... These are called diagnostic tests . General Information About Cervical Cancer Cervical cancer is a disease in which malignant (cancer) cells ... Cervical Cancer Prevention Cervical Cancer Treatment Screening for cervical cancer using the Pap test has decreased the number ...
What is cervical cancer screening? Cervical cancer screening is used to find changes in the cells of the cervix that could lead ... includes the FAQ Human Papillomavirus Infection]. How is cervical cancer screening done? Cervical cancer screening is simple and ...
Squamous cell cervical cancer incidence and mortality have been reduced dramatically as a result of successful screening in many countries. The incidence of cervical adenocarcinoma continues to increase. There has been concentrated effort toward improving early detection and screening by utilizing molecular biomarker assays. The FIGO staging system for cervical cancer was revised in 2009. Fertility preservation can be offered to patients with early-stage cervical cancer through radical trachelectomy, although radical hysterectomy remains the surgical standard of care. Concurrent chemotherapy with radiation has been shown to have a survival advantage in patients with advanced-stage disease. Improvements in radiation techniques and molecular targeted therapy are the current research venues in cervical cancer. PMID:22640713
Lea, Jayanthi S; Lin, Ken Y
To identify the genes involved in cervical carcinogenesis, we applied the mRNA differential display (DD) method to analyze normal cervical tissue, cervical cancer, metastatic lymph node, and cervical cancer cell line. We cloned a 491-bp cDNA fragment, CC231, which was present in metastatic tissue and cervical cancer cell line, but absent in normal cervical and cervical cancer tissues. The 491
Jin Woo Kim; Hyun Suk Cho; Jeong Hyun Kim; Soo Young Hur; Tae Eung Kim; Joon Mo Lee; In-Kyung Kim; Sung Eun Namkoong
Cervical Adenocarcinoma; Cervical Adenosquamous Cell Carcinoma; Cervical Squamous Cell Carcinoma; Stage IB Cervical Cancer; Stage IIA Cervical Cancer; Stage IIB Cervical Cancer; Stage IIIB Cervical Cancer; Stage IVA Cervical Cancer
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Mutations in the small GTPase R-Ras that promote constitutive activation of this signaling molecule have been observed in\\u000a a variety of invasive cancer cell types. We previously reported that expression of an oncogenic form of R-Ras (R-Ras87L) in\\u000a a cell line of cervical cancer (C33A cells) augments cell growth in vitro and tumorigenicity in vivo. Because increased tumorigenicity\\u000a in vivo
Nancy Mora; Ricardo Rosales; Carlos Rosales
... DS00167 ">Cervical cancer Guidelines for sites linking to MayoClinic.com Advertisement Mayo Clinic Store Check out these best-sellers and special offers on books and newsletters from Mayo Clinic. Try Mayo Clinic Health Letter ... answers to live stronger, longer and healthier at any age ...
This study evaluated the anti-cancer effects of a naringenin derivative in human cervical cancer cells. In this study, a synthesized naringenin derivative, diethyl 5,7,4?-trihydroxy flavanone N-phenyl hydrazone (N101-2), inhibited cervical cancer cell growth, whereas naringenin itself exhibited no anti-cancer activity. N101-2 treatment inhibited cancer cell viability in a dose- and time-dependent manner through cell cycle arrest at sub-G1 phase, accompanied
Jung-Hee Kim; Jeong Woo Kang; Man-Sub Kim; Yesol Bak; Yun Sun Park; Kang-Yeoun Jung; Yoong Ho Lim; Do-Young Yoon
A previous study showed E-cadherin expression was lost in some cervical cancer cell lines and tumours. This study was designed to clarify the significance of DNA methylation in silencing E-cadherin expression. We examined promoter methylation of E-cadherin in five cervical cancer cell lines and 20 cervical cancer tissues using methylation-specific PCR (MSP) and bisulphite DNA sequencing. The correlation of E-cadherin
T. Y Ng; S. S Liu; S.-M Ip; L. C Wong; H. Y. S Ngan
In the present study the effectiveness of methyl jasmonate (MJ) against cervical cancer cell lines was investigated. We show that MJ is cytotoxic to a range of cervical cancer lines including SiHa, CaSki and HeLa that carry human papillomavirus (HPV) DNA and wild type p53, and C33A that is negative for HPV and contains mutant p53. Primary human foreskin keratinocytes
Tatiana Kniazhanski; Anna Jackman; Alina Heyfets; Pinhas Gonen; Eliezer Flescher; Levana Sherman
Cervical Adenocarcinoma; Cervical Adenosquamous Cell Carcinoma; Cervical Squamous Cell Carcinoma; Stage IB Cervical Cancer; Stage II Vaginal Cancer; Stage IIA Cervical Cancer; Stage IIB Cervical Cancer; Stage III Vaginal Cancer; Stage IIIA Cervical Cancer; Stage IIIB Cervical Cancer; Stage IVA Cervical Cancer; Stage IVA Vaginal Cancer; Vaginal Adenocarcinoma; Vaginal Squamous Cell Carcinoma
Human papillomavirus (HPV) infection is considered to be a primary hit that causes cervical cancer. However, infection with this agent, although needed, is not sufficient for a cancer to develop. Additional cellular changes are required to complement the action of HPV, but the precise nature of these changes is not clear. Here, we studied the function of the Hedgehog (Hh) signaling pathway in cervical cancer. The Hh pathway can have a role in a number of cancers, including those of liver, lung and digestive tract. We found that components of the Hh pathway are expressed in several cervical cancer cell lines, indicating that there could exists an autocrine Hh signaling loop in these cells. Inhibition of Hh signaling reduces proliferation and survival of the cervical cancer cells and induces their apoptosis as seen by the up-regulation of the pro-apoptotic protein cleaved caspase 3. Our results indicate that Hh signaling is not induced directly by HPV-encoded proteins but rather that Hh-activating mutations are selected in cells initially immortalized by HPV. Sonic Hedgehog (Shh) ligand induces proliferation and promotes migration of the cervical cancer cells studied. Together, these results indicate pro-survival and protective roles of an activated Hh signaling pathway in cervical cancer-derived cells, and suggest that inhibition of this pathway may be a therapeutic option in fighting cervical cancer. PMID:22820185
Samarzija, Ivana; Beard, Peter
Conventional methods for cervical cancer screening usually employ microscopic observations that may require fluorescence labeling of the cells, which could be time-consuming and expensive. Development of a novel method for cervical cancer cells determination in a rapid, label-free manner may significantly improve the cervical cancer screening technique. Here two-dimensional (2D) light scattering patterns are obtained from yeast cells on a CMOS chip, where laser light is used to excite single cells via fiber-coupling under a microscope. Good agreements between the experimental and Mie theory simulation results convey that 2D light scattering patterns from cervical cancer cells may be obtained upon the apparatus developed here. Mie theory simulations on simplified normal and cancerous cervical cells show that side scattering spectrum may be used for cervical cancer cells screening. Future experiments further convincing the 2D light scattering method proposed here may bring up a powerful technique that has profound applications in cervical cancer cell determination.
Yang, Yan; Jia, Rongfeng; Sun, Qiyong; Song, Kun; Kong, Beihua; Su, Xuantao
MicroRNAs (miRNAs) are short non-coding RNA regulators that control gene expression mainly through post-transcriptional silencing. We previously identified miR-205 in a signature for human cervical cancer using a deep sequencing approach. In this study, we confirmed that miR-205 expression was frequently higher in human cervical cancer than their matched normal tissue samples. Functionally, we demonstrate that miR-205 promotes cell proliferation and migration in human cervical cancer cells. To further understand the biological roles of miR-205, we performed in vivo crosslinking and Argonaute 2 immunoprecipitation of miRNA ribonucleoprotein complexes followed by microarray analysis (CLIP-Chip) to identify its potential mRNA targets. Applying CLIP-Chip on gain- and loss-of-function experiments, we identified a set of transcripts as potential targets of miR-205. Several targets are functionally involved in cellular proliferation and migration. Two of them, CYR61 and CTGF, were further validated by Western blot analysis and quantification of mRNA enrichment in the Ago2 immunoprecipitates using qRT-PCR. Furthermore, both CYR61 and CTGF were downregulated in cervical cancer tissues. In summary, our findings reveal novel functional roles and targets of miR-205 in human cervical cancer, which may provide new insights about its role in cervical carcinogenesis and its potential value for clinical diagnosis.
Xie, Hong; Zhao, Yungang; Caramuta, Stefano; Larsson, Catharina; Lui, Weng-Onn
Mutations in the small GTPase R-Ras that promote constitutive activation of this signaling molecule have been observed in a variety of invasive cancer cell types. We previously reported that expression of an oncogenic form of R-Ras (R-Ras87L) in a cell line of cervical cancer (C33A cells) augments cell growth in vitro and tumorigenicity in vivo. Because increased tumorigenicity in vivo often precedes metastasis, we now examined whether the expression of R-Ras87L also increased the metastatic potential of C33A cells. Accelerated tumor growth was observed in athymic mice after subcutaneous injection of R-Ras87L-expressing C33A cells. In addition, increased metastasis to the liver, in immunodeficient SCID mice, was observed after intravenous injection of R-Ras87L-expressing C33A cells. Also, R-Ras87L-expressing cells presented decreased membrane expression of MHC class I molecules, and beta1 integrins, but increased levels of PI 3-K and Akt activities. C33A cells expressing R-Ras87L also migrated more over collagen I in wound assays. Inhibition of the PI 3-K/Akt/mTOR pathway by pharmacological means blocked R-Ras87L-induced accelerated growth and migration over collagen I. These results suggest oncogenic R-Ras has a central role in cancer progression towards a metastatic phenotype, through the activation of the PI 3-K/Akt/mTOR signaling pathway. PMID:16862428
Mora, Nancy; Rosales, Ricardo; Rosales, Carlos
In the present study the effectiveness of methyl jasmonate (MJ) against cervical cancer cell lines was investigated. We show that MJ is cytotoxic to a range of cervical cancer lines including SiHa, CaSki and HeLa that carry human papillomavirus (HPV) DNA and wild type p53, and C33A that is negative for HPV and contains mutant p53. Primary human foreskin keratinocytes were almost resistant to the drug. Cytotoxicity of MJ was dose and time dependent, and associated mainly with the induction of cell death and to a less extent with inhibition of cell growth. Cell death induced by MJ displayed features characteristic to both apoptosis and necrosis, and was associated with different changes in the levels of p53, p21, bcl-2 and bax in the various cervical cancer lines. In conclusion, MJ a novel anticancer agent, acts via multiple pathways to induce death of cervical cancer cells, thus making it a promising candidate for treatment of cervical cancer. PMID:18599197
Kniazhanski, Tatiana; Jackman, Anna; Heyfets, Alina; Gonen, Pinhas; Flescher, Eliezer; Sherman, Levana
The Werner (WRN) gene codes for a DNA helicase that contributes to genomic stability and has been identified as the gene responsible for progeria. Recent studies have shown reduced WRN expression due to aberrant DNA hypermethylation in cancer cells. Furthermore, WRN expression is thought to affect sensitivity to DNA topoisomerase I inhibitors in cancer therapy. In this study, we examined the relationship between aberrant DNA hypermethylation of WRN and the sensitivity of cervical cancer cells to anticancer drugs. DNA was extracted from samples from 22 patients with primary cervical cancer and 6 human cervical cancer-derived cell lines. Aberrant DNA hypermethylation was analyzed by methylation-specific PCR. WRN expression in cultured cells before and after addition of 5-aza-2-deoxycytidine, a demethylating agent, was examined using RT-PCR. The sensitivity of cells to anticancer drugs was determined using a collagen gel droplet embedded culture drug sensitivity test (CD-DST). siRNA against WRN was transfected into a cervical cancer-derived cell line with high WRN expression. Changes in drug sensitivity after silencing WRN were determined by CD-DST. Aberrant DNA hypermethylation and decreased expression of WRN were detected in 7/21 cases of primary cervical cancer and in two cervical cancer-derived cell lines. These two cell lines showed high sensitivity to CPT-11, a topoisomerase I inhibitor, but became resistant to CPT-11 after treatment with 5-aza-2-deoxycytidine. Transfection of siRNA against WRN increased the sensitivity of the cells to CPT-11. Aberrant DNA hypermethylation of WRN also increased the sensitivity of cervical cancer cells to CPT-11. Therefore, epigenetic inactivation of this gene may be a biomarker for selection of drugs for the treatment of cervical cancer. This is the first report to show a relationship between the methylation of the WRN gene and sensitivity to CPT-11 in gynecological cancers. PMID:22797812
Masuda, Kenta; Banno, Kouji; Yanokura, Megumi; Tsuji, Kosuke; Kobayashi, Yusuke; Kisu, Iori; Ueki, Arisa; Yamagami, Wataru; Nomura, Hiroyuki; Tominaga, Eiichiro; Susumu, Nobuyuki; Aoki, Daisuke
The Werner (WRN) gene codes for a DNA helicase that contributes to genomic stability and has been identified as the gene responsible for progeria. Recent studies have shown reduced WRN expression due to aberrant DNA hypermethylation in cancer cells. Furthermore, WRN expression is thought to affect sensitivity to DNA topoisomerase I inhibitors in cancer therapy. In this study, we examined the relationship between aberrant DNA hypermethylation of WRN and the sensitivity of cervical cancer cells to anticancer drugs. DNA was extracted from samples from 22 patients with primary cervical cancer and 6 human cervical cancer-derived cell lines. Aberrant DNA hypermethylation was analyzed by methylation-specific PCR. WRN expression in cultured cells before and after addition of 5-aza-2-deoxycytidine, a demethylating agent, was examined using RT-PCR. The sensitivity of cells to anticancer drugs was determined using a collagen gel droplet embedded culture drug sensitivity test (CD-DST). siRNA against WRN was transfected into a cervical cancer-derived cell line with high WRN expression. Changes in drug sensitivity after silencing WRN were determined by CD-DST. Aberrant DNA hypermethylation and decreased expression of WRN were detected in 7/21 cases of primary cervical cancer and in two cervical cancer-derived cell lines. These two cell lines showed high sensitivity to CPT-11, a topoisomerase I inhibitor, but became resistant to CPT-11 after treatment with 5-aza-2-deoxycytidine. Transfection of siRNA against WRN increased the sensitivity of the cells to CPT-11. Aberrant DNA hypermethylation of WRN also increased the sensitivity of cervical cancer cells to CPT-11. Therefore, epigenetic inactivation of this gene may be a biomarker for selection of drugs for the treatment of cervical cancer. This is the first report to show a relationship between the methylation of the WRN gene and sensitivity to CPT-11 in gynecological cancers.
MASUDA, KENTA; BANNO, KOUJI; YANOKURA, MEGUMI; TSUJI, KOSUKE; KOBAYASHI, YUSUKE; KISU, IORI; UEKI, ARISA; YAMAGAMI, WATARU; NOMURA, HIROYUKI; TOMINAGA, EIICHIRO; SUSUMU, NOBUYUKI; AOKI, DAISUKE
Inhibins are dimeric glycoproteins, composed of an alpha-subunit and one of two possible beta-subunits (betaA or betaB), with\\u000a substantial roles in human reproduction and in endocrine-responsive tumours. Recently a novel beta subunit named betaE was\\u000a described, although it is still unclear if normal or cancerous cervical epithelial cells as well as cervical cancer cell lines\\u000a can synthesise the novel inhibin-betaE
Florian BergauerAnsgar Bruning; Ansgar Brüning; Naim Shabani; Thomas Blankenstein; Julia Jückstock; Darius Dian; Ioannis Mylonas
Smoking and Cervical Cancer If you smoke, you have an increased chance of developing precancerous lesions of the cervix (called moderate or ... and an increase in the chance of developing cervical cancer. Smoking greatly increases your risk for dysplasia and ...
Cervical cancer is probably caused by a sexually transmitted agent. A case-control study was conducted in three hospitals in Thailand to investigate further the role of male sexual behavior, particularly regarding sexual contacts with prostitutes, in the development of this disease. Data were obtained from interviews with 225 manned women with invasive squamous cell cervical carcinoma and 791 hospitalized controls,
David B. Thomas; Roberta M. Ray; Tieng Pardthaisong; Supawat Chutivongse; Supom Koetsawang; Suporn Silpisornkosol; Pramuan Virutamasen; William M. Christopherson; Joseph L. Melnick; Olav Meirik; Timothy M. M. Farley; Gustave Riotton
Overexpression of metadherin (MTDH) has been reported in many solid tumors and implicated in chemoresistance. This study aimed to examine MTDH expression in cervical cancer tissues and explore its role in chemoresistance of cervical cancer. MTDH expression in cervical cancer biopsies and several cervical cancer cell lines was detected by immunoblotting and immunohistochemisty. MTDH expression level was experimentally modulated in HeLa cells to determine the effects on chemoresistance to cisplatin. The results showed that MTDH expression was higher in tissues from both cervical squamous carcinoma and cervical adenocarcinoma, compared to normal cervical tissues. MTDH expression was not correlated to patient age or cervical cancer grade, although nuclear MTDH expression was correlated with poor differentiation of cervical cancer. In SiHa, HeLa, CasKi, and C33A cells, MTDH expression level was positively correlated with chemoresistance to cisplatin. MTDH increased autophagy in HeLa cells, which was associated with decreased cleavage of Caspase-3 and the activation of EER/NF-?B pathway. In conclusion, MTDH expression is high in cervical cancer, and it contributes to chemoresistance of cervical cancer. MTDH could be utilized as a therapeutic target to overcome chemoresistance of cervical cancer. PMID:23595222
Zhang, Jingwei; Zhang, Yunyan; Liu, Shuang; Zhang, Qingmeng; Wang, Yan; Tong, Liping; Chen, Xiaohang; Ji, Yuting; Shang, Qinglong; Xu, Baozhan; Chu, Ming; Wei, Lanlan
The present study investigated the antiapoptotic effects of estrogen in normal and cancer human cervical cells and the mechanisms involved. Baseline apoptosis in human cervical epithelial cells is mediated predominantly by P2X7-receptor-induced, Ca(2+)-dependent activation of the mitochondrial (caspase-9) pathway. Treatment with 10 nM 17beta-estradiol blocked apoptosis induced by the P2X7-receptor ligands ATP and 2',3'-0-(4-benzoylbenzoyl)-ATP in normal human cervical epithelial cells (hECEs) and attenuated the effect in hECEs immortalized with human papillomavirus-16 (ECE16-1) and the cancer cervical cells HT3 and CaSki. Diethylstilbestrol and to a lesser degree estrone could mimic the effects of 17beta-estradiol, whereas actinomycin-D and cycloheximide attenuated the response. The antiapoptotic effect of estrogen did not depend on cell cycle phase, and in both normal and cancer cervical cells, it involved attenuation of activation of caspase-9 and the terminal caspase-3. However, involvement of cascades upstream to the caspase-9 differed in normal vs. cancer cervical cells. In the normal hECEs estrogen blocked P2X7-receptor-induced calcium influx. In contrast, in the cancer CaSki cells, estrogen up-regulated expression of Bcl-2 and attenuated Ca(2+)-induced mitochondrial swelling (i.e. formation of mitochondrial permeability transition pores). Estrogen had no effect on P2X7-receptor-induced apoptosis in the anaplastic SiHa and Hela cells. These results point to a novel antiapoptotic effect of estrogen in the cervix that is independent of its mitogenic function. The results also suggest that cancer cervical cells evolved antiapoptotic mechanisms that enable the cells to evade apoptosis and could therefore promote tumor progression. PMID:15319352
Wang, Qifang; Li, Xin; Wang, Liqin; Feng, Ying-Hong; Zeng, Robin; Gorodeski, George
Skip to Main Content Search International Cancer Screening Network Sponsored by the National Cancer Institute Home | About ICSN | Collaborative Projects | Meetings | Cancer Sites | Publications | Contact Us Cervical Cancer (Archived Tables): Home Other
Objective Metformin is one of the most widely used drugs for the treatment of type 2 diabetes. Recent investigations demonstrated that application of metformin reduces cancer risk. The present study aimed to determine the role of liver kinase B1 (LKB1) in the response of cervical cancer cells to metformin. Methods LKB1 expression and the integrity of LKB1-AMPK signaling were determined with immunoblot in 6 cervical cancer cell lines. Cellular sensitivity to metformin was analyzed with MTT assay. Results Metformin inhibited growth of cervical cancer cells, C33A, Me180, and CaSki, but was less effective against HeLa, HT-3, and MS751 cells. Analyzing the expression status and the integrity of LKB1-AMPK-mTOR signaling, we found that cervical cancer cells sensitive to metformin were LKB1 intact and exerted an integral AMPK-mTOR signaling response after the treatment. Ectopic expression of LKB1 with stable transduction system or inducible expression construct in endogenous LKB1 deficient cells improved the activation of AMPK, promoted the inhibition of mTOR, and prompted the sensitivity of cells to metformin. In contrast, knock-down of LKB1 compromised cellular response to metformin. Our further investigation demonstrated that metformin could induce both apoptosis and autophagy in cervical cancer cells when LKB1 is expressed. Conclusions Metformin is a potential drug for the treatment of cervical cancers, in particular to those with intact LKB1 expression. Administration of cell metabolism agonists may enhance LKB1 tumor suppression, inhibit cell growth, and reduce tumor cell viability via the activation of LKB1-AMPK signaling.
Xiao, Xuxian; He, Qiongqiong; Lu, Changming; Werle, Kaitlin D.; Zhao, Rui-Xun; Chen, Jianfeng; Davis, Ben C.; Cui, Rutao; Liang, Jiyong; Xu, Zhi-Xiang
Cervical neoplasia is one of the most frequent cancers in women and is associated with high-risk human papillomavirus (HPV) infection. Resveratrol, a natural polyphenolic phytochemical, has received considerable interest on the basis of its potential as a chemopreventive agent against human cancer. In this work, we analyzed the type of cell death induced by resveratrol in several cervical cancer cell lines. Resveratrol treatment (150-250 µmol/l) for 48 h increased cell cycle arrest at the G1 phase in C33A (with mutation in p53) and HeLa cells (HPV18 positive), as well as in CaSki and SiHa cell lines (HPV16 positive). Resveratrol treatment induced apoptosis in all cell lines, particularly in CaSki cells, as measured by Annexin-V flow cytometry analysis. There was a decrease in the mitochondrial membrane potential (apoptosis) in HeLa, CaSki, and SiHa cells and an increased lysosomal permeability (autophagy) in C33A, CaLo (HPV18 positive), and HeLa cell lines. Furthermore, when we used the IC50 of each line, we found that resveratrol produces a similar effect, suggesting that this effect is not dependent on the concentration of resveratrol. Interestingly, after resveratrol treatment, the expression of p53 was decreased in HPV18-positive cell lines (CaLo and HeLa) and increased in HPV16-positive cell lines (CaSki and SiHa) and C33A cells. The expression of p65 (an NF-?B subunit) was decreased after treatment in all cell lines except SiHa cells. These data indicate that resveratrol uses different mechanisms to induce cell death in cell lines derived from cervical cancer. PMID:23603746
García-Zepeda, Sihomara P; García-Villa, Enrique; Díaz-Chávez, José; Hernández-Pando, Rogelio; Gariglio, Patricio
The widely adopted use of tamoxifen as a chemotherapeutic agent is primarily based on its inhibition of cancer cell growth. However, we report that tamoxifen at low concentrations (10 -9 and 10 -1~ M) causes stimulation of cell proliferation in a cervical cancer cell line, SFR. The facts that SFR cells do not contain estrogen receptors and are estrogen nonresponsive
Jin-Yun Hwang; Bi-Yu Lin; Fen-Mei Tang; Winston C. Y. Yu
Overwhelming evidence has demonstrated that the aberrant expression of the human trophoblast cell-surface antigen (TROP2) was associated with tumor aggressiveness and poor prognosis in a variety of human cancers, however the roles of TROP2 in cervical cancer have not been investigated. The purpose of our study was to elucidate the prognostic significance of TROP2 expression in patients with cervical cancer and determine its effect on tumor progression. Immunohistochemistry assay showed that 88.7% (94/106 cases) of cervical cancer specimens were positively stained with TROP2, and the overexpression of TROP2 was closely related with FIGO stage, histological grades, lymphatic metastasis, invasive interstitial depth and high expression of Ki-67. Patients with TROP2-positive staining exhibited a significantly decreased overall survival and progression free survival; it was also an independent predictor for prognosis according to multivariate analysis. Moreover, down-regulation of TROP2 mediated by siRNA in Siha and CaSki cells resulted in a strong inhibition of proliferation and invasion, TROP2 abrogation also elevated the apoptotic ratio and caused G1 arrest. Conversely, enforced expression of TROP2 in HeLa and C33A cells remarkably promoted cell growth, migration and invasion. In addition, the tumorigenic function of TROP2 was associated with the increased expressions of cyclin D1, cyclin E, CDK2 and CDK4 but reduced expression of p27 and E-cadherin via the activation of Erk1/2 signaling pathway. Furthermore, the inhibition of TROP2 expression in cervical cancer cell lines enhances sensitivity to cisplatin. The present study suggest that overexpression of TROP2 may play crucial roles in the development and pathogenesis of human cervical cancer, therefore, TROP2 may represent a prospective prognostic indicator and a potential therapeutic target of cervical cancer.
Liu, Ting; Liu, Yueyang; Bao, Xiangxiang; Tian, Jiguang; Liu, Yang; Yang, Xingsheng
Overwhelming evidence has demonstrated that the aberrant expression of the human trophoblast cell-surface antigen (TROP2) was associated with tumor aggressiveness and poor prognosis in a variety of human cancers, however the roles of TROP2 in cervical cancer have not been investigated. The purpose of our study was to elucidate the prognostic significance of TROP2 expression in patients with cervical cancer and determine its effect on tumor progression. Immunohistochemistry assay showed that 88.7% (94/106 cases) of cervical cancer specimens were positively stained with TROP2, and the overexpression of TROP2 was closely related with FIGO stage, histological grades, lymphatic metastasis, invasive interstitial depth and high expression of Ki-67. Patients with TROP2-positive staining exhibited a significantly decreased overall survival and progression free survival; it was also an independent predictor for prognosis according to multivariate analysis. Moreover, down-regulation of TROP2 mediated by siRNA in Siha and CaSki cells resulted in a strong inhibition of proliferation and invasion, TROP2 abrogation also elevated the apoptotic ratio and caused G1 arrest. Conversely, enforced expression of TROP2 in HeLa and C33A cells remarkably promoted cell growth, migration and invasion. In addition, the tumorigenic function of TROP2 was associated with the increased expressions of cyclin D1, cyclin E, CDK2 and CDK4 but reduced expression of p27 and E-cadherin via the activation of Erk1/2 signaling pathway. Furthermore, the inhibition of TROP2 expression in cervical cancer cell lines enhances sensitivity to cisplatin. The present study suggest that overexpression of TROP2 may play crucial roles in the development and pathogenesis of human cervical cancer, therefore, TROP2 may represent a prospective prognostic indicator and a potential therapeutic target of cervical cancer. PMID:24086649
Liu, Ting; Liu, Yueyang; Bao, Xiangxiang; Tian, Jiguang; Liu, Yang; Yang, Xingsheng
The establishment of in vitro model will provide optimal conditions for the study of human papillomavirus (HPV)-associated cervical cancer. In this study, E6 and E7 gens of HPV31 were cloned and expressed in E. coli. The recombinant proteins were purified and used as antigens to immunize mice for the production of polyclonal antibody. Mammalian expression plasmid pBudCE4. 1-HPV31-E6/E7 was also constructed and transfected into C33A cells. The transfected cells were then selected by Zeocin. The expressions of the E6 and E7 mRNAs and proteins were detected by RT-PCR and Western blot respectively. A stable cervical cancer cell line was established as an in vitro model for the study of human papillomavirus type 31(HPV31) associated cervical cancer. PMID:23233933
Yi, Jun-Bo; Mai, Zhi-Gang; Lu, Hai-Rong; Zhang, Gang; Zhou, Zhao-Ping
We investigated the time-course tumor growth suppression effects of recombinant adenovirus expressing p53 on human cervical cancer cells and cell-specific E7 protein–protein interactions in cell lysates using surface plasmon resonance (SPR) biosensor. Six HPV-infected human cervical cancer cell lines (HPV 16-positive cells, CaSki and SiHa cells; HPV 18-positive cells, HeLa and HeLaS3 cells; and HPV negative C33A and HT3 cells)
Jeong-Woo Choi; Woong Shick Ahn; Su Mi Bae; Doo-Bong Lee; Yong-Wan Kim
Aims: The molecular mechanisms of the tumorigenesis and recurrence of cervical cancer are poorly understood. The objective of this study was to analyze the expression of phosphorylated c-Src (phospho-c-Src) and its clinical significance in human cervical cancer. Methods: The expression of phospho-c-Src was determined by immunohistochemistry in a total of 127 cervical specimens including 20 normal cervix tissues, 20 cases of carcinoma in situ of cervix (CIS), and 87 cases of cervical squamous cell carcinoma (CSCC). Results: The expression of phospho-Src in normal cervix, CIS, and CSCC increased gradually in ascending order (p=0.026). In addition, the expression of phospho-Src was correlated with overall (p=0.037) and recurrence (p=0.001) survival of cervical cancer. In multivariate Cox regression analysis, phospho-Src expression was an independent prognosis factor for recurrence-free survival (p=0.004). Conclusion: Our present study suggests that Src signaling may play essential role in cervical cancer progression. Phospho-Src expression may be considered as a prognostic marker to predict recurrence in CSCC.
Hou, Teng; Xiao, Juan; Zhang, Huiting; Gu, Haifeng; Feng, Yanling; Li, Jundong
Aberrant activation of Hedgehog (Hh) signalling has been implicated in the pathogenesis of human cancers. However, the cognate molecular mechanisms contributing to this disregulated pathway are incompletely understood. In this study, we showed that Zic2 was frequently over-expressed and associated with high-grade cervical cancer (p = 0.032), high levels of Gli1 (p < 0.001) and CyclinD1 (p < 0.001) by immunohistochemical and quantitative RT-PCR analyses. Further biochemical studies using luciferase reporter, co-immunoprecipitation, subcellular fractionation and immunofluorescence analyses demonstrated that Zic2 can physically interact with Gli1 and retain it in the nucleus, which in turn increases Gli-mediated transcriptional activity. Gain- and loss-of-function analyses of Zic2 showed that Zic2 could increase Hh signalling activity, cell proliferation and anchorage-independent growth ability in cervical cancer cells. Conversely, deletion of the zinc finger domain at C-terminus of Zic2 significantly abrogated its interaction with Gli1, the retention of Gli1 in the nucleus, effects on Hh signalling activity and oncogenic properties in cervical cancer cells. Our findings suggest that Zic2 is a positive modulator increasing Gli1 transcriptional and oncogenic activity by retaining Gli1 in the nucleus of cervical cancer cells. PMID:21661123
Chan, David W; Liu, Vincent W S; Leung, Ling Yang; Yao, Kwok Ming; Chan, Karen K L; Cheung, Annie N Y; Ngan, Hextan Y S
Exposure to cigarette smoke is well documented to increase oxidative stress and could account for higher risk of cervical cancer in smokers. Cervical pre-cancerous lesions that are initiated by human papillomavirus (HPV) infection generally regress in the absence of known risk factors such as smoking. 8-oxodeoxyguanosine (8-oxodG) is a highly mutagenic oxidative DNA lesion that is formed by the oxidation of deoxyguanosine. In the present study, we examined: a) the effect of cigarette smoke condensate (CSC) on 8-oxodG formation in and its removal from HPV-transfected (ECT1/E6 E7), HPV-positive (CaSki) and HPV-negative (C33A) human cervical cancer cells, and b) the cell cycle progression and apoptosis in CSC-treated ECT1/E6 E7 cells. CSC induced 8-oxodG in a dose- (p=0.03) and time (p=0.002)-dependent fashion in ECT1/E6 E7 cells as determined by flow cytometry. A 2.4-fold higher level of 8-oxodG was observed in HPV-positive compared with HPV-negative cells. However, 8-oxodG lesions were almost completely removed 72 h post-exposure in all cell lines as determined by ImageStream analysis. This observation correlates with the 2- and 5-fold increase in the p53 levels in ECT1/E6 E7 and CaSki cells with no significant change in C33A cells. We conclude that: a) cigarette smoke constituents induce oxidative stress with higher burden in HPV-positive cervical cancer cells and b) the significant increase observed in p53 levels in wild-type cervical cells (ECT1/E6 E7 and CaSki) may be attributed to the p53-dependent DNA repair pathway while a p53-independent pathway in C33A cells cannot be ruled out. PMID:21720711
Moktar, Afsoon; Singh, Rajesh; Vadhanam, Manicka V; Ravoori, Srivani; Lillard, James W; Gairola, C Gary; Gupta, Ramesh C
We investigated possible epigenetic regulation of Period1 (PER1), a key circadian regulator gene, in six cervical cancer cell lines which showed up to 15.4-fold differences in PER1 mRNA levels. Genomic methylation analysis showed that a discerned CpG island in the PER1 promoter remained hypomethylated in five of the cell lines. In contrast, C33A cells that showed maximal PER1 expression was
Min-Chuan Hsu; Chih-Cheng Huang; Kong-Bung Choo; Chiu-Jung Huang
Human papillomavirus type 16 DNA and RNA were characterized in the cervical cancer-derived CaSki cell line, which contains only integrated DNA, and in a cervical cancer, which contains predominantly plasmid DNA. In both, a major RNA can code for the early open reading frame E7 and a minor one can code for E6. The cervical cancer, but not the CaSki
David Smotkin; Felix O. Wettstein
Aesculetin (1) is an important coumarin found in various plant materials. It has been shown to have antiproliferative effects on several types of human cancer cells, but its effect on cervical cancer cells in vitro is unknown. In this study, we investigated that the cytotoxic effect of 1 on a non-cancer cell line (293) was smaller than on a tumor
Jin Yang; Yu-Ling Xiao; Xian-Ran He; Guo-Fu Qiu; Xian-Ming Hu
Although primary prevention of human papillomavirus (HPV) infections that are causally associated with invasive cervical cancer\\u000a may be within our grasp, it is unlikely that these approaches will replace existing cervical cancer screening strategies for\\u000a many years. Experts agree and data support periodic cytology screening for young-adult women using one of several technologies.\\u000a Recent analyses of cost-effectiveness suggest that the
Dorothy J. Wiley; Bradley J. Monk; Emmanuel Masongsong; Kristina Morgan
The aim of the present study was to determine the effect of AZD8055 on proliferation, apoptosis and glycolysis in the human cervical cancer cell line HeLa and to investigate the underlying mechanism(s) of action. HeLa human cervical cancer cells were treated with 10 nM AZD8055 for 24, 48 or 72 h. MTT was used to determine cell proliferation. Annexin V/propidium iodide staining was used to determine cell apoptosis analyzed by fluorescence-activated cell sorting (FACS). Glycolytic activity was determined by measuring the activity of the key enzyme lactate dehydrogenase (LDH) and lactate production. RNA and protein expression were examined by qRT-PCR and western blotting, respectively. Treatment with AZD8055 inhibited proliferation and glycolysis, and induced apoptosis in HeLa cells in a time-dependent manner. During the prolonged treatment with AZD8055, the phosphorylation of mammalian target of rapamycin (mTOR) C1 substrates p70S6K and phosphorylation of the mTORC2 substrate Akt were deregulated, suggesting that the activity of mTOR was downregulated. Furthermore, our study showed that the expression of miR-143 was upregulated in a time-dependent manner in HeLa cells treated with AZD8055. In summary, the present study reveals a novel antitumor mechanism of AZD8055 in HeLa human cervical cancer cells.
LI, SHAORU; LI, YAN; HU, RUILI; LI, WEIHUA; QIU, HAIFENG; CAI, HONGHUA; WANG, SHIJIN
Cervical cancer has been identified as the third leading cause of average years of life lost per person dying of cancer. Since essentially all cervical cancers contain copies of human papillomavirus (HPV) DNA, we propose a treatment that targets HPV-infected cells using strategies that re-introduce normal functions into the infected cells while sparing healthy cells. We propose the use of focused ultrasound in combination with microbubbles as means to deliver antibodies against the E6 protein present only in HPV positive cells. We conducted in vitro studies with cell cultures of SiHa cervical carcinoma cells seeded into Opticell™ chambers. An in-house ultrasound excitation apparatus was used to control and explore the optimal acoustic parameters in order to maximize delivery. We first validated the possibility of delivering the EX-EGFP-M02 vector (Genecopoeia) into the cells; 1.2 ?L of activated microbubbles (Definity®) and 50 ?g of the vector were mixed in media and then injected into the Opticell™ chamber. We used 32 ?s pulses at a central frequency of 930 KHz with a repetition frequency of 1.5 kHz and total exposure duration of 30 s; six pressure values were tested (0 to 1 MPa). Fluorescence imaging was used to determine the levels of intracellular proteins and assess delivery. The delivery of an anti-?-Tubulin antibody was next tested and confirmed that the delivery into HPV16 positive cells was successful.
Curiel, Laura; Lee, Kyle; Pichardo, Samuel; Zehbe, Ingeborg
Silymarin is an active constituent contained in the seeds of the milk thistle plant and is widely used as a hepatic protection agent due to its antioxidant-like activity. In the present study we evaluated the potential action of silymarin against cervical cancer and investigated its mechanism of action. Treatment of cervical cancer cells (C-33A) with silymarin resulted in a significant decrease in cell viability. Silymarin induced apoptosis through the modulation of Bcl-2 family proteins and activation of caspase 3. Silymarin also inhibited the phosphorylation of Akt with an increase in expression of phosphatase and tensin homolog (PTEN). We also observed that silymarin suppressed C-33A cell invasion and wound-healing migration in a concentration-dependent manner. Western-blot analysis showed that silymarin significantly inhibited the expression of matrix metalloproteinase-9 (MMP-9) in C-33A cells. Furthermore, we applied siRNA to lower the PTEN gene, which diminished the anticancer actions of silymarin. Taken together, these results show that silymarin has the potential to suppress the survival, migration and invasion of C-33A cancer cells; thus, it could be developed as a promising agent for the treatment of cervical cancer in the future. PMID:22016029
Yu, Hann-Chin; Chen, Li-Jen; Cheng, Kai-Chun; Li, Ying-Xiao; Yeh, Ching-Hua; Cheng, Juei-Tang
It was recently reported that the reduced expression of hypoxia-inducible factor prolyl 4-hydroxylase PHD2 inhuman cancers correlates with increased angiogenesis. We used HeLa, CaSki, C33A, and SiHa cervical cancer cells to show the effect of apicidin on cellular levels of PHD2 enzyme. Using reverse transcription, real-time quantitative PCR, and western blot analysis, we established that apicidin upregulates PHD2 transcript and protein levels in HeLa, CaSki, and C33A, but not in SiHa cervical cancer cells. Bisulfite sequencing showed that the increase in PHD2 expression was accompanied by demethylation ofCpG islands located in the first exon of the PHD2 gene.As decreased PHD2 expression supports tumor progression, our findings may validate the usefulness of apicidin as an anticancer drug. PMID:20527723
Durczak, Marta; Jagodzinski, Pawe? Piotr
A significant change of surface features of malignant cervical epithelial cells compared to normal cells has been previously reported. Here, we are studying the question at which progressive stage leading to cervical cancer the surface alteration happens. A non-traditional method to identify malignant cervical epithelial cells in vitro, which is based on physical (in contrast to specific biochemical) labelling of cells with fluorescent silica micron-size beads, is used here to examine cells at progressive stages leading to cervical cancer which include normal epithelial cells, cells infected with human papillomavirus type-16 (HPV-16), cells immortalized by HPV-16, and carcinoma cells. The study shows a statistically significant (at p <0.01) difference between both immortal and cancer cells and a group consisting of normal and infected. There is no significant difference between normal and infected cells. Immortal cells demonstrate the signal which is closer to cancer cells than to either normal or infected cells. This implies that the cell surface, surface cellular brush changes substantially when cells become immortal. Physical labeling of the cell surface represents a substantial departure from the traditional biochemical labeling methods. The results presented show the potential significance of physical properties of the cell surface for development of clinical methods for early detection of cervical cancer, even at the stage of immortalized, pre-malignant cells.
Iyer, K. Swaminathan; Gaikwad, R. M.; Woodworth, C. D.; Volkov, D. O.
We utilized three cervical cancer cell lines (HeLa, HT-3, and C33A) and clonogenic assays to determine whether cyclooxygenase (COX) expression is related to radiosensitivity. Using COX DNA transfection and COX inhibition by siRNA, we also examined changes in radiosensitivity caused by variations in COX expression. The survival fractions of HeLa and HT-3 cell lines, which both with COX-1 and COX-2
Yong-Tark Jeon; Yoo-Cheol Song; Su-Hyeong Kim; Hong-Gyun Wu; Il-Han Kim; In-Ae Park; Jae Weon Kim; Noh-Hyun Park; Soon-Beom Kang; Hyo-Pyo Lee; Yong-Sang Song
Cervical cancer is a disease in which cancer develops in the tissues of the cervix. The Cancer Genome Atlas is studying the two main types of cervical cancer. Squamous cell carcinoma develops in the thin, flat, squamous cells that line the vagina. Adenocarcinoma arises in the glandular cells in the vagina that secrete mucus. Risk factors for cervical cancer include smoking and human papillomavirus (HPV) infection. In the future, the HPV vaccine will lower the infection rate.
The present study further investigated the mode of action of methyl jasmonate (MJ) in different cervical cancer cell lines. We show that in addition to the short term cytotoxicity, MJ effectively reduced the survival of cervical cancer cells (clonogenicity assays). MJ induced apoptosis in all cervical cancer cells. In some cell lines, MJ caused elevation of the mitochondrial superoxide anion, notably, in HeLa and CaSki. Changes in the expression of p53 and bax were variable, yet, downregulation of survivin was common to all cervical cancer cells. MJ significantly reduced the levels of the human papillomavirus (HPV) E6 and E7 proteins without alteration of the mRNA levels. Moreover, ectopic expression of E6, E7 or both in cervical cancer cells that lack HPV (C33A), did not alter significantly their response to MJ. Our studies point to MJ as an effective anticancer agent against a variety of cervical cancer cells acting through shared and different pathways to induce cell death regardless of the presence of HPV. PMID:22198483
Milrot, Elad; Jackman, Anna; Kniazhanski, Tatiana; Gonen, Pinhas; Flescher, Eliezer; Sherman, Levana
In addition to causing regression of the Mullerian duct in the male embryo, Mullerian Inhibiting Substance (MIS) inhibits the growth of epithelial ovarian cancer cells, which are known to be of Mullerian origin. Because the uterine cervix is derived from the same Mullerian duct precursor as the epithelium of the ovary, we tested the hypothesis that cervical cancer cells might also respond to MIS. A number of cervical cancer cell lines express the MIS type II receptor, and MIS inhibits the growth of both human papilloma virus-transformed and non-human papilloma virus-transformed cervical cell lines, with a more dramatic effect seen in the latter. As in the ovarian cancer cell line OVCAR8, suppression of growth of the C33A cervical cancer cell line by MIS is associated with induction of the p16 tumor suppressor protein. However, in contrast to OVCAR8 cells, induction of p130 and p107 appears to play an important role in the inhibition of growth of C33A cells by MIS. Finally, normal cervical tissue expresses the MIS type II receptor in vivo, supporting the idea that MIS could be a targeted therapy for cervical cancer. PMID:14671316
Barbie, Thanh U; Barbie, David A; MacLaughlin, David T; Maheswaran, Shyamala; Donahoe, Patricia K
Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate, and for specific signaling pathways, notably HPV E6-targeted degradation of p53 and PDZ proteins. Natural compounds with antioxidant properties including flavonoids and triterpenoids hold promise as anticancer agents by interfering with ubiquitin-dependent protein degradation. An increasing body of evidence indicates that their ?-? unsaturated carbonyl system is the molecular determinant for inhibition of ubiquitin-mediated protein degradation up-stream of the catalytic sites of the 20S proteasome. Herein we report the identification and characterization of a new class of chalcone-based, potent and cell permeable chemical inhibitors of ubiquitin-dependent protein degradation, and a lead compound RAMB1. RAMB1 inhibits ubiquitin-dependent protein degradation without compromising the catalytic activities of the 20S proteasome, a mechanism distinct from that of Bortezomib. Treatment of cervical cancer cells with RAMB1 triggers unfolded protein responses, including aggresome formation and Hsp90 stabilization, and increases p53 steady state levels. RAMB1 treatment results in activation of lysosomal-dependent degradation pathways as a mechanism to compensate for increasing levels of poly-ubiquitin enriched toxic aggregates. Importantly, RAMB1 synergistically triggers cell death of cervical cancer cells when combined with the lysosome inhibitor Chloroquine.
Anchoori, Ravi K.; Khan, Saeed R.; Sueblinvong, Thanasak; Felthauser, Alicia; Iizuka, Yoshie; Gavioli, Riccardo; Destro, Federica; Isaksson Vogel, Rachel; Peng, Shiwen; Roden, Richard B. S.; Bazzaro, Martina
The incidence of cervical adenocarcinoma (CA) is rising, whereas the incidence of cervical squamous cell carcinoma (CSCC) continues to decrease. However, it is still unclear whether different molecular characteristics underlie these 2 types of cervical carcinoma. To better understand the epigenetic characteristics of cervical carcinoma, we investigated the DNA promoter hypermethylation profiles in CA and CSCC. In addition, we investigated whether DNA hypermethylation patterns might be used for the molecular diagnosis of CA and endometrial adenocarcinoma (EA). Using the bisulfite-modification technique and methylation-specific PCR, we examined the aberrant promoter hypermethylation patterns of 9 tumor suppressor genes (APC, DAPK, CDH1, HLTF, hMLH1, p16, RASSF1A, THBS1 and TIMP3) in 62 CSCCs, 30 CAs and 21 EAs. After Bonferroni correction adjustment (statistically significant at p < 0.0055), we found that the aberrant hypermethylations of CDH1 and DAPK were more frequent in CSCCs than in CAs (80.6% vs. 43.3%, p = 0.001; 77.4% vs. 46.7%, p = 0.005), whereas HLTF and TIMP3 were more frequently methylated in CAs (3.2% vs. 43.3%, p < 0.001; 8.1% vs. 53.3%, p = 0.001). The hypermethylations of RASSF1A and APC were more frequent in CAs than in CSCCs, but this was not significant (9.7% vs. 33.3%, p = 0.008; and 14.5% vs. 40.0%, respectively, p = 0.009). In addition, RASSF1A hypermethylation was significantly more frequent in EAs than in CAs (81.0% vs. 33.3%, p = 0.001). In conclusion, the existence of these unique methylation patterns in these cancers suggests that their tumorigenesis may involve different epigenetic mechanisms. PMID:16331610
Kang, Sokbom; Kim, Jae Weon; Kang, Gyeong Hoon; Lee, Sun; Park, Noh Hyun; Song, Yong Sang; Park, Sang Yoon; Kang, Soon Beom; Lee, Hyo Pyo
Atypical Endocervical Glandular Cell of Undetermined Significance; Atypical Endometrial Hyperplasia; Atypical Glandular Cell of Undetermined Significance; Cervical Cancer; Cervical Intraepithelial Neoplasia Grade 2; Cervical Intraepithelial Neoplasia Grade 3; Human Papilloma Virus Infection
Background:Cervical cancer (CC) annually kills 288 000 women worldwide. Unfortunately, responses to chemoradiation are partial and are of short duration. As anti-EGFR monoclonal antibodies sensitise tumours, we investigated cetuximab's toxicity plus chemoradiation on CC cells, which express different EGFR levels.Methods:EGFR, HER2, AKT and MAPK expression and phosphorylation status were determined by western blotting. Cytotoxicity was assessed by MTT or clonogenic
D D Meira; V H de Almeida; J S Mororó; I Nóbrega; L Bardella; R L A Silva; R M Albano; C G Ferreira
Visualization of cells and subcellular organelles are currently carried out using available microscopy methods such as cryoelectron microscopy, and fluorescence microscopy. These methods require external labeling using fluorescent dyes and extensive sample preparations to access the subcellular structures. However, Raman micro-spectroscopy provides a non-invasive, label-free method for imaging the cells with chemical specificity at sub-micrometer spatial resolutions. The scope of this paper is to image the biochemical/molecular distributions in cells associated with cancerous changes. Raman map data sets were acquired from the human cervical carcinoma cell lines (HeLa) after fixation under 785 nm excitation wavelength. The individual spectrum was recorded by raster-scanning the laser beam over the sample with 1?m step size and 10s exposure time. Images revealing nucleic acids, lipids and proteins (phenylalanine, amide I) were reconstructed using univariate methods. In near future, the small pixel to pixel variations will also be imaged using different multivariate methods (PCA, clustering (HCA, K-means, FCM)) to determine the main cellular constitutions. The hyper-spectral image of cell was reconstructed utilizing the spectral contrast at different pixels of the cell (due to the variation in the biochemical distribution) without using fluorescent dyes. Normal cervical squamous cells will also be imaged in order to differentiate normal and cancer cells of cervix using the biochemical changes in different grades of cancer. Based on the information obtained from the pseudo-color maps, constructed from the hyper-spectral cubes, the primary cellular constituents of normal and cervical cancer cells were identified.
