postoperatively, nerve injury including the posterior cranial nerve in two cases and abduction nerve in one case, and mutism and pulmonary infection were observed in two cases, respectively. The follow-up period ranged from 1 to 72 months, with an average of 32 months. Poor prognosis occurred significantly in the high-grade malignant tumors and PNET, AT/RT, and gliosarcoma were implicated in the death of patients within 1 year. To the best of our knowledge, the present study is the first description of clinicopathological features and the largest case analysis for GPIT. Optimal outcomes for GPIT were achieved by strict evaluation and perioperative management as well as microsurgical skills.

  19. Endoscopic Endonasal Transsphenoidal Approach for Apoplectic Pituitary Tumor: Surgical Outcomes and Complications in 45 Patients

    PubMed Central

    Zhan, Rucai; Li, Xueen; Li, Xingang

    2015-01-01

    Objective To assess the safety and effectiveness of the endoscopic endonasal transsphenoidal approach (EETA) for apoplectic pituitary adenoma. Design A retrospective study. Setting Qilu Hospital of Shandong University; Brain Science Research Institute, Shandong University. Participants Patients admitted to Qilu Hospital of Shandong University who were diagnosed with an apoplectic pituitary tumor and underwent EETA for resection of the tumor. Main Outcome Measures In total 45 patients were included in a retrospective chart review. Data regarding patient age, sex, presentation, lesion size, surgical procedure, extent of resection, clinical outcome, and surgical complications were obtained from the chart review. Results In total, 38 (92.7%) of 41 patients with loss of vision obtained visual remission postoperatively. In addition, 16 patients reported a secreting adenoma, and postsurgical hormonal levels were normal or decreased in 14 patients. All other symptoms, such as headache and alteration of mental status, recovered rapidly after surgery. Two patients (4.4%) incurred cerebrospinal fluid leakage. Six patients (13.3%) experienced transient diabetes insipidus (DI) postoperatively, but none of these patients developed permanent DI. Five patients (11.1%) developed hypopituitarism and were treated with replacement of hormonal medicine. No cases of meningitis, carotid artery injury, or death related to surgery were reported. Conclusion EETA offers a safe and effective surgical option for apoplectic pituitary tumors and is associated with low morbidity and mortality. PMID:26949589

  20. Prostate tumor DNA methylation is associated with cigarette smoking and adverse prostate cancer outcomes.

    PubMed

    Shui, Irene M; Wong, Chao-Jen; Zhao, Shanshan; Kolb, Suzanne; Ebot, Ericka M; Geybels, Milan S; Rubicz, Rohina; Wright, Jonathan L; Lin, Daniel W; Klotzle, Brandy; Bibikova, Marina; Fan, Jian-Bing; Ostrander, Elaine A; Feng, Ziding; Stanford, Janet L

    2016-07-15

    DNA methylation has been hypothesized as a mechanism for explaining the association between smoking and adverse prostate cancer (PCa) outcomes. This study was aimed at assessing whether smoking is associated with prostate tumor DNA methylation and whether these alterations may explain in part the association of smoking with PCa recurrence and mortality. A total of 523 men had radical prostatectomy as their primary treatment, detailed smoking history data, long-term follow-up for PCa outcomes, and tumor tissue profiled for DNA methylation. Ninety percent of the men also had matched tumor gene expression data. A methylome-wide analysis was conducted to identify differentially methylated regions (DMRs) by smoking status. To select potential functionally relevant DMRs, their correlation with the messenger RNA (mRNA) expression of corresponding genes was evaluated. Finally, a smoking-related methylation score based on the top-ranked DMRs was created to assess its association with PCa outcomes. Forty DMRs were associated with smoking status, and 10 of these were strongly correlated with mRNA expression (aldehyde oxidase 1 [AOX1], claudin 5 [CLDN5], early B-cell factor 1 [EBF1], homeobox A7 [HOXA7], lectin galactoside-binding soluble 3 [LGALS3], microtubule-associated protein τ [MAPT], protocadherin γ A [PCDHGA]/protocadherin γ B [PCDHGB], paraoxonase 3 [PON3], synaptonemal complex protein 2 like [SYCP2L], and zinc finger and SCAN domain containing 12 [ZSCAN12]). Men who were in the highest tertile for the smoking-methylation score derived from these DMRs had a higher risk of recurrence (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.42-3.72) and lethal disease (OR, 4.21; 95% CI, 1.65-11.78) in comparison with men in the lower 2 tertiles. This integrative molecular epidemiology study supports the hypothesis that smoking-associated tumor DNA methylation changes may explain at least part of the association between smoking and adverse PCa outcomes. Future studies

  1. Pregnancy and tumor outcomes in infertile women with macroprolactinoma on cabergoline therapy.

    PubMed

    Rastogi, Ashu; Bhadada, Sanjay K; Bhansali, Anil

    2016-12-02

    Hyperprolactinemia and prolactinomas cause infertility in significant number of women. But, pregnancy may lead to post-partum remission of hyperprolactinemia. The data on pregnancy and tumor outcome in women with macroprolactinoma conceiving on Cabergoline (CAB) therapy is increasing but still less than with Bromocriptine. We studied the incidence of fetal malformations, hyperprolactinemia and tumor course after gestation in infertile women harboring macroprolactinoma, who conceived on CAB therapy during the year 2005-2015. The cohort was divided into two groups based on the continuation of CAB therapy during gestation (Group A) or not (Group B). Forty-eight pregnancies in 33 women were recorded. CAB was continued throughout gestation in 25 pregnancies (Group A). The incidence of missed abortion (8.3%), still birth (4.2%) and low birth weight (7.7%) were not different in two groups. Neural tube defects were observed in 3 pregnancies (all in Group A). Post-partum, recurrence of hyperprolactinemia was observed in 64.6% and 60.9% (p = 0.8) of women in group A and B, respectively. Cabergoline was restarted after 60% and 60.9% (p = 0.9) pregnancies in the two groups in view of symptomatic hyperprolactinemia and/or persistence of macroadenoma. Post-partum, recurrence of hyperprolactinemia is common in spite of significant tumor reduction in infertile women with macroprolactinoma. Continuation of CAB during gestation does not influence the post-pregnancy recurrence of hyperprolactinemia or tumor remission.