Duraipandian, Shiyamala; Zheng, Wei; Huang, Zhiwei
Recent evidence has suggested that AMPK activators may be applied as therapeutic drugs in suppressing cancer cell growth. However, the molecular mechanism of their suppressive function in cancer cells is still unclear. Here we show that AMPK activators impair cervical cancer cell growth through the reduction of DVL3, a positive regulator in Wnt/?-catenin signaling and an oncogenic player in cervical cancer tumorigenesis. By western blot and immunohistochemical analyses, we demonstrated that DVL3 was frequently upregulated and significantly associated with elevated ?-catenin (P?=?0.009) and CyclinD1 (P?=?0.009) expressions in cervical cancer. Enforced expression of DVL3 elevated ?-catenin and augmented cervical cancer cell growth, verifying that DVL3-mediated Wnt/?-catenin activation is involved in cervical cancer oncogenesis. On the other aspect, we noted that the cervical cancer cell growth was remarkably suppressed by AMPK activators and such cell growth inhibition was in concomitant with the reduction of DVL3 protein level in dose- and time-dependent manners. Besides, impaired mTOR signaling activity also reduced DVL3 expression. In contrast, co-treatment with Compound C (AMPK inhibitor) could significantly abrogate metformin induced DVL3 reduction. In addition, co-treatment with AM114 or MG132 (proteosomal inhibitors) could partially restore DVL3 expression under the treatment of metformin. Further in vivo ubiquitination assay revealed that metformin could reduce DVL3 by ubiquitin/proteasomal degradation. To our knowledge, this is the first report showing the probable molecular mechanisms of that the AMPK activators suppress cervical cancer cell growth by impairing DVL3 protein synthesis via AMPK/mTOR signaling and/or partially promoting the proteasomal degradation of DVL3.
Kwan, H. T.; Chan, David W.; Cai, Patty C. H.; Mak, Celia S. L.; Yung, Mingo M. H.; Leung, Thomas H. Y.; Wong, Oscar G. W.; Cheung, Annie N. Y.; Ngan, Hextan Y. S.
PurposeHuman papillomavirus (HPV) type 16 and 18 are the most prevalent genotypes in cervical cancer. The viral oncoproteins E6 and E7 are considered to be tumor-specific targets for immunotherapy. HPV E7 antigen-loaded autologous dendritic cells (DC) were evaluated as cellular tumor vaccine in a case series of cervical cancer patients.MethodsAutologous monocyte-derived DCs were pulsed with recombinant HPV16 E7 or HPV18
Alfonso Ferrara; Marion Nonn; Peter Sehr; Carola Schreckenberger; Michael Pawlita; Matthias Dürst; Achim Schneider; Andreas M. Kaufmann
Purpose. We investigated the time-course expression patterns of p53 and E6 on cervical cancer cells to obtain a molecular level understanding of cell-dependent tumor growth suppression effects of recombinant adenovirus expressing p53 in vitro and in vivo.Methods. Four human papillomavirus (HPV)-infected human cervical cancer cell lines (HPV 16-positive cells, CaSki and SiHa cells; and HPV 18-positive cells, HeLa and HeLaS3
Woong Shick Ahn; Su Mi Bae; Keun Ho Lee; Joon Mo Lee; Sung Eun Namkoong; Heung Jae Chun; Chong Kook Kim; Yong-Wan Kim
Background Down regulation of genes coding for nucleoside transporters and drug metabolism responsible for uptake and metabolic activation of the nucleoside gemcitabine is related with acquired tumor resistance against this agent. Hydralazine has been shown to reverse doxorubicin resistance in a model of breast cancer. Here we wanted to investigate whether epigenetic mechanisms are responsible for acquiring resistance to gemcitabine and if hydralazine could restore gemcitabine sensitivity in cervical cancer cells. Methodology/Principal Findings The cervical cancer cell line CaLo cell line was cultured in the presence of increasing concentrations of gemcitabine. Down-regulation of hENT1 & dCK genes was observed in the resistant cells (CaLoGR) which was not associated with promoter methylation. Treatment with hydralazine reversed gemcitabine resistance and led to hENT1 and dCK gene reactivation in a DNA promoter methylation-independent manner. No changes in HDAC total activity nor in H3 and H4 acetylation at these promoters were observed. ChIP analysis showed H3K9m2 at hENT1 and dCK gene promoters which correlated with hyper-expression of G9A histone methyltransferase at RNA and protein level in the resistant cells. Hydralazine inhibited G9A methyltransferase activity in vitro and depletion of the G9A gene by iRNA restored gemcitabine sensitivity. Conclusions/Significance Our results demonstrate that acquired gemcitabine resistance is associated with DNA promoter methylation-independent hENT1 and dCK gene down-regulation and hyper-expression of G9A methyltransferase. Hydralazine reverts gemcitabine resistance in cervical cancer cells via inhibition of G9A histone methyltransferase.
Candelaria, Myrna; de la Cruz-Hernandez, Erick; Taja-Chayeb, Lucia; Perez-Cardenas, Enrique; Trejo-Becerril, Catalina; Gonzalez-Fierro, Aurora; Chavez-Blanco, Alma; Soto-Reyes, Ernesto; Dominguez, Guadalupe; Trujillo, Jaenai E.; Diaz-Chavez, Jose; Duenas-Gonzalez, Alfonso
In addition to causing regression of the Mullerian duct in the male embryo, Mullerian Inhibiting Substance (MIS) inhibits the growth of epithelial ovarian cancer cells, which are known to be of Mullerian origin. Because the uterine cervix is derived from the same Mullerian duct precursor as the epithelium of the ovary, we tested the hypothesis that cervical cancer cells might
Thanh U. Barbie; David A. Barbie; David T. Maclaughlin; Shyamala Maheswaran; Patricia K. Donahoe
ObjectiveTo reveal areas of research\\/knowledge related to social inequities and cervical cancer. Methods: A Medline search was performed looking for US based research on cervical cancer and social inequities since 1990. The papers found were organized into cells defined by a cancer disparities grid. Results: The majority of research published about cervical cancer and social inequities in the US, lies
Sara J. Newmann; Elizabeth O. Garner
Cervical cancer is the second most common cause of cancer in women and has a high mortality rate. Cisplatin, an antitumor agent, is generally used for its treatment. However, the administration of cisplatin is associated with side effects and intrinsic resistance. Morinda citrifolia (Noni), a natural plant product, has been shown to have anti-cancer properties. In this study, we used Noni, cisplatin, and the two in combination to study their cytotoxic and apoptosis-inducing effects in cervical cancer HeLa and SiHa cell lines. We demonstrate here, that Noni/Cisplatin by themselves and their combination were able to induce apoptosis in both these cell lines. Cisplatin showed slightly higher cell killing as compared to Noni and their combination showed additive effects. The observed apoptosis appeared to be mediated particularly through the up-regulation of p53 and pro-apoptotic Bax proteins, as well as down- regulation of the anti-apoptotic Bcl-2, Bcl-XL proteins and survivin. Augmentation in the activity of caspase-9 and -3 was also observed, suggesting the involvement of the intrinsic mitochondrial pathway of apoptosis for both Noni and Cisplatin in HeLa and SiHa cell lines. PMID:23534730
Gupta, Rakesh Kumar; Banerjee, Ayan; Pathak, Suajta; Sharma, Chandresh; Singh, Neeta
Background: Cervical cancer, the second most common cancer in women, has a high mortality rate. Cisplatin, an antitumor agent, is generally used for its treatment. However, the administration of cisplatin is associated with side effects and intrinsic resistance. Morinda citrifolia (Noni), a natural plant product, has been shown to have antioxidant activities in vitro and in vivo. Materials and Methods: Both HeLa and SiHa cervical cancer cell lines were treated with 10% Noni, 10 mg/dl cisplatin, or a combination of both 10% Noni and 10 mg/dl cisplatin for 24 hours. Post culturing, the cells were pelleted and stored at -70oC for malondialdehyde and catalase assays. Results: On treatment with Noni, CP, and their combination, the level of MDA decreased by 0.76 fold, 0.49 fold, and 0.68 fold respectively in HeLa cells; and by 0.93 fold, 0.67 fold, and 0.79 fold respectively in SiHa cells, as compared to their controls; whereas catalase activity increased by 1.61 fold, 0.54 fold, and 2.35 fold, respectively in HeLa cells; and by 0.98 fold, 0.39 fold, and 1.85 fold respectively in SiHa cells. Conclusions: A decrease in level of lipid peroxidation and an increase in catalase activity were observed with Noni by itself and the effect ameliorated changes observed with cisplatin when given in combination. PMID:24083710
Gupta, Rakesh Kumar; Singh, Neeta
Müllerian inhibiting substance (MIS), also known as anti-Müllerian hormone (AMH), is a member of the transforming growth factor-? (TGF-?) superfamily that plays an important role in the mesenchymal-epithelial interaction, cell growth and proliferation, extracellular matrix production and tissue remodeling. Previously, we demonstrated that MIS suppressed ovarian cancer cell growth and suggested large-scale genetic elements that could be responsible for anti-neoplastic effects of MIS on ovarian cancer cells. In this study, we demonstrated the expression of MIS type II receptor (MISRII) in the human papillomavirus (HPV)-16-related cervical cancer cell lines CaSki and SiHa, and a non-HPV-related cervical cancer cell line, C33A. We also showed that MIS inhibited growth of cervical cancer cells, and induced cellular apoptosis of C33A. In addition, we identified a characteristic molecular signature of MIS in CaSki cells by using whole genome expression analysis. Of the 1,690 genes that showed significant expression changes by MIS, 21 genes were related to cell cycle; 13 genes to apoptosis; and 52 genes to the cancer pathway. On performing a search for cell cycle pathways in the KEGG pathway database, several gene expressions at the G1/S checkpoint were found. In particular, the expression of p16 and p107 increased and that of E2F2 and E2F3 decreased at an early stage, whereas the expression of E2F4 and E2F5 decreased at a later stage after MIS treatment. These data suggest that MIS produces activity against HPV16-related cervical cancers in vitro, and MIS may also be an effective targeted therapy for HPV16-related cervical cancer. Genetic data obtained here could be useful in determining the treatment strategy of MISR-expressing cervical tumors in the future. PMID:21573503
Hwang, Seong Jin; Suh, Min Jung; Yoon, Joo Hee; Kim, Mee Ran; Ryu, Ki Sung; Nam, Suk Woo; Donahoe, Patricia K; Maclaughlin, David T; Kim, Jang Heub
We utilized three cervical cancer cell lines (HeLa, HT-3, and C33A) and clonogenic assays to determine whether cyclooxygenase (COX) expression is related to radiosensitivity. Using COX DNA transfection and COX inhibition by siRNA, we also examined changes in radiosensitivity caused by variations in COX expression. The survival fractions of HeLa and HT-3 cell lines, which both with COX-1 and COX-2 activity, were found to be significantly higher than that of the C33A cell line which had neither COX-1 nor COX-2 activity. Moreover, the acquisition of COX-1 in C33A cell line significantly reduced its radiosensitivity, but COX-2 transfection increased radiosensitivity in this cell line. In addition, the inhibition of COX-1 activity in HT-3 cell line using siRNA resulted in an increased radiosensitivity, but this phenomenon was not observed for COX-2 inhibition. The same experiment in HeLa cells using siRNA also showed no significant change in radiosensitivity. The results obtained during this study suggest that COX expression is associated with the radiosensitivity in uterine cervical cancer cell lines and COX-1 might have more important role than COX-2. PMID:17601662
Jeon, Yong-Tark; Song, Yoo-Cheol; Kim, Su-Hyeong; Wu, Hong-Gyun; Kim, Il-Han; Park, In-Ae; Kim, Jae Weon; Park, Noh-Hyun; Kang, Soon-Beom; Lee, Hyo-Pyo; Song, Yong-Sang
The anticarcinogenic actions of epigallocatechin-3-gallate (EGCG), one of the main ingredients of green tea, against various cancer types including cervical cancer are well documented. Studies pertaining to the exact molecular mechanism by which EGCG induces cancer cell growth inhibition needs to be investigated extensively. In the present study, we observed a stupendous dose dependent reduction in the protein expression of Fused Toes Homolog (FTS) after treatment with EGCG at 1, 10, 25 and 50 ?M. Further, we were interested in finding out whether the decrease in the protein expression of FTS was due to decreased mRNA synthesis. Real time reverse transcriptase polymerase chain reaction results revealed a similar dose dependent reduction in the FTS mRNA after EGCG treatment. Chromatin immunoprecipitation analysis revealed the interaction between p53 and the promoter region of FTS. A dose dependent increase in this interaction was evidenced at 25 and 50 ?M EGCG treatment. p53 silencing increased the expression of FTS and also decreased the reduction in the levels of FTS expression after EGCG treatment. The decrease in the levels of FTS was more significant at 25 and 50 ?M and is associated with reduced physical interaction of FTS with Akt, phosphorylation of Akt and survival of HeLa cells. Collectively, these results conclude that EGCG induced anti-proliferative action in the cervical cancer cell involves reduced mRNA expression of FTS through p53. PMID:24065519
Muthusami, Sridhar; Prabakaran, D S; An, Zhengzhe; Yu, Jae-Ran; Park, Woo-Yoon
Background Trichostatin A (TSA), a potent inhibitor of histone deacetylases exhibits strong anti-tumor and growth inhibitory activities, but its mechanism(s) of action is not completely understood. Osteopontin (OPN) is a secreted glycoprotein which has long been associated with tumor metastasis. Elevated OPN expression in various metastatic cancer cells and the surrounding stromal cells often correlates with enhanced tumor formation and metastasis. To investigate the effects of TSA on OPN transcription, we analyzed a proximal segment of OPN promoter in cervical carcinoma cells. Results In this paper, we for the first time report that TSA suppresses PMA-induced OPN gene expression in human cervical carcinoma cells and previously unidentified AP-1 transcription factor is involved in this event. Deletion and mutagenesis analyses of OPN promoter led to the characterization of a proximal sequence (-127 to -70) that contain AP-1 binding site. This was further confirmed by gel shift and chromatin immunoprecipitation (ChIP) assays. Western blot and reverse transcription-PCR analyses revealed that TSA suppresses c-jun recruitment to the OPN promoter by inhibiting c-jun levels while c-fos expression was unaffected. Silencing HDAC1 followed by stimulation with PMA resulted in significant decrease in OPN promoter activity suggesting that HDAC1 but not HDAC3 or HDAC4 was required for AP-1-mediated OPN transcription. TSA reduces the PMA-induced hyperacetylation of histones H3 and H4 and recruitment of RNA pol II and TFIIB, components of preinitiation complex to the OPN promoter. The PMA-induced expression of other AP-1 regulated genes like cyclin D1 and uPA was also altered by TSA. Interestingly, PMA promoted cervical tumor growth in mice xenograft model was significantly suppressed by TSA. Conclusions In conclusion, these findings provide new insights into mechanisms underlying anticancer activity of TSA and blocking OPN expression at transcriptional level by TSA may act as novel therapeutic strategy for the management of cervical cancer.
Pelvic lymph node metastases are regarded as the most important risk factor and a predictor of poor prognosis for patients with cervical cancer. Exploration of metastasis-related molecules is helpful toward improving the prognosis in cervical cancer. To identify the role of miR-375 in metastasis and progression of cervical cancer, we examined the expression of miR-375 in 170 cervical cancer tissues and 68 normal cervical tissues, using stem-loop quantitative PCR, and found that the expression of miR-375 in cervical cancer tissues was significantly decreased by 4.45-fold, compared with 68 normal tissues. A significant correlation existed between miR-375 expression and clinicopathologic parameters, including lymph node metastasis of cervical cancer. Overexpressed miR-375 suppressed cell proliferation, blocked G1-to-S cell-cycle transition, and inhibited cell migration and invasion in human cervical SiHa and CaSki cells. SP1, a potential target gene of miR-375, was inversely correlated with miR-375 expression in cervical cancer tissues. Moreover, SP1 was negatively regulated by miR-375, and knockdown of SP1 by siRNA inhibited cell malignant behaviors. Thus, our findings suggest that down-regulated miR-375 promotes cell malignant behaviors via the target gene SP1 and may consequently contribute to the progression of cervical cancer. PMID:21945323
Wang, Fenfen; Li, Yang; Zhou, Jiansong; Xu, Junfen; Peng, Chanjuan; Ye, Feng; Shen, Yuanming; Lu, Weiguo; Wan, Xiaoyun; Xie, Xing
\\u000a Cervical cancer became a preventable disease with the introduction of the Papanicolaou smear (Pap smear) in the 1940s. Trend\\u000a data show that incidence rates have decreased steadily over the past several decades in both white and African American women\\u000a living in the United States (American Cancer Society 2007). Mortality rates have declined steadily over the past several decades\\u000a as well
Marcela del Carmen; Teresa Diaz-Montez
Radiotherapy is the primary line of cancer treatment for cervical cancer and is known to induce cell death in tumors. Radiotherapy is however limited by the total dose that can be given without damaging normal tissue. Plumbagin, a naturally occurring naphthaquinone, has been reported to have free radical producing properties. Hence we hypothesized that plumbagin could also have properties that could modify effects of radiation on cervical cancer cells. Radiation in combination with plumbagin may thus have treatment augmenting effects. Results from our studies have shown that a lower dose of radiation in combination with plumbagin could induce apoptosis more effectively compared to a higher dose of radiation alone. Plumbagin in combination with 2 Gy of radiation was very effective in inducing apoptosis, when compared to a higher radiation dose of 10 Gy alone. This combination also showed a fivefold increase in the activation of caspase 3 in C33A cells. Activation of effector caspases confirms that the induction of apoptosis by irradiation and plumbagin involves caspase-dependent pathways. Expression of apoptotic regulatory molecules Bcl-2, Bax and Survivin was also modulated by plumbagin in combination with radiation. In summary, this study shows that a combination of plumbagin and radiation augmented cell growth inhibition compared to higher radiation dose alone, thus indicating that plumbagin may be a potential radiosensitizer acting through the induction of apoptosis. PMID:17562542
Nair, Sreekala; Nair, Raghu Ram K; Srinivas, Priya; Srinivas, Gopal; Pillai, M Radhakrishna
The STK11/LKB1 gene encodes a ubiquitously expressed serine/threonine kinase that is mutated in multiple sporadic cancers including non-small cell lung carcinomas, pancreatic cancers, and melanomas. LKB1 affects multiple cellular functions including cell growth, cell cycle progression, metabolism, cell polarity and migration. To date, only a limited number of studies have assessed the status of LKB1 in cervical cancers. Herein, we investigate DNA methylation, DNA mutation, and transcription at the LKB1 locus in cervical cancer cell lines. We identified homozygous deletions of 25–85kb in the HeLa and SiHa cell lines. Deletion breakpoint analysis in HeLa cells revealed that the deletion resulted from an Alu-recombination mediated deletion (ARMD) and generated a novel LKB1 fusion transcript driven by an uncharacterized CpG island promoter located ~11kb upstream of LKB1. Although the homozygous deletion in SiHa cells removes the entire LKB1 gene and portions of the neighboring genes SBNO2 and c19orf26, this deletion also generates a fusion transcript driven by the c19orf26 promoter and comprised of both c19orf26 and SBNO2 sequences. Further analyses of public gene expression and mutation databases suggest that LKB1 and its neighboring genes are frequently dysregulated in primary cervical cancers. Thus, homozygous deletions affecting LKB1 in cervical cancers may generate multiple fusion transcripts involving LKB1, SBNO2, and c19orf26.
McCabe, Michael T.; Powell, Doris R.; Zhou, Wei; Vertino, Paula M.
MicroRNA (miR)-92 is overexpressed in a number of tumors and has been proven to negatively regulate a number of tumor suppressor genes, including phosphatase and tensin homologue (PTEN). However, its function and molecular mechanism(s) of action in squamous cervical carcinoma (SCCs) have not been well described. Furthermore, the correlation between miR-92 and human papillomavirus (HPV)-16 E6 has not been studied. In the present study, miR-92 expression levels were quantified using quantitative PCR (qPCR) in cervical cancer tissues, normal cervical tissues and cervical cancer cell lines. SiHa cells were transfected with either miR-92-mimics, anti-miR-92 or negative controls. C33A cells were stably transfected with pEGFP-N1-16E6 and pEGFP-N1-neo plasmids. The levels of PTEN protein expression in the transfected SiHa and C33A cells were evaluated using western blot analysis. The effects of miR-92 were detected using cell counting kit (CCK)-8 and Transwell assays. HPV16 E6 siRNA was used to detect the effectiveness of the E6 protein on miR-92 in the SiHa and C33A cells. miR-92 was highly-expressed in the human cervical cancer tissues compared with the normal tissues. In the HPV16-positive cervical cancer tissues, the expression of miR-92 was higher compared with the HPV16-negative cervical cancer tissues. HPV16 E6 upregulated miR-92 expression in the SiHa- and C33A-pEGFP-N1-16E6 cells. The upregulation of miR-92 promoted cell growth and invasion in the SiHa cells. PTEN protein expression was decreased in the SiHa cells that were transfected with the miR-92 mimic. The data indicated that miR-92 may increase the migration and invasion of SiHa cells, partially through the downregulation of PTEN protein expression. HPV16 E6 was identified to upregulate miR-92 expression.
YU, YU; ZHANG, YAO; ZHANG, SHULAN
Patients with advanced cervical cancer have deficient natural killer (NK) cell activity, usually as a consequence of tumor invasion, which results in tumor NK cell sequestration. The reason for the occurrence of such alterations in patients under chemotherapy is unknown. We evaluated the activity and number of NK cells and T cell subpopulations in ten patients before and three weeks after neoadjuvant chemotherapy (CT). The schedule used was cis-platinum (100 mg/m2 per cycle) and bleomycin (15 mg/cycle), repeated every 28 days. Although there were similar levels of NK cells before and after CT in both groups, we observed greater cytotoxicity of peripheral blood lymphocytes and increased levels of CD4+ and CD8+ T cells (P < 0.01) in five patients who presented a good clinical response when compared to the group with a poor response. IL-12, known to increase NK cell activity when added to peripheral blood lymphocyte cultures, markedly increased lytic activity before and after CT only in the group with a good clinical response. These results suggest that NK cells from the poorly responding patient group express less lytic activity per NK cell and are insensitive to IL-12 stimulation, probably as a result of reduced IL-12 receptor expression or a defective intracellular transduction mechanism. The present findings may be useful as a prognostic factor in clinical practice and also provide support for human clinical trials of IL-12 and neoadjuvant CT for the treatment of malignant cervical tumors. PMID:8736110
Marana, H R; Andrade, J M; Silva, J S
Genistein, a naturally occurring isoflavonoid abundant in soy products, has anticancer activity in multiple tumor cells. In this study, we evaluated the apoptotic effect of genistein on cervical cancer cells and its mechanism of apoptosis. Genistein inhibited the proliferation of cervical cancer cells (HeLa, CaSki, and C33A). HeLa cells were the most sensitive to genistein, whereas CaSki and C33A cells were less sensitive. Sub-G(1) analysis showed that genistein increased apoptotic cells up to 45% at a concentration of 60 micromol/L in HeLa cells, whereas it produced 21% and 17% apoptotic cells in CaSki and C33A cells, respectively, at the same concentration. To determine the apoptotic pathway induced by genistein in the cervical cancer cells, we assessed activation of caspase-3, -8, and -9 by immunoblotting. Procaspase-3, -8, and -9 were decreased and PARP cleavage increased in a time-dependent manner after the treatment of genistein in HeLa cells. Also, inhibition of caspase-3, -8, and -9 with pharmacological inhibitors reduced genistein-mediated apoptosis. Interestingly, inhibition of caspase-8 resulted in remarkable reduction of genistein-induced apoptosis. Bax expression was increased and total bid decreased, whereas bcl-2 level was not changed by genistein. Taken together, these results suggest that genistein could induce apoptosis through both extrinsic and intrinsic pathways in human cervical cancer cells. PMID:19723056
Kim, Su-Hyeon; Kim, Su-Hyeong; Lee, Sang-Chul; Song, Yong-Sang
Cervical cancer is the most common cancer in Indian females and is associated with infection with high-risk Human papilloma\\u000a viruses (HPVs) which encode viral oncoprotein E6 and E7. Estradiol has been established as a risk factor for cervical cancer\\u000a and has been shown to play a synergistic role with viral oncoproteins. Curcumin (Diferuloyl methane), a chemopreventive agent,\\u000a is a natural
Mayank SinghNeeta Singh; Neeta Singh
Physical changes of the cell surface of cells during transformation from normal to cancerous state are rather poorly studied. Here we describe our recent studies of such changes done on human cervical epithelial cells during their transformation from normal through infected with human papillomavirus type-16 (HPV-16), immortalized (precancerous), to cancerous cells. The changes were studied with the help of atomic force microscopy (AFM) and through the measurement of physical adhesion of fluorescent silica beads to the cell surface. Based on the adhesion experiments, we clearly see the difference in nonspecific adhesion which occurs at the stage of immortalization of cells, precancerous cells. The analysis done with the help of AFM shows that the difference observed comes presumably from the alteration of the cellular ``brush,'' a layer that surrounds cells and which consists of mostly microvilli, microridges, and glycocalyx. Further AFM analysis reveals the emergence of fractal scaling behavior on the surface of cells when normal cells turn into cancerous. The possible causes and potential significance of these observations will be discussed.
Sokolov, Igor; Dokukin, Maxim; Guz, Nataliia; Woodworth, Craig
Here we show that the surface of human cervical epithelial cells demonstrates substantially different fractal behavior when the cell becomes cancerous. Analyzing the adhesion maps of individual cervical cells, which were obtained using the atomic force microscopy operating in the HarmoniX mode, we found that cancerous cells demonstrate simple fractal behavior, whereas normal cells can only be approximated at best as multifractal. Tested on ˜300 cells collected from 12 humans, the fractal dimensionality of cancerous cells is found to be unambiguously higher than that for normal cells.
Dokukin, M. E.; Guz, N. V.; Gaikwad, R. M.; Woodworth, C. D.; Sokolov, I.
Current therapies for treatment of advanced cervical cancer involve the use of cisplatin, often in combination with radiotherapy. These treatments do not lead to a high survival rate and furthermore, serious side effects are dose-limiting factors. Methyl jasmonate (MJ) was recently identified as potent and selective cytotoxic agent towards cervical cancer cells. In the present study we evaluated the effectiveness of combined treatments of MJ with cisplatin or X-irradiation on a variety of cervical cancer cells including SiHa, CaSki, HeLa and C33A. Cytotoxicity of alpha particles, emitted from (224)Ra atoms, was also evaluated as a single agent and in combination with MJ. Cooperation between MJ and cisplatin in reducing cell viability (XTT assays) and survival (clonogenicity assays) was exhibited towards several cancer cell lines at a range of combination doses. MJ effectively cooperated also with X-ray irradiation, significantly lowering the radiation doses required to inhibit cell survival (ID50) of all tested cells lines. We show for the first time, that alpha irradiation selectively reduced cell viability and survival of cervical cancer cells. Lower doses of ? irradiation were required as compared to X-irradiation to inhibit cell survival. Cooperation with MJ was demonstrated in part of the cancer cell lines. In conclusion, our studies point to ? irradiation and MJ, novel anticancer agents, as potent candidates for treatment of cervical cancer, in single agent regiments and in combination. MJ can be added also to conventional X-ray and cisplatin therapies to increase their cytotoxic effect while lowering the effective dose. PMID:22956285
Milrot, Elad; Jackman, Anna; Flescher, Eliezer; Gonen, Pinhas; Kelson, Itzhak; Keisari, Yona; Sherman, Levana
Although human papillomavirus was identified as an aetiological factor in cervical cancer, the key human gene drivers of this disease remain unknown. Here we apply an unbiased approach integrating gene expression and chromosomal aberration data. In an independent group of patients, we reconstruct and validate a gene regulatory meta-network, and identify cell cycle and antiviral genes that constitute two major subnetworks upregulated in tumour samples. These genes are located within the same regions as chromosomal amplifications, most frequently on 3q. We propose a model in which selected chromosomal gains drive activation of antiviral genes contributing to episomal virus elimination, which synergizes with cell cycle dysregulation. These findings may help to explain the paradox of episomal human papillomavirus decline in women with invasive cancer who were previously unable to clear the virus. PMID:23651994
Mine, Karina L; Shulzhenko, Natalia; Yambartsev, Anatoly; Rochman, Mark; Sanson, Gerdine F O; Lando, Malin; Varma, Sudhir; Skinner, Jeff; Volfovsky, Natalia; Deng, Tao; Brenna, Sylvia M F; Carvalho, Carmen R N; Ribalta, Julisa C L; Bustin, Michael; Matzinger, Polly; Silva, Ismael D C G; Lyng, Heidi; Gerbase-DeLima, Maria; Morgun, Andrey
Overexpression of human papillomavirus (HPV E6 and HPV E7) oncogenes in human cervical cells results in the development of cancer, and E6 and E7 proteins are therefore targets for preventing cervical cancer progres- sion. Here, we describe the silencing of E6 and E7 expression in cervical carcinoma cells by RNA interfer- ence. In order to increase the efficacy of the
Latifa Bousarghin; Antoine Touze; Guillaume Gaud; Sophie Iochmann; Eva Alvarez; Pascale Reverdiau; Julien Gaitan; Marie-Lise Jourdan; Pierre-Yves Sizaret; Pierre L. Coursaget
The establishment of new tumor marker combinations including strong lead-time effects in detecting recurrent cervical cancer appears to be warranted. This retrospective study includes 50 patients with recurrent squamous cell cervical cancer after operation or radiotherapy. The serial serum levels of the tumor markers tissue polypeptide specific antigen (TPS) and squamous cell carcinoma antigen (SCC) were determined. Cutoff values of 78.5 U/L for TPS and 1.5 microg/L for SCC were selected according to the 95th percentile of serum concentrations measured in healthy control patients. Comparing with other monitoring modalities, SCC and TPS showed lead-time effective in 27 and 30 cases, respectively. This difference was not statistically significant. The combination of SCC and TPS provided lead-time effects in 42 cases. Our data indicate that combination of TPS and SCC is a valuable tool in the early predicting recurrent cervical cancer. PMID:12584591
Hung, Y C; Shiau, Y C; Chang, W C; Kao, C H; Lin, C C
Cancer cells often develop drug resistance. In cisplatin-resistant HeLa cisR cells, fibroblast growth factor 13 (FGF13/FHF2) gene and protein expression was strongly upregulated, and intracellular platinum concentrations were kept low. When the FGF13 expression was suppressed, both the cells' resistance to platinum drugs and their ability to keep intracellular platinum low were abolished. Overexpression of FGF13 in parent cells led to greater resistance to cisplatin and reductions in the intracellular platinum concentration. These cisplatin-resistant cells also showed increased resistance to copper. In preoperative cervical cancer biopsy samples from poor prognoses patients after cisplatin chemoradiotherapy, FGF13-positive cells were detected more abundantly than in the biopsy samples from patients with good prognoses. These results suggest that FGF13 plays a pivotal role in mediating resistance to platinum drugs, possibly via a mechanism shared by platinum and copper. Our results point to FGF13 as a novel target and useful prognostic guide for cancer therapy. PMID:24113164
Okada, Tomoko; Murata, Kazuhiro; Hirose, Ryoma; Matsuda, Chie; Komatsu, Tsunehiko; Ikekita, Masahiko; Nakawatari, Miyako; Nakayama, Fumiaki; Wakatsuki, Masaru; Ohno, Tatsuya; Kato, Shingo; Imai, Takashi; Imamura, Toru
Cancer cells often develop drug resistance. In cisplatin-resistant HeLa cisR cells, fibroblast growth factor 13 (FGF13/FHF2) gene and protein expression was strongly upregulated, and intracellular platinum concentrations were kept low. When the FGF13 expression was suppressed, both the cells' resistance to platinum drugs and their ability to keep intracellular platinum low were abolished. Overexpression of FGF13 in parent cells led to greater resistance to cisplatin and reductions in the intracellular platinum concentration. These cisplatin-resistant cells also showed increased resistance to copper. In preoperative cervical cancer biopsy samples from poor prognoses patients after cisplatin chemoradiotherapy, FGF13-positive cells were detected more abundantly than in the biopsy samples from patients with good prognoses. These results suggest that FGF13 plays a pivotal role in mediating resistance to platinum drugs, possibly via a mechanism shared by platinum and copper. Our results point to FGF13 as a novel target and useful prognostic guide for cancer therapy.
Okada, Tomoko; Murata, Kazuhiro; Hirose, Ryoma; Matsuda, Chie; Komatsu, Tsunehiko; Ikekita, Masahiko; Nakawatari, Miyako; Nakayama, Fumiaki; Wakatsuki, Masaru; Ohno, Tatsuya; Kato, Shingo; Imai, Takashi; Imamura, Toru
Taurine is a nonessential amino acid and has a variety of physiological and pharmacological effects. Recently, protective effects of taurine against anticancer drugs on normal cells were investigated. But anticancer effects of taurine on cancer cells remain poorly understood. Therefore, we investigated the anticancer effects of taurine alone and combination of cisplatin with taurine in human cervical cancer cells. Single treatment of taurine decreased cell proliferation in a time- and dose-dependent manner. In co-treatment of cisplatin with taurine, cell proliferation was more decreased than single treatment of cisplatin. Reduced cell proliferation was caused by apoptosis induction. Thus, after treatment of cisplatin with taurine, apoptotic cells were investigated. Apoptotic cells were increased more than taurine or cisplatin alone. Induction of apoptosis was related to p53 expression and activation of caspase-3, caspase-6, caspase-7, and caspase-9. In present study, the results indicated that co-treatment of cisplatin with taurine was more effective than single treatment of cisplatin. PMID:23392883
Kim, Taehee; Kim, An Keun
Epithelial cell polarization and integration are essential to their function and loss of epithelial polarity and tissue architecture correlates with the development of aggressive tumors. Erbin is a basolateral membrane-associated protein. The roles of Erbin in establishing cell polarization and regulating cell adhesion have been suggested. Erbin is also a negative regulator in Ras-Raf-ERK (extracellular signal-regulated kinase) signaling pathway. However, the potential functions of Erbin in human cancer are basically unknown. In the present study, we show, for the first time, that loss of Erbin endows cervical cancer cells with resistance to anoikis both in vitro and in vivo and promotes the growth and metastasis of human cervical cancer xenografts in nude mice. We found that knockdown of Erbin induced the phosphorylation, nuclear translocation and transcriptional activities of signal transducer and activator of transcription factor 3 (STAT3) in cervical cancer cells. Overexpression of STAT3C or induction of endogenous STAT3 activation by interleukin (IL)-6 evidently inhibited anoikis of cervical cancer cells, whereas WP1066, a potent inhibitor of Janus-activated kinase 2 (Jak2)/STAT3, effectively blocked the effect of Erbin knockdown on cell survival under anchorage-independent conditions, indicating that loss of Erbin confers resistance of cervical cancer cells to anoikis in a STAT3-dependent manner. Interestingly, IL-6 induced STAT3 activation and Erbin expression simultaneously. Overexpression of STAT3C also significantly upregulated the level of Erbin, whereas the Jak2 inhibitor AG490 remarkably blocked not only STAT3 phosphorylation but also IL-6-induced Erbin expression. Knockdown of Erbin augmented the effects of IL-6 on STAT3 activation and anoikis resistance. In addition, by immunohistochemical analysis of Erbin expression, we demonstrate that the expression of Erbin is significantly decreased or even lost in cervical cancer tissues. These data reveal that Erbin is a novel negative regulator of STAT3, and the IL-6/STAT3/Erbin loop has a crucial role in cervical cancer progression and metastasis.
Hu, Y; Chen, H; Duan, C; Liu, D; Qian, L; Yang, Z; Guo, L; Song, L; Yu, M; Hu, M; Shi, M; Guo, N
The aim of this study was to systematically review the prognostic and predictive significance of cell biological markers in cervical cancer patients primarily treated with (chemo)radiation. A PubMed, Embase, and Cochrane literature search was performed. Studies describing a relation between a cell biological marker and survival in ?50 cervical cancer patients primarily treated with (chemo)radiation were selected. Study quality was assessed, and studies with a quality score of 4 or lower were excluded. Cell biological markers were clustered on biological function, and the prognostic and predictive significance of these markers was described. In total, 42 studies concerning 82 cell biological markers were included in this systematic review. In addition to cyclooxygenase-2 (COX-2) and serum squamous cell carcinoma antigen (SCC-ag) levels, markers associated with poor prognosis were involved in epidermal growth factor receptor (EGFR) signaling (EGFR and C-erbB-2) and in angiogenesis and hypoxia (carbonic anhydrase 9 and hypoxia-inducible factor-1?). Epidermal growth factor receptor and C-erbB-2 were also associated with poor response to (chemo)radiation. In conclusion, EGFR signaling is associated with poor prognosis and response to therapy in cervical cancer patients primarily treated with (chemo)radiation, whereas markers involved in angiogenesis and hypoxia, COX-2, and serum SCC-ag levels are associated with a poor prognosis. Therefore, targeting these pathways in combination with chemoradiation may improve survival in advanced-stage cervical cancer patients. PMID:21195874
Noordhuis, Maartje G; Eijsink, Jasper J H; Roossink, Frank; de Graeff, Pauline; Pras, Elisabeth; Schuuring, Ed; Wisman, G Bea A; de Bock, Geertruida H; van der Zee, Ate G J
Human papillomavirus (HPV) is the main risk factor for cervical cancer; however, some carcinomas occur in the absence of the virus. IGF-IR and an isoform of the insulin receptor, IR-A, play important roles in cancer. In this study we assessed the role of the IGF/insulin receptors in cervical cancer cell lines with different HPV status, SiHa (HPV positive), and C33a (HPV negative). Different patterns of receptor expression were found; while SiHa expressed IGF-IR, IR-A and IR-B, and IR/IGF-IR hybrid receptors, C33a cells expressed the IR-A only. Tyrosine phosphorylation of these receptors in response to their corresponding ligands correlated with the expression level of these receptors in the cell lines. Activation of PI3-K and MAPK pathways was revealed in both cell lines, however, no effects on proliferation, migration, or invasion were observed. Here we show that cervical cancer cell lines--positive and negative for HPV--differ in the type of insulin and IGF-1 receptors expressed. Additional studies are needed for characterization of the role of IR-A in cervical carcinogenesis. PMID:18711691
Serrano, M-L; Sánchez-Gómez, M; Bravo, M-M; Yakar, S; LeRoith, D
Human papillomavirus (HPV), particularly type 16, has been associated with more than 99% of cervical cancers. There are two HPV oncogenic proteins, E6 and E7, which play a major role in the induction and maintenance of cellular transformation. Thus, immunotherapy targeting these proteins may be employed for the control of HPV-associated cervical lesions. Although the commercially available preventive HPV vaccines are highly efficient in preventing new HPV infection, they do not have therapeutic effects against established HPV infection or HPV-associated lesions. Since T cell-mediated immunity is important for treating established HPV infections and HPV-associated lesions, therapeutic HPV vaccine should aim at generating potent E6 and E7-specific T cell-mediated immune responses. DNA vaccines have now developed into a promising approach for antigen-specific T cell-mediated immunotherapy to combat infection and cancer. Because dendritic cells are the most potent professional antigen-presenting cells, and are highly effective in priming antigen-specific T cells, several DNA vaccines have employed innovative strategies to modify the properties of dendritic cells (DCs) for the enhancement of the DNA vaccine potency. These studies have revealed impressive pre-clinical data that has led to several ongoing HPV DNA vaccine clinical trials.
Huang, Chien-Fu; Monie, Archana; Weng, Wei-Hung; Wu, TC
Progressive chromosomal changes and integration of human papillo- mavirus (HPV) sequences mark the development of invasive cervical cancer. Chromosomal localization of HPV integration is essential to the study of genomic regions involved in HPV-induced pathogenesis. Yet, the available information about HPV integration loci is still limited, especially with respect to different HPV types. We have established cell lines from five
Louise A. Koopman; Karoly Szuhai; Jaap D. H. van Eendenburg; Vladimir Bezrookove; Gemma G. Kenter; Ed Schuuring; Hans Tanke; Gert Jan Fleuren
Background Cancer cells are known to secrete the stress molecules MICA and MICB that activate cytotoxicity by lymphocytes and NK cells through their NKG2D receptor as a mechanism of immunological defense. This work was undertaken to evaluate if cancer cells can also express this receptor as a possible mechanisms of depletion of MIC molecules and thus interfere with their immune recognition. Methods Myelomonocytic leukemic (TPH-1 and U-937) and cervical cancer (CALO and INBL) cell lines were evaluated by Western Blot, ELISA, flow cytometry and immunocytochemistry to evaluate their capacity to express and secrete MICA and MICB and to be induced to proliferate by these molecules as well as to express their receptor NKG2D. Statistical analysis was performed by two-way ANOVA for time course analysis and Student's t-test for comparison between groups. Values were considered significantly different if p < 0.05. Results THP-1 and U-937 produce and secrete the stress MICA and MICB as shown by Western Blot of lysed cells and by ELISA of their conditioned media. By Western Blot and flow cytometry we found that these cells also express the receptor NKG2D. When THP-1 and U-937 were cultured with recombinant MICA and MICB they exhibited a dose dependent induction for their proliferation. CALO and INBL also produce MICA and MICB and were induced to proliferate by these stress molecules. By Western Blot, flow cytometry and immunocytochemistry we also found that these cells express NKG2D. Conclusions Our novel results that tumor cells can simultaneously secrete MIC molecules and express their receptor, and to be induced for proliferation by these stress molecules, and that tumor epithelial cells can also express the NKG2D receptor that was thought to be exclusive of NK and cytotoxic lymphocytes is discussed as a possible mechanism of immunological escape and of tumor growth induction.
A case-control study of 480 patients with invasive cervical cancer and 797 population controls, conducted in five geographic areas in the United States, included an evaluation of the relationship of several cigarette smoking variables to cervical cancer risk. Although smoking was correlated with both age at first intercourse and number of sexual partners, a significant smoking-related risk persisted for squamous cell carcinoma after adjustment for these factors (relative risk, 1.5). Twofold excess risks were seen for those smoking 40 or more cigarettes per day and those smoking for 40 or more years. Increased risks, however, were observed only among recent and continuous smokers. In contrast to squamous cell cancer, no relationship was observed between smoking and risk of adenocarcinoma or adenosquamous carcinoma. These results suggest a causal relationship between cigarette smoking and invasive squamous cell cervical cancer, perhaps through a late-stage or promotional event, although the mechanisms of action require further elucidation.
Brinton, L.A.; Schairer, C.; Haenszel, W.; Stolley, P.; Lehman, H.F.; Levine, R.; Savitz, D.A.
Cancer of the cervix is the second most common life-threatening cancer among women worldwide, with incidence rates ranging from 4.8 per 100,000 women per year in the Middle East to 44.3 per 100,000 in East Africa. Epidemiologic and clinical data demonstrate that human papillomaviruses (HPV), especially HPV-16 and HPV-18, play at least a major if not a necessary role in the etiology of cervical cancer. However, many investigators acknowledge that HPV is not sufficient to induce cervical cancer and that a multifactorial etiology is likely. HPV can be found in a growing proportion of patients with cervical cancer, approaching 100%, but is not yet found in every patient with disease. Other factors, such as herpes simplex virus type 2 infections, cigarette smoking, vaginal douching, nutrition, and use of oral contraceptives, have been proposed as contributing factors. In the first half of the 20th century, Peyton Rous and colleagues demonstrated the joint action of tars and Shope papillomavirus to consistently induce squamous cell carcinomas in rabbits. Using the Rous model as a prototype, one might hypothesize that some cases of cervical cancer arise from an interaction between oncogenic viruses and cervical tar exposures. Cervical tar exposures include cigarette smoking, use of tar-based vaginal douches, and long years of inhaling smoke from wood- and coal-burning stoves in poorly ventilated kitchens.
Haverkos, Harry W.
We used oligonucleotide microarrays to investigate gene expression changes associated with multi-step human papillomavirus type 16 (HPV16)-mediated carcinogenesis in vitro. Gene expression profiles in 4 early passage HPV16-immortalized human keratinocyte (HKc) lines derived from different donors were compared with their corresponding 4 late-passage, differentiation-resistant cell lines, and to 4 pools of normal HKc, each composed of 3 individual HKc strains, on Agilent 22 k human oligonucleotide microarrays. The resulting data were analyzed using a modified T-test coded in R to obtain lists of differentially expressed genes. Gene expression changes identified in this model system were then compared with gene expression changes described in published studies of cervical intraepithelial neoplasia (CIN) and cervical cancer. Common genes in these lists were further studied by cluster analysis. Genes whose expression changed in the same direction as in CIN or cervical cancer (concordant) at late stages of HPV16-mediated transformation in vitro formed one major cluster, while those that changed in the opposite direction (discordant) formed a second major cluster. Further annotation found that many discordant expression changes involved gene products with an extracellular localization. Two novel genes were selected for further study: overexpression of SIX1 and GDF15, observed during in vitro progression in our model system, was confirmed in tissue arrays of cervical cancer. These micro-array-based studies show that our in vitro model system reflects many cellular and molecular alterations characteristic of cervical cancer, and identified SIX1 and GDF15 as 2 novel potential bio-markers of cervical cancer progression.
Wan, Fang; Miao, Xijiang; Quraishi, Iram; Kennedy, Valerie; Creek, Kim E.; Pirisi, Lucia
Background Cervical cancer is strongly associated with high-risk human papillomavirus (HPV) and viral oncoproteins E5, E6 and E7 can transform cells by various mechanisms. It is proposed that oncogenic virus-induced cell fusion may contribute to oncogenesis if p53 or apoptosis is perturbed simultaneously. Recently, HPV-16 E5 was found to be necessary and sufficient for the formation of tetraploid cells, which are frequently found in precancerous cervical lesions and its formation is strongly associated with HPV state. Presentation of the hypothesis We propose that high-risk HPV E5-induced cell fusion is a critical initiating event in the early stage of HPV-associated cervical cancer. Testing the hypothesis Our hypothesis can be tested by comparing the likelihood for colony formation or tumorigenic ability in nude mice between normal HaCaT cells expressing all three oncogenic proteins and E5-induced bi-nucleated HaCaT cells expressing E6 and E7. Moreover, investigating premature chromosome condensation (PCC) in HPV-positive and negative precancerous cervical cells is another way to assess this hypothesis. Implication of the hypothesis This viewpoint would change our understanding of the mechanisms by which HPV induces cervical cancer. According to this hypothesis, blocking E5-induced cell fusion is a promising way to prevent the progression of cervical cancer. Additionally, establishment of a role of cell fusion in cervical carcinogenesis is of reference value for understanding the pathogenesis of other virus-associated cancers.
The buccal mucosa is the site with the highest risk of contracting a malignancy in habitual betel quid chewers who expose the buccal mucosa to high doses of carcinogens. Of all oral cancers, those of the buccal mucosa are associated with the poorest prognoses. Therefore, it would be helpful to have an animal model to evaluate new treatment modalities for buccal mucosa cancer. In the present study, we evaluated whether the imprinting control region (ICR) mouse animal model could be employed as a cancer model for buccal mucosa cancer. Sixty male ICR mice were randomly divided into two groups, a normal group (n=10) and a cancer-induced group (n=50). Each mouse in the cancer group was inoculated with 0.05 ml U14 cancer cell suspension (1×107/ml) on the buccal mucosa. Histological staining and gene expression assays revealed that neck lymph node metastasis animal models were established. After 20 days, the cheek tumor formation rate of the ICR mice reached 100%. Furthermore, the neck lymph node metastasis rate was 53%. We identified that U14 cells produce strong metastasis in ICR mice. Metastasis of the tumor to the lymph node began with carcinoma metastasis encroaching on the marginal sinus. Then it infiltrated to the cortex and medulla and the infiltration continued until the normal lymph node structure was completely damaged. This animal model may be employed in medical research on buccal mucosa cancer and cervical lymph node metastasis. In conclusion, our findings indicate that U14 cell-induced mouse buccal mucosa cancer may be a potential cancer model for human buccal mucosa squamous cell carcinoma.
ZHAO, XIN; PANG, LIANG; QIAN, YU; WANG, QIANG; LI, YONG; WU, MINGYI; OUYANG, ZILAN; GAO, ZHI; QIU, LIHUA
We investigated possible epigenetic regulation of Period1 (PER1), a key circadian regulator gene, in six cervical cancer cell lines which showed up to 15.4-fold differences in PER1 mRNA levels. Genomic methylation analysis showed that a discerned CpG island in the PER1 promoter remained hypomethylated in five of the cell lines. In contrast, C33A cells that showed maximal PER1 expression was hypermethylated; however, demethylation treatment of C33A cells resulted in small but significant elevated PER1 mRNA levels suggesting a secondary role for promoter hypermethylation in PER1 transcriptional regulation. A discerned hypomethylated zone that harbours crucial transcriptional elements including the critical proximal E-box progressively diminished in size in the cell lines until a methylation-resistant core was retained in C33A. Our data indicate that PER1 transcription is mainly uncoupled from promoter methylation but probably involves availability and interactions of trans-acting factors with differentially methylated cis elements in the promoter hypomethylated zone. PMID:17592726
Hsu, Min-Chuan; Huang, Chih-Cheng; Choo, Kong-Bung; Huang, Chiu-Jung
Objectives. The aim of this study was to determine cervical cancer cell sensitivity to chemotherapy-induced apoptosis based on human papillomavirus (HPV) status.Methods. CaSki (HPV-positive) and C33A (HPV-negative) cells were treated with camptothecin or cisplatin. Cellular viability was determined by trypan blue exclusion. Apoptotic indexes were determined by flow cytometric analysis of annexin V labeling and morphological changes. Mitochondrial release of
Luis A. Padilla; Benjamin S. Leung; Linda F. Carson
Galectin-1 is a lectin recognized by galactoside-containing glycoproteins, and is involved in cancer progression and metastasis. The role of galectin-1 in radiosensitivity has not previously been investigated. Therefore, this study tests whether galectin-1 is involved in the radiosensitivity mediated by the H-Ras signaling pathway using cervical carcinoma cell lines. A knockdown of galectin-1 expression in HeLa cells decreased clonogenic survival
E-Y Huang; Y-F Chen; Y-M Chen; I-H Lin; C-C Wang; W-H Su; P-C Chuang; K-D Yang
Six human cervical cancer cell lines (five human papillomavirus (HPV) positive, one HPV negative) for induction and rejoining of DNA strand breaks and for kinetics of formation and loss of serine 139 phosphorylated histone H2AX (H2AX). X-rays induced the same level of DNA breakage for all cell lines. By 8 hours after 20 Gy, <2% of the initial single-strand breaks
Judit P. Banath; Susan H. MacPhail; Peggy L. Olive
Several copy number-altered regions (CNAs) have been identified in the genome of cervical cancer, notably, amplifications of 3q and 5p. However, the contribution of copy-number alterations to cervical carcinogenesis is unresolved because genome-wide there exists a lack of correlation between copy-number alterations and gene expression. In this study, we investigated whether CNAs in the cell lines CaLo, CaSki, HeLa, and SiHa were associated with changes in gene expression. On average, 19.2% of the cell-line genomes had CNAs. However, only 2.4% comprised minimal recurrent regions (MRRs) common to all the cell lines. Whereas 3q had limited common gains (13%), 5p was entirely duplicated recurrently. Genome-wide, only 15.6% of genes located in CNAs changed gene expression; in contrast, the rate in MRRs was up to 3 times this. Chr 5p was confirmed entirely amplified by FISH; however, maximum 33.5% of the explored genes in 5p were deregulated. In 3q, this rate was 13.4%. Even in 3q26, which had 5 MRRs and 38.7% recurrently gained SNPs, the rate was only 15.1%. Interestingly, up to 19% of deregulated genes in 5p and 73% in 3q26 were downregulated, suggesting additional factors were involved in gene repression. The deregulated genes in 3q and 5p occurred in clusters, suggesting local chromatin factors may also influence gene expression. In regions amplified discontinuously, downregulated genes increased steadily as the number of amplified SNPs increased (p<0.01, Spearman's correlation). Therefore, partial gene amplification may function in silencing gene expression. Additional genes in 1q, 3q and 5p could be involved in cervical carcinogenesis, specifically in apoptosis. These include PARP1 in 1q, TNFSF10 and ECT2 in 3q and CLPTM1L, AHRR, PDCD6, and DAP in 5p. Overall, gene expression and copy-number profiles reveal factors other than gene dosage, like epigenetic or chromatin domains, may influence gene expression within the entirely amplified genome segments. PMID:22412903
Vazquez-Mena, Oscar; Medina-Martinez, Ingrid; Juárez-Torres, Eligia; Barrón, Valeria; Espinosa, Ana; Villegas-Sepulveda, Nicolás; Gómez-Laguna, Laura; Nieto-Martínez, Karem; Orozco, Lorena; Roman-Basaure, Edgar; Muñoz Cortez, Sergio; Borges Ibañez, Manuel; Venegas-Vega, Carlos; Guardado-Estrada, Mariano; Rangel-López, Angélica; Kofman, Susana; Berumen, Jaime
Background Cervical cancer represents the third most commonly diagnosed cancer and the fourth leading cause of cancer-related deaths in women worldwide. Natural killer (NK) cells play an important role in the defense against viruses, intracellular bacteria and tumors. NKG2D, an activating receptor on NK cells, recognizes MHC class I chain-related molecules, such as MICA/B and members of the ULBP/RAET1 family. Tumor-derived soluble NKG2D-ligands have been shown to down-modulate the expression of NKG2D on NK cells. In addition to the down-modulation induced by soluble NKG2D-ligands, it has recently been described that persistent cell-cell contact can also down-modulate NKG2D expression. The goal of this study was to determine whether the NKG2D receptor is down-modulated by cell-cell contact with cervical cancer cells and whether this down-modulation might be associated with changes in NK cell activity. Results We demonstrate that NKG2D expressed on NKL cells is down-modulated by direct cell contact with cervical cancer cell lines HeLa, SiHa, and C33A, but not with non-tumorigenic keratinocytes (HaCaT). Moreover, this down-modulation had functional implications. We found expression of NKG2D-ligands in all cervical cancer cell lines, but the patterns of ligand distribution were different in each cell line. Cervical cancer cell lines co-cultured with NKL cells or fresh NK cells induced a marked diminution of NKG2D expression on NKL cells. Additionally, the cytotoxic activity of NKL cells against K562 targets was compromised after co-culture with HeLa and SiHa cells, while co-culture with C33A increased the cytotoxic activity of the NKL cells. Conclusions Our results suggest that differential expression of NKG2D-ligands in cervical cancer cell lines might be associated with the down-modulation of NKG2D, as well as with changes in the cytotoxic activity of NKL cells after cell-cell contact with the tumor cells.
Aesculetin (1) is an important coumarin found in various plant materials. It has been shown to have antiproliferative effects on several types of human cancer cells, but its effect on cervical cancer cells in vitro is unknown. In this study, we investigated that the cytotoxic effect of 1 on a non-cancer cell line (293) was smaller than on a tumor cell line (HeLa). This is the first report showing the possible mechanism of antiproliferative effect of 1 for the prevention of cervical cancer in cell culture models. It was found that 1 inhibited cell viability by inducing apoptosis, as evidenced by the formation of apoptotic bodies, generation of reactive oxygen species (ROS), and the accumulation of cells in the sub-G1 phase. Treatment with compound 1 decreased the cell growth in a dose-dependent manner with an IC(50) value of 37.8 microM. Aesculetin-induced apoptosis was correlated with mitochondrial dysfunction (DeltaPsi(m)), leading to the release of cytochrome c from the mitochondria to the cytosol, as well as the proteolytic activation of caspases in HeLa cells. These results indicate that 1 induces apoptosis in HeLa cells through a ROS-mediated mitochondrial dysfunction pathway. PMID:20390763
Yang, Jin; Xiao, Yu-Ling; He, Xian-Ran; Qiu, Guo-Fu; Hu, Xian-Ming
Infection with high-risk human papillomaviruses is causally linked to cervical carcinogenesis. However, most lesions caused by high-risk HPV infections do not progress to cancer. Host cell mutations contribute to malignant progression but the molecular nature of such mutations is unknown. Based on a previous study that reported an association between liver kinase B1 (LKB1) tumor suppressor loss and poor outcome in cervical cancer, we sought to determine the molecular basis for this observation. LKB1-negative cervical and lung cancer cells were reconstituted with wild type or kinase defective LKB1 mutants and we examined the importance of LKB1 catalytic activity in known LKB1-regulated processes including inhibition of cell proliferation and elevated resistance to energy stress. Our studies revealed marked differences in the biological activities of two kinase defective LKB1 mutants in the various cell lines. Thus, our results suggest that LKB1 may be a cell-type specific tumor suppressor. PMID:24074562
Mack, Hildegard I D; Munger, Karl
Our recent studies of microRNA (miRNA) expression signatures indicated that microRNA-29a (miR-29a) was significantly downregulated in several types of human cancers, suggesting that miR-29a may be a putative tumor-suppressive miRNA in human cancers. The aim of this study was to investigate the functional significance of miR-29a in cervical squamous cell carcinoma (SCC) and to identify novel miR-29a-regulated cancer pathways and target genes involved in cervical SCC oncogenesis and metastasis. Restoration of miR-29a in cervical cancer cell lines (CaSKi, HeLa, ME180 and Yumoto) revealed that this miRNA significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that heat-shock protein 47 (HSP47), a member of the serpin superfamily of serine proteinase inhibitors and a molecular chaperone involved in the maturation of collagen molecules, was a potential target of miR-29a regulation. Luciferase reporter assays showed that miR-29a directly regulated HSP47. Moreover, silencing of the HSP47 gene significantly inhibited cell migration and invasion in cancer cells and the expression of HSP47 was upregulated in cancer tissues and cervical intraepithelial neoplasia (CIN), as demonstrated by immunostaining. Downregulation of miR-29a was a frequent event in cervical SCC and miR-29a acted as a tumor suppressor by directly targeting HSP47. Recognition of tumor-suppressive miRNA-regulated molecular targets provides new insights into the potential mechanisms of cervical SCC oncogenesis and metastasis and suggests novel therapeutic strategies for treatment of this disease. PMID:24141696
Yamamoto, Noriko; Kinoshita, Takashi; Nohata, Nijiro; Yoshino, Hirofumi; Itesako, Toshihiko; Fujimura, Lisa; Mitsuhashi, Akira; Usui, Hirokazu; Enokida, Hideki; Nakagawa, Masayuki; Shozu, Makio; Seki, Naohiko
Cervical cancer is the third most common cancer in women worldwide and often affects women under 40 years with young families. Vaccination against the human papillomavirus (HPV) is a major advance, since it offers primary prevention against the infectious agent that is the main cause of the disease. Two prophylactic vaccines have shown great promise in clinical trials. One of these (Gardasil(®)) contains all four HPV types, offering protection against genital warts (types 6 and 11) as well as cervical cancer (types 16 and 18). The other (Cervarix(®)) contains types 16 and 18, targeting cervical cancer alone, but also has a degree of cross-protection against types 31 and 45, which could significantly increase the level of protection. Adolescent girls remain the primary target of vaccination programmes, but the issues of vaccinating boys and older women are increasingly debated. PMID:22890794
Radiotherapy is a well established treatment for cervical cancer, the second most common cancer in women worldwide. However, metastasis often circumvents the efficacy of radiotherapy. This study was conducted to elucidate the molecular mechanism of radioresistance-associated metastatic potential of cervical cancer cells. We established three radioresistant cervical cancer cell lines by exposure of cells to a sublethal dose of radiation and screened for lines that exhibited an increased migration phenotype for at least 6 months before undertaking mechanistic studies. Radiation-associated metastatic potential was evaluated using a wound-healing assay, time-lapse recording, and cell locomotion into the lungs of BALB/c nude mice. The radioresistant C33A and CaSki cell lines, but not the radioresistant HeLa cell line, exhibited significantly increased cell migration and wound healing than did wild-type cells. Furthermore, K-Ras played a prometastatic role via the activation of c-Raf/p38, whereas interference of those mediators via either RNA interference-mediated knockdown or the use of chemical inhibitors substantially reversed the radioresistance-associated increase in cell migration. Clinical examination further showed the relative up-regulation of the K-Ras/c-Raf/p38 pathway in locally recurring tumors and distant metastases compared with in the primary cervical tumor. These findings demonstrate that a sublethal dose of radiation can enhance the metastatic potential of human cervical cancer cells via K-Ras/c-Raf/p38 signaling, highlighting the potential development of specific inhibitors for reducing metastatic potential during radiotherapy. PMID:22138581
Su, Wen-Hong; Chuang, Pei-Chin; Huang, Eng-Yen; Yang, Kuender D
... Issues Sexually Transmitted Diseases NIH Research Leads to Cervical Cancer Vaccine Past Issues / Fall 2008 Table of Contents ... in women, the cause of the majority of cervical cancers. Photo courtesy of Judy Folkenberg, NLM Writer By ...
Recently, thioridazine (10-[2-(1-methyl-2-piperidyl) ethyl]-2-methylthiophenothiazine), a well-known anti-psychotic agent was found to have anti-cancer activity in cancer cells. However, the molecular mechanism of the agent in cellular signal pathways has not been well defined. Thioridazine significantly increased early- and late-stage apoptotic fraction in cervical and endometrial cancer cells, suggesting that suppression of cell growth by thioridazine was due to the induction of apoptosis. Cell cycle analysis indicated thioridazine induced the down-regulation of cyclin D1, cyclin A and CDK4, and the induction of p21 and p27, a cyclin-dependent kinase inhibitor. Additionally, we compared the influence of thioridazine with cisplatin used as a control, and similar patterns between the two drugs were observed in cervical and endometrial cancer cell lines. Furthermore, as expected, thioridazine successfully inhibited phosphorylation of Akt, phosphorylation of 4E-BP1 and phosphorylation of p70S6K, which is one of the best characterized targets of the mTOR complex cascade. These results suggest that thioridazine effectively suppresses tumor growth activity by targeting the PI3K/Akt/mTOR/p70S6K signaling pathway. PMID:22460505
Kang, Sokbom; Dong, Seung Myung; Kim, Boh-Ram; Park, Mi Sun; Trink, Barry; Byun, Hyun-Jung; Rho, Seung Bae
New Papillomavirus tests are ready to come to the aid of the standard Papanicolauo test in screening for cervical cancer. The new tests, which detect the strains of human papillomavirus (HPV) most commonly associated with human cervical cancer, are designed to be used as an adjunct to rather than as a replacement for the Papanicolaou smears. Their developers say that they can be used to indicated a risk of developing cancer in women whose Papanicolaou smears indicate mild cervical dysplasia, and, eventually, to detect papillomavirus infection in normal Papanicolaou smears. The rationale for HPV testing is derived from a growing body of evidence that HPV is a major factor in the etiology of cervical cancer. Three HPV tests were described recently in Chicago at the Third International Conference on Human Papillomavirus and Squamous Cervical Cancer. Each relies on DNA probes to detect the presence of papillomavirus in cervical cells and/or to distinguish the strain of papillomavirus present.
Purpose To test whether pharmacologic inhibition of ribonucleotide reductase (RNR) by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) enhances radiation sensitivity during low-dose-rate ionizing radiation provided by a novel purpose-built iridium-192 cell irradiator. Methods and Materials Cells were exposed to low (11, 23, 37, 67 cGy/hour) dose-rate radiation using a custom-fabricated cell irradiator or to high (330 cGy/min) dose-rate radiation using a conventional cell irradiator. Radiation sensitivity of human cervical (CaSki, C33-a) cancer cells with or without RNR inhibition by 3-AP was evaluated by clonogenic survival and RNR activity assay. Alteration in cell cycle distribution was monitored by flow cytometry. Results Increasing radiation sensitivity of both CaSki and C33-a cells was observed with incremental rise in radiation dose-rates. 3-AP treatment led to enhanced radiation sensitivity in both cell lines, eliminating differences in cell cytotoxicity due to radiation dose rate. RNR blockade by 3-AP during low-dose-rate irradiation was associated with low RNR activity and an extended G1-phase cell cycle arrest. Conclusions We conclude that RNR inhibition by 3-AP impedes DNA damage repair mechanisms that rely on deoxyribonucleotide production, and thereby increases radiation sensitivity of human cervical cancers to low-dose-rate radiation.
Kunos, Charles A.; Colussi, Valdir C.; Pink, John; Radivoyevitch, Tomas; Oleinick, Nancy L.
Following the demonstration of the superior validity of human papillomavirus (HPV) tests in screening for cervical cancer and the arrival of highly efficacious HPV 16 and 18 vaccines, cervical cancer prevention enters a time of sustainable introduction in developing countries. Multidisciplinary efforts and novel protocols are being developed, and challenging situations are being faced to make cervical cancer, still the
F X Bosch; X Castellsagué; S de Sanjosé
Using seven monoclonal SN38-resistant subclones established from ME180 human cervical squamous cell carcinoma cells, we examined the demethylation effects of 5-aza-2'-deoxycytidine (5-aza-CdR) on the SN38-sensitivity of the cells as well as the expression of death-associated protein kinase (DAPK) in the SN38-resistant cells. The DAPK expression levels were evaluated among parent ME180 cells, SN38-resistant ME180 cells and cisplatin-resistant ME180 cells by methylation-specific DAPK-PCR, quantitative RT-PCR and western blot analysis. The SN38-resistant cells co-treated with SN38 and 5-aza-CdR strongly exhibited enhanced SN38-sensitivities resembling those found in the parent cells. In the SN38-resistant subclones, no relationships were found between the restored SN38 sensitivity and hypermethylation of the DAPK promoter, DAPK mRNA expression, DAPK protein expression and induction of DAPK protein after 5-aza-CdR treatment, unlike the strong suppression of 5-aza-CdR-induced DAPK protein expression in the cisplatin-resistant subclones. These findings indicate that reversibly methylated molecules, but not DAPK, may regulate SN38 resistance, and that demethylating agents can be strong sensitizing anticancer chemotherapeutic drugs for SN38-resistant cancers. PMID:22246465
Tanaka, Tetsuji; Bai, Tao; Toujima, Saori; Utsunomiya, Tomoko; Matsuoka, Toshihide; Kobayashi, Aya; Yamamoto, Madoka; Sasaki, Noriyuki; Tanizaki, Yuko; Utsunomiya, Hirotoshi; Tanaka, Junko; Yukawa, Kazunori
Amplification of chromosome arm 3q is the most consistent aberration in cervical cancer, and is implicated in the progression of dysplastic uterine cervical cells into invasive cancer. The present study employed the ‘positional candidate gene’ strategy to determine the contribution of PIK3CA, which is located in 3q26.3, in cervical tumorigenesis. PIK3CA is known to be involved in the PI 3-kinase\\/AKT
Yen-Ying Ma; Sung-Jen Wei; Yu-Chen Lin; Jia-Chyi Lung; Ting-Chang Chang; Jacqueline Whang-Peng; Jacqueline M Liu; Deng-Mei Yang; Wen K Yang; Chen-Yang Shen
Cervical cancer is caused by human papillomavirus infection. Most human papillomavirus infection is harmless and clears spontaneously but persistent infection with high-risk human papillomavirus (especially type 16) can cause cancer of the cervix, vulva, vagina, anus, penis, and oropharynx. The virus exclusively infects epithelium and produces new viral particles only in fully mature epithelial cells. Human papillomavirus disrupts normal cell-cycle control, promoting uncontrolled cell division and the accumulation of genetic damage. Two effective prophylactic vaccines composed of human papillomavirus type 16 and 18, and human papillomavirus type 16, 18, 6, and 11 virus-like particles have been introduced in many developed countries as a primary prevention strategy. Human papillomavirus testing is clinically valuable for secondary prevention in triaging low-grade cytology and as a test of cure after treatment. More sensitive than cytology, primary screening by human papillomavirus testing could enable screening intervals to be extended. If these prevention strategies can be implemented in developing countries, many thousands of lives could be saved. PMID:23618600
Crosbie, Emma J; Einstein, Mark H; Franceschi, Silvia; Kitchener, Henry C
Valproic acid (VPA) as a histone deacetylase (HDAC) inhibitor has an anticancer effect. In the present study, we evaluated the effects of VPA on the growth and death of HeLa cervical cancer cells in relation to reactive oxygen species (ROS) and glutathione (GSH). Dose- and time-dependent growth inhibition was observed in HeLa cells with an IC50 of approximately 10 mM at 24 h. DNA flow cytometric analysis indicated that 10 mM VPA induced a G2/M phase arrest of the cell cycle. This agent also induced apoptosis, which was accompanied by the cleavage of PARP, the activation of caspase-3, -8 and -9, and the loss of mitochondrial membrane potential (MMP; ??m). All the tested caspase inhibitors significantly prevented HeLa apoptotic cell death induced by VPA, whereas TNF-? intensified the apoptotic cell death. With respect to ROS and GSH levels, VPA increased ROS levels and induced GSH depletion. However, N-acetyl cysteine (NAC; an antioxidant) and L-buthionine sulfoximine (BSO; a GSH synthesis inhibitor) did not significantly affect cell death in VPA-treated HeLa cells. In conclusion, VPA inhibits the growth of HeLa cervical cancer cells via caspase-dependent apoptosis and the growth inhibition is independent of ROS and GSH level changes. PMID:24064712
Han, Bo Ram; You, Bo Ra; Park, Woo Hyun
Octamer-binding transcription factor 4 (OCT4) is a key regulatory gene that maintains the pluripotency and self-renewal properties of embryonic stem cells. Although there is emerging evidence that it can function as oncogene in several cancers, the role in mediating cervical cancer remains unexplored. Here we found that OCT4 protein expression showed a pattern of gradual increase from normal cervix to cervical carcinoma in situ and then to invasive cervical cancer. Overexpression of OCT4 in two types of cervical cancer cells promotes the carcinogenesis, and inhibits cancer cell apoptosis. OCT4 induces upregulation of miR-125b through directly binding to the promoter of miR-125b-1 confirmed by chromatin immunoprecipitation analysis. MiRNA-125b overexpression suppressed apoptosis and expression of BAK1 protein. In contrast, miR-125b sponge impaired the anti-apoptotic effect of OCT4, along with the upregulated expression of BAK1. Significantly, Luciferase assay showed that the activity of the wild-type BAK1 3?-untranslated region reporter was suppressed and this suppression was diminished when the miR-125b response element was mutated or deleted. In addition, we observed negative correlation between levels of BAK1 and OCT4, and positive between OCT4 and miR-125b in primary cervical cancers. These findings suggest an undescribed regulatory pathway in cervical cancer, by which OCT4 directly induces expression of miR-125b, which inhibits its direct target BAK1, leading to suppression of cervical cancer cell apoptosis.
Wang, Y-D; Cai, N; Wu, X-L; Cao, H-Z; Xie, L-L; Zheng, P-S
Genetic changes orchestrated by human papillomaviruses are the most important known factors in carcinogenesis of the uterine cervix. However, it is clear that additional genetic events are necessary for tumour progression. We have used comparative genomic hybridization to document non-random chromosomal gains and losses within a subset of 37 cervical carcinomas matched for clinical stage Ib, but with different lymph node status. There were significantly more chromosomal changes in the primary tumours when the lymph nodes were positive for metastases. The most frequent copy number alterations were loss of 3p, 11q, 6q and 10q and gain of 3q. The smallest areas of loss and gain on chromosome 3 were 3p14-22 and 3q24-26. The study identifies progressive DNA copy number changes associated with early-stage invasive cervical cancers with and without lymph node metastases, a factor of potential prognostic and therapeutic value. PMID:11104563
Allen, D G; White, D J; Hutchins, A M; Scurry, J P; Tabrizi, S N; Garland, S M; Armes, J E
We characterizedmechanisms of growth control Involvinginsulin-like growth factor-i (IGF-1), IGF-2, and IGF-l receptor (IGF-1R) by hives tigating their expression in human cervical cancer cell lines, primary cervicaltumor cell cultures,andnormaleCtOCervICaI epithelialcellsmain tamedIn short-term culture. By reversetranscrlpflon followedby PCR, IGF-1 mRNA was not detectedin any of the ceHlines, whereasIGF-2 mRNA transcripts weredetectedIn all of them.Usingthe RNaseprotec lion assay,low levelsof IGF-2 mRNA werealsodetectedIn
Michael A. Steller; Cynthia H. Delgado; Christopher J. Bartels; Craig D. Woodworth; Zhiqiang Zou
Plexin-B1, the receptor for Sema4D, has been reported to trigger multiple and sometimes opposing cellular responses in various types of tumor cells. It has been implicated in the regulation of tumor-cell survival, proliferation, angiogenesis, invasion and metastasis. However, the plexin-B1 gene expression and its regulatory mechanism in cervical cancer remain unclear. The present study shows that plexin-B1 is over-expressed in cervical tumor tissues compared to normal cervical tissues by immunohistochemistry, Western blotting and quantitative RT-PCR. The expression of plexin-B1 is significantly associated with cervical tumor metastasis and invasion according to the analysis of the clinicopathologic data. Plexin-B1 also promotes proliferation, migration and invasion in human cervical cancer HeLa cells. We also found that the plexin-B1 levels are inversely correlated with miR-214 amounts in both cervical cancer tissues and HeLa cells. And miR-214 expression level is also associated with metastasis and invasion of cervical tumor. Furthermore, we demonstrate that plexin-B1 is inhibited by miR-214 through a miR-214 binding site within the 3'UTR of plexin-B1 in HeLa cells. Ectopic expression of miR-214 could inhibit the proliferation capacity, migration and invasion ability of HeLa cells. Our findings suggest that plexin-B1, a target of miR-214, may function as an oncogene in human cervical cancer HeLa cells. PMID:21216304
Qiang, Ran; Wang, Fang; Shi, Li-Ying; Liu, Min; Chen, Shuang; Wan, Hai-Ying; Li, Yi-Xuan; Li, Xin; Gao, Song-Yuan; Sun, Bao-Cun; Tang, Hua
The antiproliferative effect of different extracts obtained from Retama monosperma L. was investigated on human SiHa and HeLa cervical cancer cell lines using a MTT colorimetric assay. The Retama monosperma L. dichloromethane fraction (Rm-DF) was the most active extract, exhibiting a significant cytotoxic activity on both cell lines in a dose-dependent manner, after 72 h of treatment. IC50 values obtained were 14.57 ± 4.15 ?g/ml and 21.33 ± 7.88 ?g/ml, for SiHa and HeLa cell lines respectively. The morphological features assessment of apoptosis in Rm-DF-treated cells showed a condensation of chromatin and apoptotic bodies, accompanied by a decrease in mitochondrial membrane potential (??m) and an increase in reactive oxygen species in both cell lines. The induction of apoptosis was further confirmed by Western blotting pro-caspase 3, Bcl2 and PARP; caspase 3 activity assay; and Annexin V labelling. Analysis of Rm-DF by CG/MS revealed the presence of five known quinolizidine alkaloids as well as, sparteine (10,97%), L-methyl cytisine (9.11%), 17-oxosparteine (3.49%), lupanine (0.93%) and anagyrine (39.63%). This study shows that Retama monosperma L. extract exhibits a potential anticancer activity against cervical cancer cell lines in vitro through the inhibition of proliferation and induction of apoptosis, which may involve a mitochondria-mediated signaling pathway. PMID:22000488
Merghoub, N; Benbacer, L; El Btaouri, H; Ait Benhassou, H; Terryn, C; Attaleb, M; Madoulet, C; Benjouad, A; El Mzibri, M; Morjani, H; Amzazi, S
Carbon nanotubes are capable of penetrating the cell membrane and are widely considered as potential carriers for gene or drug delivery. Because the C-C and C=C bonds in carbon nanotubes are nonpolar, functionalization is required for carbon nanotubes to interact with genes or drugs as well as to improve their biocompatibility. In this study, polyethylenimine (PEI)-functionalized single-wall (PEI-NH-SWNTs) and multiwall carbon nanotubes (PEI-NH-MWNTs) were produced by direct amination method. PEI functionalization increased the positive charge on the surface of SWNTs and MWNTs, allowing carbon nanotubes to interact electrostatically with the negatively charged small interfering RNAs (siRNAs) and to serve as nonviral gene delivery reagents. PEI-NH-MWNTs and PEI-NH-SWNTs had a better solubility in water than pristine carbon nanotubes, and further removal of large aggregates by centrifugation produced a stable suspension of reduced particle size and improved homogeneity and dispersity. The amount of grafted PEI estimated by thermogravimetric analysis was 5.08% (w/w) and 5.28% (w/w) for PEI-NH-SWNTs and PEI-NH-MWNTs, respectively. For the assessment of cytotoxicity, various concentrations of PEI-NH-SWNTs and PEI-NH-MWNTs were incubated with human cervical cancer cells, HeLa-S3, for 48 h. PEI-NH-SWNTs and PEI-NH-MWNTs induced cell deaths in a dose-dependent manner but were less cytotoxic compared to pure PEI. As determined by electrophoretic mobility shift assay, siRNAs directed against glyceraldehyde-3-phosphate dehydrogenase (siGAPDH) were completely associated with PEI-NH-SWNTs or PEI-NH-MWNTs at a PEI-NH-SWNT/siGAPDH or PEI-NH-MWNT/siGAPDH mass ratio of 80:1 or 160:1, respectively. Furthermore, PEI-NH-SWNTs and PEI-NH-MWNTs successfully delivered siGAPDH into HeLa-S3 cells at PEI-NH-SWNT/siGAPDH and PEI-NH-MWNT/siGAPDH mass ratios of 1:1 to 20:1, resulting in suppression of the mRNA level of GAPDH to an extent similar to that of DharmaFECT, a common transfection reagent for siRNAs. Our results indicate that the PEI-NH-SWNTs and PEI-NH-MWNTs produced in this study are capable of delivering siRNAs into HeLa-S3 cells to suppress gene expression and may therefore be considered as novel nonviral gene delivery reagents. PMID:23742156
Huang, Yuan-Pin; Lin, I-Jou; Chen, Chih-Chen; Hsu, Yi-Chiang; Chang, Chi-Chang; Lee, Mon-Juan
The aim of this study was to describe the state of the art in cervical cancer screening in Greece by presenting the two regionally organised screening programmes that currently operate in the country. Both programmes were initiated in 1991 and are partly funded by the European Union. The Ormylia screening programme covers the population of Halkidiki (Northern Greece), a predominantly
E Riza; P Kyriakogianni-Psaropoulou; E Koumantakis; H Symiakaki; I Garas; A Linos
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The carcinoma of the uterine cervix is the second most common cancer among women worldwide, with its higher incidence in developing\\u000a countries (1). Strong clinical and experimental evidence demonstrated that the high-risk (HR) types of human papilloma virus (HPV) play\\u000a a central role in causing cervical cancer, although a role of multiple risk factors has been suggested too. Not only
Valeria Masciullo; Antonio Giordano
Up-regulation of proliferating cell nuclear antigen (PCNA) is closely associated with high-risk human papillomavirus (HPV) and progression of cervical intraepithelial neoplasia (CIN), but does not predict disease outcome in cervical cancer
ObjectiveProliferating cell nuclear antigen (PCNA) is essential for DNA replication of mammalian cells and their small DNA tumour viruses. The E7 oncoprotein of high-risk human papillomavirus (HPV) is known to activate PCNA, shown to be up-regulated in CIN and cervical cancer (CC), but still incompletely studied as an intermediate endpoint marker in this disease.
M. Branca; M. Ciotti; C. Giorgi; D. Santini; L. Di Bonito; S. Costa; A. Benedetto; D. Bonifacio; P. Di Bonito; P. Paba; L. Accardi; S Syrjänen; C. Favalli; K. Syrjänen
Background T cell immunoglobulin mucin-3 (Tim-3) has been identified as a negative regulator of anti-tumor immunity. Recent studies highlight the important role of Tim-3 in the CD8+ T cell exhaustion that takes place in both human and animal cancer models. However, the nature of Tim-3 expression in the tumor cell and the mechanism by which it inhibits anti-tumor immunity are unclear. This present study aims to determine Tim-3 is expressed in cervical cancer cells and to evaluate the role of Tim-3 in cervical cancer progression. Methodology A total of 85 cervical tissue specimens including 43 human cervical cancer, 22 cervical intraepithelial neoplasia (CIN) and 20 chronic cervicitis were involved. Tim-3 expression in tumor cells was detected and was found to correlate with clinicopathological parameters. Meanwhile, expression of Tim-3 was assessed by RT-PCR, Western Blot and confocal microscopy in cervical cancer cell lines, HeLa and SiHa. The migration and invasion potential of Hela cells was evaluated after inhibiting Tim-3 expression by ADV-antisense Tim-3. Conclusions We found that Tim-3 was expressed at a higher level in the clinical cervical cancer cells compared to the CIN and chronic cervicitis controls. We supported this finding by confirming the presence of Tim-3 mRNA and protein in the cervical cell lines. Tim-3 expression in tumor cells correlated with clinicopathological parameters. Patients with high expression of Tim-3 had a significant metastatic potential, advanced cancer grades and shorter overall survival than those with lower expression. Multivariate analysis showed that Tim-3 expression was an independent factor for predicting the prognosis of cervical cancer. Significantly, down-regulating the expression of Tim-3 protein inhibited migration and invasion of Hela cells. Our study suggests that the expression of Tim-3 in tumor cells may be an independent prognostic factor for patients with cervical cancer. Moreover, Tim-3 expression may promote metastatic potential in cervical cancers.
Cao, Yang; Zhou, Xiaoxi; Huang, Xiaoyuan; Li, Qinlu; Gao, Lili; Jiang, Lijun; Huang, Mei; Zhou, Jianfeng
Opinion statement There are limited treatment options for patients with recurrent cervical carcinoma. Because of low response rates and a negligible\\u000a impact on long-term survival, the use of chemotherapy in patients with unresectable recurrent disease should be considered\\u000a palliative. Generally, radiation therapy in previously irradiated patients is considered palliative. For patients who develop\\u000a recurrent disease after definitive surgery who have not
Mario M. Leitao; Dennis S. Chi
Human papillomavirus (HPV) E2 gene disruption is one of the key features of HPV-induced cervical malignant transformation. Though it is thought to prevent\\u000a progression of carcinogenesis, the pro-apoptotic function of E2 protein remains poorly understood. This study shows that expression\\u000a of HPV16 E2 induces apoptosis both in HPV-positive and -negative cervical cancer cell lines and leads to hyperactivation of\\u000a caspase-8
Wei Wang; Yong Fang; Ni Sima; Yan Li; Wei Li; Li Li; Linfei Han; Shujie Liao; Zhiqiang Han; Qinglei Gao; Kezhen Li; Dongrui Deng; Li Meng; Jianfeng Zhou; Shixuan Wang; Ding Ma
Using a panel of 21 monoclonal and 2 polyclonal keratin antibodies, capable of detecting separately 11 subtypes of their epithelial intermediate filament proteins at the single cell level, we investigated keratin expression in 16 squamous cell carcinomas, 9 adenocarcinomas, and 3 adenosquamous carcinomas of the human uterine cervix. The keratin phenotype of the keratinizing squamous cell carcinoma was found to be most complex comprising keratins 4, 5, 6, 8, 13, 14, 16, 17, 18, 19, and usually keratin 10. The nonkeratinizing variety of the squamous cell carcinoma expressed keratins 6, 14, 17, and 19 in all cases, usually 4, 5, 7, 8, and 18, and sometimes keratins 10, 13, and 16. Adenocarcinomas displayed a less complex keratin expression pattern comprising keratins 7, 8, 17, 18, and 19, while keratin 14 was often present and keratins 4, 5, 10 and 13 were sporadically found in individual cells in a few cases. These keratin phenotypes may be useful in differential diagnostic considerations when distinguishing between keratinizing and nonkeratinizing carcinomas (using keratin 10, 13, and 16 antibodies), and also in the distinction between nonkeratinizing carcinomas and poorly differentiated adenocarcinomas, which do not express keratins 5 and 6. Keratin 17 may also be useful in distinguishing carcinomas of the cervix from those of the colon and also from mesotheliomas. Furthermore the presence of keratin 17 in a CIN I, II, or III lesion may indicate progressive potential while its absence could be indicative of a regressive behavior. Because most carcinomas express keratins 8, 14, 17, 18, and 19, we propose that this expression pattern reflects the origin of cervical cancer from a common progenitor cell, i.e., the endocervical reserve cell that has been shown to express keratins 5, 8, 14, 17, 18, and 19. PMID:1379783
Smedts, F; Ramaekers, F; Troyanovsky, S; Pruszczynski, M; Link, M; Lane, B; Leigh, I; Schijf, C; Vooijs, P
Fluorescent molecular probes offer a potential for early cancer detection. Indocyanine green (ICG) is an FDAapproved near-infrared (NIR) fluorescent dye used in ophthalmic angiography and assessment of cardiac and hepatic functions. However, clinical applications of ICG remain very limited due to its rapid clearance from vascular circulation, unstable optical properties, non-specific interactions with plasma proteins, and inability for localized targeting. To overcome these limitations, we have encapsulated ICG within nanoconstructs composed of poly(allylamine) hydrochloride and disodium hydrogen phosphate salt. To understand the effects of coating materials on the cellular uptake of the nanocapsules, we have measured the uptake of ICG-loaded nanocapsules (ICG-NCs) with various coating materials by HeLa cancerous cervical epithelial cells in-vitro. Results of this study provide important information for the choice of appropriate coating materials that will result in maximal uptake of ICG-NCs in optical and phototherapy of cancerous tissue.
Jung, Bongsu; Lomeli, Eulieses; Anvari, Bahman
Objectives Hemoglobin (Hgb) is the main oxygen and carbon dioxide carrier in cells of erythroid lineage and is responsible for oxygen delivery to the respiring tissues of the body. However, Hgb is also expressed in nonerythroid cells. In the present study, the expression of Hgb in human uterine cervix carcinoma cells and its role in cervical cancer were investigated. Methodology The expression level of Hgb in cervical cancer tissues was assessed by quantitative reverse transcriptase-PCR (qRT-PCR). We applied multiple methods, such as RT-PCR, immunoblotting, and immunohistochemical analysis, to confirm Hgb expression in cervical cancer cells. The effects of ectopic expression of Hgb and Hgb mutants on oxidative stress and cell viability were investigated by cellular reactive oxygen species (ROS) analysis and lactate dehydrogenase (LDH) array, respectively. Both Annexin V staining assay by flow cytometry and caspase-3 activity assay were used, respectively, to evaluate cell apoptosis. Results qRT-PCR analysis showed that Hgb-?- (HBA1) and Hgb-?-globin (HBB) gene expression was significantly higher in cervical carcinoma than in normal cervical tissues, whereas the expression of hematopoietic transcription factors and erythrocyte specific marker genes was not increased. Immunostaining experiments confirmed the expression of Hgb in cancer cells of the uterine cervix. Hgb mRNA and protein were also detected in the human cervical carcinoma cell lines SiHa and CaSki, and Hgb expression was up-regulated by hydrogen peroxide-induced oxidative stress. Importantly, ectopic expression of wild type HBA1/HBB or HBA1, rather than mutants HBA1H88R/HBBH93R unable to bind hemo, suppressed oxidative stress and improved cell viability. Conclusions The present findings show for the first time that Hgb is expressed in cervical carcinoma cells and may act as an antioxidant, attenuating oxidative stress-induced damage in cervical cancer cells. These data provide a significant impact not only in globin biology but also in understanding of cervical cancer pathogenesis associated with oxidative stress.
Mei, Qian; Fu, Xiaobing; Han, Weidong
In this article we review the ever increasing role of imaging in endometrial and cervical cancer. Magnetic resonance imaging\\u000a (MRI) has emerged as the most widely used technique in the management of women with gynaecological cancer. In endometrial\\u000a cancer, MRI is reliable in identifying myometrial and cervical invasion and extra-uterine disease, thereby informing preoperative\\u000a surgical planning. In cervical cancer, MRI
Shilpa Patel; Sidath H. Liyanage; Anju Sahdev; Andrea G. Rockall; Rodney H. Reznek
Cervical and vaginal cancers remain serious health problems. Worldwide, more than 530,000 women annually are diagnosed with these diseases, with most new incident cases occurring in nations with limited health resources and underdeveloped screening programs. For women whose disease is too bulky or widespread for surgery, radiochemotherapy should be looked upon as the standard of care. Randomized clinical trials have indicated that radiochemotherapy strategies that disrupt the repair of damaged DNA are key to the management of advanced stage cervical and vaginal cancers. Here, from a viewpoint of cancer cell molecular biology, treatments for advanced stage cervical and vaginal cancers are discussed.
Kunos, Charles A
Genetic changes orchestrated by human papillomaviruses are the most important known factors in carcinogenesis of the uterine cervix. However, it is clear that additional genetic events are necessary for tumour progression. We have used comparative genomic hybridization to document non-random chromosomal gains and losses within a subset of 37 cervical carcinomas matched for clinical stage Ib, but with different lymph node status. There were significantly more chromosomal changes in the primary tumours when the lymph nodes were positive for metastases. The most frequent copy number alterations were loss of 3p, 11q, 6q and 10q and gain of 3q. The smallest areas of loss and gain on chromosome 3 were 3p14–22 and 3q24–26. The study identifies progressive DNA copy number changes associated with early-stage invasive cervical cancers with and without lymph node metastases, a factor of potential prognostic and therapeutic value. © 2000 Cancer Research Campaign http://www.bjcancer.com
Allen, D G; White, D J; Hutchins, A-M; Scurry, J P; Tabrizi, S N; Garland, S M; Armes, J E
Anti-tumor activity of the proteins from Gecko (GP) on cervical cancer cells, and its signaling mechanisms were assessed by viable cell counting, propidium iodide (PI) staining, and Western blot analysis. GP induced the cell death of HeLa cells in a dose-dependent manner while it did not affect the viability of normal cells. Western blot analysis showed that GP decreased the activation of Akt, and co-administration of GP and Akt inhibitors synergistically exerted anti-tumor activities on HeLa cells, suggesting the involvement of PI3-kinase/Akt pathway in GP-induced cell death of the cancer cells. Indeed, the cytotoxic effect of GP against HeLa cells was inhibited by overexpression of constituvely active form of Akt in HeLa cells. The candidates of the functional proteins in GP were analyzed by Mass-spectrum. Taken together, our results suggest that GP elicits anti-tumor activity against HeLa cells by inhibition of PI3-kinase/Akt pathway.
Jeong, Ae-Jin; Chung, Chung-Nam; Kim, Hye-Jin; Bae, Kil Soo; Choi, Song; Jun, Woo Jin; Shim, Sang In; Kang, Tae-Hong; Leem, Sun-Hee
Background In Greenland, the incidence of cervical cancer caused by human papillomavirus (HPV) is 25 per 100,000 women; 2.5 times the Danish rate. In Greenland, the disease is most frequent among women aged 30–40. Systematic screening can identify women with cervical cell changes, which if untreated may cause cervical cancer. In 2007, less than 40% of eligible women in Greenland participated in screening. Objective To examine Greenlandic women's perception of disease, their understanding of the connection between HPV and cervical cancer, and the knowledge that they deem necessary to decide whether to participate in cervical cancer screening. Study design The methods used to perform this research were 2 focus-group interviews with 5 Danish-speaking women and 2 individual interviews with Greenlandic-speaking women. The analysis involved a phenomenological-hermeneutic approach with 3 levels of analysis: naive reading, structural analysis and critical interpretation. Results These revealed that women were unprepared for screening results showing cervical cell changes, since they had no symptoms. When diagnosed, participants believed that they had early-stage cancer, leading to feelings of vulnerability and an increased need to care for themselves. Later on, an understanding of HPV as the basis for diagnosis and the realization that disease might not be accompanied by symptoms developed. The outcome for participants was a life experience, which they used to encourage others to participate in screening and to suggest ways that information about screening and HPV might reach a wider Greenlandic population. Conclusion Women living through the process of cervical disease, treatment and follow-up develop knowledge about HPV, cervical cell changes, cervical disease and their connection, which, if used to inform cervical screening programmes, will improve the quality of information about HPV, cervical cancer and screening participation. This includes that verbal and written information given at the point of screening and diagnosis needs to be complemented by visual imagery.
Hounsgaard, Lise; Augustussen, Mikaela; M?ller, Helle; Bradley, Stephen K.; M?ller, Suzanne
Cervical cancer is preventable and curable if detected early. Timely cervical cancer screening through Papanicolaou (Pap) tests has been recognized as the most effective way to identify the earliest signs of cervical cancer. Although the number of women n...
A. Elixhauser C. A. Russo M. Milenkovic
Cancer of the uterine cervix is the second largest cause of cancer deaths in women, and its toll is greatest in populations that lack screening programmes to detect precursor lesions. Persistent infection with 'high risk' genotypes of human papillomavirus (HPV) is necessary, although not sufficient, to cause cervical carcinoma. Therefore, HPV vaccination provides an opportunity to profoundly affect cervical cancer
Richard Roden; T.-C. Wu
Cervical cancer is a major cause of mortality and premature death among women in their most productive years in low- and medium-resourced countries in Asia, Africa and Latin America, despite the fact that it is an eminently preventable cancer. While cytology screening programmes have resulted in a substantial reduction of cervical cancer mortality in developed countries, they have been shown
Rengaswamy Sankaranarayanan; Somanathan Thara; Pulikottil Okkuru Esmy; Partha Basu
Nestin expression reportedly correlates with aggressive growth, metastasis, poor prognosis and presence of cancer stem cells (CSCs) in various tumors. In this study, we determined the expression and role of nestin in cervical intraepithelial neoplasia (CIN) and cervical cancer. We performed immunohistochemical and in situ hybridization analyses of nestin in 26 cases for each stage of CIN and 55 cervical cancer tissue samples. To examine the role of nestin in cervical cancer cells, we stably transfected expression vectors containing nestin cDNA into ME-180 cells. We studied the effects of increased nestin expression on cell proliferation, cell motility, invasion as well as sphere and soft agar formation. Nestin was not localized in the squamous epithelium in normal cervical tissues, but it was weakly expressed in the basal squamous epithelium of CIN 1. In CIN 2, nestin was localized to the basal to lower 2/3 of the squamous epithelium, whereas in CIN 3, it was localized to the majority of the squamous epithelium. Nestin was detected in all cases of invasive cervical cancer. Nestin mRNA was expressed in both ME-180 and CaSki cells. Growth rate, cell motility and invasion ability of stably nestin-transfected ME-180 cells were not different from empty vector-transfected ME-180 (mock cells). However, the nestin-transfected ME-180 cells formed more colonies and spheres compared to the mock cells. These findings suggest that nestin plays important roles in carcinogenesis and tumor formation of cervical cancer cells. Nestin may closely correlate with regulation of CSCs.
SATO, ATSUKI; ISHIWATA, TOSHIYUKI; MATSUDA, YOKO; YAMAMOTO, TETSUSHI; ASAKURA, HIROBUMI; TAKESHITA, TOSHIYUKI; NAITO, ZENYA
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is suggested to be a long (?7 kb) non-coding RNA. MALAT1 is overexpressed in many human carci- nomas, but its function remains unknown. To investigate the role of MALAT1 in human cervical cancer pro- gression, we designed and used short hairpin RNA to inhibit MALAT1 expression in CaSki cells and validated its effect on
Fengjie Guo; Yalin Li; Yan Liu; Jiajia Wang; Yuehui Li; Guancheng Li
In this study, we compared the effects of SKI-606 with Iressa, Src/Abl and EGF-R kinase inhibitors, respectively, on selected parameters in HeLa and SiHa cervical cancer cell lines, which express E6/E7 oncoproteins of high-risk HPV types 18 and 16, respectively. Our results show that SKI-606 and Iressa inhibit cell proliferation and provoke G0-G1 cell cycle arrest and reduction of S and G2-M phase using 2 and 5??M concentrations of these inhibitors. In contrast, SKI-606 induces differentiation to an epithelial phenotype “mesenchymal-epithelial transition”; thus SKI-606 causes a dramatic decrease in cell motility and invasion abilities of HeLa and SiHa cancer cells, in comparison to untreated cells and Iressa-treated cells in which these parameters are only slightly affected. These changes are accompanied by a regulation of the expression patterns of E-cadherin and catenins. The molecular pathway analysis of Src/Abl inhibitor revealed that SKI-606 blocks the phosphorylation of ?-catenin and consequently converts its role from a transcriptional regulator to a cell-cell adhesion molecule. Our findings indicate that SKI-606 inhibits signaling pathways involved in regulating tumor cell migration and invasion genes via ?-catenin alteration, suggesting that Src inhibitor, in comparison to EGF-R, is a promising therapeutic agent for human cervical cancer.
Yasmeen, Amber; Alachkar, Amal; Dekhil, Hafedh; Gambacorti-Passerini, Carlo; Al Moustafa, Ala-Eddin
Background/Aims 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG) is one of the most active antiproliferative compounds in a series of acyclic nucleoside phosphonates and is active in intraperitoneal P388 tumors in mice. Methods We synthesized octadecyloxyethyl (ODE) and hexadecyloxypropyl esters of PMEG and compared their antiproliferative activity with unmodified PMEG in primary human fibroblasts and CaSki, Me-180 and HeLa human cervical cancer cell lines in vitro. Results ODE-PMEG had excellent antiproliferative activity in vitro in this panel of human cervical cancers. We compared the effects of ODE-PMEG and ODE-cidofovir (ODE-CDV) in a solid tumor model using Me-180 human cervical cancer cell lines in athymic nude mice. Intratumoral injection of 25 ?g of ODE-PMEG or 100 ?g of ODE-CDV daily for 21 days followed by observation for 20–35 days resulted in near-complete disappearance of measurable cervical cancers. Conclusion ODE-PMEG may be suitable for local or topical treatment of cervical dysplasia.
Valiaeva, Nadejda; Trahan, Julissa; Aldern, Kathy A.; Beadle, James R.; Hostetler, Karl Y.
Keratinocyte growth factor receptor (KGFR), also known as FGFR2 IIIb, is a splice variant of FGFR-2. KGFR is expressed in many types of epithelial cell and is activated with four known ligands [FGF-1, FGF-3, FGF-7 (also known as KGF) and FGF-10] that are predominantly synthesized by mesenchymal cells. KGFR is highly expressed in the late-proliferative phase of a normal endometrium and in endometrial adenocarcinoma. In the present study, we attempted to determine the expression and localization of KGFR in human cervical cancer cell lines and cervical cancer tissues. The KGFR protein was detected in CaSki and HeLa cells, but not in ME-180 cells of cervical cancer cell lines. In non-cancer cervical tissues, KGFR immunoreactivity was weakly expressed in the surface of squamous epithelial cells and vascular smooth muscle cells. Immunohistochemically, the KGFR protein was detected in squamous cell carcinoma in 36 of 42 (86%) cervical cancer patients. In cervical cancer tissues, KGFR was detected in 17 of 18 (94%) of patients with the keratinizing type and 19 of 24 (79%) of patients with the non-keratinizing type of cervical cancer. Furthermore, KGFR was prominently localized in proliferating reserve cells and squamous metaplastic reserve cells adjacent to cancer cells. In contrast, KGFR was not detected in cervical ductal cells in cancer or non-cancer cervical tissues. These findings may indicate that KGFR mediates the growth and differentiation of reserve cells and squamous cell carcinoma in the cervix. PMID:15069536
Kurban, Gulnar; Ishiwata, Toshiyuki; Kudo, Mitsuhiro; Yokoyama, Munehiro; Sugisaki, Yuichi; Naito, Zenya
The 9-hydroxypheophorbide-? (9-HPbD) is a chlorophyll derivative and was found to be very effective for photodynamic therapy of tumor cells. The current study investigates uptake, retention, and intracellular localization of 9-HPbD by HeLa, human cervical cancer cells via fluorescence spectrophotometry and confocal laser scanning microscopy, and its photodynamic effect against human cervical carcinoma cell. HeLa cells exposed to 9-HPbD exhibited a linear uptake of photosensitizer during the first 12 h, and after removal of 9-HPbD, cell fluorescence was observed to decrease gradually over the next 12 h. Cells treated with 9-HPbD and stained with a panel of organelle-specific fluorescence probes (MitoTracker, LysoTracker, and ER-Tracker) revealed an intracellular fluorescence distribution restricted to cytoplasmic compartments with no detectable fluorescence in the nucleus. The 9-HPbD showed cytotoxicity effect against HeLa cells in 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Endoplasmic reticulum (ER) disruption and cellular calcium dynamics also showed a photoactivation followed by cell death. The apoptotic effect of 9-HPbD was confirmed by caspase 3 activity study and immunofluorescence study of caspase 12. Morphological observation through the transmission electron microscopy and scanning electron microscopy also confirmed that 9-HPbD can induce apoptosis in HeLa cells. Therefore, it can be concluded that maximum uptake and clearance time of 9-HPbD was 12 h with endoplasmic reticulum as the major organelle site in cellular uptake, and 9-HPbD can induce apoptosis in HeLa cells through ER stress-related pathways via activation of caspase 12. PMID:23649612
Ahn, Jin Chul; Biswas, Raktim; Moon, Jeong Hwan; Chung, Phil Sang
The main aetiology of cervical cancer is infection with high-risk human papillomavirus (HPV). Cervical cancer is almost 100% curable if detected in the early stages. Thus, information about the presence and levels of HPV in patient samples has high clinical value. As current screening methods, such as the Pap smear test, are highly subjective and in many cases show low sensitivity and specificity, new supportive techniques are desirable to improve the quality of cervical cancer screening. In this study, vibrational spectroscopic techniques (Raman and Fourier Transform Infra Red absorption) have been applied to the investigation of four cervical cancer cell lines: HPV negative C33A, HPV-18 positive HeLa with 20-50 integrated HPV copies per cell, HPV-16 positive SiHa with 1-2 integrated HPV strands per cell and HPV-16 positive CaSki containing 60-600 integrated HPV copies per cell. Results show that vibrational spectroscopic techniques can discriminate between the cell lines and elucidate cellular differences originating from proteins, nucleic acids and lipids. Similarities between C33A and SiHa cells were exhibited in the Raman and infrared spectra and were confirmed by Principal Component Analysis (PCA). Analysis of the biochemical composition of the investigated cells, with the aid of PCA, showed a clear discrimination between the C33A-SiHa group and HeLa and CaSki cell lines indicating the potential of vibrational spectroscopic techniques as a support to current methods for cervical cancer screening. PMID:20967345
Ostrowska, Kamila Magdalena; Malkin, Alison; Meade, Aidan; O'Leary, John; Martin, Cara; Spillane, Cathy; Byrne, Hugh James; Lyng, Fiona Maria
In the present study, we compare the sensitivity of CaSki and HeLa cells (HPV positive, wild-type p53) and C33A cells (HPV negative, mutated p53) to a protein kinase inhibitor, the staurosporine (ST). We show that ST can reversibly arrest the three cervical-derived cell lines, either in G1 or in G2\\/M. Beyond certain ST concentrations or\\/and over 24 h exposure, the
B Bernard; T Fest; J-L Prétet; C Mougin
Nordihydroguaiaretic acid (NDGA) and its derivatives possess anti-cancer effects on various types of cancer via the induction of apoptosis or cell cycle arrest. This study proved that NDGA inhibited cervical cancer SiHa cell growth and induced cell cycle arrest at the G1 phase, which may be a consequence of cell cycle kinase inhibitor p21 induction. NDGA promoted acetylation of histone H3 in total and p21 gene-associated chromatin. This effect is gene selective, since NDGA has no impact on the p27 gene. NDGA also inhibited HPV-16 E6 gene transcription, which in turn resulted in the restoration of p53 protein levels. The silencing mediator for retinoid and thyroid hormone receptors (SMRT) is a key component of the HDAC3-HDAC4-N-CoR/SMRT complex. We found that NDGA significantly inhibited the transcription of SMRT, which, together with p53, may aid in the detection of the increase of histone H3 acetylation within the p21 gene. Our results suggest that NDGA induces p21 transcription by selectively elevating histone H3 acetylation associated with p21 gene and p53 protein levels via the inhibition of HPV-16 E6 expression.
GAO, PENG; ZHAI, FEI; GUAN, LEI; ZHENG, JIE
The aim of this study was to determine the frequency of abnormal cervical cytology in preoperative cervical cytology of patients diagnosed with uterine papillary serous carcinoma (UPSC) and endometrioid endometrial carcinoma (EEC). In addition, associations between abnormal cervical cytology and clinicopathologic factors were evaluated. In this multicentre study, EEC patients diagnosed at two hospitals from 1999 to 2009 and UPSC patients diagnosed at five hospitals from 1992 to 2009, were included. Revision of the histologic slides was performed systematically and independently by 3 gynecopathologists. Cervical cytology within six months before histopathologic diagnosis of endometrial carcinoma was available for 267 EEC and 80 UPSC patients. Cervical cytology with atypical, malignant, or normal endometrial cells in postmenopausal women was considered as abnormal cytology, specific for endometrial pathology. Abnormal cervical cytology was found in 87.5% of UPSC patients, compared with 37.8% in EEC patients. In UPSC, abnormal cytology was associated with extrauterine spread of disease (P=0.043). In EEC, abnormal cytology was associated with cervical involvement (P=0.034). In both EEC and UPSC patients, abnormal cervical cytology was not associated with survival. In conclusion, abnormal cervical cytology was more frequently found in UPSC patients. It was associated with extrauterine disease in UPSC patients, and with cervical involvement in EEC patients. More prospective research should be performed to assess the true clinical value of preoperative cervical cytology in endometrial cancer patients. PMID:23722512
Roelofsen, Thijs; Geels, Yvette P; Pijnenborg, Johanna M A; van Ham, Maaike A P C; Zomer, Saskia F; van Tilburg, Johanna M Wiersma; Snijders, Marc P M L; Siebers, Albert G; Bulten, Johan; Massuger, Leon F A G
Administration of natural or synthetic agents to inhibit, delay, block, or reverse the initiation and promotional events associated with carcinogenesis opens a new avenue for cancer prevention and treatment to reduce cancer morbidity and mortality. Eugenol, a potential chemopreventive agent, is a component of clove and several other spices such as basil, cinnamon, and bay leaves. A number of reports have shown that eugenol possesses antiseptic, analgesic, antibacterial, and anticancer properties. The present study was undertaken to evaluate the chemopreventive potential of eugenol alone and in combination with a chemotherapeutic agent such as gemcitabine. Eugenol showed dose-dependent selective cytotoxicity toward HeLa cells in comparison to normal cells, pointing to its safe cytotoxicity profile. A combination of eugenol and gemcitabine induced growth inhibition and apoptosis at lower concentrations, compared with the individual drugs. The analysis of the data using a combination index showed combination index values of <1 indicating strong synergistic interaction. The combination thus may enhance the efficacy of gemcitabine at lower doses and minimize the toxicity on normal cells. In addition, the expression analysis of genes involved in apoptosis and inflammation revealed significant downregulation of Bcl-2, COX-2, and IL-1? on treatment with eugenol. Thus, the results suggest that eugenol exerts its anticancer activities via apoptosis induction and anti-inflammatory properties and also provide the first evidence demonstrating synergism between eugenol and gemcitabine, which may enhance the therapeutic index of prevention and/or treatment of cervical cancer. PMID:21939359
Hussain, Arif; Brahmbhatt, Kruti; Priyani, Anita; Ahmed, Musthaq; Rizvi, Tahir A; Sharma, Chhavi
We conducted a hospital-based case-control study in Peru of 198 women with histologically confirmed cervical cancer (173 squamous cell carcinomas and 25 cases of adenocarcinoma\\/adenosquamous carcinoma) and 196 control women. Information on risk factors was obtained by personal interview. Using PCR-based assays on exfoliated cervical cells and biopsy specimens, HPV DNA was detected in 95.3% of women with squamous cell
C Santos; N Muñoz; S Klug; M Almonte; I Guerrero; M Alvarez; C Velarde; O Galdos; M Castillo; J Walboomers; C Meijer; E Caceres
Human papillomaviruses (HPVs) are the primary etiologic agents of cervical cancer. Thus, cervical cancer and other HPV-associated malignancies might be prevented or treated by HPV vaccines. Transmission of papillomavirus may be prevented by the generation of antibodies to capsid proteins L1 and L2 that neutralize viral infection. However, because the capsid proteins are not expressed at detectable levels by infected
Richard B. S Roden; Morris Ling; T.-C Wu
It will likely be more than 20 years before there is unequivocal evidence available that HPV vaccination decreases the incidence of invasive cervical cancer. However, existing data strongly suggests that as many as 440,000 cervical cancer cases and 220,000 deaths due to this malignancy will be prevented with the establishment of an effective worldwide HPV immunization program. PMID:23016781
Background Decay-accelerating factor (DAF) and membrane cofactor protein (MCP) are the key molecules involved in cell protection against autologus complement, which restricts the action of complement at critical stages of the cascade reaction. The cooperative effect of DAF and MCP on the survival of human cervical cancer cell (ME180) has not been demonstrated. Methods In this study we applied, for the first time, short hairpin RNA (shRNA) to knock down the expression of the DAF and MCP with the aim of exploiting complement more effectively for tumor cell damage. Meanwhile, we investigated the cooperative effects of DAF and MCP on the viability and migration, moreover the proliferation of ME180 cell. Results The results showed that shRNA inhibition of DAF and MCP expression enhanced complement-dependent cytolysis (CDC) up to 39% for MCP and up to 36% for DAF, and the combined inhibition of both regulators yielded further additive effects in ME180 cells. Thus, the activities of DAF and MCP, when present together, are greater than the sum of the two protein individually. Conclusion These data indicated that combined DAF and MCP shRNA described in this study may offer an additional alternative to improve the efficacy of antibody-and complement-based cancer immunotherapy.
Cervical cancer, mainly caused by Human Papillomavirus infection, is the leading cancer in Indian women and the second most common cancer in women worldwide. Though there are several methods of prevention of cervical cancer, prevention by vaccination is emerging as the most effective option, with the availability of two vaccines. Several studies have been published examining the vaccine's efficacy, immunogenicity and safety. Questions and controversy remain regarding mandatory vaccination, need for booster doses and cost-effectiveness, particularly in the Indian context.
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Worldwide, cervical cancer is a leading cause of cancer related morbidity and mortality. For over 50 years, cervical cytology has been the gold standard for cervical cancer screening. Because of its profound effect on cervical cancer mortality in nations that have adopted screening programs, the Pap smear is widely accepted as the model screening test. Since its introduction, many studies have analyzed the Pap smear and found that it is not without its shortcomings including low sensitivity for detection of cervical intraepithelial neoplasia 2/3. Additionally, the discovery of infection with the human papillomavirus (HPV) as a necessary step in the development of cervical cancer has led to the development of HPV testing as an adjunct to cytology screening. More recently, researchers have compared HPV testing and cytology in the primary screening of cervical cancer. In this review, we will discuss cytologic testing limitations, the role of HPV DNA testing as an alternative screening tool, the impact of the HPV vaccine on screening, and future directions in cervical cancer screening.
Boone, Jonathan D.; Erickson, Britt K.
Hesperetin, a flavonoid from citrus fruits, has several bioactivities such as anti-inflammatory, antihypertensive, antiatherogenic effects. However, studies elucidating the role and the mechanism(s) of action of hesperetin in cervical cancer are sparse. In this study, we investigated the mechanism of the antiproliferative and apoptotic actions exerted by hesperetin on human cervical cancer SiHa cells. The viability of SiHa cells was evaluated using the MTT assay, apoptosis by acridine orange/ethidium bromide, propidium iodide, TUNEL assay, and Annexin V-Cy3, cell cycle distribution and mitochondrial transmembrane potential using flow cytometry, and apoptotic marker genes using quantitative real-time PCR. The treatment of SiHa cells with hesperetin (IC50, 650 ?m) showed a marked concentration- and time-dependent inhibition of proliferation and induced the G2/M phase in a dose-dependent manner after 24 h. There was an attenuation of mitochondrial membrane potential with increased expression of caspase-3, caspase-8, caspase-9, p53, Bax, and Fas death receptor and its adaptor protein Fas-associated death domain-containing protein (FADD), indicating the participation of both death receptor- and mitochondria-related mechanisms. Furthermore, hesperetin-induced apoptosis was confirmed by TUNEL and Annexin V-Cy3. This study shows that hesperetin exhibits a potential anticancer activity against human cervical cancer cell lines in vitro through the reduction in cell viability and the induction of apoptosis. Altogether, these data sustain our contention that hesperetin has anticancer properties and merits further investigation as a potential therapeutic agent. PMID:22913657
Alshatwi, Ali A; Ramesh, E; Periasamy, V S; Subash-Babu, P
OBJECTIVE: To review the literature regarding the molecular events which occur in the development of uterine cervical cancer, with particular reference to human papillomavirus (HPV) infection. METHODOLOGY: Bibliographic searches of Medline and the ISI citation databases using appropriate keywords, including the following: papillomavirus, cervix, pathology, cyclin, chromosome, heterozygosity, telomerase, smoking, hormones, HLA, immune response, HIV, HSV, EBV. CONCLUSIONS: It has become clear that most cervical neoplasia, whether intraepithelial or invasive, is attributable in part to HPV infection. However, HPV infection alone is not sufficient, and, in a small proportion of cases, may not be necessary for malignant transformation. There is increasing evidence that HPV gene products interfere with cell cycle control leading to secondary accumulation of small and large scale genetic abnormalities. This may explain the association of viral persistence with lesion progression but, in many patients, secondary factors, such as smoking and immune response, are clearly important. However, the mechanisms involved in the interaction between HPV and host factors are poorly understood. ???
Southern, S. A.; Herrington, C. S.
Melatonin was previously shown to inhibit proliferation of MCF-7 human breast cancer cells. In this study the effect of melatonin on MCF-7 cells was further examined, while human cervical carcinoma (HeLa), osteosarcoma (MG-63) and lymphoblastoid (TK6) cells were tested for the first time. Haemocytometer counts, DNA content, flow cytometry and indirect immunofluorescence for nucleolar proteins, actin and ?-tubulin showed no
Annie Panzer; Mona-Lisa Lottering; Pepita Bianchi; Deborah K Glencross; Jenny H Stark; Johanna C Seegers
Objective To investigate the utility of serum squamous cell carcinoma antigen (SCC-Ag) levels upon the diagnosis of recurrent cervical cancer for decision making in patient management. Methods Clinical records from 167 cervical cancer patients who developed recurrence between April 1996 and September 2010 were reviewed. A Cox proportional hazards regression model was used to investigate the prognostic significance of serum SCC-Ag levels at the time of recurrence. The effects of various salvage treatments on survival outcomes of recurrent cervical cancer were examined with respect to serum SCC-Ag levels. Results Serum SCC-Ag levels were elevated (>2.0 ng/mL) in 125 patients (75%) when recurrence was diagnosed. These patients exhibited significantly shorter postrecurrence survival than those with normal SCC-Ag levels (log-rank; p=0.033). Multivariate analyses revealed that an elevated serum SCC-Ag level was an independent prognostic factor for poor postrecurrence survival. In patients with SCC-Ag levels <14.0 ng/mL, radiotherapy or surgery resulted in improved survival compared with chemotherapy or supportive care. In contrast, in patients with SCC-Ag levels of ?14.0 ng/mL, salvage treatment with radiotherapy had only a minimal impact on postrecurrence survival. Conclusion The serum SCC-Ag level measured when cervical cancer recurrence is diagnosed can be useful for deciding upon the appropriate salvage treatment.
Shimura, Kotaro; Yokoi, Takeshi; Sasano, Tomoyuki; Sawada, Kenjirou; Hamasaki, Toshimitsu; Kimura, Tadashi
Human papillomavirus type 16 (HPV16) E6 and E7 oncoproteins are required for cellular transformation and represent candidate targets for HPV-specific and major histocompatibility complex class I-restricted CD8-T-cell responses in patients with cervical cancer. Recent evidence suggests that cross-reactivity repre- sents the inherent nature of the T-cell repertoire. We identified HLA-A2 binding HPV16 E7 variant peptides from human, bacterial, or viral
Katja Nilges; Hanni Hohn; Henryk Pilch; Claudia Neukirch; Kirsten Freitag; P. J. Talbot; Markus J. Maeurer
Human papillomavirus (HPV) infection is a common sexually transmitted infection which a majority of infected women are able to clear by mounting an effective immune response. Individuals with a suboptimal immune response may be at increased risk of persistent HPV infection leading to sequelae of various grades of dysplasias and / or associated malignancy. Both cell intrinsic and extrinsic phenomena work in concert to bring about oncogenesis. Cell intrinsic factors for cervical carcinogenesis are: integration of the viral genome into the genome of the host's cell which correlates with the progression of low grade lesions into high grade ones, inactivation of tumor suppressor genes like p53 and pRB by HPV oncoproteins particularly E6 and E7, deregulation of cell cycle regulators, host DNA synthesis and apoptosis. Cell extrinsic elements include factors contributing towards immune tolerance; some incriminated in the multistep carcinogenesis of HPV induced cervical cancer are: immunoregulatory enzyme indoleamine 2,3-dioxygenase expressing antigen presenting cells, low numbers of invariant Natural Killer T cells, anergic cytotoxic T lymphocytes, regulatory T cells (Tregs), an immunoregulatory microenvironment comprising of increased IL10, TGF and reduced IL2; reduced intralesional ratios of effectors (CD4 and CD8) vs. Tregs; and different types of Tregs in the lesions of invasive squamous cell carcinoma. Notch signaling plays a crucial role in regulating T cell differentiation and activation including induction of Tregs. Increased expression of Notch receptor-Jagged 1 and number of Tregs were seen in invasive disease when compared to precancer in cervical cancer. Tregs impart their function either through cytokines or by cell to cell contact. Investigation of the consequences of interference of Notch signaling in terms of the dynamics of intratumoral Tregs in cervical cancer would be interesting. PMID:19901438
Jayshree, R S; Sreenivas, Adurthi; Tessy, Maliekal; Krishna, Sudhir
Phytochemicals present in tea, particularly polyphenols, have anticancer properties against several cancer types. However, studies elucidating the role and the mechanism(s) of action of tea polyphenols in cervical cancer are sparse. In this study, we investigated the mechanism of antiproliferative and apoptotic actions exerted by tea polyphenols on human papilloma virus-18-positive HeLa cervical cancer cells. Treatment of green tea polyphenol (-)-epigallocatechin gallate (EGCG) and black tea polyphenol theaflavins (TF) in HeLa cells showed a marked concentration- and time-dependent inhibition of proliferation and induced sub-G1 phase in a dose-dependent manner after 24 h. There was an attenuation of mitochondrial membrane potential with the increase of reactive oxygen species generation, p53 expression, Bax/Bcl-2 ratio, cytochrome-c release, and cleavage of procaspase-3 and -9 and poly(ADP-ribose)-polymerase, indicating the participation of a mitochondria related mechanism. In addition, EGCG as well as TF inhibited activation of Akt and nuclear factor-kappaB (NF-kappaB) via blocking phosphorylation and subsequent degradation of inhibitor of kappaBalpha and kappaBbeta subunits, thereby downregulating cyclooxygenase-2. Additionally, the protein level of cyclin D1, a transcriptional target of NF-kappaB, was also reduced significantly. Thus, we can conclude that tea polyphenols inhibit the growth of cervical cancer cells by inducing apoptosis and regulating NF-kappaB and Akt. PMID:21776820
Singh, Madhulika; Singh, Richa; Bhui, Kulpreet; Tyagi, Shilpa; Mahmood, Zafar; Shukla, Yogeshwer
In this clinical trial, women with cervical cancer that has recurred or demonstrated resistance to previous chemotherapy and that cannot be treated surgically will be treated with the drug ixabepilone.
... ensure coverage of cervical cancer screening for private health insurance Twenty-six states and the District of Columbia ... large employers. Women who have self-insured based health insurance should check with their health plans to see ...
... Local Program Web Badges Cancer Home Breast and Cervical Cancer Prevention and Treatment Act of 2000 On October ... William Clinton signed into law the Breast and Cervical Cancer Prevention and Treatment Act of 2000 (Public Law ...
Objective. The aim of this study was to describe recruitment strategies for a single-visit cervical cancer prevention study.Methods. From January through December 1999, low-income, predominantly Latino women were recruited to participate in a single-visit cervical cancer prevention study. For the first 6 months, all women who had ever visited one of two community-based study clinics were invited to participate (clinic
W. R. Brewster; H. Anton-Culver; A. Ziogas; J. Largent; S. Howe; F. A. Hubbell; A. Manetta
Dehydroepiandrosterone (DHEA) has a protective role against epithelial-derived carcinomas; however, the mechanisms remain unknown. We determined the effect of DHEA on cell proliferation, the cell cycle and cell death in three cell lines derived from human uterine cervical cancers infected or not with human papilloma virus (HPV). We also determined whether DHEA effects are mediated by estrogen and androgen receptors. Proliferation of C33A (HPV-negative), CASKI (HPV16-positive) and HeLa (HPV18-positive) cells was evaluated by violet crystal staining and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction. Flow cytometry was used to evaluate the phases of the cell cycle, and cell death was detected using a commercially available carboxyfluorescein apoptosis detection kit that determines caspase activation. DNA fragmentation was determined using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Flutamide and ICI 182,780 were used to inhibit androgen and estrogen receptors, respectively, and letrozol was used to inhibit the conversion of DHEA to estradiol. Our results show that DHEA inhibited cell proliferation in a dose-dependent manner in the three cell lines; the DHEA IC(50) doses were 50, 60 and 70 mum for C33A, CASKI and HeLa cells, respectively. The antiproliferative effect was not abrogated by inhibitors of androgen and estrogen receptors or by an inhibitor of the conversion of testosterone to estradiol, and this effect was associated with an increase in necrotic cell death in HPV-negative cells and apoptosis in HPV-positive cells. These results suggest that DHEA strongly inhibits the proliferation of cervical cancer cells, but its effect is not mediated by androgen or estrogen receptor pathways. DHEA could therefore be used as an alternative in the treatment of cervical cancer. PMID:19702826
Girón, Roma A; Montaño, Luis F; Escobar, María L; López-Marure, Rebeca
ObjectivesTumor stage, age, and cell type are well-characterized predictors for cervical cancer survival; socioeconomic factors may also play an important role. The purpose of this study is to estimate cervical cancer survival by socioeconomic indicators and race\\/ethnicity among elderly women diagnosed with cervical cancer.
Ann L. Coker; Xianglin L. Du; Shenying Fang; Katherine S. Eggleston
Purpose: The squamous cell carcinoma (SCC) antigen is still considered the most accurate serologic tumor marker in cervical carcinoma. We assessed the contribution of the SCC assay to the detection of recurrences in patients treated with radiotherapy. Methods and Materials: The pattern of recurrence and follow-up data were prospectively recorded for 135 patients. Of the 135 patients, 103 (76.3%) had primary cervical carcinoma and 32 (23.7%) had already experienced disease recurrence that had been successfully treated with surgery (n = 2), surgery plus radiotherapy (n = 2), radiotherapy (n = 5), or concomitant chemoradiotherapy (n = 23). The follow-up evaluations (chest X-ray, abdominopelvic magnetic resonance imaging, gynecologic examination with colposcopy, Papanicolaou smear, and SCC assay) were performed at 6-month intervals; the evaluation was done earlier if recurrent disease was suspected. The median follow-up time was 29 months (range, 6-131). The SCC serum levels were assayed, and a cost analysis was done. Results: A total of 481 SCC determinations were performed. Of the 135 patients, 43 (31.8%) experienced disease recurrence. The SCC levels were higher in those with recurrent disease than in the disease-free patients. Elevation of SCC was documented in 34 (79.1% sensitivity) of 43 recurrences before symptoms appeared. Of the 38 patients with serum SCC elevation, 34 developed a recurrence (positive predictive value, 89.5%). Of the 97 patients with negative SCC serum levels, 88 had negative findings at the clinicoradiologic evaluation (negative predictive value, 90.7%). A simplified approach (SCC plus gynecologic examination) was evaluated. Compared with the complete follow-up program, the rate of missed recurrence was 2.2%. The total projected cost per patient for 5 years of follow-up for the simplified procedure was approximately 12.2-fold lower than the standard approach. Conclusions: Our results have shown that a simplified diagnostic approach, including the SCC assay and gynecologic examination, can detect a high rate of recurrence from cervical cancer, with a very favorable cost-effective profile.
Forni, Franca [Institute of Biochemistry and Clinical Biochemistry, Catholic University, Rome (Italy); Ferrandina, Gabriella [Gynecologic Oncology Unit, Catholic University, Rome (Italy); Department of Oncology, Catholic University, Campobasso (Italy); Deodato, Francesco [Department of Oncology, Catholic University, Campobasso (Italy); Macchia, Gabriella [Department of Oncology, Catholic University, Campobasso (Italy)], E-mail: email@example.com; Morganti, Alessio G. [Department of Oncology, Catholic University, Campobasso (Italy); Department of Radiotherapy, Catholic University, Rome (Italy); Smaniotto, Daniela; Luzi, Stefano; D'Agostino, Giuseppe; Valentini, Vincenzo; Cellini, Numa [Department of Radiotherapy, Catholic University, Rome (Italy); Giardina, Bruno [Institute of Biochemistry and Clinical Biochemistry, Catholic University, Rome (Italy); Scambia, Giovanni [Gynecologic Oncology Unit, Catholic University, Rome (Italy); Department of Oncology, Catholic University, Campobasso (Italy)
Genetic changes orchestrated by human papillomaviruses are the most important known factors in carcinogenesis of the uterine cervix. However, it is clear that additional genetic events are necessary for tumour progression. We have used comparative genomic hybridization to document non-random chromosomal gains and losses within a subset of 37 cervical carcinomas matched for clinical stage Ib, but with different lymph
D G Allen; D J White; A-M Hutchins; J P Scurry; S N Tabrizi; S M Garland; J E Armes
Cervical cancer is a major health problem worldwide and is the most frequent cause of cancer in women in India. Early detection and affordable drugs with clinical efficacy have to go hand-in-hand in order to comprehensibly address this serious health challenge. Plant-based drugs with potent anticancer effects should add to the efforts to find a cheap drug with limited clinical side effects. Keeping this very purpose in mind, an attempt has been made in this review to explore the potential of plant extracts or constituents known to exhibit antitumorigenic activity or exert cytotoxic effect in human cervical carcinoma cells. Alkaloids such as those isolated from C. vincetoxicum and T. Tanakae, naucleaorals A and B, isolated from the roots of N. orientalis, (6aR)-normecambroline, isolated from the bark of N. dealbata appear promising in different human cervical carcinoma cells with the IC50 of 4.0-8 ?g/mL. However, other compounds such as rhinacanthone and neolignans isolated from different plants are not far behind and kill cervical cancer cells at a very low concentrations. Among plant extracts or its constituents that enhance the effect of known anticancer drugs, noni, derived from the plant M. citrifolia perhaps is the best candidate. The cytotoxic potency and apoptotic index of cisplatin was found to significantly enhanced in combination with noni in different human cervical carcinoma cells and it therefore holds significance as promising herbal-based anticancer agent. However, efficacy needs to be further investigated in various cervical cell lines and more importantly, in in vivo cervical cancer models for possible use as an alternative and safe anticancer drug. PMID:23886123
Background To investigate the significance of monitoring the levels of the serum squamous cell carcinoma antigen (SCC-Ag) for the detection of recurrent disease in patients with cervical cancer treated by concurrent chemoradiotherapy. Methods The records of 112 patients with cervical cancer were reviewed. Serum SCC-Ag levels were measured at regular follow-up visits. A SCC-Ag level of 2 ng/mL was considered the upper limit of normal. Biochemical failure was defined as two consecutively increasing SCC-Ag values above normal. Recurrent disease was confirmed by histologic and radiographic studies. Results Eighteen patients (16%) developed recurrent disease. Sixteen patients had initially elevated SCC-Ag, post-treatment normalization of SCC-Ag, and tumor recurrence. The SCC-Ag difference (?SCC-Ag), defined as the difference between the last value after two consecutively increases above normal and the value immediately before the elevation, had good clinical performance in predicting cancer recurrence. The cutoff value of ?SCC-Ag was 0.95 ng/mL. Conclusions SCC-Ag is a relatively good method for the detection of disease recurrence in patients with cervical cancer who were treated by concurrent chemoradiotherapy.
This study determined the distribution of high-risk HPV type infection in cervical cancer using newly developed oligonucleotide chips (HPVDNAChips™). The study subjects included 80 cases of cervical neoplasia and 746 controls with a normal Pap smear. For HPV genotyping, the commercially available HPVDNAChips™ was used. The risk of cervical cancer was increased in women with a family history of cervical
Sang Ah Lee; Daehee Kang; Sang Soo Seo; Jeongmi Kim Jeong; Keun Young Yoo; Yong Tark Jeon; Jae Weon Kim; Noh Hyun Park; Soon Beom Kang; Hyo Pyo Lee; Yong Sang Song
KEYWORDS Human papillmoa virus; cervical cancer; genetic susceptibility; polymorphisms ABSTRACT Research in relation to the etiology of cervical cancer has made substantial progress in the last two decades both in scientific and operational terms. In many countries, HPV is the most common sexually transmitted infection (STI) and cervical cancer remains the second most common cancer among women worldwide. Although high
Sreekala Nair; M Radhakrishna Pillai
Cervical cancer and precancerous lesions of the genital tract are major threats to the health of women world- wide. The introduction of screening tests to detect cer- vical cancer precursor lesions has reduced cervical cancer rates in the developed world, but not in devel- oping countries. Human papillomavirus (HPV) is the primary etiologic agent of cervical cancer and dyspla- sia.
Ali Mahdavi; Bradley J. Monk
Cervical cancer is a leading cause of cancer deaths in woman worldwide. New approach to the analysis of risk factors and management of cervical cancer is discussed in this study. We identified the combined patterns of cervical cancer risk factors including demographic, environmental and genetic factors using induction technique. We compared logistic regression and a decision tree algorithm, CHAID (Chi-squared
Seung Hee Ho; Sun Ha Jee; Jong-eun Lee; Jong Sup Park
... service covered? Search Medicare.gov for covered items Cervical & vaginal cancer screenings How often is it covered? Medicare Part ... doctor accepts assignment . Related resources National Cancer Institute—cervical cancer information CDC—cervical cancer information U.S. Preventive Services ...
Cervical cancer is the second most common malignant neoplasm in women, in terms of incidence and mortality rates worldwide,\\u000a and is associated with excessive inflammation. This involves the expression of both pro- and anti-apoptotic proteins that\\u000a have varied effect on tumor growth and metastasis. The objective of the present study was to elucidate the effect of hydrogen\\u000a peroxide (H2O2) on
Mayank Singh; Neeta Singh
p63 and p73, the p53 family proteins, are similar to p53 in many aspects: structural homology, transactivation of p53-downstream genes, and induction of apoptosis. Interestingly, they also differ from p53; in particular, they are not inhibited by viral oncoproteins such as HPV E6. This feature would be an advantage over p53 in HPV-associated cancers and therefore, we evaluated the therapeutic potentials of various p53 family proteins (p73alpha, p73beta, p63alpha and p63gamma) against HPV-infected cervical cancers. In clonogenic assay, exogenous expression of p73alpha, p73beta and p63gamma inhibited the colony formation of HPV-positive cervical cancer cells under G418- selection while p53 could not. Recombinant adenoviruses Ad/CMVp73alpha, Ad/CMVp73beta and Ad/CMVp63gamma induced potent apoptosis in all infected cervical cancers (CasKi, SiHa, HeLa, C33A, SNU682, SNU17, SNU1005, SNU703), irrespective of their HPV-infection status. Unfortunately however, Ad/CMVp73alpha, Ad/CMVp73beta, and Ad/CMVp63gamma inhibited also normal cells such as endothelial cells, fibroblasts, and keratinocytes thus, tumorspecific promoter was indispensable to the p53 family proteins-based therapy. Here we report a stringent tumor killing by p73beta in combination with ESM6, a synthetic promoter targeting the DNA tumor virusassociated cancers. Recombinant adenoviruses encoding p73beta by ESM6 (Ad/ESM6p73beta and Ad/ESM6p73bENH) expressed p73beta and induced apoptosis only in the cancer cells but not in normal cells. Collectively, we suggest that the p53 family proteins are potent therapeutic agents for HPV-associated uterine cervical cancers and ESM6 mediated expression of the p53 family proteins would be a safe and strong tumor targeting strategy. PMID:17012841
Lee, Jae-Jung; Kim, Soyeon; Yeom, Young Il; Heo, Dae Seog
In India, cervical cancer is the most common woman-related cancer, followed by breast cancer. The rate of cervical cancer in India is fourth worldwide. Two vaccines, Gardasil and Cervarix, both targeting HPV-16 and 18 which account for 70% of invasive cervical carcinomas, are licensed in the United States and numerous countries worldwide. Both vaccine formulations have shown excellent efficacy with minimal toxicity in active female population but numerous questions arise in vaccinating like cost effectiveness, lack of proven efficacy against other HPV strains, social acceptance of HPV vaccination and other ethical issues. The main objective of this study is to emphasis the advantages and disadvantages of the vaccination in India. PMID:23725195
Farhath, Seema; Vijaya, P P; Mumtaj, P
Background. Cutaneous lymphangitis carcinomatosis from cervical carcinoma is a very rare form of tumor metastatization; only anecdotal cases are reported in the literature. Most of the patients with skin relapse experienced metastasis as a single or multiple nodules.Case. A case of cutaneous lymphangitis carcinomatosis mimicking contact dermatitis was diagnosed at our institution in a patient affected by cervical carcinoma stage
Innocenza Palaia; Roberto Angioli; Giuseppe Cutillo; Natalina Manci; Pierluigi Benedetti Panici
Most cervical cancer is caused by Human papillomavirus (HPV). Protection against the major cancer-causing serotypes of this virus by vaccination is now a reality for New Zealand women. Internationally two manufacturers have candidate HPV vaccines: the bivalent Cervarix (GlaxoSmith Kline) and the tetravalent Gardasil (CSL and Merck & Co). This article focuses on Gardasil, as this vaccine is now available
N. Desmond; H. Petousis-Harris; N. Turner
Purpose: To investigate the potential of irradiation in combination with drugs targeting the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor (DR)4 and DR5 and their mechanism of action in a cervical cancer cell line. Methods and Materials: Recombinant human TRAIL (rhTRAIL) and the agonistic antibodies against DR4 and DR5 were added to irradiated HeLa cells. The effect was evaluated with apoptosis and cytotoxicity assays and at the protein level. Membrane receptor expression was measured with flow cytometry. Small-interfering RNA against p53, DR4, and DR5 was used to investigate their function on the combined effect. Results: rhTRAIL and the agonistic DR4 and DR5 antibodies strongly enhanced 10-Gy-induced apoptosis. This extra effect was 22%, 23%, and 29% for rhTRAIL, DR4, and DR5, respectively. Irradiation increased p53 expression and increased the membrane expression of DR5 and DR4. p53 suppression, as well as small-interfering RNA against DR5, resulted in a significant downregulation of DR5 membrane expression but did not affect apoptosis induced by irradiation and rhTRAIL. After small-interfering RNA against DR4, rhTRAIL-induced apoptosis and the additive effect of irradiation on rhTRAIL-induced apoptosis were abrogated, implicating an important role for DR4 in apoptosis induced through irradiation in combination with rhTRAIL. Conclusion: Irradiation-induced apoptosis is strongly enhanced by targeting the pro-apoptotic TRAIL receptors DR4 or DR5. Irradiation results in a p53-dependent increase in DR5 membrane expression. The sensitizing effect of rhTRAIL on irradiation in the HeLa cell line is, however especially mediated through the DR4 receptor.
Maduro, John H. [Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen (Netherlands); Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen (Netherlands); Vries, Elisabeth de [Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen (Netherlands); Meersma, Gert-Jan [Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen (Netherlands); Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen (Netherlands); Hougardy, Brigitte; Zee, Ate G.J. van der [Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen (Netherlands); Jong, Steven de [Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen (Netherlands)], E-mail: firstname.lastname@example.org
Purpose of review: The aim of this study was to describe fertility preservation methods to improve quality of life of early stages of cervical cancer. Recent finding: Although definite treatment of early stages of cervical cancer including stages IA,IB1 and IIA non-bulky is radial hysterectomy, this method is used in perimenopousal period in which fertility preservation is not important. Whenever fertility preservation is so important, some methods like radical trachelectomy and laparoscopic lymphadenectomy are used to rule out lymphatic metastases. Summary: If any visible lesion on cervix is found, pelvic MRI is helpful and during operation, trachelectomy samples are sent for frozen section and margin study. Radical trachelectomy is done vaginal or abdominal. Overall relapse rate of cervical cancer in radical trachelectomy and radical hysterectomy is the same. Complications of radical trachelectomy include chronic vaginal discharge, abnormal uterine bleeding, dysmenorrhea, inflammation and ulcer due to cercelage, amenorrhea, cervical stenosis and pregnancy complications following trachelectomy including 2nd trimester abortion and premature labor following cervical prematurity.The best and preferred method of labor is cesarean section. Neoadjuant chemotherapy followed by radical trachelectomy in large cervical lesions is a suitable treatment. Ultraconservative operations like large cold knife conization, simple trachelectomy with laparoscopic lymphadenectomy and sentinel lymph node mapping are suitable for very small lesions.
Karimi-Zarchi, Mojgan; Mousavi, Azamsadat; Gilani, Mitra Modares; Barooti, Esmat; Miratashi-Yazdi, Ashrafosadat; Dehghani, Atefe
Leea indica is a medicinal plant traditionally used to treat cancer. Through bioassay-guided approach, we isolated mollic acid arabinoside (MAA), for the first time from Leea indica. Here, we present the apoptosis-inducing effect of MAA on Ca Ski cervical cancer cells. Based on DAPI staining, MAA-treated cells manifested nuclear shrinkage, condensation, and fragmentation. We further confirmed the fragmentation of DNA using TUNEL assay. During early apoptosis, MAA caused the perturbation of plasma membrane through externalization of PS, followed by the formation of apoptotic blebs. Prior to these events, MAA triggered rapid dissipation of the mitochondrial membrane potential. In the upstream, MAA increased the expression of Bax, decreased the expression of Bcl-2, and augmented the Bax/Bcl-2 ratio. These findings suggested that MAA induced mitochondrial-mediated apoptosis in Ca Ski cells and thus provide the scientific explanation for the traditional application of this herbal medicine in cancer treatment.
Wong, Yau Hsiung; Abdul Kadir, Habsah
The incidence of cervical cancer is high among Southeast Asian American women, but their participation in preventive cervical\\u000a cancer screening is alarmingly low. This paper reviews the literature on factors associated with participation in cervical\\u000a cancer screening among women of Vietnamese, Cambodian and Hmong descent in the United States. These factors include acculturation,\\u000a age, marital status, knowledge about cervical cancer,
Ivy K. HoKhanh; Khanh T. Dinh
The main aetiology of cervical cancer is infection with high risk human papillomavirus (HPV). Cervical cancer is almost 100% curable if detected in the early stages. Thus, information about the presence and levels of HPV in patient samples has high clinical value. As current screening methods, such as the Pap smear test, are highly subjective and in many cases show
Kamila Magdalena Ostrowska; Alison Malkin; Aidan Meade; John O'Leary; Cara Martin; Cathy Spillane; Hugh James Byrne; Fiona Maria Lyng
MicroRNAs (miRNAs) play important roles in cancer development. By cloning and sequencing of a HPV16+ CaSki cell small RNA library, we isolated 174 miRNAs (including the novel miR-193c) which could be grouped into 46 different miRNA species, with miR-21, miR-24, miR-27a, and miR-205 being most abundant. We chose for further study 10 miRNAs according to their cloning frequency and associated
Xiaohong Wang; Shuang Tang; Shu-Yun Le; Robert Lu; Janet S. Rader; Craig Meyers; Zhi-Ming Zheng; Dong-Yan Jin
Screening with Pap cytology has substantially reduced cervical cancer morbidity and mortality during the last 50 years in high-income countries. Unfortunately, in resource-poor countries, Pap screening has either not been effectively implemented or has failed to reduce cervical cancer rates. Cervical cancer in these countries thus remains a major public health problem. Infection with certain human papillomavirus (HPV) types is
Eduardo L. Franco; François Coutlée; Alex Ferenczy
A Phase II trial of edatrexate in patients with recurrent cervical carcinoma was conducted by the Gynecologic Oncology Group (GOG). Twenty patients were treated with edatrexate at a dose of 80 mg/m2 i.v. weekly for 5 consecutive weeks per cycle. Four patients received an inadequate trial and were inevaluable for response. Among the 16 patients evaluable for response, there were no objective responses: 50% had stable disease, 50% had progressive disease. All 20 patients were evaluable for toxicity, predominantly stomatitis and bone marrow suppression were substantial. Grades 3-4 bone marrow toxicity were observed in eight of 20 (40%) patients, and there were two deaths due to neutropenic sepsis. Fanconi's syndrome, possibly treatment related, was seen in two patients. Edatrexate administered in this dose and schedule has no demonstrated activity and has severe toxicity in patients with previously-treated advanced cervical cancer. PMID:9020294
Broun, E R; Iseminger, K A; Rose, P G; Lentz, S L; Malfetano, J H; Lincoln, S; Mannel, R
Striking shifts in gene expression at different time points in the process of cervical cancer development, from human papillomavirus (HPV) infection to invasive carcinoma, may help reveal how HPV goads cervical cells into becoming cancerous and why the process of carcinogenesis varies so much from woman to woman.
Alteration of the apoptosis pathway, as well as the presence of human papilloma virus (HPV), has been linked to the proliferative capacity and drug resistant phenotype of SiHa cervical cancer. We investigated the roles of E6 and E7 HPV oncoproteins in the expression of apoptosis regulating genes in cervical cancer cells that contain the characteristics of apoptosis resistance, and also
Despite its history of success in cancer screening, Pap cytol- ogy has important limitations, particularly its high false- negative rate, which carries important public health impli- cations. Since the mid-1990s, there has been substantial interest in the use of human papillomavirus (HPV) DNA testing in cervical cancer screening under the premise that the testing of cervical cells for the causative
Eduardo L. Franco
Background: Our aim was to examine the structural integrity of red blood cells in cervical cancer patients by measuring the concentrations of thiobarbituric acid reactive substances (TBARS), antioxidant status, cholesterol\\/phospholipid (C\\/P) molar ratio, enzyme activity and osmotic fragility of erythrocytes. Methods: This study has been conducted on 32 adult female cervical cancer patients and an equal number of age- and
K. Kolanjiappan; S. Manoharan; M. Kayalvizhi
Cervical cancer is one of the most common cancers among women in the world. 6-Shogaol is a natural compound isolated from the rhizome of ginger (Zingiber officinale). In this paper, we demonstrated that 6-shogaol induced apoptosis and G2/M phase arrest in human cervical cancer HeLa cells. Endoplasmic reticulum stress and mitochondrial pathway were involved in 6-shogaol-mediated apoptosis. Proteomic analysis based on label-free strategy by liquid chromatography chip quadrupole time-of-flight mass spectrometry was subsequently proposed to identify, in a non-target-biased manner, the molecular changes in cellular proteins in response to 6-shogaol treatment. A total of 287 proteins were differentially expressed in response to 24 h treatment with 15 ?M 6-shogaol in HeLa cells. Significantly changed proteins were subjected to functional pathway analysis by multiple analyzing software. Ingenuity pathway analysis (IPA) suggested that 14-3-3 signaling is a predominant canonical pathway involved in networks which may be significantly associated with the process of apoptosis and G2/M cell cycle arrest induced by 6-shogaol. In conclusion, this work developed an unbiased protein analysis strategy by shotgun proteomics and bioinformatics analysis. Data observed provide a comprehensive analysis of the 6-shogaol-treated HeLa cell proteome and reveal protein alterations that are associated with its anticancer mechanism.
Liu, Qun; Peng, Yong-Bo; Qi, Lian-Wen; Cheng, Xiao-Lan; Xu, Xiao-Jun; Liu, Le-Le; Liu, E-Hu; Li, Ping
Virtually all cervical cancers are caused by HPV infections, with just two HPV types, 16 and 18, responsible for about 70 percent of all cases, according to the National Cancer Institute. Scientists have presumed for decades that the cervical cancers that develop from HPV infection arise in a specific location in the cervix. Now, new research from Brigham and Women's Hospital (BWH) in close collaboration with Harvard Medical School and the Agency for Science Technology and Research in Singapore finds that a specific population of cells that are found only in the region of the cervix called the "squamo-columnar junction" can become cancerous when infected with HPV while other cells in the cervix apparently do not. This research is published online the week of June 11 in the Proceedings of the National Academy of Sciences (PNAS).
The aim of this study is to develop a new screening method, molecular beacon (MB) imaging, for detection of cervical cancer and to determine its potential clinical applications by examining the sensitivity and specificity of target-specific MBs. Two target-specific molecular beacons were designed and synthesized for survivin and HPV16E6 mRNA. The two designed MBs and a random control MB were used to detect cervical cancer cell lines and a normal cell line. RT-PCR and western blot targeting survivin and HPV16E6 was done for verification. Furthermore the sensitivity and the specificity of the survivin and HPV16E6 mRNA MBs were examined in smears from 125 clinical cervical patients. The survivin and HPV16E6 mRNA MBs generated a strong fluorescence signal in cervical cancer cell lines, but not in the normal cell line, while the random control MB did not generated any signal in both cell lines. The fluorescence intensity correlated well with the gene expression levels in the cells determined by reverse transcription-PCR and Western blot analysis. The clinical sensitivity and the specificity of survivin MB-FITC were 72.5 and 77% while those of HPV16E6 MB-Cy3 were 96.1% and 71.6%, respectively. A parallel test of the two target MBs showed that the sensitivity increased to 98% and the specificity was 70.2%. The survivin and HPV16E6 mRNA MBs showed good reliability and sensitivity. They have great potential for clinical use in cervical cancer screening. PMID:23421207
Han, Suxia; Li, Ling; Jia, Xi; Ou, Wei; Ma, Jinlu; Wang, Hao; Zhao, Jing; Zhu, Qing
Cluster of differentiation 146 (CD146) is an endothelial cell adhesion molecule which is overexpressed in various types of malignant cancer, including ovarian cancer. However, whether CD146 is overexpressed in another two types of gynecological cancer, cervical cancer and endometrial cancer, remains unclear. In the present study, we showed that CD146 expression levels were higher in cells from cervical cancer and endometrial cancer compared with their corresponding normal tissues, using anti-CD146 mouse antibody AA4 (mAb AA4) and that mAb AA4 exhibited a high performance for specificity, sensitivity and positive predictive value in the detection of these two types of cancer. CD146 expression was positively and significantly correlated with the pathological subtype of cervical cancer and with the histological grade and depth of myometrial invasion in endometrial cancer. In addition, we confirmed that CD146 is present in the majority of blood vessels in cervical and endometrial cancer, suggesting that CD146 may be actively implicated in the metastasis of cervical and endometrial cancer via the vascular system. Thus, this study provides insights for further development of CD146 mAb in the detection of gynecological malignant cancer types and implies that a combined treatment strategy of anti-CD146 immunotherapy with other traditional chemo- or radiotherapy treatments may be a promising approach against cervical and endometrial cancer.
ZHANG, HAOFENG; ZHANG, JUN; WANG, ZHAOQING; LU, DI; FENG, JING; YANG, DONGLING; CHEN, XIUQIN; YAN, XIYUN
In Indian traditional medicine, Boerhaavia diffusa (punarnava) roots have been widely used for the treatment of dyspepsia, jaundice, enlargement of spleen, abdominal pain and as an anti-stress agent. Pharmacological evaluation of the crude ethanolic extract of B. diffusa roots has been shown to possess antiproliferative and immunomodulatory properties. The extract of B. diffusa was studied for anti-proliferative effects on the growth of HeLa cells and for its effect on cell cycle. Bio-assays of extracts from B. diffusa root showed that a methanol?:?chloroform fraction (BDF 5) had an antiproliferative effect on HeLa cells. After 48?h of exposure, this fraction at a concentration of 200??g?mL?1 significantly reduced cell proliferation with visible morphological changes in HeLa cells. Cell cycle analysis suggests that antiproliferative effect of BDF 5 could be due to inhibition of DNA synthesis in S-phase of cell cycle in HeLa cells, whereas no significant change in cell cycle was detected in control cells. The fraction BDF 5 caused cell death via apoptosis as evident from DNA fragmentation and caspase-9 activation. Thus the extract has potential to be evaluated in detail to assess the molecular mechanism-mediated anticancer activities of this plant.
Srivastava, Rakhi; Saluja, Daman; Dwarakanath, Bilikere S.; Chopra, Madhu
The optoelectronic method is one of the most promising concepts of biophysical program of the diagnostics of CIN and cervical cancer. Objectives of the work are evaluation of sensitivity and specificity of the optoelectronic method in the detection of CIN and cervical cancer. The paper shows correlation between the pNOR number and sensitivity/specificity of the optoelectronic method. The study included 293 patients with abnormal cervical cytology result and the following examinations: examination with the use of the optoelectronic method — Truscreen, colposcopic examination, and histopathologic biopsy. Specificity of the optoelectronic method for LGSIL was estimated at 65.70%, for HGSIL and squamous cell carcinoma of cervix amounted to 90.38%. Specificity of the optoelectronic method used to confirm lack of cervical pathology was estimated at 78.89%. The field under the ROC curve for the optoelectronic method was estimated at 0.88 (95% CI, 0.84-0.92) which shows high diagnostic value of the test in the detection of HGSIL and squamous cell carcinoma. The optoelectronic method is characterised by high usefulness in the detection of CIN, present in the squamous epithelium and squamous cell carcinoma of cervix.
Pruski, D.; Przybylski, M.; K?dzia, W.; K?dzia, H.; Jagielska-Pruska, J.; Spaczy?ski, M.
Cervical cancer still remains the most common cancer affecting the Indian women. India alone contributes 25.41% and 26.48% of the global burden of cervical cancer cases and mortality, respectively. Ironically, unlike most other cancers, cervical cancer can be prevented through screening by identifying and treating the precancerous lesions, any time during the course of its long natural history, thus preventing the potential progression to cervical carcinoma. Several screening methods, both traditional and newer technologies, are available to screen women for cervical precancers and cancers. No screening test is perfect and hence the choice of screening test will depend on the setting where it is to be used. Similarly, various methods are available for treatment of cervical precancers and the selection will depend on the cost, morbidity, requirement of reliable biopsy specimens, resources available, etc. The recommendations of screening for cervical cancer in the Indian scenario are discussed.
Mishra, Gauravi A.; Pimple, Sharmila A.; Shastri, Surendra S.
The level of beta-galactoside alpha2,6-sialyltransferase I (ST6Gal I) mRNA, encoded by the gene siat1, is increased in malignant tissues. Expression is regulated by different promoters - P1, P2 and P3 - generating three mRNA isoforms H, X and YZ. In cervical cancer tissue the mRNA isoform H, which results from P1 promoter activity, is increased. To study the regulation of P1 promoter, different constructs from P1 promoter were evaluated by luciferase assays in cervical and hepatic cell lines. Deletion of a fragment of 1048 bp (-89 to +24 bp) increased 5- and 3-fold the promoter activity in C33A and HepG2 cell lines, respectively. The minimal region with promoter activity was a 37 bp fragment in C33A cells. The activity of this region does not require the presence of an initiator sequence. In HepG2 cells the minimal promoter activity was detected in the 66 bp fragment. Sp1 (-32) mutation increased the promoter activity only in HepG2 cells. HNF1 mutation decreased promoter activity in HepG2 cell line but not in C33A cells. We identified a large region that plays a negative regulation role. The regulation of promoter activity is cell type specific. Our study provides new insights into the complex transcriptional regulation of siat1 gene. PMID:22581331
Milflores-Flores, Lorena; Millán-Pérez, Lourdes; Santos-López, Gerardo; Reyes-Leyva, Julio; Vallejo-Ruiz, Verónica
Cervical cancer screening is ideally suited for the development of biomarkers due to the ease of tissue acquisition and the well-established histological transitions. Furthermore, cell and biologic fluid obtained from cervix samples undergo specific molecular changes that can be profiled. However, the ideal manner and techniques for preparing cervical samples remains to be determined. To address this critical issue a patient screening protein and nucleic acid collection protocol was established. RNAlater was used to collect the samples followed by proteomic methods to identify proteins that were differentially expressed in normal cervical epithelial versus cervical cancer cells. Three hundred ninety spots were identified via 2-D DIGE that were expressed at either higher or lower levels (>three-fold) in cervical cancer samples. These proteomic results were compared to genes in a cDNA microarray analysis of microdissected neoplastic cervical specimens to identify overlapping patterns of expression. The most frequent pathways represented by the combined dataset were: cell cycle: G2/M DNA damage checkpoint regulation; aryl hydrocarbon receptor signaling; p53 signaling; cell cycle: G1/S checkpoint regulation; and the ER stress pathway. HNRPA2B1 was identified as a biomarker candidate with increased expression in cancer compared to normal cervix and validated by Western blot. PMID:21136816
Rader, Janet S; Malone, James P; Gross, Julia; Gilmore, Petra; Brooks, Rebecca A; Nguyen, Loan; Crimmins, Dan L; Feng, Sheng; Wright, Jason D; Taylor, Nicholas; Zighelboim, Israel; Funk, Margo C; Huettner, Phyllis C; Ladenson, Jack H; Gius, David; Townsend, R Reid
Objective We compared the immune system state in metastatic tumour draining lymph nodes (mTDLN) and metastasis free TDLN (mfTDLN) in\\u000a 53 early stage cervical cancer patients to assess whether the presence of metastatic tumour cells worsen the balance between\\u000a an efficacious anti-tumour and a tolerogenic microenvironment.\\u000a \\u000a \\u000a \\u000a Methods The immune system state was measured by immunophenotypic and functional assessment of suppressor and effector
Alessandra Battaglia; Alexia Buzzonetti; Cinzia Baranello; Gabriella Ferrandina; Enrica Martinelli; Francesco Fanfani; Giovanni Scambia; Andrea Fattorossi
Purpose: To identify women's sources of information about cervical cancer screening, information which women report receiving during Pap consultations, information they would like to receive, and the relationships between perceived information needs, personal characteristics and information sources. Design/methodology/approach: Logistic regression…
Whynes, David K.; Clarke, Katherine; Philips, Zoe; Avis, Mark
|Purpose: To identify women's sources of information about cervical cancer screening, information which women report receiving during Pap consultations, information they would like to receive, and the relationships between perceived information needs, personal characteristics and information sources. Design/methodology/approach: Logistic…
Whynes, David K.; Clarke, Katherine; Philips, Zoe; Avis, Mark
Myeloid-derived dendritic cells (DCs) generated from monocytes obtained from stage IIIB cervical cancer (CaCx IIIB) patients show dysfunctional maturation; thus, antitumor T cell functions are dysregulated. In an objective to optimize these dysregulated immune functions, the present study is focused on the ability of neem leaf glycoprotein (NLGP), a nontoxic preparation of the neem leaf, to induce optimum maturation of dendritic cells from CaCx IIIB patients. In vitro NLGP treatment of immature DCs (iDCs) obtained from CaCx IIIB patients results in upregulated expression of various cell surface markers (CD40, CD83, CD80, CD86, and HLA-ABC), which indicates DC maturation. Consequently, NLGP-matured DCs displayed balanced cytokine secretions, with type 1 bias and noteworthy functional properties. These DCs displayed substantial T cell allostimulatory capacity and promoted the generation of cytotoxic T lymphocytes (CTLs). Although NLGP-matured DCs derived from CaCx monocytes are generally subdued compared to those with a healthy monocyte origin, considerable revival of the suppressed DC-based immune functions is noted in vitro at a fairly advanced stage of CaCx, and thus, further exploration of ex vivo and in vivo DC-based vaccines is proposed. Moreover, the DC maturating efficacy of NLGP might be much more effective in the earlier stages of CaCx, where the extent of immune dysregulation is less and, thus, the scope of further investigation may be explored.
Roy, Soumyabrata; Goswami, Shyamal; Bose, Anamika; Chakraborty, Krishnendu; Pal, Smarajit; Haldar, Atanu; Basu, Parthasarathi; Biswas, Jaydip; Baral, Rathindranath
Myeloid-derived dendritic cells (DCs) generated from monocytes obtained from stage IIIB cervical cancer (CaCx IIIB) patients show dysfunctional maturation; thus, antitumor T cell functions are dysregulated. In an objective to optimize these dysregulated immune functions, the present study is focused on the ability of neem leaf glycoprotein (NLGP), a nontoxic preparation of the neem leaf, to induce optimum maturation of dendritic cells from CaCx IIIB patients. In vitro NLGP treatment of immature DCs (iDCs) obtained from CaCx IIIB patients results in upregulated expression of various cell surface markers (CD40, CD83, CD80, CD86, and HLA-ABC), which indicates DC maturation. Consequently, NLGP-matured DCs displayed balanced cytokine secretions, with type 1 bias and noteworthy functional properties. These DCs displayed substantial T cell allostimulatory capacity and promoted the generation of cytotoxic T lymphocytes (CTLs). Although NLGP-matured DCs derived from CaCx monocytes are generally subdued compared to those with a healthy monocyte origin, considerable revival of the suppressed DC-based immune functions is noted in vitro at a fairly advanced stage of CaCx, and thus, further exploration of ex vivo and in vivo DC-based vaccines is proposed. Moreover, the DC maturating efficacy of NLGP might be much more effective in the earlier stages of CaCx, where the extent of immune dysregulation is less and, thus, the scope of further investigation may be explored. PMID:21307275
Roy, Soumyabrata; Goswami, Shyamal; Bose, Anamika; Chakraborty, Krishnendu; Pal, Smarajit; Haldar, Atanu; Basu, Parthasarathi; Biswas, Jaydip; Baral, Rathindranath
Tolerogenic dendritic cells (DCs) are a subset of DCs characterized by abundant indoleamine 2,3 dioxygenase (IDO) expressions. IDO may be co-operatively induced in DCs by regulatory T (Tregs) cells and various DC maturation agents. Tregs are markedly amplified in the physiological system of cancer patients, inducing over tolerance in DCs that leads to the hyper accumulation of immunosuppressive IDO in tumor microenvironment, thereby, hampering anti-tumor immunity. Consequently, a major focus of current immunotherapeutic strategies in cancer is to minimize IDO, which is possible by reducing Tregs and using various IDO inhibitors. Neem leaf glycoprotein (NLGP), a natural and nontoxic immunomodulator, demonstrated several unique immunoregulatory activities. Noteworthy activities of NLGP are to mature DCs and to inhibit Tregs. As Tregs are inducer of IDO in DCs and hyperactive Tregs is a hallmark of cancer, we anticipated that NLGP might abrogate IDO induction in DCs by inhibiting Tregs. Evidences are presented here that in a co-culture of DCs and Tregs isolated from cervical cancer stage IIIB (CaCx-IIIB) patients, NLGP does inhibit IDO induction in DCs by curtailing the over expression of Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) on Tregs and concomitantly induces optimal DC maturation. In contrast, in the presence of LPS as maturation agent the DCs displays a tolerogenic profile. This finding suggests the reduction of tolerogenecity of DCs in CaCx-IIIB patients by reducing the IDO pool using NLGP. Accordingly, this study sheds more light on the diverse immunomodulatory repertoire of NLGP. PMID:23628394
Roy, Soumyabrata; Barik, Subhasis; Banerjee, Saptak; Bhuniya, Avishek; Pal, Smarajit; Basu, Parthasarathi; Biswas, Jaydip; Goswami, Shyamal; Chakraborty, Tathagata; Bose, Anamika; Baral, Rathindranath
In this study we investigated E6 and E7 oncogenes from the Human Papilloma Virus as targets for siRNA knockdown in order to boost the efficacy of the anti-cancer drug 'tumor necrosis factor-related apoptosis inducing ligand' (TRAIL). SiHa cells were treated with TRAIL following transfection with E6/E7 siRNA and the expression of death receptors DR4 and DR5, cell viability, apoptosis, senescence and cell cycle analysis were undertaken using flow cytometry, MTT viability assay and cellular ?-galactosidase activity assays. E6/E7 siRNA resulted in significant upregulation of death receptors DR4 and DR5 but did not result in an enhanced sensitivity to TRAIL. Our results indicate that E6/E7-siRNA induces senescence rather than apoptosis in SiHa cells. The occurrence of senescence in drug resistant cervical cancer cells such as the SiHa cell line by E6/E7 siRNA, among other factors, may prevent TRAIL induced activation of extrinsic and intrinsic pathways that lead to apoptotic cell death. Our findings are significant for combinatorial strategies for cancer therapy since the induction of senescence can preclude apoptosis rendering cells to be recalcitrant to TRAIL treatment. PMID:21167816
Eaton, Seron; Wiktor, Peter; Thirstrup, Derek; Lake, Douglas; Nagaraj, Vinay Janthakahalli
We examined the phenotype and function of CD4+ T cells expressing the semaphorin III receptor neuropilin-1 (Nrp1) in human lymph nodes and peripheral blood. In lymph nodes, Nrp1 identified a small regulatory CD4+ CD25high T-cell subpopulation (Nrp1+ Treg) that expressed higher levels of Forkhead box P3 (Foxp3) message and protein than Nrp1? Treg, and various molecular markers of activated Treg, i.e. CD45RO, human leucocyte antigen (HLA)-DR and glucocorticoid-induced tumour necrosis factor receptor (GITR). Similarly to conventional Treg, Nrp1+ Treg proliferated poorly in vitro, and exerted contact-dependent in vitro suppression of T-cell proliferation and cytokine secretion. However, Nrp1+ Treg were more efficient than Nrp1? Treg at inducing suppression. Nrp1 was also expressed on a small subpopulation of CD25int and CD25? CD4+ T cells that expressed more Foxp3, CD45RO, HLA-DR and GITR than their Nrp1? counterparts. In contrast, in peripheral blood Nrp1 identified a minor CD4+ T-cell subset that did not display the phenotypic features of Treg lacking Foxp3 expression and marginally expressing CD25. Hence, the function of Nrp1+ CD4+ T cells seemingly depends on their anatomical location. In a previous report, we proposed that Treg may curb the anti-tumour T-cell response in cervical cancer. We show here that Treg and Nrp1+ Treg levels dropped in the tumour-draining lymph nodes of patients with cervical cancer following preoperative chemoradiotherapy in a direct relationship with the reduction of tumour mass, suggesting that suppressor cell elimination facilitated the generation of T cells mediating the destruction of the neoplastic cells left behind after cytotoxic therapy.
Battaglia, Alessandra; Buzzonetti, Alexia; Monego, Giovanni; Peri, Laura; Ferrandina, Gabriella; Fanfani, Francesco; Scambia, Giovanni; Fattorossi, Andrea
A study to comprehensively assess biomarkers of risk for progressive cervical neoplasia, and thus develop a new set of biomarkers that can distinguish those at highest risk of cervical cancer from those with benign infection
Objective To determine whether detection of invasive cervical cancer by screening results in better prognosis or merely increases the lead time until death. Design Nationwide population based cohort study. Setting Sweden. Participants All 1230 women with cervical cancer diagnosed during 1999-2001 in Sweden prospectively followed up for an average of 8.5 years. Main outcome measures Cure proportions and five year relative survival ratios, stratified by screening history, mode of detection, age, histopathological type, and FIGO (International Federation of Gynecology and Obstetrics) stage. Results In the screening ages, the cure proportion for women with screen detected invasive cancer was 92% (95% confidence interval 75% to 98%) and for symptomatic women was 66% (62% to 70%), a statistically significant difference in cure of 26% (16% to 36%). Among symptomatic women, the cure proportion was significantly higher for those who had been screened according to recommendations (interval cancers) than among those overdue for screening: difference in cure 14% (95% confidence interval 6% to 23%). Cure proportions were similar for all histopathological types except small cell carcinomas and were closely related to FIGO stage. A significantly higher cure proportion for screen detected cancers remained after adjustment for stage at diagnosis (difference 15%, 7% to 22%). Conclusions Screening is associated with improved cure of cervical cancer. Confounding cannot be ruled out, but the effect was not attributable to lead time bias and was larger than what is reflected by down-staging. Evaluations of screening programmes should consider the assessment of cure proportions.
Cervical cancer remains one of the most significant problem in oncogynecology. It tends towards treatment approaches that provide termination of pathological processes along with preservation of the patient's life quality. There is a need in earlier and more accurate diagnosis of pathological states, objective assessment of physiological processes, and adequate monitoring of the course of treatment. In our previous publications we have reported unique capabilities of the Optical Coherence Tomography (OCT) to image in vivo the mucosa structure of the cervix and to monitor various physiological and pathological alterations. In this report, we present results of OCT application to diagnose different stages of cervical cancer and to control its treatment at early stages. We have performed OCT-colposcopy in 11 female patients with cervical cancer to derive OCT criteria of this disease, to provide exact demarcation of a pathological area, and to determine a real size of a tumor. We have found that, in general, borders of a tumor, defined visually and detected with OCT by violation of the basement membrane in exocervix, do not coincide. The mismatch depends on a stage of cancer and can be as much as several millimeters. This information is especially important for evaluation of linear dimension of tumors with 3 - 5 mm invasion and also for differential diagnosis between the T1 and T2 stages with cancer extension onto vagina.
Kouznetsova, Irina A.; Shakhova, Natalia M.; Kachalina, Tatiana S.; Gladkova, Natalia D.; Myakov, Aleksey V.; Iksanov, Rashid R.; Feldchtein, Felix I.
Although many human cancers can be imaged by 2-(18F)-fluoro- 2-deoxy-D-glucose (FDG) and PET,there is little clinical experi ence with FDG PET in cervical cancer. The purpose of this study was to evaluate the feasibility of FDG PET scans on patients with cervical cancer. Methods: FDG PET scans were performed on 21 patients with histologically proven uterine cervical cancer (17 newly
Yoshifumi Sugawara; Avraham Eisbruch; Shigeru Kosuda; Betty E. Recker; Paul V. Kison; Richard L. Wahl
Molecular, clinical and epidemiological studies have established beyond doubt that human papiloma viruses (HPV) cause cervical cancer. The virus is also associated with genital warts and other less common cancers in oropharynx, vulva, vagina and penis. Worldwide, VPH genotypes 16 and 18 are the most common high risk genotypes, detected in near 70% of women with cervical cancer. The discovery of a cause-effect relationship between several carcinogenic microorganisms and cancer open avenues for new diagnostic, treatment and prevention strategies. In this issue of Revista Médica de Chile, two papers on HPV are presented. Guzman and colleagues demonstrate that HPV can be detected in 66% to 77% of healthy male adolescents bypolymerase chain reaction and that positivity depends on the site of the penis that is sampled. These results support the role of male to female transmission of high risk HPVs in Chile and should lead to even more active educational campaigns. The second paper provides recommendations for HPV vaccine use in Chile, generated by the Immunization Advisory Committee of the Chilean Infectious Disease Society. To issue these recommendations, the Committee analyzes the epidemiological information available on HPV infection and cervical cancer in Chile, vaccine safety and effectiveness data, and describes cost-effectiveness studies. Taking into account that universal vaccination is controversial, the Committee favors vaccine use in Chile and it's incorporation into a national program. However, there is an indication that the country requires the implementation of an integrated surveillance approach including cross matching of data obtained from HPV genotype surveillance, monitoring of vaccination coverage, and surveillance of cervical cancer. The final decision of universal vaccine use in Chile should be based on a through analysis of information.ev Mid Chile PMID:19301766
O'Ryan, Miguel; Valenzuela, María Teresa
Deregulation of the expression of human papillomavirus (HPV) oncogenes E6 and E7 plays a pivotal role in cervical carcinogenesis because the E6 and E7 proteins neutralize p53 and Rb tumor suppressor pathways, respectively. In approximately 90% of all cervical carcinomas, HPVs are found to be integrated into the host genome. Following integration, the core-enhancer element and P105 promoter that control expression of E6 and E7 adopt a chromatin structure that is different from that of episomal HPV, and this has been proposed to contribute to activation of E6 and E7 expression. However, the molecular basis underlying this chromatin structural change remains unknown. Previously, BAF53 has been shown to be essential for the integrity of higher-order chromatin structure and interchromosomal interactions. Here, we examined whether BAF53 is required for activated expression of E6 and E7 genes. We found that BAF53 knockdown led to suppression of expression of E6 and E7 genes from HPV integrants in cervical carcinoma cell lines HeLa and SiHa. Conversely, expression of transiently transfected HPV18-LCR-Luciferase was not suppressed by BAF53 knockdown. The level of the active histone marks H3K9Ac and H4K12Ac on the P105 promoter of integrated HPV 18 was decreased in BAF53 knockdown cells. BAF53 knockdown restored the p53-dependent signaling pathway in HeLa and SiHa cells. These results suggest that activated expression of the E6 and E7 genes of integrated HPV is dependent on BAF53-dependent higher-order chromatin structure or nuclear motor activity. PMID:21821000
Lee, Kiwon; Lee, Ah-Young; Kwon, Yunhee Kim; Kwon, Hyockman
Cervical cancer, a potentially preventable disease, has its main aetiology in infection by high risk human papillomavirus (HR-HPV). Approaches to improving cervical cancer screening and diagnostic methodologies include molecular biological analysis, targeting of biomarker proteins, but also exploration and implementation of new techniques such as vibrational spectroscopy. This study correlates the biomarker protein p16INK4A expression levels dependent on HPV copy
Kamila M. Ostrowska; Amaya Garcia; Aidan D. Meade; Alison Malkin; Ifeoluwapo Okewumi; John J. O'Leary; Cara Martin; Hugh J. Byrne; Fiona M. Lyng
Absolute cancer risk is the probability that an individual with given risk factors and a given age will develop cancer over a defined period of time. Examples of these risk factors include race, age, sex, genetics, body mass index, family history of cancer, history of tobacco use, use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS), physical activity, use of hormone replacement therapy, reproductive factors, history of cancer screening, and dietary factors.
Objective The aim of the present study was to assess prognostic factors for patients with locally advanced cervical cancer treated with radiotherapy as the primary treatment and to assess the posttreatment cut-off levels of squamous cell carcinoma antigen (SCC-Ag) to predict three-year overall survival (OS) rates. Methods One hundred and twenty-eight patients with cervical squamous cell carcinoma (International Federation of Gynecology and Obstetrics [FIGO] stage IIB-IVA) treated using radiotherapy or concurrent chemoradiotherapy were identified. Of these patients, 116 who had SCC-Ag levels >1.5 ng/mL prior to treatment were analyzed retrospectively. Results Median age was 68 years (range, 27 to 79 years). The complete response rate was 70.7% and the three-year OS rate was 61.1%. The median levels of pretreatment and posttreatment SCC-Ag were 11.5 ng/mL (range, 1.6 to 310.0 ng/mL) and 0.9 ng/mL (range, 0.4 to 41.0 ng/mL), respectively. Multivariate analysis showed that pretreatment anemia (p=0.041), pelvic lymph node metastasis (p=0.016) and posttreatment SCC-Ag levels (p=0.001) were independent prognostic factors for three-year OS. The SCC-Ag level cut-off point for three-year OS rates, calculated using a receiver operating characteristic curve, was 1.15 ng/mL (sensitivity, 80.0%; specificity, 74.0%). Conclusion Pretreatment anemia and pelvic lymph node metastasis are poor prognostic factors in locally advanced cervical cancer. Furthermore, posttreatment SCC-Ag levels <1.15 ng/mL predicted better three-year OS rates.
Furukawa, Naoto; Kobayashi, Hiroshi; Asakawa, Isao
Cervical cancer is the most common cancer in Indian women. Oxidative stress is potentially harmful to cells and ROS are involved\\u000a in multistage carcinogenesis, in initiation and promotion. The aim was to study the alterations in the circulating pro-\\/anti-oxidants\\u000a in advanced cervical cancer patients, before and after neoadjuvant chemoradiation and to assess the relevance of the variation\\u000a in the levels
Alpana Sharma; Medha Rajappa; Abhigyan Satyam; Manoj Sharma
Cervical cancer, a potentially preventable disease, has its main aetiology in infection by high risk human papillomavirus (HR-HPV). Approaches to improving cervical cancer screening and diagnostic methodologies include molecular biological analysis, targeting of biomarker proteins, but also exploration and implementation of new techniques such as vibrational spectroscopy. This study correlates the biomarker protein p16(INK4A) expression levels dependent on HPV copy number with the infrared absorption spectral signatures of the cervical cancer cell lines, HPV negative C33A, HPV-16 positive SiHa and CaSki and HPV-18 positive HeLa. Confocal fluorescence microscopy demonstrated that p16(INK4A) is expressed in all investigated cell lines in both nuclear and cytoplasmic regions, although predominantly in the cytoplasm. Flow cytometry was used to quantify the p16(INK4A) expression levels and demonstrated a correlation, albeit nonlinear, between the reported number of integrated HPV copies and p16(INK4A) expression levels. CaSki cells were found to have the highest level of expression, HeLa intermediate levels, and SiHa and C33A the lowest levels. FTIR spectra revealed differences in nucleic acid, lipid and protein signatures between the cell lines with varying HPV copy number. Peak intensities exhibited increasing tendency in nucleic acid levels and decreasing tendency in lipid levels with increasing HPV copy number, and although they were found to be nonlinearly correlated with the HPV copy number, their dependence on p16(INK4A) levels was found to be close to linear. Principal Component Analysis (PCA) of the infrared absorption spectra revealed differences between nuclear and cytoplasmic spectroscopic signatures for all cell lines, and furthermore clearly differentiated the groups of spectra representing each cell line. Finally, Partial Least Squares (PLS) analysis was employed to construct a model which can predict the p16(INK4A) expression level based on a spectral fingerprint of a cell line, demonstrating the diagnostic potential of spectroscopic techniques. PMID:21290054
Ostrowska, Kamila M; Garcia, Amaya; Meade, Aidan D; Malkin, Alison; Okewumi, Ifeoluwapo; O'Leary, John J; Martin, Cara; Byrne, Hugh J; Lyng, Fiona M
Background Tissue factor pathway inhibitor-2 (TFPI-2) is an extracellular matrix associated broad-spectrum Kunitz-type serine proteinase inhibitor. Recently, down regulation of TFPI-2 was suggested to be involved in tumor invasion and metastasis in some cancers. Methods This study involved 12 normal cervical squamous epithelia, 48 cervical intraepithelial neoplasia (CIN), and 68 cervical cancer. The expression of TFPI-2, Ki-67 and vascular endothelial growth factor (VEGF) were investigated by immunohistochemistry staining. The apoptolic index(AI) was determined with an in situ end-labeling assay(TUNEL). And the marker of CD34 staining was used as an indicator of microvessel density (MVD). Results TFPI-2 expression has a decreasing trend with the progression of cervical cancer and was significantly correlated with FIGO stage, lymph node metastasis and HPV infection. In addition, there were significant positive correlations between the grading of TFPI-2 expression and AI(P = 0.004). In contrast, the expression of TFPI-2 and VEGF or MVD was negatively correlated (both p < 0.001). However, we did not establish any signi?cant correlation between Ki-67 and TFPI-2 expression in cervical cancer. Conclusions The results suggested that the expression of TFPI-2 had a decreasing trend with tumor progression of cervical cancer. There was a close association between the expression of TFPI-2 and tumor cell apoptosis and angiogenesis in patients with cervical cancer. TFPI-2 may play an inhibitive role during the development of cervical cancer.
Conventional analysis of a cervical histology image, such a pap smear or a biopsy sample, is performed by an expert pathologist manually. This involves inspecting the sample for cellular level abnormalities and determining the spread of the abnormalities. Cancer is graded based on the spread of the abnormal cells. This is a tedious, subjective and time-consuming process with considerable variations in diagnosis between the experts. This paper presents a computer aided decision support system (CADSS) tool to help the pathologists in their examination of the cervical cancer biopsies. The main aim of the proposed CADSS system is to identify abnormalities and quantify cancer grading in a systematic and repeatable manner. The paper proposes three different methods which presents and compares the results using 475 images of cervical biopsies which include normal, three stages of pre cancer, and malignant cases. This paper will explore various components of an effective CADSS; image acquisition, pre-processing, segmentation, feature extraction, classification, grading and disease identification. Cervical histological images are captured using a digital microscope. The images are captured in sufficient resolution to retain enough information for effective classification. Histology images of cervical biopsies consist of three major sections; background, stroma and squamous epithelium. Most diagnostic information are contained within the epithelium region. This paper will present two levels of segmentations; global (macro) and local (micro). At the global level the squamous epithelium is separated from the background and stroma. At the local or cellular level, the nuclei and cytoplasm are segmented for further analysis. Image features that influence the pathologists' decision during the analysis and classification of a cervical biopsy are the nuclei's shape and spread; the ratio of the areas of nuclei and cytoplasm as well as the texture and spread of the abnormalities. Similar features are extracted towards the automated classification process. This paper will present various feature extraction methods including colour, shape and texture using Gabor wavelet as well as various quantative metrics. Generated features are used to classify cells or regions into normal and abnormal categories. Following the classification process, the cancer is graded based on the spread of the abnormal cells. This paper will present the results of the grading process with five stages of the cancer spectrum.
Rahmadwati, Rahmadwati; Naghdy, Golshah; Ros, Montserrat; Todd, Catherine
2-Methyl-1,3,6-trihydroxy-9,10-anthraquinone (MTA), one of the major components isolated from the traditional Chinese medicine Rubia yunnanensis, exhibited inhibitory activity on the proliferation of several human cancer cell lines. The results from an annexin V-FITC (fluoresein-5-isothiocyanate) apoptosis assay and DNA content analysis showed that MTA exerted cytotoxicity via apoptosis induction and G2/M cell cycle arrest in human cervical carcinoma HeLa cells. Further, MTA was found to induce apoptosis of HeLa cells through the mitochondria-mediated pathway. It caused the translocation of Bax to the mitochondria and release of cytochrome c into the cytosol, which caused the cleavage of caspase and poly(ADP-ribose) polymerase and finally triggered the apoptosis. Furthermore, the p53/p21/Cdc2-cyclin B1 signaling was found related to the G2/M arrest caused by MTA. The over-expression of p21 and down-expression of cyclin B1 caused by MTA inactivated the Cdc2-cyclin B1 complex of G2/M checkpoint and finally caused the G2/M arrest in HeLa cells. This study demonstrated that MTA is a potential anti-cancer component of R. yunnanensis, a folk anti-cancer herb used in Yunnan, China. PMID:23700797
Zeng, Guang-Zhi; Fan, Jun-Ting; Xu, Jun-Ju; Li, Yan; Tan, Ning-Hua
The aim of this retrospective analysis was to evaluate the survival rate in 661 patients with cervical cancer regarding two time periods 1990-1996 and 1997-2003 and the specific stage related risk factors. The respective five-year survival was 71.7% and 80.0%. Analyzing the risk factors in the univariate and multivariate regression modalities ultimately only two parameters, the two time periods and FIGO staging were found to be independent prognostic factors. The observed total improvement in the survival rate of the second time period is followed by an increase in conservative surgery in stage TIA1, a reduction in the use of adjuvant radiotherapy among operable stages Tlbl, Tlb2 and T2A, while the treatment of locally advanced cervical cancer did not differ significantly. PMID:17598517
Haller, Herman; Rupci?, Stanislav; Kratevi?, Maja; Begonia, Ruzica; Stamatovi?, Miroslav; Mamula, Ozren
Marriages between third-degree and more distant relatives are common in many parts of the world. Offspring of consanguineous parents have increased morbidity and mortality related to recessive gene disorders. In a population with a high frequency of consanguinity, we examined the frequency of breast cancer (related in part to tumour genes) and cervical cancers (related to virus infection) among offspring of consanguineous and non-consanguineous parents. Study was done prospectively in the United Arab Emirates. Selected were married female citizens, ages 40–65, who attended 12 primary health care clinics for whatever reason. In a face-to-face interview, subjects were asked: (a) about consanguineous marriages in family; (b) if they have or have had breast or cervical cancer; (c) about family history of cancer, cancer screening and other parameters. Tumour diagnosis was confirmed by review of medical records. Of 1750 women invited into study, 1445 (79%) could be used in analysis. Among 579 (40%) women of consanguineous and 866 (60%) of non-consanguineous parents there were 24 and 54 with breast cancer, respectively (RR = 0.66, CI 0.42?–?1.06). In the 40 to 50 age group, breast cancer reported 13 of 446 women of consanguineous and 37 of 633 of non-consanguineous parents (RR = 0.50, Cl 0.27?–?0.93). Cervical cancer had 15 women in consanguineous and 32 in non-consanguineous group (RR = 0.70, Cl 0.38?–?1.28). Number of families with history of breast cancer in consanguineous and non-consanguineous group was 21 and 23, respectively (P = 0.29). The cancer screening rates and other variable values had fairly balanced distribution between the 2 groups. Having consanguineous parents decreases the risk of breast cancer especially in younger women, risk of cervical cancer being unaffected. © 2001 Cancer Research Campaign http://www.bjcancer.com
Denic, S; Bener, A
Cost-effectiveness analyses are an important tool for the evaluation and modification of many health care services. Given the variety of screening tests and treatments available for cervical cancer screening and prevention, the costs associated with these options and with their alternatives, and the differences in resources and settings in which these tests are applied worldwide, cost-effectiveness analyses evaluation can be very useful to help determine best practices. PMID:23318570
Esselen, Katharine M; Feldman, Sarah
Study purpose: Chinese women in North America have high rates of invasive cervical cancer and low levels of Papanicolaou (Pap) testing use. This study examined Pap testing barriers and facilitators among Chinese American women. Basic procedures: A community-based, in-person survey of Chinese women was conducted in Seattle, Washington during 1999. Four hundred and thirty-two women in the 20–79 years age-group
Victoria M. Taylor; J. Carey Jackson; Shin-Ping Tu; Yutaka Yasui; Stephen M. Schwartz; Alan Kuniyuki; Elizabeth Acorda; Kathy Lin; Gregory Hislop
Cervical cancer is the second largest cause of death among women worldwide. Nowadays, this disease is preventable and curable at low cost and low risk when an accurate diagnosis is done in due time, since it is the neoplasm with the highest prevention potential. This work describes the development of an expert system able to provide a diagnosis to cervical neoplasia (CN) precursor injuries through the integration of fuzzy logics and image interpretation techniques. The key contribution of this research focuses on atypical cases, specifically on atypical glandular cells (AGC). The expert system consists of 3 phases: (1) risk diagnosis which consists of the interpretation of a patient's clinical background and the risks for contracting CN according to specialists; (2) cytology images detection which consists of image interpretation (IM) and the Bethesda system for cytology interpretation, and (3) determination of cancer precursor injuries which consists of in retrieving the information from the prior phases and integrating the expert system by means of a fuzzy logics (FL) model. During the validation stage of the system, 21 already diagnosed cases were tested with a positive correlation in which 100% effectiveness was obtained. The main contribution of this work relies on the reduction of false positives and false negatives by providing a more accurate diagnosis for CN.
Dominguez Hernandez, Karem R.; Aguilar Lasserre, Alberto A.; Posada Gomez, Ruben; Palet Guzman, Jose A.; Gonzalez Sanchez, Blanca E.
Cervical cancer is the second largest cause of death among women worldwide. Nowadays, this disease is preventable and curable at low cost and low risk when an accurate diagnosis is done in due time, since it is the neoplasm with the highest prevention potential. This work describes the development of an expert system able to provide a diagnosis to cervical neoplasia (CN) precursor injuries through the integration of fuzzy logics and image interpretation techniques. The key contribution of this research focuses on atypical cases, specifically on atypical glandular cells (AGC). The expert system consists of 3 phases: (1) risk diagnosis which consists of the interpretation of a patient's clinical background and the risks for contracting CN according to specialists; (2) cytology images detection which consists of image interpretation (IM) and the Bethesda system for cytology interpretation, and (3) determination of cancer precursor injuries which consists of in retrieving the information from the prior phases and integrating the expert system by means of a fuzzy logics (FL) model. During the validation stage of the system, 21 already diagnosed cases were tested with a positive correlation in which 100% effectiveness was obtained. The main contribution of this work relies on the reduction of false positives and false negatives by providing a more accurate diagnosis for CN. PMID:23690881
Domínguez Hernández, Karem R; Aguilar Lasserre, Alberto A; Posada Gómez, Rubén; Palet Guzmán, José A; González Sánchez, Blanca E
...Disease Control and Prevention Breast and Cervical Cancer Early Detection and Control...aforementioned committee: Name: Breast and Cervical Cancer Early Detection and Control...detection and control of breast and cervical cancer. The committee makes...
...Disease Control and Prevention Breast and Cervical Cancer Early Detection and Control...detection and control of breast and cervical cancer. The committee makes recommendations...Reform and its impact for breast and cervical cancer screening; updates on...
...Disease Control and Prevention Breast and Cervical Cancer Early Detection and Control...detection and control of breast and cervical cancer. The committee makes recommendations...Task Force guidelines for breast and cervical cancer screening; Impact of...
Most invasive cervical cancer research in the United States has been conducted on non-Latino-White (NLW) and African-American women. Incidence, mortality, stage at diagnosis and survival indicators for invasive cervical cancer in Latino women in California are compared to NLW and African-American women. A model is presented which depicts structural, behavioral, genetic and biological risk factors for invasive cervical cancer. A
Anna Nápoles-Springer; Eugene Washington
Summary Proceeding from an account of the development, struc ture, and function of the uterine cervix, the cytology and histology of cancer of the cervix is presented by stage of the disease. The concept of biological progression in the patho- genesis of cancer of the cervix is utilized to consider a gra dient of changes in the endocervical mucosa: reserve
Abstract Objective To evaluate cervical cancer screening practices and barriers to screening in a sample of lesbians. Methods Cross-sectional survey data were collected from 225 self-identified lesbians who completed an online questionnaire. Results Of the respondents, 71% reported receiving a Pap screening test in the past 24 months (routine screeners), and 29% reported receiving a Pap screening test >24 months ago or never (nonroutine screeners). Routine screeners were more likely to be older (p?0.01), white (p?=?0.04), and college graduates (p?0.01) than nonroutine screeners. Nonroutine screeners were more likely to delay seeking healthcare because of fear of discrimination (p?0.01) and were less likely than routine screeners to disclose orientation to their primary care physician (p?0.01). After adjusting for age, race, and education, nonroutine screeners perceived fewer benefits from (p?0.01) and more barriers (p?0.01) to Pap screening tests and were less knowledgeable about screening guidelines (p?0.01) than routine screeners, but there was no difference in perceived susceptibility (p?=?0.68), perceived seriousness (p?=?0.68), or risk factor knowledge (p?=?0.35) of cervical cancer. Conclusions Many lesbians do not screen for cervical cancer at recommended rates. Nonroutine screeners perceive fewer benefits, more barriers, and more discrimination and are less knowledgeable about screening guidelines than routine screeners.
Lydecker, Alison D.; Ireland, Lynda
Background: The human papiloma virus (HPV), which is sexually transmitted, and most commonly causes genital warts, has been linked to cervical intraepithelial neoplasia and invasive carcinoma. Of ninety plus types of HPV, HPV-16 is the most prevalent in cervical cancer, followed by HPV-18, and HPV-33. As HPV's implication has not been assessed in the Middle East the main focus of this retrospective study was to determine the prevalence of HPV -16,18, and 33 in cases of cervical cancer from Iran. Material and Methods: This retrospective study covered 100 patients with uterine cervical carcinomas who were referred to two referral centers for cancer in Tehran-Iran. Pathological blocks were collected for these cases and initial review of the blocks showed poor specimens in 18 cases, which left 82 cases for the study. These samples were histologically examined to verify the presence and the type of carcinoma. The next step was in situ hybridzation for the detection of HPV common DNA. In Situ hybridization was preformed on all samples. Finally, Polymerase Chain Reaction (PCR) was preformed for the HPV types 16, 18, and 33. PCR amplification of exon 5 of the p53 gene was used as an internal control for the integrity of DNA. Takara PCR Human papilloma Detection method was used which includes primer for HPV 16, 18, and 33. Three primers were used alone, or in combination, in order to increase the sensitivity of the detection. Results: The majority of tumors were squamous cell carcinomas (87%). The rest were adenosquamous carcinoma and adenocarcinomas. None of the 82 different cervical carcinoma tissue samples were found to be positive by in situ hybridization. In the PCR samples, amplification of DNA was observed for 69 tumor specimens. In the remainning13 cases, the DNA in fixed tissue was degraded, as verified by the absence of an internal control band (p53). Out of the total 69 tumors (85.5%) with adequate DNA contained HPV band on PCR. The majority (73.9%) of HPV positive tumors contained HPV-16; the rest (11.6%) demonstrated type 18 and 33. There was no correlation between the histology of carcinoma and presence of types of HPV. Conclusion: The prevalence of HPV in carcinomas of uterine cervix in Iran is similar to those reported in other regions of the world. Similarly, it appears that HPV-16 is the most common type associated with cervical cancer in Iran. Further studies on larger samples of patients, particularly in those with pre-invasive forms of the disease, are needed to elucidate the carcinogenic role of HPV types in cervical cancer in Iranian women. PMID:12718611
Mortazavi, SH; Zali, MR; Raoufi, M; Nadji, M; Kowsarian, P; Nowroozi, A
Marriages between third-degree and more distant relatives are common in many parts of the world. Offspring of consanguineous parents have increased morbidity and mortality related to recessive gene disorders. In a population with a high frequency of consanguinity, we examined the frequency of breast cancer (related in part to tumour genes) and cervical cancers (related to virus infection) among offspring of consanguineous and non-consanguineous parents. Study was done prospectively in the United Arab Emirates. Selected were married female citizens, ages 40-65, who attended 12 primary health care clinics for whatever reason. In a face-to-face interview, subjects were asked: (a) about consanguineous marriages in family; (b) if they have or have had breast or cervical cancer; (c) about family history of cancer, cancer screening and other parameters. Tumour diagnosis was confirmed by review of medical records. Of 1750 women invited into study, 1445 (79%) could be used in analysis. Among 579 (40%) women of consanguineous and 866 (60%) of non-consanguineous parents there were 24 and 54 with breast cancer, respectively (RR = 0.66, CI 0.42 - 1.06). In the 40 to 50 age group, breast cancer reported 13 of 446 women of consanguineous and 37 of 633 of non-consanguineous parents (RR = 0.50, Cl 0.27 - 0.93). Cervical cancer had 15 women in consanguineous and 32 in non-consanguineous group (RR = 0.70, Cl 0.38 - 1.28). Number of families with history of breast cancer in consanguineous and non-consanguineous group was 21 and 23, respectively (P = 0.29). The cancer screening rates and other variable values had fairly balanced distribution between the 2 groups. Having consanguineous parents decreases the risk of breast cancer especially in younger women, risk of cervical cancer being unaffected. PMID:11742487
Denic, S; Bener, A
NEDD9, a focal adhesion scaffolding protein, has been recently proposed to regulate invasion and metastasis in some cancer types, but unknown in cervical cancer. The aim of this study was to determine if NEDD9 was involved in the progression and metastasis of cervical cancer. The experimental results showed NEDD9 protein was overexpressed in cervical cancer compared with normal cervical epithelium tissues. Overexpression of NEDD9 was correlated with histological grading, lymph node metastasis, and FIGO stage of cervical cancer. Silencing NEDD9 resulted in tyrosine dephosphorylation of FAK and SRC oncoproteins, and decreased cell migration and invasion in the cervical carcinoma SiHa and HeLa cells. Overexpression of NEDD9 led to tyrosine phosphorylation of FAK and SRC oncoproteins, and increased cell migration and invasion. Moreover, tyrosine phosphorylation of NEDD9 was significantly decreased via suppressing tyrosine phosphorylation of FAK or SRC, suggesting a positive feedback loop of tyrosine phosphorylation between NEDD9 and FAK or SRC. In addition, our data showed that silencing NEDD9 decreased Vimentin expression and increased E-cadherin expression in cervical cancer cells, and vice versa. E-cadherin was subject to regulation of NEDD9, FAK and SRC, but altered neither tyrosine-phosphorylated nor total NEDD9. Our findings suggest that NEDD9 is overexpressed in cervical cancer tissues and cells, and overexpressed NEDD9 promotes migration and invasion in cervical carcinoma cells, probably via a positive feedback loop of tyrosine phosphorylation between NEDD9 and FAK or SRC.
Ye, Feng; Ma, Ding; Xie, Xing; Lu, Weiguo
A system for screening cervical cytological preparations is described which employs the Leitz Texture Analyzer System (E. Leitz, Rockleigh, N. J.) quantitative staining with acridine orange, and a fluorescence standard. The instrumentation scans cells on microscope slides and detects objects which it interprets to be nuclei with excess total nuclear green fluorescence intensity (Previous results employing manual measurements have indicated
JAMES F. GOLDEN; SEYMOUR S. WEST; HUGH M. SHINGLETON; ACE K. ECHOLS
Objective To examine perceptions of cervical cancer risk in elevated-risk Appalachians. Methods Appalachian women (n=571) completed interviews examining self-regulation model factors relevant to perceived risk of cervical cancer. Results Women with good/very good knowledge of cervical cancer, greater worry, and history of sexually transmitted infection had higher odds of rating their perceived risk as somewhat/much higher than did other women. Former smokers, compared to never smokers, had lower risk perceptions. Conclusions Self-regulation model factors are important to understanding perceptions of cervical cancer risk in underserved women. The relationship of smoking and worry to perceived risk may be a target for intervention.
Kelly, Kimberly M.; Ferketich, Amy K.; Ruffin, Mack T.; Tatum, Cathy; Paskett, Electra D.
Goniothalamus species (Annonaceae) is a shrub that grows in the rainforest of tropical Asia. Several compounds have been isolated and exhibit the potential use for cancer treatment. In this work, altholactone isolated from Goniothalamus macrophyllus was investigated for its cytotoxicity, apoptosis signalling and the expression of cancer-related genes in the cervical carcinoma HeLa cells. Cytotoxicity was evaluated by MTT assay. Apoptotic characteristics were evaluated by morphological studies. Caspase-3 activity was detected using a fluorogenic substrate. Cytochrome c release from mitochondria and protein Bid were determined by Western blotting and cancer-related genes expression by RT-PCR. The results demonstrated that altholactone was cytotoxic to HeLa (IC50 ?=?9.6??g/mL), and apoptotic cell death was manifested by appearance of chromatin condensation and caspase-3 activation, which was inhibited by specific inhibitors of both caspase-8 and -9. Release into the cytosol of cytochrome and cleavage of Bid occurred. Altholactone also caused a decrease in bcl-2 and an increase in p53 expression. These unique properties of altholactone suggest a potential for cancer chemotherapy. PMID:23494867
Uthaisang-Tanechpongtamb, Wanlaya; Sriyabhaya, Promjit; Wilairat, Prapon
Objective To evaluate the effects of HPV16 E6\\/E7 siRNAs on cervical cancer SiHa cells.\\u000a \\u000a \\u000a \\u000a Methods The expressions of the E6, E7, p53 and Rb genes were assayed by RT-PCR and Western-bloting respectively. The proliferation\\u000a and apoptosis of the cells were evaluated by MTT and flow cytometry.\\u000a \\u000a \\u000a \\u000a Results HPV 16 E6 and E7 oncogenes were selectivly downregulated by HPV 16 E6 and E7 siRNAs,
Chun-lian Nie; Guo-lan Gao; Jie Han; Hua Li; He-ping Chen; Ming He
Cervical cancer is a commonly-encountered malignant tumor in women. Cervical screening is particularly important due to early symptoms being deficient in specificity. The main purpose of the study is to assess the application value of cervical thinprep cytologic test (TCT) and human papillomavirus (HPV) detection in screening for cervical cancer and precancerous lesions. In the study, cervical TCT and HPV detection were simultaneously performed on 12,500 patients selected in a gynecological clinic. Three hundred patients with positive results demonstrated by cervical TCT and/or HPV detection underwent cervical tissue biopsy under colposcopy, and pathological results were considered as the gold standard. The results revealed that 200 out of 12,500 patients were abnormal by TCT, in which 30 cases pertained to equivocal atypical squamous cells (ASCUS), 80 cases to low squamous intraepithelial lesion (LSIL), 70 cases to high squamous intraepithelial lesion (HSIL) and 20 cases to squamous cell carcinoma (SCC). With increasing pathological grade of cervical biopsy, however, TCT positive rates did not rise. Two hundred and eighty out of 12,500 patients were detected as positive for HPV infection, in which 50 cases were chronic cervicitis and squamous metaplasia, 70 cases cervical intraepithelial neoplasia (CIN) I, 60 cases CIN II, 70 cases CIN III and 30 cases invasive cervical carcinoma. Two hundred and thirty patients with high-risk HPV infection were detected. With increase in pathological grade, the positive rate of high-risk HPV also rose. The detection rates of HPV detection to CIN III and invasive cervical carcinoma as well as the total detection rate of lesions were significantly higher than that of TCT. Hence, HPV detection is a better method for screening of cervical cancer at present. PMID:23803065
Wang, Jin-Liang; Yang, Yi-Zhuo; Dong, Wei-Wei; Sun, Jing; Tao, Hai-Tao; Li, Rui-Xin; Hu, Yi
Cervical cancer screening with Pap smear test is a cost-effective method. The Ministry of Health in Turkey recommends that it be performed once every five years after age 35. The purpose of this study was to determine the cervical cancer risk levels of women between 35 and 69, and the intervals they have the Pap smear test, and to investigate the relation between the two. This study was performed on 227 women aged between 35 and 69 living in Balçova District of ?zmir province. Using the cervical cancer risk index program of Harvard School of Public Health, the cervical cancer risk level of 70% of the women was found below average, 22.1% average, and 7.9% above average. Only 52% of the women have had Pap smear test at least once in their lives. The percentage screening regularly in conformity with the national screening standard was 39.2%. Women in the 40-49 age group, were married, conformed significantly more (p<0.05) to the national screening standard. Compliance also increased with the level of education and decreased with the cervical cancer risk level (p<0.05). A logistic regression model was constructed including age, education level, menstruation state of the women and the economic level of the family. Not having the Pap smear test in conformity with the national cervical cancer screening standard in 35-39 age group was 2.52 times more than 40-49 age group, while it was 3.26 times more in 60-69 age group (p< 0.05). Not having Pap smear test in 35-39 age group more than other groups might result from lack of information on the cervical cancer national screening standard and the necessity of having Pap smear test. As for 60-69 age group, the low education level might cause not having Pap smear test. Under these circumstances, the cervical cancer risk levels should be determined and the individuals should be informed. Providing Pap smear test screening service to individuals in the target group of national screening standard, as a public service may resolve the inequalities due to age and educational differences. PMID:21790227
Açikgöz, Ayla; Ergör, Gül
As iron ions may participate in the pathogenesis of cancer and viral infections, the aim of this study was to monitor their influence on proliferation, E6 and E7 oncogene expression and reactive oxygen species (ROS) production in two human papilloma virus (HPV) positive cervical carcinoma cell lines (HeLa and SiHa) and one HPV negative vulvar cell line (A431). The anti-anaemic drug, ferric-sorbitol-citric acid complex (FSC) as a source of Fe(III) ions was used. Cells were treated with FSC at the concentrations between 0.001 and 1 mM Fe(III) for different time periods. Fe(III) ions inhibited the viability of HeLa and A431 cells while it had no influence on SiHa cells. Furthermore, Fe(III) treatment showed a time-dependent and a higher stimulatory effect on E6/E7 expression in SiHa cells than in HeLa cells. Fe(III) ion treatment with concentrations lower than 0.1mM showed a time and a concentration dependent intracellular ROS production in all tested cell lines, while the treatment with 1mM concentration decreased ROS production in all tested cell lines. In conclusion, Fe(III) ion treatment apart from having an anti-tumour effect, as we previously described, enhances survival of HPV 16-positive cells and might be associated with HPV oncogenesis. PMID:21044880
Poljak-Blazi, Marija; Jaganjac, Morana; Sabol, Ivan; Mihaljevic, Branka; Matovina, Mihaela; Grce, Magdalena
Incidence-based evaluations of cervical cancer screening programs have suggested age-specific impacts and there is uncertainty regarding the effectiveness of screening outside the ages of 30-60 years. We audited the screening histories of cervical cancer deaths and conducted a case-control evaluation of the effectiveness of organized screening in different ages with mortality as outcome. We included all 506 cervical cancer deaths in Finland in 2000-2009 due to cancers diagnosed in 1990 or later, and 3,036 controls matched by age at diagnosis to the cases. Squamous cell carcinoma constituted 59% of the cases, adenocarcinomas 29%, and the remaining 12% were other specified and unspecified cervical malignancies. Most deaths (54%) were due to cancers diagnosed more than 5 years after last screening invitation, 24% were diagnosed among nonattenders and only 14% of deaths occurred among women who had attended invitational screening. The risk reduction associated with attending a single program screen at an age below 40 was nonsignificant (OR 0.70; 95% CI 0.33-1.48), while clear risk reductions were observed after screening at the age of 40-54 (OR 0.33; CI 0.20-0.56) and 55-69 (OR 0.29; CI 0.16-0.54). This study also provides some indication of a long-lasting additional effect of screening at the age of 65. Possible avenues for improving the effectiveness of the Finnish screening program include efforts to increase attendance and an extension of the target ages to include 65-to 69-year-old women. The potential benefit of increasing the sensitivity of the screening test or shortening the screening interval is smaller. PMID:22987437
Lönnberg, Stefan; Nieminen, Pekka; Luostarinen, Tapio; Anttila, Ahti
AMP-activated protein kinase (AMPK) is a critical energy-balancing sensor in the regulation of cellular metabolism in response to external stimuli. Emerging evidence has suggested that AMPK is a potential therapeutic target for human cancers. AICAR, one of the pharmacological AMPK activators, has been widely used to suppress cancer cell growth through activation of LKB1, an upstream kinase of AMPK. However,
Sandy Yee Man Yu; David Wai Chan; Vincent Wing Sun Liu; Hextan Yuen Sheung Ngan
Bone metastasis in cancer of uterine cervix, especially in the form of isolated bone involvement is a rare manifestation. Herein, we report the first case of isolated humeral metastasis in a known case of locally advanced cervical cancer. A fifty-six-year old female presented with International Federation of Gynecology and Obstetrics (FIGO) Stage IV A squamous cell carcinoma of uterine cervix. She was treated with a combination of radiation and chemotherapy and then total abdominal hysterectomy with bilateral salpingo-oophorectomy. Seven months later, she developed an isolated lytic lesion in the left humerus, which turned out to be a bone metastatic lesion.
Malek, Mahrooz; Kanafi, Alireza Rajabzadeh; Pourghorban, Ramin; Nafisi-Moghadam, Reza
Deregulated expression of high-risk human papillomavirus oncogenes (E6 and E7) is a pivotal event for pathogenesis and progression in cervical cancer. Both viral oncogenes are therefore regarded as ideal therapeutic targets. Small interfering RNAs (siRNA) or double-stranded RNAs can knock down target genes effectively through siRNA-induced transcriptional gene silencing (TGS). Here, we established lentiviral-vector mediated shRNA (LV-shRNA) targeting common promoter of HPV16 E6/E7 and targeting E6 transcript, transduced the lentiviral construct into cervical HPV16-positive cell lines Siha and Caski, then selected and established stably transduced monoclonal cell lines. The results showed that LV-shRNA targeting promoter, as well as targeting E6 transcript, effectively knocked down E6 and E7 expression, resulted in accumulation of p53 and pRB protein and decrease of MCM7 and p16 protein, and consequently remarkably reduced the abilities of proliferation and invasiveness of cervical cancers cells in vitro. Then we inoculated subcutaneously those monoclonal cells into nude mice to establish the transplanted tumor animal models, and found dramatically inhibited tumorigenesis and growth, as well as prolonged survival time of mice incubated by cells with LV-shRNA targeting promoter and E6 transcript. Our results may provide evidence for application of LV-shRNA targeting HR-HPV key oncogenes, as a new treatment strategy, in cervical and other HPV-associated cancer therapy. PMID:23523766
Zhou, Jiansong; Li, Baohua; Peng, Chanjuan; Wang, Fenfen; Fu, Zhiqin; Zhou, Caiyun; Hong, Die; Ye, Feng; Lü, Weiguo; Xie, Xing
Strong evidence now supports the adoption of cervical cancer prevention strategies that explicitly focus on persistent infection with the causal agent, human papillomavirus (HPV). To inform an evidence-based transition to a new public health approach for cervical cancer screening, we summarize the natural history and cervical carcinogenicity of HPV and discuss the promise and uncertainties of currently available screening methods. New HPV infections acquired at any age are virtually always benign, but persistent infections with one of approximately 12 carcinogenic HPV types explain virtually all cases of cervical cancer. In the absence of an overtly persistent HPV infection, the risk of cervical cancer is extremely low. Thus, HPV test results predict the risk of cervical cancer and its precursors (cervical intraepithelial neoplasia grade 3) better and longer than cytological or colposcopic abnormalities, which are signs of HPV infection. The logical and inevitable move to HPV-based cervical cancer prevention strategies will require longer screening intervals that will disrupt current gynecologic and cytology laboratory practices built on frequent screening. A major challenge will be implementing programs that do not overtreat HPV-positive women who do not have obvious long-term persistence of HPV or treatable lesions at the time of initial evaluation. The greatest potential for reduction in cervical cancer rates from HPV screening is in low-resource regions that can implement infrequent rounds of low-cost HPV testing and treatment.
Wentzensen, Nicolas; Wacholder, Sholom; Kinney, Walter; Gage, Julia C.; Castle, Philip E.
Mechanisms of growth inhibition in human papillomavirus positive and negative cervical cancer cells by the chloromethyl ketone protease inhibitor, succinyl-alanine-alanine-proline-phenylalanine chloromethyl ketone.
The chymotrypsin-like serine protease inhibitor, succinyl-alanine-alanine-proline-phenylalanine chloromethyl ketone (AAPF(CMK)), has been shown to have anticarcinogenic activity in a number of model systems and to be relatively selective for a nuclear protease. This inhibitor also has substantial effects on growth of tumorigenic human papillomavirus (HPV)-infected keratinocytes in organotypic raft cultures. Here, we examined the effects of AAPF(CMK) on cell growth, cell-cycle kinetics, apoptosis induction, and DNA synthesis in two human cervical carcinoma cell lines: SiHa cells, which have integrated high-risk HPV-16; and C33a cells, which do not contain HPV DNA. AAPF(CMK) inhibited growth of both cell lines in a time- and dose-dependent manner. Apoptosis studies showed no significant difference in drug-treated versus vehicle-treated cells in the C33a cell line. However, a significant dose-dependent increase in apoptosis occurred at a late time point in SiHa cells. Cell-cycle progression and DNA synthesis assays showed that the cellular mechanisms of growth inhibition by AAPF(CMK) differ between the HPV16-positive and HPV-negative tumorigenic cell lines. Drug-treated C33a cells showed a significant accumulation of cells in the G(2) phase of the cell cycle. In SiHa cells, growth inhibition produced by AAPF(CMK) seemed to result from a global arrest of the cell cycle. Although the molecular mechanisms involved in AAPF(CMK)-induced growth inhibition are distinct between the two tumorigenic cell lines, such differences may ultimately prove to have therapeutic utility. Novel therapies for treating established HPV infections are needed, because HPV is a causative agent in the development of multiple types of cancer. PMID:19401497
Duncan, Kimberly J; Eckert, Kristin A; Clawson, Gary A
Purpose: The aim of this study was to evaluate efficacy of gynecologic examination under general anesthesia with cervical biopsies after (chemo) radiation for cervical cancer to identify patients with residual disease who may benefit from salvage surgery. Methods and Materials: In a retrospective cohort study data of all cervical cancer patients with the International Federation of Gynecology and Obstetrics (FIGO) Stage IB1 to IVA treated with (chemo) radiation between 1994 and 2001 were analyzed. Patients underwent gynecologic examination under anesthesia 8 to 10 weeks after completion of treatment. Cervical biopsy samples were taken from patients judged to be operable. In case of residual cancer, salvage surgery was performed. Results: Between 1994 and 2001, 169 consecutive cervical cancer patients received primary (chemo) radiation, of whom 4 were lost to follow-up. Median age was 56 years (interquartile range [IQR], 44-71) and median follow-up was 3.5 years (IQR, 1.5-5.9). In each of 111 patients a biopsy sample was taken, of which 90 (81%) showed no residual tumor. Vital tumor cells were found in 21 of 111 patients (19%). Salvage surgery was performed in 13 of 21 (62%) patients; of these patients, 5 (38%) achieved long-term, complete remission after salvage surgery (median follow-up, 5.2 years; range, 3.9-8.8 years). All patients with residual disease who did not undergo operation (8/21) died of progressive disease. Locoregional control was more often obtained in patients who underwent operation (7 of 13) than in patients who were not selected for salvage surgery (0 of 8 patients) (p < 0.05). Conclusions: Gynecologic examination under anesthesia 8 to 10 weeks after (chemo) radiation with cervical biopsies allows identification of those cervical cancer patients who have residual local disease, of whom a small but significant proportion may be salvaged by surgery.
Nijhuis, Esther R. [Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, Groningen (Netherlands); Zee, Ate G.J. van der [Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, Groningen (Netherlands); Hout, Bertha A. in 't [Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, Groningen (Netherlands); Boomgaard, Jantine J. [Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, Groningen (Netherlands); Hullu, Joanne A. de [Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Pras, Elisabeth [Department of Radiation Oncology, University Medical Centre Groningen, University of Groningen, Groningen (Netherlands); Hollema, Harry [Department of Pathology, University Medical Centre Groningen, University of Groningen, Groningen (Netherlands); Aalders, Jan G. [Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, Groningen (Netherlands); Nijman, Hans W. [Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, Groningen (Netherlands); Willemse, Pax H.B. [Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen (Netherlands); Mourits, Marian J.E. [Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, Groningen (Netherlands)]. E-mail: email@example.com
Cervical cancer and its precursor intra-epithelial lesions are linked to infection by a subset of so-called “highrisk” human papillomavirus types, which are estimated to infect nearly four hundred million women worldwide. Two prophylactic vaccines have been commercialized recently targeting HPV16 and 18, the most prevalent viral types found in cervical cancer, which operate through induction of capsid-specific neutralizing antibodies. However, in patients with persistent infection these vaccines have not been found to protect against progression to neoplasia. Attempts are being made to develop therapeutic vaccines targeting nonstructural early viral proteins. Among these, E6 and E7 are the preferred targets, since they are essential for induction and maintenance of the malignant phenotype and are constitutively expressed by the transformed epithelial cells. Here are reviewed the most relevant potential vaccines based on HPV early antigens that have shown efficacy in preclinical models and that are being tested in clinical studies, which should determine their therapeutic capacity for eradicating HPV-induced premalignant and malignant lesions and cure cervical cancer.
More than 99% of cervical cancers have been asso- ciated with human papillomaviruses (HPVs), partic- ularly HPV type 16. The clear association between HPV infection and cervical cancer indicates that HPV serves as an ideal target for development of preventive and therapeutic vaccines. Although the recently licensed preventive HPV vaccine, Gardasil, has been shown to be safe and capable of
Chien-Fu Hung; Archana Monie; Ronald D. Alvarez; T.-C. Wu
Since 1976 a clinical trial has been conducted to test the feasibility, the potential, and to develop methods for using the neutron-emitting radioactive isotope, californium-252 (Cf-252), for the treatment of cervical cancer. A total of 218 patients were treated in the initial study period from 1976 until 1983. The trials initially treated advanced cervical cancer patients using different doses and
Yosh Maruyama; John R. van Nagell; Justine Yoneda; Elvis S. Donaldson; Holly H. Gallion; Deborah Powell; Richard J. Kryscio
While the incidence of cervical cancer has declined significantly in the United States, it still remains a serious American health threat. When detected early, cervical cancer is generally curable. Early lesions are treated surgically, and locally advanced lesions are managed with concurrent cisplatin chemotherapy and pelvic radiation. Metastatic disease or recurrent lesions not amenable to radical local excision or regional
Bradley J. Monk; Lyndsay J. Willmott; Daniele A. Sumner
Significant disparities in cervical cancer incidence and mortality rates among minority groups have been documented in the United States, despite an overall decline in these rates for the population as a whole. Differences in cervical cancer screening practices have been suggested as an explanation for these disparities, as have differences in treatment among various racial and ethnic groups. A number
Levi S. Downs; Jennifer S. Smith; Isabel Scarinci; Lisa Flowers; Groesbeck Parham
Background: Despite increasingly widespread use of the Papanicolaou smear, almost half of all women with in- vasive cervical cancer are diagnosed at a late stage (re- gional or distant). Little is known about factors associ- ated with late-stage diagnosis of cervical cancer. Objective: To examine the relationship of age, race, edu- cation level, income level, smoking, marital status, health insurance
Jeanne M. Ferrante; Eduardo C. Gonzalez; Richard G. Roetzheim; Naazneen Pal; Laurie Woodard
Purpose. We investigated the validity of sentinel lymph node (SLN) detection after radioactive isotope and\\/or blue dye injection in patients with cervical cancer.Patients and methods. Between December 1998 and May 2000, 50 patients (mean age 44 years) with cervical cancer FIGO stage I (n = 32), stage II (n = 16), or stage IV (n = 2) underwent SLN detection
Sabine Malur; Norman Krause; Christhardt Köhler; Achim Schneider
OBJECTIVE: The purpose of this study was to investigate whether the intensity of tumor angiogenesis, expressed as microvessel density, is a parameter predicting the probability of lymph node metastasis and survival in patients with cervical cancer stages IB and IIA. STUDY DESIGN: In a retrospective study of 114 patients with cervical cancer stages IB and IIA, microvessel density, lymph node
Gerard L. Bremer; Anton T. M. G. Tiebosch; Hans W. H. M. van der Putten; Hubert J. A. Schouten; Jelte de Haan; Jan-Willem Arends
The purpose of this paper was to review the literature on Hispanic populations to outline: 1) demographics; 2) general health status; 3) cervical cancer incidence and mortality; 4) Pap smear screening rates; and 5) barriers to preventive care services. The methods: MEDLINE, Med66, Med75, and Med85 files, from 1966 to 1999, were searched for key words Hispanic health, cervical cancer
Faith Boucher; Marc B. Schenker
Objective: Screening for cervical cancer has been one of the major successes in American health care. The reasons for screening failure have not been well described. We have encountered 24 patients in the past year on our gynecologic oncology service who have presented with grossly visible stage IB or higher cervical cancers. A questionnaire was developed to determine why these
Melissa Dworkin; Maureen Killackey; Jacqueline C. Johnson
|Background: Understanding how "health issues" are socially constructed may be useful for creating culturally relevant programs for Hispanic/Latino populations. Purpose: We explored the constructed meanings of cervical cancer and cervical cancer screening among Panamanian women, as well as socio-cultural factors that deter or encourage screening…
Calvo, Arlene; Brown, Kelli McCormack; McDermott, Robert J.; Bryant, Carol A.; Coreil, Jeanine; Loseke, Donileen
More than 99% of cervical cancers have been associated with human papillomaviruses (HPVs), particularly HPV type 16. The clear association between HPV infection and cervical cancer indicates that HPV serves as an ideal target for development of preventive and therapeutic vaccines. Although the recently licensed preventive HPV vaccine, Gardasil, has been shown to be safe and capable of generating significant protection against specific HPV types, it does not have therapeutic effect against established HPV infections and HPV-associated lesions. Two HPV oncogenic proteins, E6 and E7, are consistently co-expressed in HPV-expressing cervical cancers and are important in the induction and maintenance of cellular transformation. Therefore, immunotherapy targeting E6 and/or E7 proteins may provide an opportunity to prevent and treat HPV-associated cervical malignancies. It has been established that T cell-mediated immunity is one of the most crucial components to defend against HPV infections and HPV-associated lesions. Therefore, effective therapeutic HPV vaccines should generate strong E6/E7-specific T cell-mediated immune responses. DNA vaccines have emerged as an attractive approach for antigen-specific T cell-mediated immunotherapy to combat cancers. Intradermal administration of DNA vaccines via a gene gun represents an efficient way to deliver DNA vaccines into professional antigen-presenting cells in vivo. Professional antigen-presenting cells, such as dendritic cells, are the most effective cells for priming antigen-specific T cells. Using the gene gun delivery system, we tested several DNA vaccines that employ intracellular targeting strategies for enhancing MHC class I and class II presentation of encoded model antigen HPV-16 E7. Furthermore, we have developed a strategy to prolong the life of DCs to enhance DNA vaccine potency. More recently, we have developed a strategy to generate antigen-specific CD4+ T cell immune responses to further enhance DNA vaccine potency. The impressive preclinical data generated from our studies have led to several HPV DNA vaccine clinical trials.
Hung, Chien-Fu; Monie, Archana; Alvarez, Ronald D.; Wu, T.-C.
Cervical cancer is one of the most preventable forms of cancer and the Pap smear test is one of the most widely accessible\\u000a forms of cancer screening. An important public health issue is the extent to which Canadian women are engaging in regular\\u000a screening for cervical cancer, particularly potentially at-risk groups such as recent immigrants and women from minority ethnic
James Ted McDonald; Steven Kennedy
A series of organically functionalized, MCM-41 type mesoporous silica nanoparticle materials (PAP-LP-MSN and AP-PAP-MSN) with different pore sizes (5.7 nm and 2.5 nm, respectively) were synthesized and characterized. We selectively decorated the exterior particle surface of PAP-LP-MSN and the interior pore surface of AP-PAP-MSN with an oligonucleotide intercalating phenanthridinium functionality. While phenanthridinium itself is a cell membrane impermeable molecule, we demonstrated that both phenanthridinium-immobilized PAP-LP-MSN and AP-PAP-MSN materials could indeed be internalized by live human cervical cancer cells (HeLa). We discovered that the PAP-LP-MSN nanoparticles with the phenanthridium groups located on the exterior surface were able to bind to cytoplasmic oligonucleotides, such as messenger RNAs, of HeLa cells resulting in severe cell growth inhibition. In contrast, the cytotoxicity of AP-PAP-MSN, where the same oligonucleotide intercalating molecules were anchored inside the pores, was significantly lowered upon the endocytosis by HeLa cells. We envision that this approach of combining the selective functionalization of the two different surfaces (exterior particle and interior pore surfaces) with morphology control of mesoporous silica nanoparticles would lead to a new generation of nanodevices with tunable biocompatibility and cell membrane trafficking properties for many biomedical applications. PMID:19932923
Vivero-Escoto, Juan L; Slowing, Igor I; Lin, Victor S-Y
The oncogenic E6 proteins produced by high-risk human papillomaviruses (HPVs) are invariably expressed in cervical carcinomas and are multifunctional proteins capable of affecting host-cell proliferation by binding and deregulating key host molecules such as p53. High-risk HPVs, including HPV16, have the unique ability to splice the E6 viral transcript, resulting in the production of a truncated E6 protein known as E6*I whose precise biological function is unclear. This study explored the changes in gene expression of the cervical cancer C33A cell line stably expressing HPV16 E6*I (16E6*I) and observed the upregulation of ten genes. Two of these genes were aldo-keto reductases (AKR1Cs), AKR1C1 and AKR1C3, which have been implicated in drug resistance. The results demonstrated that expression of 16E6*I, but not full-length E6, specifically increased AKR1C1 transcript levels although it did not alter AKR1C2 transcript levels. HPV16 E7 alone also had the ability to cause a moderate increase in AKR1C3 at both mRNA and protein levels. Site-directed mutagenesis of 16E6*I revealed that transactivation activity was abolished in R8A, R10A and T17A 16E6*I mutants without altering their intracellular localization patterns. Loss of transactivation activity of the 16E6*I mutants resulted in a significant loss of AKR1C expression and a decrease in drug resistance. Analysis of the AKR1C1 promoter revealed that, unlike the E6 protein, 16E6*I does not mediate transactivation activity solely through Sp1-binding sites. Taken together, it was concluded that 16E6*I has a novel function in upregulating expression of AKR1C and, in concert with E7, has implications for drug treatment in HPV-mediated cervical cancer. PMID:22278827
Wanichwatanadecha, Panata; Sirisrimangkorn, Sasinan; Kaewprag, Jittranan; Ponglikitmongkol, Mathurose
Cervical cancer is the second most common female tumor worldwide and its incidence is disproportionately high (>80%) in the developing world. In the U.S., where Pap tests have reduced the annual incidence to approximately 11,000 cervical cancers, more than 60% of cases occur in medically-underserved populations as part of a complex of diseases linked to poverty, race/ethnicity, and/or health disparities. Because carcinogenic human papillomavirus (HPV) infections cause virtually all cervical cancer, two new approaches for cervical cancer prevention have emerged: 1) HPV vaccination to prevent infections in younger women (?18 years old) and 2) carcinogenic HPV detection in older women (?30 years old). Together, HPV vaccination and testing, if used in an age-appropriate manner, have the potential to transform cervical cancer prevention particularly among underserved populations. Yet significant barriers of access, acceptability, and adoption to any cervical cancer prevention strategy remain. Without understanding and addressing these obstacles, these promising new tools for cervical cancer prevention may be futile. We share our experiences in the delivery of cervical cancer prevention strategies to U.S. populations experiencing high cervical cancer burden: African-American women in South Carolina, Alabama, Mississippi; Haitian immigrant women in Miami; Hispanic women in the U.S.-Mexico Border; Sioux/Native American women in the Northern Plains; white women in the Appalachia; and Vietnamese-American women in Pennsylvania and New Jersey. Our goal is to inform future research and outreach efforts to reduce the burden of cervical cancer in underserved populations.
Scarinci, Isabel C.; Garcia, Francisco A. R.; Kobetz, Erin; Partridge, Edward E.; Brandt, Heather M.; Bell, Maria C.; Dignan, Mark; Ma, Grace X.; Daye, Jane L.; Castle, Philip E.
Incidence of second primary cancers was evaluated in 7,127 women with invasive cancer of the cervix uteri, diagnosed between 1935 and 1978, and followed up to 38 years (average, 8.9 yr) in Connecticut. Among 5,997 women treated with radiation, 449 developed second primary cancers compared with 313 expected (relative risk . 1.4) on the basis of rates from the Connecticut Tumor Registry. Excess incidence was noticeable 15 years or more after radiotherapy and attributed mostly to cancers of sites in or near the radiation field, especially the bladder, kidneys, rectum, corpus uteri, and ovaries. No excess was found for these sites among the 1,130 nonirradiated women. The ratio of observed to expected cancers for these sites did not vary appreciably by age at irradiation. The data suggested that high-dose pelvic irradiation was associated with increase in cancers of the bladder, kidneys, rectum, ovaries, corpus uteri, and non-Hodgkin's lymphoma but, apparently, not leukemia, Hodgkin's disease, breast cancer, or colon cancer.
Kleinerman, R.A.; Curtis, R.E.; Boice, J.D. Jr.; Flannery, J.T.; Fraumeni, J.F. Jr.
AIM--To assess the value of detecting human papillomavirus (HPV) DNA in false negative archival cervical smears in population based screening programmes for cervical cancer. METHODS--Cytomorphologically classified false negative archival Pap smears (n = 27) taken from 18 women up to six years before cervical cancer was diagnosed were blindly mixed with 89 smears from hospital patients with a variety of gynaecological complaints and tested for HPV by the polymerase chain reaction (PCR). Corresponding cervical cancer biopsy specimens were also available for HPV analysis. Neither the examining cytopathologist nor the molecular biologist was aware of the study design. RESULTS--HPV DNA was detected in the smears of 16 patients with cervical cancer missed previously by cytology. HPV 16 and 18 were found predominantly in those smears taken up to six years before the diagnosis of cervical cancer. The smears of the two remaining patients were reclassified as inadequate for cytology or contained no suitable DNA for PCR. In 15 patients the same HPV type could be found in the smears and the cervical cancer biopsy specimens. CONCLUSIONS--The results indicate that high risk HPV types can be detected in archival smears classified as false negative on cytology and that cytological screening errors may be reduced if combined with PCR testing for HPV.
Walboomers, J M; de Roda Husman, A M; Snijders, P J; Stel, H V; Risse, E K; Helmerhorst, T J; Voorhorst, F J; Meijer, C J
Background: Recent studies have revealed a possible role for the human papillomavirus (HPV) in the pathogenesis of breast cancer. In this study, patients having both a history of invasive cervical cancer and breast cancer as second primary cancer were selected for enrolment in a study of breast carcinomas for the presence of HPV. Methods: Paraffin-embedded tissue from cervical cancer, pelvic
Andreas Widschwendter; Thomas Brunhuber; Annemarie Wiedemair; Elisabeth Mueller-Holzner; Christian Marth
Objective To evaluate patterns of cervical cancer incidence in Peru by examining variation in 2 common histopathologic types, squamous cell carcinoma (SCC) and adenocarcinoma (ADC), and analyzing trends over time. Methods Data on the incidence of invasive cervical cancer between 1984 and 2006 were obtained from 3 population-based cancer registries in Peru: Lima, Trujillo, and Arequipa. For each registry, data quality assessment was performed, crude and age-specific incidence was calculated, and time trends were analyzed. Results Overall and SCC incidence varied across registries but incidence of ADC did not. Overall and SCC incidence showed significant declines in Trujillo (P<0.05) and modest declines in Lima (P>0.05) over time. ADC incidence showed marginally significant increases among women aged 15–29 years in Trujillo (P=0.10) and modest increases among young women in Lima (P>0.05). Conclusion Population-based cancer registries were an efficient source of data for evaluating the incidence of cervical cancer once data quality had been established. Geographic and temporal variations in cervical cancer burden were documented in Peru. The trends suggest that cervical ADC is increasing among young women in urban Peru, particularly in Trujillo. We recommend supplementing current Papanicolaou test screening with complementary methods of cervical cancer control, including human papillomavirus (HPV) vaccination and HPV DNA testing.
Pierce Campbell, Christine M.; Curado, Maria P.; Harlow, Sioban D.; Soliman, Amr S.
Cervical cancer (CC) is the second most common cause of death from cancer among women worldwide and about 80% of the half of million new cases detected every year, occurs in less-developed countries. Human papillomavirus is an obligate factor for the development of CC, since some HPVtype are detected in 100% of CC. HPV16 and HPV18 are the most common viral types, accounting for about 50% and 15% of CC, respectively. HPV infection is the most common sexual transmitted infection, with an estimated prevalence of about 2-44% among sexually active young women. However, only a very small fraction of these infections evolve to CC (1-2 out of 1000), indicating that some other factors should be important in the evolution of the disease. Preventive vaccines against HPVs 16 and 18 have been developed, and in phase III clinical trials they have demonstrated 100% efficacy for prevention of persistent infection and high risk cervical squamous intraepithelial neoplasias positive for these HPV types, suggesting that these vaccines, if made widely available, will dramatically reduce the burden of CC. PMID:19031679
An audit of the screening history of all new cervical cancer cases has been a requirement since April 2007. While NHS cervical screening programmes (NHSCSP) guidance requires that women diagnosed with cervical cancer are offered the findings of the audit, as yet there has been no research to investigate the psychological impact that meeting to discuss the findings might have on patients. This is in spite of the fact that cytological under-call may play a role in as many as 20% of cervical cancer cases. This review draws on the literature concerning breaking bad news, discussing cancer and disclosing medical errors, in order to gain insight into both the negative and positive consequences that may accompany a cervical screening review meeting. We conclude that while patients are likely to experience some distress at disclosure, there are also likely to be positive aspects, such as greater trust and improved perception of care. PMID:23506198
Sherman, S M; Moss, E; Redman, C W E
Common warts could indicate cervical cancer susceptibility, as both are caused by human papillomavirus (HPV). Eczema was also investigated, as atopic eczema has been negatively associated with warts, but non-atopic eczema may be associated with compromised host defences, as observed in patients with HIV, suggesting increased susceptibility to HPV infection and cervical cancer. 'Cervical cancer' was self-reported during an interview by 87 of 7594 women members of two longitudinal British birth cohorts. The accuracy of the diagnoses is limited by lack of confirmation using medical records. Odds ratios are adjusted for common warts and eczema in childhood; and cigarette smoking, number of cohabiting partners and social class in early adult life. The odds ratios of warts and eczema with cervical cancer are 2.50 (95% confidence interval 1.14-5.47) and 3.27 (1.95-5.49), respectively. The association of eczema with cervical cancer is independent of hay fever as a marker of atopy, suggesting the importance of non-atopic eczema. Both heavier smoking compared with non-smoking and four or more cohabiting partners compared with one/none have odds ratios for cervical cancer of 8.26 (4.25-15.10) and 4.89 (1.39-17.18), respectively. Common warts in childhood may indicate cervical cancer susceptibility; this and the relationship with eczema deserves investigation. PMID:12434290
Montgomery, S M; Ehlin, A G C; Sparén, P; Björkstén, B; Ekbom, A
Background: Infection with human papillomavirus (HPV) is the main cause of cervical cancer and its precursor lesion, cervical intraepithelial neoplasia (CIN). Variability in host immunogenetic background is important in determining the overall cellular immune response to HPV infections. Objective: To determine whether the HLA-DQ or HLA-DR genes, or others in their vicinity, are associated with cervical cancer. Methods: Markers covering the entire HLA region were genotyped in a large sample of CIN and cervical cancer patients and in controls (311 CIN, 695 cervical cancer, 115 family controls, and 586 unrelated controls). Results: Two markers were associated with susceptibility to cervical neoplasia, G511525 and MICA. G511525, close to the region containing the HLA-DQ and HLA-DR genes, was most strongly associated, showing a decrease in frequency of allele 221 from 6.7% to 3.3% in patients with squamous cell cancer (SCC). An association was found for MICA (allele 184) with SCC (odds ratio (OR) = 1.31 (95% confidence interval, 1.13 to 1.53); homozygotes, OR = 1.48 (1.06 to 2.06)). No associations were observed with adenocarcinoma or CIN. Conclusions: There is an association of the region containing the HLA-DQ and HLA-DR genes with the risk of developing squamous cell carcinoma. An increased risk was observed for carriers of allele 184 at the MICA locus, in particular for homozygotes, suggesting a recessive effect.
Zoodsma, M; Nolte, I; Schipper, M; Oosterom, E; van der Steege, G; de Vries, E G E; te Meerman, G J; van der Zee, A G J
Large cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is very rare and aggressive. The prognosis is very poor despite multimodal treatment. We report a virgin woman with FIGO stage 4b LCNEC of uterine cervix coexisting with squamous cell carcinoma. An early thirties virgin woman presented with 2-month history of abdominal pain. A chest X-ray showed multiple lung metastatic tumors. A vaginal smear showed malignant cells, and a biopsy specimen had features of LCNEC. The tumor showed trabecular patterns. Tumor cells possessed a moderate amount of cytoplasm, prominent nucleoli, and large nuclei. The tumor cells are stained positive for synaptophysin, chromogranin A, and neuron specific enolase (NSE). The invasive tumor cells in connection with cervical squamous epithelium were focally positive for 34bE12. We made a diagnosis of composite LCNEC and nonkeratinizing squamous cell carcinoma. High-risk HPV test was negative with hybridized captured method 2. PMID:24062959
Murakami, Ryusuke; Kou, Iemasa; Date, Kenjiro; Nakayama, Hirofumi
Large cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is very rare and aggressive. The prognosis is very poor despite multimodal treatment. We report a virgin woman with FIGO stage 4b LCNEC of uterine cervix coexisting with squamous cell carcinoma. An early thirties virgin woman presented with 2-month history of abdominal pain. A chest X-ray showed multiple lung metastatic tumors. A vaginal smear showed malignant cells, and a biopsy specimen had features of LCNEC. The tumor showed trabecular patterns. Tumor cells possessed a moderate amount of cytoplasm, prominent nucleoli, and large nuclei. The tumor cells are stained positive for synaptophysin, chromogranin A, and neuron specific enolase (NSE). The invasive tumor cells in connection with cervical squamous epithelium were focally positive for 34bE12. We made a diagnosis of composite LCNEC and nonkeratinizing squamous cell carcinoma. High-risk HPV test was negative with hybridized captured method 2.
Kou, Iemasa; Date, Kenjiro; Nakayama, Hirofumi
Objective PR (PRDI-BF1 and RIZ) domain proteins (PRDM) are a subfamily of the kruppel-like zinc finger gene products and play key roles\\u000a during cell differentiation and malignant transformation. PRDM5 (PR domain containing 5 PFM2) is a new PR-domain-containing\\u000a gene. The purpose of the present study was to examine the expression of PRDM5 and evaluate its carcinogenesis in cervical\\u000a cancer. The relationship
Hai-Yan ChengXiu-Wei; Xiu-Wei Chen; Li Cheng; Yun-Duo Liu; Ge Lou
For repair of damaged DNA, cells increase de novo synthesis of deoxyribonucleotide triphosphates through the rate-limiting, p53-regulated ribonucleotide reductase (RNR) enzyme. In this study we investigated whether pharmacological inhibition of RNR by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) enhanced chemoradiation sensitivity through a mechanism involving sustained DNA damage. RNR inactivation by 3-AP and resulting chemoradiosensitization were evaluated in human cervical (CaSki, C33-a) cancer cells through study of DNA damage (?-H2AX signal) by flow cytometry, RNR subunit p53R2 and p21 protein steady-state levels by Western blot analysis and laser scanning imaging cytometry, and cell survival by colony formation assays. 3-AP treatment led to sustained radiation- and cisplatin-induced DNA damage (i.e. increased ?-H2AX signal) in both cell lines through a mechanism of inhibited RNR activity. Radiation, cisplatin and 3-AP exposure resulted in significantly elevated numbers and persistence of ?-H2AX foci that were associated with reduced clonogenic survival. DNA damage was associated with a rise in p53R2 but not p21 protein levels 6 h after treatment with radiation and/or cisplatin plus 3-AP. We conclude that blockage of RNR activity by 3-AP impairs DNA damage responses that rely on deoxyribonucleotide production and thereby may substantially increase chemoradiosensitivity of human cervical cancers. PMID:20954859
Kunos, Charles A; Radivoyevitch, Tomas; Pink, John; Chiu, Song-Mao; Stefan, Tammy; Jacobberger, James; Kinsella, Timothy J
For repair of damaged DNA, cells increase de novo synthesis of deoxyribonucleotide triphosphates through the rate-limiting, p53-regulated ribonucleotide reductase (RNR) enzyme. In this study we investigated whether pharmacological inhibition of RNR by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) enhanced chemoradiation sensitivity through a mechanism involving sustained DNA damage. RNR inactivation by 3-AP and resulting chemoradiosensitization were evaluated in human cervical (CaSki, C33-a) cancer cells through study of DNA damage (?-H2AX signal) by flow cytometry, RNR subunit p53R2 and p21 protein steady-state levels by Western blot analysis and laser scanning imaging cytometry, and cell survival by colony formation assays. 3-AP treatment led to sustained radiation- and cisplatin-induced DNA damage (i.e. increased ?-H2AX signal) in both cell lines through a mechanism of inhibited RNR activity. Radiation, cisplatin and 3-AP exposure resulted in significantly elevated numbers and persistence of ?-H2AX foci that were associated with reduced clonogenic survival. DNA damage was associated with a rise in p53R2 but not p21 protein levels 6 h after treatment with radiation and/or cisplatin plus 3-AP. We conclude that blockage of RNR activity by 3-AP impairs DNA damage responses that rely on deoxyribonucleotide production and thereby may substantially increase chemoradiosensitivity of human cervical cancer.
Kunos, Charles A.; Radivoyevitch, Tomas; Pink, John; Chiu, Song-Mao; Stefan, Tammy; Jacobberger, James; Kinsella, Timothy J.
A group of 47 experts representing 23 professional societies, national and international health organizations, and federal agencies met in Bethesda, MD, September 14-15, 2012, to revise the 2006 American Society for Colposcopy and Cervical Pathology Consensus Guidelines. The group's goal was to provide revised evidence-based consensus guidelines for managing women with abnormal cervical cancer screening tests, cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS) following adoption of cervical cancer screening guidelines incorporating longer screening intervals and co-testing. In addition to literature review, data from almost 1.4 million women in the Kaiser Permanente Northern California Medical Care Plan provided evidence on risk after abnormal tests. Where data were available, guidelines prescribed similar management for women with similar risks for CIN 3, AIS, and cancer. Most prior guidelines were reaffirmed. Examples of updates include: Human papillomavirus-negative atypical squamous cells of undetermined significance results are followed with co-testing at 3 years before return to routine screening and are not sufficient for exiting women from screening at age 65 years; women aged 21-24 years need less invasive management, especially for minor abnormalities; postcolposcopy management strategies incorporate co-testing; endocervical sampling reported as CIN 1 should be managed as CIN 1; unsatisfactory cytology should be repeated in most circumstances, even when HPV results from co-testing are known, while most cases of negative cytology with absent or insufficient endocervical cells or transformation zone component can be managed without intensive follow-up. PMID:23519301
Massad, L Stewart; Einstein, Mark H; Huh, Warner K; Katki, Hormuzd A; Kinney, Walter K; Schiffman, Mark; Solomon, Diane; Wentzensen, Nicolas; Lawson, Herschel W
The nuclear microRNA (miRNA) processing enzyme Drosha is upregulated in cervical cancer, and its overexpression is related to an invasive tumour phenotype. However, the mechanisms that underlie this effect remain poorly understood. The aim of this study was to identify the potential targets of Drosha in cervical cancer. Here, we demonstrated that Drosha knockdown (Drosha-KD) inhibited proliferation, colony formation and the migration of cervical cancer cells in vitro. A global upregulation of proteins in Drosha-KD cells was revealed by two-dimensional gel electrophoresis (2-DE). Eighteen proteins were identified by liquid chromatography and tandem mass spectrometry technology (LC-MS/MS) from 21 selected protein spots that exhibited significant alterations in Drosha-KD cells. The majority of the identified proteins have been previously associated with tumour formation. The downregulation of tubulin 5? in Drosha-KD cervical cancer cells was further confirmed by western blotting. Our results suggest that Drosha affects the biological activity of cervical cancer cells by regulating the expression of numerous tumour-associated proteins. PMID:23969986
Zhou, Jun; Cai, Jing; Huang, Zaiju; Ding, Hui; Wang, Junjie; Jia, Jinghui; Zhao, Yong; Huang, Da; Wang, Zehua
Cervical cancer is an important cause of cancer-related deaths in women in developing countries. In Korea, cervical cancer is the third leading cancer among females and is fifth highest in mortality. The persistent oncogenic human papillomavirus (HPV) infections are the greatest risk of developing cervical intraepithelial neoplasia and invasive cancer. The overall prevalence of HPV was 10.4% in Korea and strong risk factors for HPV infection included a young age at sexual debut. The National Cancer Screening Program, which includes cervical cancer screening, has the following principles: the main screening tool is the Papanicolaou test conducted by gynecologists, which targets all women age 30 and over, and which is done every 2 years. HPV DNA tests have not yet been permitted as a screening test for cervical cancer in Korea; however, these are conducted along with a Pap test for screening cervical cancer in the clinic. The use of prophylactic HPV vaccine has been accepted in Korea; The Korean Society of Gynecologic Oncology and Colposcopy's recommendation for routine vaccination is for females aged 15-17 years with a catch-up vaccination recommended for females aged 18-26 years who have not been previously vaccinated. However, many people in Korea are not familiar with the HPV vaccine. Therefore, it is necessary to improve awareness for the disease and HPV vaccination and to establish the effective strategies to obtain funding for HPV vaccination. In the future, cervical cancer is expected to disappear throughout the world, including the Asia Pacific region, through a combination of vaccination and qualified screening programs for cervical cancer.
Our earlier study showed that the autophagy gene Beclin 1 could affect cell proliferation in a cervical cancer HeLa cell line. In this study, we examined Beclin 1 protein expression in 81 specimens of cervical squamous carcinoma by immunohistochemistry. Meanwhile, we detected E6 and E7 genes of human papillomavirus 16 in these tissues by polymerase chain reaction. Beclin 1 expression significantly decreased in samples of malignant cervical cancer tissues than in those of normal or cervical intraepithelial neoplasia tissues. The expression of Beclin 1 was associated with pelvic lymph node metastasis and histological grade, but did not correlate with International Federation of Gynecology and Obstetrics stage, age, depth of cervical infiltration, tumor size, and gross type of cervical lesion. The expression of Beclin 1 was not obviously correlated with E6 and E7 genes statistically. Therefore, decreased expression of Beclin 1 may be related to tumorigenesis and the development of cervical cancer, but is not significantly relevant with human papillomavirus 16 infection. PMID:21623196
Wang, Zan-Hong; Xu, Li; Wang, Yong; Cao, Ming-Qin; Li, Li; Bai, Tao
Previous infections with high-risk types (type 16 and 18) of human papillomaviruses (HPVs) are necessary causes of cervical cancer. Giving thought to the importance of cervix and the severe side effects resulting from traditional cancer therapies, this study intends to achieve targeted inhibition of oncogenes in tumor cells based on small interference (siRNA) technique. To this aim, we constructed 7
Ya-Ching Lu; Ann-Joy Cheng
Several reports have described the potential effects of natural compounds as anti-cancer agents in vitro as well as in vivo. The aim of this study was to evaluate the anti-cancer effect of Limoniastrum guyonianum aqueous gall extract (G extract) and luteolin in the human cervical cancer HeLa cell line, and, if so, to clarify the underlying mechanism. Our results show that G extract and luteolin inhibited cell proliferation and induced G2/M cell cycle arrest in a concentration and time-dependent manner. Both natural products induced programmed cell death as confirmed by the presence of hypodiploid G0/G1 cells. These effects are associated with an up-regulation of the expression of the tumor suppressor gene p16INK4A and a down-regulation of the expression of the anti-apoptotic actor UHRF1 and its main partner DNMT1. Moreover, G extract- and luteolin-induced UHRF1 and DNMT1 down-regulation is accompanied with a global DNA hypomethylation in HeLa cell line. Altogether our results show that G extract mediates its growth inhibitory effects on human cervical cancer HeLa cell line likely via the activation of a p16INK4A -dependent cell cycle checkpoint signalling pathway orchestrated by UHRF1 and DNMT1 down-regulation.
Background The purpose of this community-based study was to develop a structural equation model for factors contributing to cervical cancer screening among Chinese American women. Methods A cross-sectional design included a sample of 573 Chinese American women aged 18 years and older. The initial step involved use of confirmatory factor analysis, that included the following variables: access to and satisfaction with health care, and enabling and predisposing cultural and health beliefs. Structural equation model analyses were conducted on factors related to cervical cancer screening. Results Age, marital status, employment, household income, and having health insurance, but not educational level, were significantly related to cervical screening status. Predisposing and enabling factors were positively associated with cervical cancer screening. The cultural factor was significantly related to the enabling factor or the satisfaction with health care factor. Conclusion This model highlights the significance of sociocultural factors in relation to cervical cancer screening. These factors were significant, with cultural, predisposing, enabling, and health belief factors and access to and satisfaction with health care reinforcing the need to assist Chinese American women with poor English fluency in translation and awareness of the importance of cervical cancer screening. Community organizations may play a role in assisting Chinese American women, which could enhance cervical cancer screening rates.
Ma, Grace X; Wang, Min Qi; Ma, Xiang S; Shive, Steven E; Tan, Yin; Toubbeh, Jamil I
Background Merkel cell polyomavirus (MCPyV) was identified originally in Merkel cell carcinoma (MCC), a rare form of human skin neuroendocrine carcinoma. Evidence of MCPyV existence in other forms of malignancy such as cutaneous squamous cell carcinomas (SCCs) is growing. Cervical cancers became the focus of our interest in searching for potentially MCPyV-related tumors because: (i) the major histological type of cervical cancer is the SCC; (ii) the uterine cervix is a common site of neuroendocrine carcinomas histologically similar to MCCs; and (iii) MCPyV might be transmitted during sexual interaction as demonstrated for human papillomavirus (HPV). In this study, we aimed to clarify the possible presence of MCPyV in cervical SCCs from Japanese patients. Cervical adenocarcinomas (ACs) were also studied. Results Formalin-fixed paraffin-embedded tissue samples from 48 cervical SCCs and 16 cervical ACs were examined for the presence of the MCPyV genome by polymerase chain reaction (PCR) and sequencing analyses. PCR analysis revealed that 9/48 cervical SCCs (19%) and 4/16 cervical ACs (25%) were positive for MCPyV DNA. MCPyV-specific PCR products were sequenced to compare them with reference sequences. The nucleotide sequences in the MCPyV large T (LT)-sequenced region were the same among MCPyV-positive cervical SCCs and AC. Conversely, in the MCPyV viral protein 1 (VP1)-sequenced region, two cervical SCCs and three cervical ACs showed several nucleotide substitutions, of which three caused amino acid substitutions. These sequencing results suggested that three MCPyV variants of the VP1 were identified in our cases. Immunohistochemistry showed that the LT antigen was expressed in tumor cells in MCPyV-positive samples. Genotyping of human HPV in the MCPyV-positive samples revealed that infected HPVs were HPV types 16, 31 and 58 for SCCs and HPV types 16 and 18 for ACs. Conclusions This study provides the first observation that MCPyV coexists in a subset of HPV-associated cervical cancers from Japanese patients. The prevalence of MCPyV in these lesions was close to that observed in the cutaneous SCCs. Further worldwide epidemiological surveys are warranted to determine the possible association of MCPyV with pathogenesis of cervical cancers.
Background Retinoid-inducible gene 1 (RIG1), also known as tazarotene-induced gene 3 or retinoic-acid receptor responder 3, is a growth regulator, which induces apoptosis and differentiation. RIG1 is classified into the NC protein family. This study investigated functional domains and critical amino acids associated with RIG1-mediated cell death and apoptosis. Results Using enhanced green fluorescence protein (EGFP)-tagged RIG1 variants, RIG1 proteins with deletion at the NC domain significantly decreased cell death induced by RIG1, and fusion variants containing only the NC domain significantly induced apoptosis of HtTA cervical cancer cells. The EGFP-RIG1-induced apoptosis was significantly decreased in cells expressing N112C113 motif double- (NC?FG) or triple- (NCR?FGE) mutated RIG1 variants. Using dodecapeptides, nuclear localization and profound cell death was observed in HtTA cells expressing wild type RIG1111–123 or Leu121-mutated RIG1111–123:L? C peptide, but peptides double- or triple-mutated at the NC motif alone, RIG1111–123:NC?FG or RIG1111–123:NCR?FGE, were cytoplasmically localized and did not induce apoptosis. The RIG1111–123 also induced apoptosis of A2058 melanoma cells but not normal human fibroblasts. Conclusion The NC domain, especially the NC motif, plays the major role in RIG1-mediated pro-apoptotic activity. The RIG1111–123 dodecapeptide exhibited strong pro-apoptotic activity and has potential as an anticancer drug.
Tsai, Fu-Ming; Shyu, Rong-Yaun; Lin, Su-Ching; Wu, Chang-Chieh; Jiang, Shun-Yuan
The epithelial-to-mesenchymal transition (EMT) promotes cervical cancer progression, and microRNAs have been found to be master regulators of EMT. The aim of the present study was to investigate the functional roles of miR-361-5p in EMT and cervical cancer progression. Differentially expressed miRNAs were screened with microarray analysis in SiHa and CasKi cells; cellular and animal studies were used to observe the impact of miR-361-5p on cell proliferation; invasion and migration ability of cervical cancer cells were investigated by Transwell and wound-healing studies; enzyme-linked immunosorbent assay and Western blot methods were used to test protein levels; miR-361-5p level in cervical cancer specimens was detected with in situ hybridization. MicroRNA-361-5p (miR-361-5p) was found to be the most upregulated microRNA in transferred cervical cancer cells. MiR-361-5p acts as an oncogene to enhance cell proliferation and promote cell invasion, and these changes were accompanied by the characteristics of EMT. miR-361-5p is increasingly elevated during cervical carcinoma progression and inversely correlated with E-cadherin, a marker of EMT. These findings suggest that miR-361-5p is an oncomicroRNA and an important factor in the progression of cervical cancer. PMID:24158756
Wu, Xiaomei; Xi, Xiaowei; Yan, Qin; Zhang, Zhenbo; Cai, Bin; Lu, Wen; Wan, Xiaoping
The EUROGIN 2008 Roadmap represents a continuing effort to provide updated information on primary and secondary prevention of cervical cancer. The report addresses several areas including the progress made toward global implementation of currently licensed human papillomavirus (HPV) vaccines, the possibilities and value of future-generation HPV vaccines, endpoints under consideration for evaluation of candidate HPV vaccines, and monitoring impact of HPV vaccination programmes that can be implemented within developed and less-developed countries. For the sake of completeness, a short update on the evolution of HPV testing in primary screening programmes at present and after HPV vaccine introduction has also been included. The report is available on the EUROGIN website (www.eurogin.com). PMID:19521965
Franceschi, Silvia; Cuzick, Jack; Herrero, Rolando; Dillner, Joakim; Wheeler, Cosette M
\\u000a Abstract\\u000a \\u000a \\u000a Purpose:\\u000a To evaluate the acute toxicity of simultaneous integrated boost (SIB) technique for dose escalation with helical tomotherapy\\u000a (HT) in patients with locally advanced cervical cancer.\\u000a \\u000a \\u000a \\u000a \\u000a \\u000a Patients and Methods:\\u000a 20 patients (FIGO IB1 pN1-IIIB) underwent primary chemoradiation. Prior to chemoradiation, a laparoscopic\\u000a pelvic and para-aortic lymphadenectomy was performed. A boost region was defined using titanium clips during staging for
Simone Marnitz; Carmen Stromberger; Michael Kawgan-Kagan; Waldemar Wlodarczyk; Ulrich Jahn; Achim Schneider; Uwe Ulrich; Volker Budach; Christhardt Köhler
To develop a comprehensive intervention policy for future management of cervical cancer in China and Mongolia, it is essential to review the prevalence of human papillomavirus (HPV) infection, cervical cancer incidence and mortality, status of cervical screening and issues related to prophylactic HPV vaccines. Invasive cervical cancer (ICC) remains an important health problem among women in both China and Mongolia.
Ju-Fang Shi; You-Lin Qiao; Jennifer S. Smith; Bolormaa Dondog; Yan-Ping Bao; Min Dai; Gary M. Clifford; Silvia Franceschi
Cervical cytologic screening and early management of abnormal pap smears played an important role in reducing invasive cervical cancer incidence and mortality over the past decades. Despite widely available cost effective screening for cervical cancer in the United States, women in lower socioeconomic groups and minorities continue to suffer from a higher incidence and mortality from cervical cancer and national
Josephine R Fowler; Raja Sayegh
The effects of As4O6 as adjuvant on photodynamic therapy (PDT) were studied. As4O6 is considered to have anticancer activity via several biological actions, such as free radical production and inhibition of VEGF expression. PDT or As4O6 significantly inhibited TC-1 cell proliferation in a dose-dependent manner (P<0.05) by MTT assay. The anti-proliferative effect of the combination treatment was significantly higher than in TC-1 cells treated with either photodynamic therapy or As4O6 alone (62.4 and 52.5% decrease compared to vehicle-only treated TC-1 cells, respectively, P<0.05). In addition, cell proliferation in combination of photodynamic therapy and As4O6 treatment significantly decreased by 77.4% (P<0.05). Cell survival pathway (Naip1, Tert and Aip1) and p53-dependent pathway (Bax, p21Cip1, Fas, Gadd45, IGFBP-3 and Mdm-2) were markedly increased by combination treatment of photodynamic therapy and As4O6. In addition, the immune response in the NEAT pathway (Ly-12, CD178 and IL-2) was also modulated after combination treatment, suggesting improved antitumor effects by controlling unwanted growth-stimulatory pathways. The combination effect apparently reflected concordance with in vitro data, in restricting tumor growth in vivo and in relation to some common signaling pathways to those observed in vitro. These findings suggest the benefit of combinatory treatment with photodynamic therapy and As4O6 for inhibition of cervical cancer cell growth.
Kim, Yong-Wan; Bae, Su Mi; Battogtokh, Gantumur; Bang, Hyo Joo; Ahn, Woong Shick
Cervical cancer remains to be one of the leading malignancies among Filipino women. High-risk human papillomavirus (HPV) types, such as 16 and 18, are consistently identified in Filipino women with cervical cancer. Factors identified to increase the likelihood of HPV infection and subsequent development of cervical cancer include young age at first intercourse, low socioeconomic status, high parity, smoking, use of oral contraception and risky sexual behaviors. Cancer screening programs presently available in the Philippines include Pap smears, single visit approach utilizing visual inspection with acetic acid followed by cryotherapy, as well as colposcopy. However, the uptake of screening remains low and is further compounded by the lack of basic knowledge women have regarding screening as an opportunity for prevention of cervical cancer. Prophylactic HPV vaccination of both quadrivalent and bivalent vaccines has already been approved in the Philippines and is gaining popularity among the Filipinos. However, there has been no national or government vaccination policy implemented as of yet. The standard of treatment of cervical cancer is radiotherapy concurrent with chemotherapy. Current researches are directed towards improving availability of both preventive and curative measures of cervical cancer management.
Dy Echo, Ana Victoria V.
This hospital-based study in New Delhi, North India was performed to evaluate the prevalence of human papillomavirus (HPV) in cases of invasive cervical carcinoma (ICC). A total of 10 cases presenting with an obvious cervical growth were included in this study. 108 cases that was shown to be ICC on histology (101 squamous cell carcinomas, 4 adenocarcinomas, and one neuroendocrine carcinoma) were included in the analysis. DNA was extracted from tumor tissue and HPV genotype was determined by a consensus PCR assay using a reverse line blot hybridization assay. Of 106 evaluable cases, 104 (98.1%) were positive for HPV infection. Twelve different high-risk HPV types were found. There were 125 infections, 119 of which were high risk. Six cases had associated low risk infections. HPV 16 was the commonest type, seen in 73.6% cases followed by HPV 18 (14.2%) and 45 (11.3%). A vaccine with 100% efficacy in prevention of HPV 16 and 18 infections would theoretically reduce the total cancer burden in New Delhi by more than 75% (assuming 100% coverage). Increasing the genotype spectrum (e.g. valency) if the existing vaccines would be expected to have only a modest impact on the potential for cervical protection. PMID:16990719
Bhatla, Neerja; Dar, Lalit; Patro, A Raj Kumar; Kriplani, Alka; Gulati, Arti; Verma, Kusum; Broor, Shobha; Shah, Keerti V; Gravitt, Patti E
In the current study, the fluorescence emission spectra (FES) and Stokes shift spectra (SSS) of blood and urine samples of cervical cancer patients were obtained and compared to those of normal controls. Both spectra showed that the relative intensity of biomolecules such as porphyrin, collagen, Nicotinamide adenine dinucleotide, and flavin were quite out of proportion in cervical cancer patients. The biochemical mechanism for the elevation of these fluorophores is not yet definitive; nevertheless, these biomolecules could serve as tumor markers for diagnosis, screening, and follow-up of cervical cancers. To the best of our knowledge, this is the first report on FES and SSS of blood and urine of cervical cancer patients to give a sensitivity of 80% and specificity of 78%.
Masilamani, Vadivel; AlSalhi, Mohamad Saleh; Vijmasi, Trinka; Govindarajan, Kanaganaj; Rathan Rai, Ram; Atif, Muhammad; Prasad, Saradh; Aldwayyan, Abdullah S.
Approximately 90 million people in the United States lack basic literacy skills, which affect health behaviors. Cervical cancer is preventable and treatable, yet few older Hispanic women seek screening and continue to be a high-risk group for cervical cancer. A literature review was conducted to address the relationship between cervical cancer screening, health literacy, and older Hispanic women. Eighty studies were reviewed, and nine addressed health literacy and Hispanic women. One study addressed the association between functional health literacy and Pap smear screening among older Hispanic women. Few studies have explored the association between preventive cervical cancer screening and health literacy among older Hispanic women. Nurses must assess health literacy and be prepared to provide care, which is culturally, and linguistically appropriate to improve health outcomes. Further research is needed to be inclusive of all populations including older Hispanic women. PMID:23729023
Flores, Bertha E; Acton, Gayle J
Breast and cervical cancer screening rates among low-income, uninsured, and underinsured women are low (1, 2). Timely breast cancer screening with mammography and routine Papanicolaou (Pap) testing for cervical cancer have helped to reduce the incidence o...
B. O'Hara F. Tangka J. Gardner J. Turner M. Bauder
Background.Nicaragua has some of the highest rates of cervical cancer in Latin America and the world [Arrossi S, Sankaranarayanan R, Parkin DM. Incidence and mortality of cervical cancer in Latin America. Salud Publica Mex. 2003;45 (Suppl 3):S306–14]. In 2003, the Nicaraguan Ministry of Health, the Central American Institute of Health and the Maria Luisa Ortiz Clinic combined efforts to create
Susan L. Howe; Dora E. Vargas; Dorothy Granada; Janice K. Smith
Abstract Background. Nicaragua has some of the highest rates of cervical cancer in Latin America and the world [Arrossi S, Sankaranarayanan R, Parkin DM. Incidence and mortality of cervical cancer in Latin America. Salud Publica Mex. 2003;45 (Suppl 3):S306–14]. In 2003, the Nicaraguan Ministry of Health, the Central American Institute of Health and the Maria Luisa Ortiz Clinic combined efforts
Susan L. Howe; Dora E. Vargas; Dorothy Granada; Janice K. Smith
Cervical cancer is one of the most common and lethal gynecological malignancies in both developing and developed countries,\\u000a and therefore, there is a considerable interest in early diagnosis and treatment of precancerous lesions. Although the current\\u000a standard care mainly based on cytology and colposcopy has reduced rates of cervical cancer morbidity and mortality, many lesions\\u000a are still missed or overcalled
Irene M. Orfanoudaki; Dimitra Kappou; Stavros Sifakis
Human papillomavirus (HPV) is a significant source of morbidity and mortality throughout the world and is the most common\\u000a sexually transmitted infection in the United States. HPV is the primary etiologic agent of cervical cancer and dysplasia.\\u000a Thus, cervical cancer and other HPV-associated malignancies might be prevented or treated by HPV vaccines. Recent research\\u000a on the safety and efficacy of
Bradley J. Monk; Ali Mahdavi
This study is designed to assess gene expression of squamous cell carcinoma antigen (SCCA) mRNA to detect micrometastases\\u000a in cervical lymph nodes (LNs) of head and neck cancer. We examined the expression of SCCA mRNA in 12 primary tumors and 212\\u000a cervical LNs (101 LNs taken from 8 patients with tongue cancer, 71 from 7 patients with gingival cancer, 19
Hiroyuki Hamakawa; Masakuni Fukizumi; Yang Bao; Tomoki Sumida; Akiko Onishi; Hiroaki Tanioka; Hidemitsu Sato; Eiji Yumoto
Protein profiles of homogenized normal cervical tissue samples from hysterectomy subjects and cancerous cervical tissues from biopsy samples collected from patients with different stages of cervical cancer were recorded using High Performance Liquid Chromatography coupled with Laser Induced Fluorescence (HPLC-LIF). The Protein profiles were subjected to Principle Component Analysis to derive statistically significant parameters. Diagnosis of sample types were carried out by matching three parameters--scores of factors, squared residuals, and Mahalanobis Distance. ROC and Youden's Index curves for calibration standards were used for objective estimation of the optimum threshold for decision making and performance.
Patil, Ajeetkumar; Bhat, Sujatha; Rai, Lavanya; Kartha, V. B.; Chidangil, Santhosh
To investigate the relation between the prevalence of human papillomavirus (HPV) and age in cervical cancer patients, material from 93 patients with Ia-IIb cervical carcinoma was analyzed for the presence of HPV by both type-specific and general primer polymerase chain reaction. Patients were divided into 2 groups: 64 years or younger, and 65 years and older. There was no statistically significant difference in either the prevalence of HPV DNA or distribution of genotypes amongst the 2 groups. Therefore, HPV detection can be equally well used in the management and follow-up of elderly cervical cancer patients. PMID:11729338
Baay, M F; Tjalma, W A; Weyler, J; Pattyn, G G; Lambrechts, H A; Goovaerts, G; Baekelandt, M; Buytaert, P; Van Marck, E A; Lardon, F; Vermorken, J B
Background Cervical cancer is the second most common cancer in women worldwide. NK and cytotoxic T cells play an important role in the elimination of virus-infected and tumor cells through NKG2D activating receptors, which can promote the lysis of target cells by binding to the major histocompatibility complex class I-related chain A (MICA) proteins. Increased serum levels of MICA have been found in patients with epithelial tumors. The aim of this study was to compare the levels of soluble MICA (sMICA) and NKG2D-expressing NK and T cells in blood samples from patients with cervical cancer or precursor lesions with those from healthy donors. Methods Peripheral blood with or without heparin was collected to obtain mononuclear cells or sera, respectively. Serum sMICA levels were measured by ELISA and NKG2D-expressing immune cells were analyzed by flow cytometry. Also, a correlation analysis was performed to associate sMICA levels with either NKG2D expression or with the stage of the lesion. Results Significant amounts of sMICA were detected in sera from nearly all patients. We found a decrease in the number of NKG2D-expressing NK and T cells in both cervical cancer and lesion groups when compared to healthy donors. Pearson analysis showed a negative correlation between sMICA and NKG2D-expressing T cells; however, we did not find a significant correlation when the analysis was applied to sMICA and NKG2D expression on NK cells. Conclusion Our results show for the first time that high sMICA levels are found in sera from patients with both cervical cancer and precursor lesions when compared with healthy donors. We also observed a diminution in the number of NKG2D-expressing NK and T cells in the patient samples; however, a significant negative correlation between sMICA and NKG2D expression was only seen in T cells.
Arreygue-Garcia, Naela A; Daneri-Navarro, Adrian; del Toro-Arreola, Alicia; Cid-Arregui, Angel; Gonzalez-Ramella, Oscar; Jave-Suarez, Luis F; Aguilar-Lemarroy, Adriana; Troyo-Sanroman, Rogelio; Bravo-Cuellar, Alejandro; Delgado-Rizo, Vidal; Garcia-Iglesias, Trinidad; Hernandez-Flores, Georgina; del Toro-Arreola, Susana
Cervical cancer is a major cause of cancer mortality in women worldwide and is initiated by infection with high-risk human papillomaviruses (HPVs). High-risk HPVs, especially HPV-16, are associated with other anogenital cancers and a subgroup of head-and-neck cancers. Indeed, HPV infection could account for the development of head-and-neck cancer in certain individuals that lack the classical risk factors for this
Daniel DiMaio; Amanda Psyrri
In this study, plasma-free amino acid profiles were used to investigate pre-cancerous cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma (CSCC) metabolic signatures in plasma. Additionally, the diagnostic potential of these profiles was assessed, as well as their ability to provide novel insight into CSCC metabolism and systemic effects. Plasma samples from CIN patients (n = 26), CSCC patients (n = 22), and a control healthy group (n = 35) were analyzed by high-performance liquid chromatography, and their spectral profiles were subjected to the t test for statistical significance. Potential metabolic biomarkers were identified using database comparisons that examine the significance of metabolites. Compared with healthy controls, patients with CIN and CSCC demonstrated lower levels of plasma amino acids; plasma levels of arginine and threonine were increased in CIN patients but were decreased in cervical cancer patients. Additionally, the levels of a larger group of amino acids (aspartate, glutamate, asparagine, serine, glycine, histidine, taurine, tyrosine, valine, methionine, lysine, isoleucine, leucine, and phenylalanine) were gradually reduced from CIN to invasive cancer. These findings suggest that plasma-free amino acid profiling has great potential for improving cancer screening and diagnosis and for understanding disease pathogenesis. Plasma-free amino acid profiles may have the potential be used to determine cancer diagnoses in the early stage from a single blood sample and may enhance our understanding of its mechanisms. PMID:24068431
Hasim, Ayshamgul; Aili, Aixingzi; Maimaiti, Aminigul; Mamtimin, Batur; Abudula, Abulizi; Upur, Halmurat
Treatment of advanced-stage cervical cancers with (chemo)radiation causes cytotoxicity through induction of high levels of DNA damage. Tumour cells respond to DNA damage by activation of the 'DNA damage response' (DDR), which induces DNA repair and may counteract chemoradiation efficacy. Here, we investigated DDR components as potential therapeutic targets and verified the predictive and prognostic value of DDR activation in patients with cervical cancer treated with (chemo)radiation. In a panel of cervical cancer cell lines, inactivation of ataxia telangiectasia mutated (ATM) or its substrate p53-binding protein-1 (53BP1) clearly gave rise to cell cycle defects in response to irradiation. Concordantly, clonogenic survival analysis revealed that ATM inhibition, but not 53BP1 depletion, strongly radiosensitised cervical cancer cells. In contrast, ATM inhibition did not radiosensitise non-transformed epithelial cells or non-transformed BJ fibroblasts. Interestingly, high levels of active ATM prior to irradiation were related with increased radioresistance. To test whether active ATM in tumours prior to treatment also resulted in resistance to therapy, immunohistochemistry was performed on tumour material of patients with advanced-stage cervical cancer (n = 375) treated with (chemo)radiation. High levels of phosphorylated (p-)ATM [p = 0.006, hazard ratio (HR) = 1.817] were related to poor locoregional disease-free survival. Furthermore, high levels of p-ATM predicted shorter disease-specific survival (p = 0.038, HR = 1.418). The presence of phosphorylated 53BP1 was associated with p-ATM (p = 0.001, odds ratio = 2.206) but was not related to any clinicopathological features or survival. In conclusion, both our in vitro and patient-related findings indicate a protective role for ATM in response to (chemo)radiation in cervical cancer and point at ATM inhibition as a possible means to improve the efficacy of (chemo)radiation. PMID:22323184
Roossink, Frank; Wieringa, Hylke W; Noordhuis, Maartje G; ten Hoor, Klaske A; Kok, Mirjam; Slagter-Menkema, Lorian; Hollema, Harry; de Bock, Geertruida H; Pras, Elisabeth; de Vries, Elisabeth G E; de Jong, Steven; van der Zee, Ate G J; Schuuring, Ed; Wisman, G Bea A; van Vugt, Marcel A T M
Treatment of advanced-stage cervical cancers with (chemo)radiation causes cytotoxicity through induction of high levels of DNA damage. Tumour cells respond to DNA damage by activation of the ‘DNA damage response’ (DDR), which induces DNA repair and may counteract chemoradiation efficacy. Here, we investigated DDR components as potential therapeutic targets and verified the predictive and prognostic value of DDR activation in patients with cervical cancer treated with (chemo)radiation. In a panel of cervical cancer cell lines, inactivation of ataxia telangiectasia mutated (ATM) or its substrate p53-binding protein-1 (53BP1) clearly gave rise to cell cycle defects in response to irradiation. Concordantly, clonogenic survival analysis revealed that ATM inhibition, but not 53BP1 depletion, strongly radiosensitised cervical cancer cells. In contrast, ATM inhibition did not radiosensitise non-transformed epithelial cells or non-transformed BJ fibroblasts. Interestingly, high levels of active ATM prior to irradiation were related with increased radioresistance. To test whether active ATM in tumours prior to treatment also resulted in resistance to therapy, immunohistochemistry was performed on tumour material of patients with advanced-stage cervical cancer (n = 375) treated with (chemo)radiation. High levels of phosphorylated (p-)ATM [p = 0.006, hazard ratio (HR) = 1.817] were related to poor locoregional disease-free survival. Furthermore, high levels of p-ATM predicted shorter disease-specific survival (p = 0.038, HR = 1.418). The presence of phosphorylated 53BP1 was associated with p-ATM (p = 0.001, odds ratio = 2.206) but was not related to any clinicopathological features or survival. In conclusion, both our in vitro and patient-related findings indicate a protective role for ATM in response to (chemo)radiation in cervical cancer and point at ATM inhibition as a possible means to improve the efficacy of (chemo)radiation.
Roossink, Frank; Wieringa, Hylke W; Noordhuis, Maartje G; ten Hoor, Klaske A; Kok, Mirjam; Slagter-Menkema, Lorian; Hollema, Harry; de Bock, Geertruida H; Pras, Elisabeth; de Vries, Elisabeth GE; de Jong, Steven; van der Zee, Ate GJ; Schuuring, Ed; Wisman, G Bea A; van Vugt, Marcel ATM
Common warts could indicate cervical cancer susceptibility, as both are caused by human papillomavirus (HPV). Eczema was also investigated, as atopic eczema has been negatively associated with warts, but non-atopic eczema may be associated with compromised host defences, as observed in patients with HIV, suggesting increased susceptibility to HPV infection and cervical cancer. ‘Cervical cancer’ was self-reported during an interview by 87 of 7594 women members of two longitudinal British birth cohorts. The accuracy of the diagnoses is limited by lack of confirmation using medical records. Odds ratios are adjusted for common warts and eczema in childhood; and cigarette smoking, number of cohabiting partners and social class in early adult life. The odds ratios of warts and eczema with cervical cancer are 2.50 (95% confidence interval 1.14–5.47) and 3.27 (1.95–5.49), respectively. The association of eczema with cervical cancer is independent of hay fever as a marker of atopy, suggesting the importance of non-atopic eczema. Both heavier smoking compared with non-smoking and four or more cohabiting partners compared with one/none have odds ratios for cervical cancer of 8.26 (4.25–15.10) and 4.89 (1.39–17.18), respectively. Common warts in childhood may indicate cervical cancer susceptibility; this and the relationship with eczema deserves investigation. British Journal of Cancer (2002) 87, 989–993. doi:10.1038/sj.bjc.6600585 www.bjcancer.com © 2002 Cancer Research UK
Montgomery, S M; Ehlin, A G C; Sparen, P; Bjorksten, B; Ekbom, A
Although human papillomavirus (HPV) infections are the primary cause of cervical cancer, the molecular mechanism by which HPV induces cervical cancer remains largely unclear. We used two-dimensional electrophoresis with mass spectrometry to study protein expression profiling between HPV16-positive cervical mucosa epithelial H8 cells and cervical cancer Caski cells to identify 18 differentially expressed proteins. Among them, retinoblastoma-binding protein 4 (RbAp48) was selected, and its differentiation expression was verified with both additional cervical cancer-derived cell lines and human tissues of cervical intraepithelial neoplasia and cervical cancer. Suppression of RbAp48 using small interfering RNA approach in H8 cells significantly stimulated cell proliferation and colony formation and inhibited senescence-like phenotype. Remarkably, H8 cells acquired transforming activity if RpAp48 was suppressed, because H8 cells stably transfected with RbAp48 small interfering RNA led to tumor formation in nude mice. In addition, overexpression of RbAp48 significantly inhibited cell growth and tumor formation. This RbAp48-mediated transformation of HPV16 is probably because of the regulation by RbAp48 of tumor suppressors retinoblastoma and p53, apoptosis-related enzymes caspase-3 and caspase-8, and oncogenic genes, including E6, E7, cyclin D1 (CCND1), and c-MYC. In brief, RbAp48, previously unknown in cervical carcinogenesis, was isolated in a global screen and identified as a critical mediator controlling the transforming activity of HPV16 in cervical cancer. PMID:17616526
Kong, Li; Yu, Xiu-Ping; Bai, Xiao-Hui; Zhang, Wei-Fang; Zhang, Yan; Zhao, Wei-Ming; Jia, Ji-Hui; Tang, Wei; Zhou, Ya-Bin; Liu, Chuan-ju
N-(4-hydroxyphenyl)retinamide (4-HPR) is a synthetic apoptosis-inducing retinoid with cancer chemopreventive properties and lower toxicity than all-trans retinoic acid. BAG-1 is an antiapoptotic gene that is overexpressed in cervical and other cancers. In this study, we examined whether BAG-1 can inhibit 4-HPR-induced apoptosis in the C33A cervical carcinoma cell line. Surprisingly, although it inhibited apoptosis induced by five different apoptotic stimuli,
Xiaolong Yang; Yawei Hao; Zhihu Ding; Alan Pater
Neoplasm of the cervix, especially squamous cell cancer, is one of the most common malignancy of female genital organs. It etiology is complex; however, human papilloma virus (mostly HPV type 18, 16 and 45) infection seems to be the most important one. Other risk factors include: early sexual initiation, multiple pregnancies and labors, concomitant infections (Chlamydia trachomatis, Neisseria gonorrhea, HSV2 - herpes simplex virus) of the genital tract, AIDS, immunosuppressive therapy, smoking and low socioeconomic status. The incidence of cervical cancer is particularly high in developing countries, while in countries where government founding for the prevention and health education is high, the diseases is significantly less likely to occur. The incidence and mortality rate of the cervical cancer can be substantially reduced by systematic screening cytological examinations. For such reason a liquid-based cytology is currently preferred. Implementation of HPV vaccines decrease the risk of infection, but effect on rate of the cervical cancer has to be confirmed in long-time prospective clinical and epidemiological studies. PMID:23009008
Mocarska, Agnieszka; Staros?awska, Elzbieta; Zelazowska-Cie?li?ska, Iwonna; ?osicki, Marek; Stasiewicz, Dominika; Kieszko, Dariusz; Burdan, Franciszek
|At least 12,000 women are diagnosed with cervical cancer each year in the United States, accounting for at least 4,000 deaths. Worldwide, cervical cancer is the second most common type of cancer among women. The human papilloma virus (HPV) has been linked to at least 70% of all cervical cancer. HPV can be divided into 2 categories: (a) low risk,…
The metalloproteinases (MMP) 11 and 12 have been shown to be expressed in cervical cancer (CC). In order to extend our previous results, these MMPs were evaluated in cervical precursor lesions. One hundred seventeen cervical scrapes: thirty-six normal, thirty-six Low grade squamous lesions (LSIL), thirty-six High grade (HSIL), nine CC; and, also ninety-nine paraffin-embedded cervical lesions: fifteen normal cervices, thirty eight LSIL, sixteen HSIL, and five CC were collected. The samples were analyzed for relative expression by real time RT-PCR or immunohistochemistry assay. We were able to identify a relative increased expression of MMP11 in 75% and 78% from LSIL and HSIL samples, respectively. While MMP12 expression was 64% and 75% in LSIL and HSIL, respectively. Positive samples for MMP11 expression were also positive for MMP12 expression and also increased according to illness progression. In the tissues, MMP11 or MMP12 expression was observed in the cytoplasm of the neoplastic cells, while in the normal epithelium was absent. The reaction was always stronger for MMP12 than MMP11. MMP11 expression was present in 77% and 66% of LSIL and HSIL, while MMP12 expression was 73% and 68%. There was a relationship between MMP11 or MMP12 expression and HPV infection. Our data are showing a relationship between diagnostic of precursor lesions and the MMP11 and 12 expressions, suggesting that their expression could be an early event in the neoplastic lesions of the cervix and could have clinical significance.
Valdivia, Alejandra; Peralta, Raul; Matute-Gonzalez, Manuel; Garcia Cebada, Juan Manuel; Casasola, Ivonne; Jimenez-Medrano, Cristina; Aguado-Perez, Rogelio; Villegas, Vanessa; Gonzalez-Bonilla, Cesar; Manuel-Apolinar, Leticia; Ibanez, Miguel; Salcedo, Mauricio
Abstract Background Women in criminal justice settings have an increased prevalence of cervical cancer compared with the general population. However, little is known about abnormal cervical cancer screening results among women in jail and community-based criminal justice settings. Thus, the aims of this study were to compare the prevalence of self-reported abnormal Papanicolou (Pap) test results in women in jail and under community criminal justice supervision and to examine factors associated with abnormal Pap tests in these criminal justice settings. Methods We analyzed data from two cross-sectional surveys of women in jails and community corrections in two Southern cities (n=380) about their history of abnormal Pap tests and risk factors for cervical cancer. Univariate analyses (analysis of variance [ANOVA] and chi-square) and a binary logistic regression analysis were conducted to test associations between a history of abnormal Pap testing and factors known to be associated with cervical cancer. Results Nearly half of the women surveyed (n=163, 43%) reported ever having an abnormal Pap test. There was a high prevalence of risk factors for cervical cancer among women with and without an abnormal Pap test. After controlling for age and race, there were significant associations between an abnormal Pap test and inconsistent use of barrier protection (odds ratio [OR] 2.01, 95% confidence interval [CI] 1.18-3.43), having a history of gynecologic infections (OR 1.68, 95% CI 1.05-2.67), and having a history of sexually transmitted diseases (OR 1.92, 95% CI 1.17-3.15). Conclusions Women in jail and under community justice supervision reported a high prevalence of risk factors for cervical cancer. Because of their high prevalence of abnormal Pap testing, women in criminal justice settings may be appropriate targets for improved cervical cancer screening, prevention with human papillomavirus (HPV) vaccination, risk reduction education, and treatment.
Mueller, Shane; Clark, C. Brendan; Cropsey, Karen L.
Background Lesbians have low rates of cervical cancer screening, even though they are at risk of developing the disease. The aim of this study was to examine cervical cancer screening behaviors in a national sample of lesbians. Methods A standardized internet survey was sent to 3,000 self-identified lesbians to assess cervical cancer screening behaviors and barriers to screening. The sample consisted of 1,006 respondents. Results Sixty-two percent of the weighted sample of respondents were routine screeners. Lack of a physician referral (17.5%) and lack of a physician (17.3%) were the most commonly-cited top reasons for lack of screening. Adjusting for age, education, relationship status, employments status, and insurance status, women who had disclosed their sexual orientation to their primary care physician (adjusted odds ratio [OR] 2.84 [95% confidence interval 1.82-4.45]) or gynecologist (OR 2.30 [1.33-3.96]) had greater odds of routine screening than those who did not. Those who knew that lack of Pap testing is a risk factor for cervical cancer were also more likely to be routine screeners (OR 1.95 [1.30-2.91]), although no association with screening was apparent for women who had more knowledge of general cervical cancer risk factors. Physician recommendation appeared to be a potent determinant of regular screening behavior. Routine screeners perceived more benefits and fewer barriers to screening, as well as higher susceptibility to cervical cancer. Conclusions Some women who identify as lesbian are at a potentially elevated risk of cervical cancer because they are not routinely screened. Evidence-based interventions should be developed to address critical health beliefs that undermine participation in screening. Given the value placed on physician recommendation, patient-provider communication may serve as the optimal focus of effective intervention.
In cervical cancer, glycosylation has been suggested as being involved in both its carcinogenesis and invasive capacity. In this work, we analyzed mucin type O-glycosylation in biopsies of invasive cervical cancer in FIGO stage II B through histochemistry using lectins specific for O-glycosidically linked glycans. Our results reveal that the lectin Machaerocereus eruca (MeA, specific for Gal in a Fuc?1,2 (GalNAc?1,3) Gal?1,4) showed increased recognition of tumoral cells and tumoral stroma tissue compared to other lectins with similar specificity; healthy cervical tissue was negative for MeA. Trypsin treatment of recognized tissues abolished MeA's recognition;moreover, interaction of MeA was inhibited with oligosaccharides from mucin. As demonstrated by Western blot of 2-D electrophoresis, MeA recognized ten glycoproteins in the range from 122 to 42 kDa in cervical cancer lysates. The LC-ESI-MS/MS analysis of the MeAs' recognized peptides revealed that the latter matched mainly with the amino acid sequences of lamin A/C, vimentin, elongation factor 2, keratin 1, and beta actin. Our results suggest that MeA recognizes a complex of over-expressed O-glycosidically-linked proteins that play a relevant role in cervical cancer's invasive capacity. O-glycosylation participates in the disassembly of intercellular junctions favoring cancer progression. PMID:23042270
Solórzano, Carlos; Angel Mayoral, Miguel; de los Angeles Carlos, María; Berumen, Jaime; Guevara, Jorge; Raúl Chávez, Francisco; Mendoza-Hernández, Guillermo; Agundis, Concepción; Zenteno, Edgar
An assessment of women's knowledge of cervical screening and cervical cancer was considered important as up to 92% of those dying from this form of cancer had never been tested. What were the reasons which determined their non-attendance? Issues to be addressed were reactions to invitation, women's knowledge of screening, and the possible factors which they envisaged as being associated with cervical cancer. Other issues to be considered were practical problems associated with attendance, and preference for the sex and professional status of the health professionals involved; 187 women in a general practitioner practice in Lothian, Scotland were targeted by questionnaire. As with other studies in this field 50% of those contacted were ineligible for a variety of reasons. Seventy-two women completed the questionnaire, providing a mix of qualitative and quantitative data. Although the majority of women felt the invitation to attend screening was clear and easy to understand, there was a lack of knowledge with regard to both the screening itself and the possible causes of cervical cancer. The main 'causes' were seen as higher sexual activity among those aged under 37 and smoking and a virus by those over 37. The majority of women showed preference for a female professional to take the smear. Practical problems of time and venue were not considered insurmountable. The main reasons cited for non-compliance were the fear and dislike of the test itself. PMID:9756225
Neilson, A; Jones, R K
Dendritic cell (DC) based therapy for cervical cancer: use of DC pulsed with tumour lysate and matured with a novel synthetic clinically non-toxic double stranded RNA analogue poly [I]:poly [C(12)U] (Ampligen R).
Human papilloma virus (HPV) found in 99.7% of cervical cancers represents an attractive immunotherapeutic target for novel adjuvant dendritic cell (DC) immunotherapy. DC primed with HPV antigens have been shown to be capable of inducing CTL responses powerful enough to eradicate established murine tumours expressing HPV16 antigen. The use of tumour lysate has been found to be an effective means of priming DC with tumour associated antigens in animal models and in clinical trials leading to significant anti-tumour responses. Autologous DC primed with sonicated HPV expressing tumour lysate have been shown to be capable of inducing HPV specific classes I and II T-cell immunity in a pilot clinical study.Synthetic double stranded polyribonucleotides are effective in vitro activation/maturation agents capable of inducing a stable mature DC phenotype producing high levels of IL12. However, the prototype polymer poly [I]:poly [G] has proved to be clinically toxic. Preliminary in vitro data have demonstrated that a novel clinically non-toxic analogue polymer poly [I]:poly [C(12)U] (Ampligen R) can effectively induce in vitro maturation of human monocyte derived DC with sustained bioactive IL12 production. Human monocyte derived DC primed with tumour lysate and matured with synthetic dsRNA may therefore offer an effective way of optimising Th1 specific anti-cancer T-cell responses in cancer patients. This strategy is currently being tested in a clinical trial in patients with cervical cancer. PMID:12531360
Adams, M; Navabi, H; Jasani, B; Man, S; Fiander, A; Evans, A S; Donninger, C; Mason, M
Combined E7-dendritic cell-based immunotherapy and human sodium/iodide symporter radioiodine gene therapy with monitoring of antitumor effects by bioluminescent imaging in a mouse model of uterine cervical cancer.
Using a uterine cervical cancer cell line expressing human papillomavirus (HPV) 16 E7 antigen and bioluminescent imaging (BLI), we evaluated the therapeutic potential of combined immunotherapy using transfected dendritic cells (DC-E7) and human sodium/iodide symporter (hNIS) radioiodine gene therapy in a xenograft animal cancer model. Dendritic cells expressing either E7 antigen (DC-E7) or no-insert (DC-no insert) were made for immunization materials, and murine uterine cervical cancer cell line coexpressing E7, firefly luciferase, hNIS, and EGFP genes (TC-1/FNG) were prepared for the animal tumor model. C57BL/6 mice were divided into five therapy groups (phosphate-buffered saline [PBS], DC-no insert, DC-E7, I-131, and DC-E7+I-131 groups). Single therapy with either DC-E7 or I-131 induced greater retardation in tumor growth compared with PBS or DC-no insert groups, and it resulted in some tumor-free mice (DC-E7 and I-131 groups, 40% and 20%, respectively). Combination therapy with DC-E7 and I-131 dramatically inhibited tumor growth, thus causing complete disappearance of tumors in all mice, and these effects were further confirmed by BLI in vivo. In conclusion, complete disappearance of the tumor was achieved with combined DC-E7 vaccination and hNIS radioiodine gene therapy in a mouse model with E7-expressing uterine cervical cancer, and serial BLIs successfully demonstrated antitumor effects in vivo. PMID:22091632
Jeon, Yong Hyun; Lee, Ho Won; Lee, You La; Kim, Jung Eun; Hwang, Mi-Hye; Jeong, Shin Young; Lee, Sang-Woo; Ahn, Byeong-Cheol; Ha, Jeoung-Hee; Lee, Jaetae
Cervical cancer is the most common cancer affecting women in developing countries. It has been estimated to have been responsible for almost 260 000 deaths annually, of which about 80% occurred in developing countries.Persistent infection by certain oncogenic HPV types is firmly established as the necessary cause of most premalignant and malignant epithelial lesions of the cervix and of a
|Purpose: Studies have shown that women who engage in high levels of physical activity have higher rates of cancer screening, including Papanicalaou (Pap) tests. Because American Indian (AI) women are at high risk for cervical cancer morbidity and mortality, we examined Pap screening prevalence and assessed whether physical activity was associated…
Muus, Kyle J.; Baker-Demaray, Twyla B.; Bogart, T. Andy; Duncan, Glen E.; Jacobsen, Clemma; Buchwald, Dedra S.; Henderson, Jeffrey A.
Human papillomaviruses (HPV) are responsible for causing cervical cancer and anogenital warts. The UK considered a national\\u000a vaccine program introducing one of two licensed vaccines, GardasilTM and CervarixTM. The impact of vaccination is, however, difficult to predict due to uncertainty about the prevalence of HPV infection, pattern\\u000a of sexual partnerships, progression of cervical neoplasias, accuracy of screening as well as
Yoon Hong Choi; Mark Jit
Cervical carcinoma is a growing menace to women health worldwide. This study reports the apoptotic cell death in human cervical cancer HeLa and SiHa cells by a pentacyclic triterpenediol (TPD) from Boswellia serrata by a mechanism different from reported in HL-60 cells. It caused oxidative stress by early generation of nitric oxide and reactive oxygen species that robustly up regulated time-dependent expression of p53/p21/PUMA while conversely abrogating phosphatidylinositol-3-kinase (PI3K)/Akt pathways in parallel. TPD also decreased the expression of PI3K/pAkt, ERK1/2, NF-kappaB/Akt signaling cascades which coordinately contribute to cancer cell survival through these distinct pathways. The tumor suppressor p53 pathway predominantly activated by TPD further up-regulated PUMA, which concomitantly decreased the Bcl-2 level, caused mitochondrial membrane potential loss with attendant translocation of Bax and drp1 to mitochondria and release of pro-apoptotic factors such as cytochrome c and Smac/Diablo to cytosol leading to caspases-3 and -9 activation. In addition both the phospho-p53 and p21 were found to accumulate heavily in the nuclear fraction with attendant decrease in topoisomarase II and survivin levels. On the contrary, TPD did not affect the extrinsic signaling transduction pathway effectively through apical death receptors. Interestingly, N-acetyl cysteine, ascorbate and s-methylisothiourea (sMIT) rescued cells significantly from TPD induced DNA damage and caspases activation. TPD may thus find usefulness in managing and treating cervical cancer. PMID:19544329
Bhushan, Shashi; Malik, Fayaz; Kumar, Ajay; Isher, Harpreet Kaur; Kaur, Indu Pal; Taneja, Subhash Chandra; Singh, Jaswant
Every year approximately half a million women worldwide develop cervical cancer (CC) of whom 80% live in poor countries where population-based screening programmes are virtually non-existent. The role of sexually transmitted agents in the aetiology of cervical cancer has been suspected for more than a century, but knowledge in this field has rapidly expanded only in the last 20 years,
This study investigated regional variations in the contribution made by different human papilloma (HPV) types to invasive cervical cancer (ICC). A total of 85 studies using polymerase chain reaction to estimate HPV prevalence in ICC were identified. Data on HPV prevalence were extracted separately for squamous cell carcinoma (SCC) and for adeno- and adenosquamous-carcinoma (ADC). A total of 10 058
G M Clifford; J S Smith; M Plummer; N Muñoz; S Franceschi
Cervical cancer is an important problem. The incidence of cervical pre-cancer is increasing, and unless current diagnostic techniques are improved, mortality and cost may increase substantially. The goal of our project is to find the most cost-effective optical system for the detection of cervical pre-cancer. Our hypothesis is that using fluorescence spectroscopy, a new technique for detection of cervical cancer
E. V. Trujillo; D. Sandison; N. Ramanujam; M. Follen-Mitchell; S. Cantor; R. Richards-Kortum
Cervical cancer is the second most common cancer in women worldwide. This is caused by oncogenic types of human papillomavirus (HPV) infection. Although large numbers of young sexually active women get HPV-infected, only a small fraction develop cervical cancer. This points to different co-factors for regression of HPV infection or progression to cervical cancer. Host genetic factors play an important role in the outcome of such complex or multifactor diseases such as cervical cancer and are also known to regulate the rate of disease progression. The aim of this review is to compile the advances in the field of host genetics of cervical cancer. MEDLINE database was searched using the terms, ‘HPV’, ‘cervical’, ‘CIN’, ‘polymorphism(s)’, ‘cervical’+ *the name of the gene* and ‘HPV’+ *the name of the gene*. This review focuses on the major host genes reported to affect the progression to cervical cancer in HPV infected individuals.
Preservation of fertility is a major concern for premenopausal women after diagnosis of cervical cancer. Successful surrogate pregnancy after treatment for cervical cancer has very rarely been reported. In the present report, a case of successful surrogate pregnancy after radical hysterectomy, lymphadenectomy and ovarian transposition for cervical cancer, followed by radiation therapy, is presented. After stimulation of the transposed ovaries
T Agorastos; M Zafrakas; M Mastrominas
The national cervical cancer incidence rate is 7.9 per 100,000 and the mortality rate is 2.3 per 100,000; a Healthy People 2020 goal is to reduce cervical cancer mortality to 2.0 per 100,000. Cervical cancer incidence and mortality rates are markedly high...
A. Gallagher J. C. Probst J. D. Bellinger S. A. Adams
Cervical cancer is an important public health problem among adult women in developing countries in South and Central America, sub-Saharan Africa, and south and south-east Asia. Frequently repeated cytology screening programmes — either organized or opportunistic — have led to a large decline in cervical cancer incidence and mortality in developed countries. In contrast, cervical cancer remains largely uncontrolled in
Rengaswamy Sankaranarayanan; Atul Madhukar Budukh; Rajamanickam Rajkumar
Investigated college students' knowledge of the relationship between human papillomavirus (HPV) and cervical cancer. Few students knew what HPV was. Most of the females who had been screened knew that a Pap smear could detect HPV and cervical cancer. Over half of the students did not realize the link between HPV and cervical cancer. Students…
Applegate, Trent E.; Jones, Iesha K.
|The high cervical cancer mortality rate among Latinas compared with other ethnic groups in the United States is of major concern. Latina women are almost twice as likely to die from cervical cancer as non-Hispanic white women. To improve Latina cervical cancer screening rates, interventions have been developed and tested. This systematic review…
Corcoran, Jacqueline; Dattalo, Patrick; Crowley, Meghan
|Investigated college students' knowledge of the relationship between human papillomavirus (HPV) and cervical cancer. Few students knew what HPV was. Most of the females who had been screened knew that a Pap smear could detect HPV and cervical cancer. Over half of the students did not realize the link between HPV and cervical cancer. Students…
Applegate, Trent E.; Jones, Iesha K.
Background Evidence for the association between Human immunodeficiency virus infection and cervical cancer has been contrasting, with some studies reporting increased risk of cervical cancer among HIV positive women while others report no association. Similar evidence from Tanzania is scarce as HIV seroprevalence among cervical cancer patients has not been rigorously evaluated. The purpose of this study was to determine the association between HIV and tumor differentiation among patients with cervical cancer at Bugando Medical Centre and Teaching Hospital in Mwanza, North-Western Tanzania. Methods This was a descriptive analytical study involving suspected cervical cancer patients seen at the gynaecology outpatient clinic and in the gynaecological ward from November 2010 to March 2011. Results A total of 91 suspected cervical cancer patients were seen during the study period and 74 patients were histologically confirmed with cervical cancer. The mean age of those confirmed of cervical cancer was 50.5?±?12.5?years. Most patients (39 of the total 74–52.7%) were in early disease stages (stages IA-IIA). HIV infection was diagnosed in 22 (29.7%) patients. On average, HIV positive women with early cervical cancer disease had significantly more CD4+ cells than those with advanced disease (385.8?±?170.4 95% CI 354.8-516.7 and 266.2?±?87.5, 95% CI 213.3-319.0 respectively p?=?0.042). In a binary logistic regression model, factors associated with HIV seropositivity were ever use of hormonal contraception (OR 5.79 95% CI 1.99-16.83 p?=?0.001), aged over 50?years (OR 0.09 95% CI 0.02-0.36 p?=?0.001), previous history of STI (OR 3.43 95% CI 1.10-10.80 p?=?0.035) and multiple sexual partners OR 5.56 95% CI 1.18-26.25 p?=?0.030). Of these factors, only ever use of hormonal contraception was associated with tumor cell differentiation (OR 0.16 95% CI 0.06-0.49 p?=?0.001). HIV seropositivity was weakly associated with tumor cell differentiation in an unadjusted analysis (OR 0.21 95% CI 0.04-1.02 p?=?0.053), but strong evidence for the association was found after adjusting for ever use of hormonal contraception with approximately six times more likelihood of HIV infection among women with poorly differentiated tumor cells compared to those with moderately and well differentiated cells (OR 5.62 95% CI 1.76-17.94 p?=?0.004). Conclusion Results from this study setting suggest that HIV is common among cervical cancer patients and that HIV seropositivity may be associated with poor tumour differentiation. Larger studies in this and similar settings with high HIV prevalence and high burden of cervical cancer are required to document this relationship.
Cervical cancer is recognized as tobacco-related malignancy. HPV vaccination and introducing screening protocols were found as the best way to decrease cervical cancer related mortality. Besides the cytological screening programs of the uterine cervix smear, nowadays co-factors of carcinogenesis are taken into consideration, also. The aim of our study was to analyse data included in questionnaire of 310 women who underwent cytological examination wi thin cervical cancer screening program in our Department in 2011. There were no differences found between studied groups on rate of oral contraceptive or hormonal therapy use, as well as age and tobacco smoking. However, taking into account education and smoking, there was a significant correlation observed. Patients with higher education level smoked less often. The special attention should be paid to promote smoking cessation in the group of women who finished education on elementary level. PMID:23421059
Walentowicz-Sad?ecka, Ma?gorzata; Sad?ecki, Pawe?; Marsza?ek, Andrzej; Grabiec, Marek
This study examines the effects of a large-scale cervical cancer prevention campaign in Recife, Brazil between 1994 and 1995. It suggests that while this program effectively motivated women to get pap smears, it reinforced local understandings of the pap smear that ultimately had unintended negative consequences for women's health. It argues that because the campaign connected female sexual activity directly with cervical cancer, the program's message was interpreted by many women to mean that cervical cancer was a sexually transmitted disease and that it would behave like one. Women who were no longer sexually active believed that they did not need to be screened. In addition, women who were sexually active believed that they could use pap smears to diagnose and cure sexually transmitted diseases. PMID:11833970
Ras association (RalGDS/AF-6) domain family member 2 (RASSF2) is a gene involved in the progression of several human cancers, including breast, colorectal and lung cancer. The aims of this study were to determine the hypermethylation of the gene in squamous cervical cancer and precursor lesions, along with that of RASSF1 and the recently described EPB41L3, and to analyze the potential prognostic role of these genes. Methylation-specific PCR and bisulfite sequencing were used to analyze the methylation status of RASSF2 and EPB41L3 gene in 60 squamous cervical cancer, 76 cervical intraepithelial neoplasias grade III, 16 grade II, 14 grade I and 13 cases of normal tissue adjacent to cervical intraepithelial neoplasia. RASSF2 expression was evaluated by immunohistochemistry and the re-expression of RASSF2 and EPB41L3 was analyzed by quantitative reverse-transcription PCR in HeLa, SiHa, C33A and A431 cell lines treated with 5-aza-2'-deoxycytidine and/or trichostatin. RASSF1 hypermethylation and human papillomavirus type were also analyzed in all the cases by methylation-specific PCR and reverse line blot, respectively. RASSF2 hypermethylation was predominant in squamous cervical cancer (60.9%) compared with cervical intraepithelial neoplasias (4.2%) and was associated with a lower level of RASSF2 expression and vascular invasion in squamous cervical cancer. EPB41L3 and RASSF1 hypermethylations were also more frequent in cancer than in precursor lesions. Patients with RASSF2 hypermethylation had shorter survival time, independent of tumor stage (hazard ratio: 6.0; 95% confidence interval: 1.5-24.5). Finally, the expressions of RASSF2 and EPB41L3 were restored in several cell lines treated with 5-aza-2'-deoxycytidine. Taken together, our results suggest that RASSF2 potentially functions as a new tumor-suppressor gene that is inactivated through hypermethylation in cervical cancer and is related to the bad prognosis of these patients. PMID:23542458
Guerrero-Setas, David; Pérez-Janices, Noemí; Blanco-Fernandez, Laura; Ojer, Amaya; Cambra, Koldo; Berdasco, María; Esteller, Manel; Maria-Ruiz, Sergio; Torrea, Natalia; Guarch, Rosa
This project explores the combination of computerized automated primary screening of cervical cytology specimens in remote sites with interpretation of device-selected images transmitted via the Internet. The project is in 3 phases: (1) hardware/software ...
B. A. Crothers D. C. Wilbur J. A. Gelfand J. H. Eichhorn M. S. Ro
We studied whether induction of glucose transporters (GLUTs) 1 to 4 correlates with human papillomavirus (HPV)-dependent malignant transformation of cervical epithelium. Tissue samples of cervical intraepithelial neoplasia (CIN; grades 1 to 3), invasive carcinomas, and lymph node metastasis were examined. HPV typing was performed. Tissue sections were immunostained with GLUT1 to GLUT4 antibodies. Messenger RNA (mRNA) in situ hybridization confirmed GLUT1 protein expression. Weak expression of GLUT1 was found in nondysplastic HPV-positive and HPV-negative epithelium; significant expression was observed in preneoplastic lesions, correlating with the degree of dysplasia. In CIN 3 high-risk HPV lesions, cervical cancer, and metastasis, GLUT1 was expressed at highest levels with a strong correlation of GLUT1 mRNA and protein expression. Immunostains for GLUT2 to GLUT4 were negative. Cervical tumor cells respond to enhanced glucose utilization by up-regulation of GLUT1. The strong induction of GLUT1 mRNA and protein in HPV-positive CIN 3 lesions suggests GLUT1 overexpression as an early event in cervical neoplasia. GLUT1 is potentially relevant as a diagnostic tool and glucose metabolism as a therapeutic target in cervical cancer. PMID:14608894
Rudlowski, Christian; Becker, Albert J; Schroder, Willibald; Rath, Werner; Büttner, Reinhard; Moser, Markus
Cervical screening presents several ethical dilemmas to family physicians. The author reviews the risks associated with screening, costs versus benefits of running a screening program, and the issues surrounding patient autonomy and patient coercion. Is saving one life worthwhile, and at what cost? Cervical screening programs are imperative in family practice, but only if harm to the patient is minimized and ethical objections are addressed.
Southeast Asian women have higher invasive cervical cancer incidence rates and lower Pap testing frequencies than most other racial/ethnic groups in the United States. However, there is little information about the cervical cancer screening behavior of Cambodian-American women. Cambodian residents of Seattle were surveyed in person during late 1997 and early 1998. The PRECEDE model was used to guide the development of items that assessed predisposing, reinforcing, and enabling factors associated with cervical cancer screening participation. The estimated overall survey response was 72%. Four hundred thirteen women completed our questionnaire. Approximately one-quarter (24%) of the respondents had never had a Pap test, and over one-half (53%) had not been screened recently. The following variables were positively associated with a history of at least one Pap smear: younger age, greater number of years since immigration, belief about Pap testing for postmenopausal women, prenatal care in the United States, and physician recommendation. Women who believed in karma were less likely to have ever been screened for cervical cancer than those who did not. Six variables independently predicted recent screening: age; beliefs about regular checkups, cervical cancer screening for sexually inactive women, and the prolongation of life; having a female doctor; and a previous physician recommendation for Pap testing. The study findings indicate that culturally specific approaches might be effective in modifying the cervical cancer screening behavior of immigrant women. Programs targeting Cambodian-Americans are likely to be more effective if they are multifaceted and simultaneously address predisposing, reinforcing, and enabling factors. PMID:10385145
Taylor, V M; Schwartz, S M; Jackson, J C; Kuniyuki, A; Fischer, M; Yasui, Y; Tu, S P; Thompson, B
Contents: How Can We Strengthen Efforts To Prevent Cervical Cancer (Epidemiology of Cervical Cancer, The Bethesda System; Pathology of Preinvasive Lesions; Screening Technology, Cervical Intraepithelial Neoplasia. Diagnosis, Management, and Treatment Stra...
E. L. Trimble A. Epstein J. M. Elliott
Gallic acid (GA) is widely distributed in various plants and foods, and its various biological effects have been reported. Here, we evaluated the effects of GA on HeLa cells in relation to cell growth inhibition and death. HeLa cell growth was diminished with an IC50 of approximately 80?M GA at 24h whereas an IC50 of GA in human umbilical vein
Bo Ra You; Hwa Jin Moon; Yong Hwan Han; Woo Hyun Park
Human papillomavirus (HPV) infection is considered to be the necessary cause of cervical cancer. E6 and E7 oncoproteins of HPV have been known to play major roles in malignant transformation of cervical cells, inhibiting the tumor suppressors p53 and Rb. However, the role of E5 oncoprotein has been relatively less defined. HPV 16 E5 is a hydrophobic membrane-bound protein which associates with the Golgi apparatus, endoplasmic reticulum and perinuclear membrane. Accumulating evidences have suggested that E5 oncoprotein may also contribute to cervical carcinogenesis through modulating cellular signaling pathways in addition to augmenting the immortalization potential of E6 and E7. Multiple mechanisms, including activation of EGFR or inflammatory cell signaling pathway, have been implicated in malignant transformation by HPV 16 E5. Therefore, targeting E5 may be a rational approach for chemoprevention and treatment of cervical cancer, and understanding its oncogenic processes may help us to design novel therapeutic strategies. In this review, we discussed the roles of HPV 16 E5 in cervical carcinogenesis, altering several cellular signaling pathways involved in cell proliferation, angiogenesis and apoptosis. PMID:20643111
Kim, Mi-Kyung; Kim, Hee Seung; Kim, Su-Hyeong; Oh, Jung-Min; Han, Jae Yong; Lim, Jeong Mook; Juhnn, Yong-Sung; Song, Yong-Sang
We investigated the relationships between intakes of selected dietary nutrients and food groups and risk of cervical cancer in a hospital-based, case-control study including 239 cases diagnosed with squamous cell carcinoma of the cervix and 979 hospital patients with nonneoplastic diagnoses who completed a self-administered questionnaire between 1982 and 1998 at Roswell Park Cancer Institute. Odds ratios (OR) and 95%
Chaitali Ghosh; Julie A. Baker; Kirsten B. Moysich; Ruqayyah Rivera; John R. Brasure; Susan E. McCann
The efficacy of immunotherapy using a streptococcal preparation, OK-432, was evaluated in each clinical stage of uterine cervical cancer. The 382 eligible patients were stratified by clinical stage and presence/absence of surgery. Within each stratum, patient's were randomly allocated to OK-432 treatment or to control treatment. OK-432 significantly inhibited recurrence in patients with stage II cervical cancer; the recurrence-free interval and survival time were remarkably prolonged in patients with stage II disease who underwent surgery. However, OK-432 did not significantly prolong these parameters in patients with stage III disease. Retrospective analyses revealed that in patients with or without lymph node metastases who underwent surgery, the recurrence-free interval and survival time were significantly prolonged by OK-432 treatment. These results indicate that OK-432 is an effective and useful postoperative immunotherapeutic agent for uterine cervical cancer. PMID:2689304
Noda, K; Teshima, K; Tekeuti, K; Hasegawa, K; Inoue, K; Yamashita, K; Sawaragi, I; Nakajima, T; Takashima, E; Ikeuchi, M
Integrins are cell-surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Besides playing an important role in tumour angiogenesis, ?3-integrin is also expressed in several types of epithelial cancer cells. It was the purpose of the present study to evaluate the prognostic value of ?3-integrin expression in patients with cervical cancer. Biopsies were taken from 82 patients with squamous cell
G Gruber; J Hess; C Stiefel; D M Aebersold; Y Zimmer; R H Greiner; U Studer; H J Altermatt; R Hlushchuk; V Djonov
Ovarian cancer is the fifth most common cancer (neoplasm) among women and the third most common gynecological cancer behind endometrial and cervical cancer (1). Epithelial ovarian cancer (EOC) represents ~90% of all ovarian cancers. Recently, we have observed the novel expression of the nuclear receptor, the germ cell nuclear factor (GCNF) in several ovarian cancer cell lines. This is noteworthy
Sowmya Srikanthan; Jeffrey V. May
Summary Inflammation and infection play an important role in the pathogenesis of many cancers. Toll-like receptors (TLRs) are a class\\u000a of pattern recognition receptors that recognize conserved components of microbes and trigger the immune response against invading\\u000a microorganisms. Toll-like receptor 9 (TLR9) recognizes non-methylated cytosine-phosphateguanosine (CpG) DNA sequences which\\u000a are the surrogate for viral DNA. TLR9 may react to tumor development
Yanjie Weng; Yongjun Wang; Ying Shi; Wenjuan Zhou; Hongyan Wang; Changyu Wang
Expression of keratins 5, 14 and 17 in endocervical subcolumnar reserve cells was detected by means of immunohistochemical studies using polypeptide specific monoclonal antibodies. These particular keratins that were found among others in basal cells could also be detected to a variable extent in metaplastic and dysplastic cervical lesions. In some cases of immature squamous metaplasia all three keratin subtypes were expressed throughout the full thickness of the epithelium. In contrast, in mature squamous metaplasia a compartmentalization of these keratins was observed. Mature squamous metaplastic epithelium showed a keratin distribution pattern comparable to ectocervical squamous epithelium, with the exception of keratin 17, which was only sporadically found in the basal layer of ectocervical epithelium and was always present in the basal cells of mature squamous metaplastic epithelium. During progression of cervical intraepithelial neoplasia a clear increase in the expression of keratin 17 was observed. However, also keratins 5 and 14 were expressed. Our results demonstrate that a considerable number of premalignant lesions of the uterine cervix express the same keratins as found in the progenitor reserve cells. Lesions that lack expression of keratin 17 may form a distinct group, which are regressive in nature and do not progress into cervical cancer. Images Figure 1 Figure 3 Figure 4 Figure 5
Smedts, F.; Ramaekers, F.; Troyanovsky, S.; Pruszczynski, M.; Robben, H.; Lane, B.; Leigh, I.; Plantema, F.; Vooijs, P.
Expression of keratins 5, 14 and 17 in endocervical subcolumnar reserve cells was detected by means of immunohistochemical studies using polypeptide specific monoclonal antibodies. These particular keratins that were found among others in basal cells could also be detected to a variable extent in metaplastic and dysplastic cervical lesions. In some cases of immature squamous metaplasia all three keratin subtypes were expressed throughout the full thickness of the epithelium. In contrast, in mature squamous metaplasia a compartmentalization of these keratins was observed. Mature squamous metaplastic epithelium showed a keratin distribution pattern comparable to ectocervical squamous epithelium, with the exception of keratin 17, which was only sporadically found in the basal layer of ectocervical epithelium and was always present in the basal cells of mature squamous metaplastic epithelium. During progression of cervical intraepithelial neoplasia a clear increase in the expression of keratin 17 was observed. However, also keratins 5 and 14 were expressed. Our results demonstrate that a considerable number of premalignant lesions of the uterine cervix express the same keratins as found in the progenitor reserve cells. Lesions that lack expression of keratin 17 may form a distinct group, which are regressive in nature and do not progress into cervical cancer. PMID:1372156
Smedts, F; Ramaekers, F; Troyanovsky, S; Pruszczynski, M; Robben, H; Lane, B; Leigh, I; Plantema, F; Vooijs, P
Background We conducted a study aiming to describe Human Papillomavirus (HPV) type distribution in invasive cervical carcinoma in Uganda. Methods 191 archival cervical carcinoma samples diagnosed in the Department of Pathology, Makerere University in Kampala between 1968 and 1992 were analysed using a sensitive PCR-Reverse Hybridization Line Probe Assay. Results Out of the 186 cases of confirmed invasive cervical cancer in the study paraffin blocks, 114 were positive for HPV DNA. Specific HPV genotypes were identifiable in 109 cases: HPV 16, 18, 31, 35, 39, 44, 45, 51, 52 and 70. These occurred as single infections in 105 cases (96.3%) and as multiple infections in 4 cases (3.7%). HPV 16 or 18 accounted for 80% (84/105) of cases with single infection. Conclusion The results of this study confirm the role of HPV 16 and 18 in cervical cancer pathogenesis in the Ugandan population. The results suggest that the currently available HPV vaccines against HPV 16 and 18 could possibly prevent the majority of invasive cervical cancers in Uganda.
Odida, Michael; de Sanjose, Silvia; Quint, Wim; Bosch, Xavier F; Klaustermeier, Joellen; Weiderpass, Elisabete
The Human Papillomavirus type-16 (HPV-16) E6 and E7 oncogenes are selectively retained and expressed in cervical carcinomas, and expression of E6 and E7 is sufficient to immortalize human cervical epithelial cells. Expression of the epidermal growth factor receptor (EGFR) is often increased in cervical dysplasia and carcinoma, and HPV oncoproteins stimulate cell growth via the EGFR pathway. We found that erlotinib, a specific inhibitor of EGFR tyrosine kinase activity, prevented immortalization of cultured human cervical epithelial cells by the complete HPV-16 genome or the E6/E7 oncogenes. Erlotinib stimulated apoptosis in cells that expressed HPV-16 E6/E7 proteins and induced senescence in a subpopulation of cells that did not undergo apoptosis. Since immortalization by HPV E6/E7 is an important early event in cervical carcinogenesis, the EGFR is a potential target for chemoprevention or therapy in women who have a high risk for cervical cancer. PMID:21982220
Woodworth, Craig D; Diefendorf, Laura P; Jette, David F; Mohammed, Abdulmajid; Moses, Michael A; Searleman, Sylvia A; Stevens, Dan A; Wilton, Katelynn M; Mondal, Sumona
Purpose: To test whether pharmacologic inhibition of ribonucleotide reductase (RNR) by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC no. 663249) enhances radiation sensitivity during low-dose-rate ionizing radiation provided by a novel purpose-built iridium-192 cell irradiator. Methods and Materials: The cells were exposed to low-dose-rate radiation (11, 23, 37, 67 cGy\\/h) using a custom-fabricated cell irradiator or to high-dose-rate radiation (330 cGy\\/min) using a
Charles A. Kunos; Valdir C. Colussi; John Pink; Tomas Radivoyevitch; Nancy L. Oleinick
DNA of human papillomavirus (HPV) types 16 and 18 has been found closely associated with human genital cancer1,2, supporting the concept that members of this virus group are key factors in the aetiology of genital cancer3. HPV 18 DNA sequences were also detected in cell lines derived from cervical cancer2. We have now analysed these cell lines, HeLa, C4-1 and
Elisabeth Schwarz; Ulrich Karl Freese; Lutz Gissmann; Wolfgang Mayer; Birgit Roggenbuck; Armin Stremlau; Harald Zur Hausen
MicroRNAs (miRNAs) act as important gene regulators in human genomes and their aberrant expression links to many malignancies. We previously identified a different characteristic miRNA expression profile in cervical cancer from that in cervical normal tissues, including the downregulated miR-424. However, the role and mechanism of miR-424 in cervical cancer still remain unknown. Here, we focused on identifying the tumor-suppressive function and clinical significance of miR-424 and exploring the mechanistic relevance by characterizing its target. We showed a significantly decreased expression of miR-424 in 147 cervical cancer tissues versus 74 cervical normal tissues by performing quantitative RT-PCR. In 147 cervical cancer tissue samples, low-level expression of miR-424 was positively correlated with poor tumor differentiation, advanced clinical stage, lymph node metastasis and other poor prognostic clinicopathological parameters. Further in vitro observations showed that enforced expression of miR-424 inhibited cell growth by both enhancing apoptosis and blocking G1/S transition, and suppressed cell migration and invasion in two human cervical cancer cell lines, SiHa and CaSki, implying that miR-424 functions as a tumor suppressor in the progression of cervical cancer. Interestingly, overexpression of miR-424 inhibited the expression of protein checkpoint kinase 1 (Chk1) and phosphorylated Chk1 (p-Chk1) at residues Ser345 and decreased the activity of luciferase-reporter containing the 3'-untranslated region (UTR) of Chk1 with predicted miR-424-binding site. Moreover, miR-424 expression levels were inversely correlated with Chk1 and p-Chk1 protein levels in both cervical cancer and normal tissues. Furthermore, RNAi-mediated knockdown of Chk1 decreased matrix metalloproteinase 9 expression and phenocopied the tumor suppressive effects of miR-424 in cell models. Taken together, our results identify a crucial tumor suppressive role of miR-424 in the progression of cervical cancer at least partly via upreglating the expression of Chk1 and p-Chk1, and suggest that miR-424 might be a candidate of prognostic predictor or an anticancer therapeutic target for cervical cancer patients. PMID:22469983
Xu, J; Li, Y; Wang, F; Wang, X; Cheng, B; Ye, F; Xie, X; Zhou, C; Lu, W
The role of HPV in the carcinogenesis of intraepithelial and invasive anogenital lesions is currently well established. E6 and E7 oncoproteins of high-risk HPV genotypes are known to inactivate p53 and pRb pathways. Several studies have described an increased prevalence and recurrence of both cervical HPV infection and invasive cervical cancer among HIV-1 positive women compared to HIV-1 negative cases. For these reasons, cervical cancer is considered an AIDS-defining neoplasm. Unlike other AIDS-associated neoplasms, the occurrence of cervical cancer is independent of immune suppression. HIV-1 infection in patients with high grade precancerous lesions and invasive cervical cancers results in a therapy refractory and more aggressive disease phenotype, which is not yet well understood at the molecular level. An upregulation of HPV E6 and E7 gene expressions by HIV-1 proteins such as Tat has been documented by some authors. However, the role of HIV-1 in cervical carcinomas is still unclear. It is already known that HIV-1 Tat protein is able to influence cell cycle progression. Altogether, these facts led us to investigate the effects of Tat on the expression of cell cycle regulator genes. After transfection of HeLa cells with Tat, we analyzed the expression of cell cycle regulators from these cells by IHC and Real-time PCR. A significant reduction in the expression of cell cycle inhibitors of transcription and an increase in the levels of proliferation markers were observed. These results suggest that HIV-1 may enhance cervical carcinogenesis by promoting cell cycle progression. We also found that this HIV-1 Tat-induced cell proliferation was not dependent on the E2F family of transcription factors, and therefore postulate that Sp factors may be involved. PMID:16855377
Nyagol, J; Leucci, E; Onnis, A; De Falco, G; Tigli, C; Sanseverino, F; Torriccelli, M; Palummo, N; Pacenti, L; Santopietro, R; Spina, D; Gichangi, P; Muchiri, L; Lazzi, S; Petraglia, F; Leoncini, L; Giordano, A
Background: The majority of cervical cancers, the most prevalent cancer among Nepali women, are diagnosed in advanced stage leading to high mortality in Nepal. The present study explored factors associated with late diagnosis. Materials and Methods: A cross-sectional study was carried out in two specialized cancer hospitals of Nepal from August 12 to October 12, 2012. Randomly selected 110 cervical cancer patients were interviewed and their medical records were reviewed. Multivariate logistic regression analysis was performed to predict associations. Results: Mean age of patients was 52.7years (SD=10.6), 66% were illiterate and 77% were rural inhabitants. Medical shops (33.6%) and private hospitals (31%) were major first contact points of patients with health care providers (HCP). There was no cervical/per-speculum examination (78.2%) and symptoms misinterpretation (90%) of patients occurred in initial consultation with HCP. Four in every five cases (80.9%) of cervical cancer had late diagnosis. Literate women (adjusted OR=0.121, CI: 0.030-0.482) and women having abnormal vaginal bleeding as early symptom (adjusted OR=0.160, CI: 0.035-0.741) were less likely to suffer late diagnosis. Women who shared their symptoms late (adjusted OR=4.272, CI: 1.110-16.440) and did so with people other than their husband (adjusted OR=12.701, CI: 1.132-142.55) were more likely for late diagnosis. Conclusions: High level of illiteracy among women and their problematic health seeking behavior for gynecological symptoms are responsible for late diagnosis of cervical cancer in Nepal. In the absence of a routine screening program, prevention interventions should be focused on raising awareness of gynecological symptoms and improving health seeking behavior of women for such symptoms. PMID:23992006
Gyenwali, Deepak; Pariyar, Jitendra; Onta, Sharad Raj
The purpose of this qualitative study (N = 98, 11 focus groups) is to investigate how low-income, African American and Hispanic older women make decisions about cervical cancer screening. Using the health belief model to guide content analysis of transcripts, we found that primary barriers to screening were; embarrassment with, fear of, and pain from the test, difficulty in accessing
Sharon Guilfoyle; Rebeca Franco; Sherri Sheinfeld Gorin
Effective cytotoxic treatment options for advanced cervical cancer are exceedingly limited. Cisplatin-based combination chemotherapy, the most commonly used cytotoxic therapy, has produced response rates ranging from 20% to 30% and overall survival of less than 10 months. Because of the minimal degree of success with cytotoxic therapies and the poor prognosis of patients with this disease, interest has increased in
Josep Maria del Campo; Aleix Prat; Antonio Gil-Moreno; José Pérez; Marta Parera
Cervical cancer is a diagnosis that has a profound psychosocial impact, constituting a physical and emotional crisis for patients as well as family. In general, research indicates that the choice of treatment and the stage of the disease are instrumental in determining the psychosocial adjustment. Disruptions are likely to occur in self-esteem,…
Gilliland, Kevin Clark
|Cervical cancer is a diagnosis that has a profound psychosocial impact, constituting a physical and emotional crisis for patients as well as family. In general, research indicates that the choice of treatment and the stage of the disease are instrumental in determining the psychosocial adjustment. Disruptions are likely to occur in self-esteem,…
Gilliland, Kevin Clark
|In Zambezia province, Mozambique, cervical cancer (CC) screening was introduced to rural communities in 2010. Our study sought to determine whether women would accept screening via pelvic examination and visual inspection with acetic acid (VIA) at two clinical sites near the onset of a new CC screening program. A cross-sectional descriptive study…
Audet, Carolyn M.; Matos, Carla Silva; Blevins, Meridith; Cardoso, Aventina; Moon, Troy D.; Sidat, Mohsin
Background and Objective: In less than 2 decades, laparoscopy has contributed to modification in the management of early cervical cancer patients, and all comparisons between open and laparoscopic-based radical operations showed an identical oncological outcome. The aim of this study is to describe surgical instrumentations and technique to perform total microlaparoscopy radical hysterectomy in early cervical cancer patients and report our preliminary results in terms of operative time and perioperative outcomes. Methods: Between January 1, 2012, and March 25, 2012, 4 consecutive early cervical cancer patients were enrolled in this study. Results: We performed 3 type B2 and 1 type C1-B2 total microlaparoscopy radical hysterectomy, and in all cases concomitant bilateral salpingo-oophorectomy and pelvic lymphadenectomy were carried out. Median operative time was 165 minutes (range: 155 to 215) (mean: 186), and median estimated blood loss was 30 mL (range: 20 to 50). Median number of pelvic lymph nodes removed was 12 (range: 11 to 15). All procedures were completed without 5-mm port insertion and without conversion. No intraoperative or early postoperative complications were reported. Conclusions: This report suggests a role of microlaparoscopy in the surgical management of early cervical cancer with adequate oncological results, superimposable operative time, and perioperative outcomes with respect to standard laparoscopy.
Gallotta, Valerio; Fagotti, Anna; Rossitto, Cristiano; Piovano, Elisa; Scambia, Giovanni
The objective of the study was to develop a culturally relevant video and a pamphlet for use as a cervical cancer screening educational intervention among North-American Chinese women. The project conducted 87 qualitative interviews and nine focus groups to develop a culturally tailored intervention to improve Pap testing rates. The intervention consisted of an educational\\/motivational video, a pamphlet, and home
J. Carey Jackson; Hoai Do; Kamolthip Chitnarong; Shin-Ping Tu; Ann Marchand; Gregory Hislop; Vicky Taylor
The spindle checkpoint proteins (SCPs), which sense the existence of misaligned sister chromatids during mitosis and meiosis, are essential for cell proliferation and differentiation. Therefore, the role of SCPs in carcinogenesis is gaining increased attention. In this study, we analysed the expression of Bub1 and Mad2 in clinical samples by immunohistochemistry (IHC) during the development of cervical cancer (CC), and we explored the interaction of Bub1/Mad2 with different proteins through immunoprecipitation (IP). Furthermore, we analysed the characteristics of four different cell models of human papillomavirus (HPV)16/18 E5. We demonstrated that with the progression of CC, the expression of Bub1 and Mad2 was gradually reduced under the influence of HPVE5. Overexpression of HPV16/18 E5 significantly increased cell proliferation, as well as the percentage of cells in the S phase. In addition, the levels of p21, Bub1 and Mad2 were markedly decreased in E5-expressing cells. Therefore, HPV16/18 E5 plays a critical role in carcinogenesis and is a potential therapeutic target in CC treatment. PMID:23128250
Liao, Shujie; Deng, Dongrui; Hu, Xiaoji; Wang, Wei; Li, Li; Li, Wei; Zhou, Jianfeng; Xu, Gang; Meng, Li; Wang, Shixuan; Ma, Ding
Langerhans cell histiocytosis (LCH), a disorder of the phagocytic system, is a rare condition. Moreover, spinal involvement causing myelopathy is even rare and unusual. Here, we report a case of atypical LCH causing myelopathy, which was subsequently treated by corporectomy and fusion. An 8-year-old boy presented with 3 weeks of severe neck pain and limited neck movement accompanying upper and lower limbs motor weakness. CT scans revealed destruction of C5 body and magnetic resonance imaging showed a tumoral process at C5 with cord compression. Interbody fusion using anterior cervical plate packed by autologus iliac bone was performed. Pathological examination confirmed the diagnosis of LCH. After the surgery, the boy recovered from radiating pain and motor weakness of limbs. Despite the rarity of the LCH in the cervical spine, it is necessary to maintain our awareness of this condition. When neurologic deficits are present, operative treatment should be considered. PMID:22552159
Doléagbénou, A K; Mukengeshay Ntalaja, J; Derraz, S; El Ouahabi, A; El Khamlichi, A
Apoptosis is an intrinsic and fundamental biologic process that plays a critical role in the normal development of multicellular organisms and in the maintainance of tissue homeostasis. Some of the well known regulators of apoptosis are cytokines of the tumor necrosis factor (TNF) ligand family, such as Fas ligand (Fas L) and TNF, which induce apoptosis by activation of their corresponding receptors, Fas and TNFR-1. Recently, a new member of the TNF family known as TRAIL (TNF-related apoptosis-inducing ligand) was identified and shown to induce p53-independent apoptosis in a variety of tumor cell lines but not in normal cells. Four human receptors for TRAIL were also recently identified and designated TRAIL-R1, -R2, -R3, and -R4. The aim of this study is to examine whether TRAIL and TRAIL receptors (-R1, -R2, -R3) are expressed in uterine cervical cancer and whether it is correlated with apoptosis, TRAIL, and TRAIL receptors. The subjects were 20 patients who were diagnosed with cervical cancer. Western blotting was performed in nine cases and immunohistochemical staining for TRAIL and TRAIL receptors (-R1, -R2, -R3) and TUNEL method for detection of apoptosis was performed in 11 cases. There were proteins for TRAIL, TRAIL-R1, -R2, and -R3 in tissues from cervical cancer. All TRAIL receptors were expressed in both normal cervical epithelium and tumor cells, and TRAIL-R1 and -R2 were more strongly expressed in tumor cells than normal epithelium (P < 0.05). Apoptosis correlated with expression of TRAIL-R1 and -R2 (P < 0.05). This study suggests that TRAIL induces apoptosis in cervical cancer through its receptors. PMID:11240708
Ryu, H. S.; Chang, K. H.; Chang, S. J.; Kim, M. S.; Joo, H. J.; Oh, K. S.
The knowledge that the persistent infection with high-risk (HR) human papillomavirus (HPV) is the etiological factor in the development of cervical cancer has led to the development of the HPV DNA detection methods as well as the prophylactic vaccine against the most common HR-HPV types, HPV 16 and 18. Despite HPV vaccination, cervical cancer screening will remain the main preventive measure for both vaccinated and non-vaccinated women, but the nature of screening and management of women with cervical disease is being adapted to the new technologies. Although, HPV DNA detection is more sensitive that cytology, its specificity is lower, since most HPV infections are transient. Therefore, other methods are considered to improve the management of women with cervical disease. Typing of HPV DNA and viral load measurements are still used for research purposes only. Detection of viral oncogene E6/E7 transcripts, which is the marker of the productive infection, is a promising tool for follow-up of HPV DNA-positive women. The detection of p16INK4a over-expression, as an indirect test of E6/E7 expression, is used for confirmation of cervical neoplasia. Despite the lack of standardization, the detection of p16INK4a is useful in clinical settings, however its reproducibility in the management of low-grade and borderline cases is low. Future perspectives include the determination of the methylation status of several cellular genes that could predict the progression of the disease. PMID:20698164
Grce, Magdalena; Matovina, Mihaela; Milutin-Gasperov, Nina; Sabol, Ivan
Pap smear testing continues to be the single most effective tool in reducing deaths due to cervical cancer (Watkins, Gabali, Winkleby, Gaona & Lebaron, 2002). Despite the creation of a national cervical cancer screening program, more than 4,000 women die every year in Mexico from this disease. This study explored the knowledge, attitudes, and behaviors of Mexican women regarding cervical
Myriam Leyva; Theresa Byrd; Patrick Tarwater
Cervical cancer is the major cause of death in women of reproductive age in parts of the developing world. Thanks to the effectiveness of national screening programs, the incidence and mortality rates for cervical cancer have declined dramatically in developed countries. According to many researchers, human papillomavirus (HPV) infection has an important role in the development of cervical neoplasm. The
A. Mandic; T. Vujkov
Previous studies suggest that high parity increases the risk of cervical cancer. We studied the risk of cervical cancer (CC) and cervical intraepithelial neoplasia (CIN3) in a Finnish cohort of grand multiparous (GM) women (at least five children) with low prevalence of sexually transmitted infections (STI). The Finnish Cancer Registry data revealed 220 CC and 178 CIN3 cases among 86
M Hinkula; E Pukkala; P Kyyrönen; P Laukkanen; P Koskela; J Paavonen; M Lehtinen; A Kauppila
Oncology Overviews are a service of the International Cancer Research Data Bank (ICRDB) Program of the National Cancer Institute, intended to facilitate and promote the exchange of information between cancer scientists by keeping them aware of literature ...