  2. SPINAL MAST CELL TUMORS IN DOGS: IMAGING FEATURES AND CLINICAL OUTCOME OF FOUR CASES.

    PubMed

    Moore, Trevor W; Bentley, R Timothy; Moore, Sarah A; Provencher, Michele; Warry, Emma E; Kohnken, Rebecca; Heng, Hock Gan

    2017-01-01

    Published information regarding canine vertebral column mast cell tumors (MCTs) is limited. The objectives of this study were to report clinical and advanced imaging findings for a group of dogs with confirmed spinal MCT. Inclusion criteria for this retrospective case series were dogs with spinal magnetic resonance imaging (MRI) or computed tomography (CT) scans and a histological diagnosis of spinal MCT. Clinical, imaging, treatment, and outcome data were recorded. Four dogs met inclusion criteria. One dog had primary spinal MCT and three dogs had metastatic spinal MCT. All four dogs presented for paraspinal hyperesthesia and subacute progressive or acute myelopathy. All CT and MRI lesions were extradural. Two cases exhibited distinct masses in the epidural space. In one case, an epidural tumor invaded from the paravertebral musculature. One case exhibited polyostotic lesions indistinguishable from multiple myeloma by MRI. One dog with a primary epidural low-grade MCT remains clinically normal 4 years postoperatively, following adjunctive lomustine. An epidural high-grade MCT, metastatic from a cutaneous tumor, recurred within 2 months of surgery despite adjunctive vinblastine. Two high-grade cases with concurrent visceral involvement were euthanized immediately after imaging. In dogs, MCT should be considered as a differential diagnosis for a progressive painful myelopathy and CT or MRI evidence of an extradural spinal lesion (epidural, paravertebral, or polyostotic). While more often associated with cutaneous or disseminated disease, MCT may also occur as a primary tumor of the epidural space in dogs. © 2016 American College of Veterinary Radiology.

  3. Overexpression of forkhead Box C2 promotes tumor metastasis and indicates poor prognosis in colon cancer via regulating epithelial-mesenchymal transition.

    PubMed

    Li, Qingguo; Wu, Jitao; Wei, Ping; Xu, Ye; Zhuo, Changhua; Wang, Yuwei; Li, Dawei; Cai, Sanjun

    2015-01-01

    Forkhead box protein C2 (FOXC2) plays a vital role in carcinogenesis; however, its significance and prognostic value in colon cancer remain unclear. In this study, FOXC2 expression was analyzed in a tissue microarray (TMA) containing 185 samples of primary colon cancer tumor samples and in human colon cancer cell lines. The effect of FOXC2 on cell proliferation, tumorigenesis, and metastasis was examined in vitro and in vivo. FOXC2 was overexpressed in human colon cancer cells and tissues, and correlated with colon cancer progression and patient survival. Functional study demonstrated that FOXC2 promoted cell growth, cell migration, and tumor formation in nude mice, whereas knockdown of FOXC2 by short hairpin RNA (shRNAs) significantly suppressed cell growth, cell migration and tumor formation. Further study found that FOXC2 enhanced AKT activity with subsequent GSK-3β phosphorylation and Snail stabilization, and then induced epithelial-mesenchymal transition (EMT) and promoted tumor invasion and metastasis. Collectively, FOXC2 promotes colon cancer metastasis by facilitating EMT and acts as a potential prognostic factor and therapeutic target in colon cancer.

  4. Silencing Snail suppresses tumor cell proliferation and invasion by reversing epithelial-to-mesenchymal transition and arresting G2/M phase in non-small cell lung cancer.

    PubMed

    Yang, Xueying; Han, Mengmeng; Han, Haibo; Wang, Bingjing; Li, Sheng; Zhang, Zhiqian; Zhao, Wei

    2017-04-01

    Epithelial-to-mesenchymal transition (EMT) is essential for tumor invasion and metastasis. Snail has been proven to be a key regulator of EMT. Several studies have shown compelling evidence that Snail is also an important regulator of tumor growth and aggression; however, the role of Snail in the cell cycle has not been clarified. We decreased Snail expression by siRNA transfection and lentiviral‑mediated RNAi, to explore the effect of silencing Snail on the tumorigenicity and migration of lung carcinoma (lung cancer) cells. The results showed that silencing Snail conferred significant anti-proliferative activity and inhibited cell migration, tumor growth and metastasis both in vitro and in vivo. To understand the mechanism of these effects, we further investigated correlations among Snail expression, EMT and cell cycle. Significantly, Snail knockdown reversed EMT processes in lung cancer cells. Furthermore, the cyclin-dependent kinase inhibitor P21 was upregulated after silencing Snail. P21 upregulation manifested its tumor suppressor effects and arrested cells in the G2/M phase, not the G1/S phase following Snail depletion in lung cancer cells. These data suggest that silencing Snail decreases the malignant behaviors of lung cancer cells by reversing EMT processes and causing cell cycle defects.

  5. Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment.

    PubMed

    Xiao, Deyi; Barry, Samantha; Kmetz, Daniel; Egger, Michael; Pan, Jianmin; Rai, Shesh N; Qu, Jifu; McMasters, Kelly M; Hao, Hongying

    2016-07-01

    The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironmen