Classification of cellular malignancy associated changes in cervical cancer

Cervical cancer is the leading cause of death and disease from malignant neoplasms among women in developing countries. Even though the Pap smear has significantly decreased the number of deaths from cervical cancer in the past years, it has its limitations. Researchers have developed an automated screening machine which can potentially detect abnormal cases that are overlooked by conventional screening. The goal of quantitative cytology is to classify the patient's tissue sample based on quantitative measurements of the individual cells. It is also much cheaper and potentially can take less time. One of the major challenges of collecting cells with a cytobrush is the possibility of not sampling any existing dysplastic cells on the cervix. Being able to correctly classify patients who have disease without the presence of dysplastic cells could improve the accuracy of quantitative cytology algorithms. Subtle morphologic changes in normal-appearing tissues adjacent to or distant from malignant tumors have been shown to exist, but a comparison of various statistical methods, including many recent advances in the statistical learning field, has not previously been done. The objective of this thesis is to use different classification methods applied to quantitative cytology data for the detection of malignancy associated changes (MACs). In this thesis, Elastic Net is the best algorithm. When we applied the Elastic Net algorithm to the test set, we combined the training set and validation set as "training" set and used 5-fold cross validation to choose the parameter for Elastic Net. It has a sensitivity of 47% at 80% specificity, an AUC 0.52, and a partial AUC 0.10 (95% CI 0.09-0.11).^

Insulin-like growth factor II mediates epidermal growth factor-induced mitogenesis in cervical cancer cells.

There is increasing evidence that activation of the insulin-like growth factor I (IGF-I) receptor plays a major role in the control of cellular proliferation of many cell types. We studied the mitogenic effects of IGF-I, IGF-II, and epidermal growth factor (EGF) on growth-arrested HT-3 cells, a human cervical cancer cell line. All three growth factors promoted dose-dependent increases in cell proliferation. In untransformed cells, EGF usually requires stimulation by a "progression" factor such as IGF-I, IGF-II, or insulin (in supraphysiologic concentrations) in order to exert a mitogenic effect. Accordingly, we investigated whether an autocrine pathway involving IGF-I or IGF-II participated in the EGF-induced mitogenesis of HT-3 cells. With the RNase protection assay, IGF-I mRNA was not detected. However, IGF-II mRNA increased in a time-dependent manner following EGF stimulation. The EGF-induced mitogenesis was abrogated in a dose-dependent manner by IGF-binding protein 5 (IGFBP-5), which binds to IGF-II and neutralizes it. An antisense oligonucleotide to IGF-II also inhibited the proliferative response to EGF. In addition, prolonged, but not short-term, stimulation with EGF resulted in autophosphorylation of the IGF-I receptor, and coincubations with both EGF and IGFBP-5 attenuated this effect. These data demonstrate that autocrine secretion of IGF-II in HT-3 cervical cancer cells can participate in EGF-induced mitogenesis and suggest that autocrine signals involving the IGF-I receptor occur "downstream" of competence growth factor receptors such as the EGF receptor.

Implicating the mechanisms of ADP-ribosylation factor activation in the resistance of invasive breast cancer cells to EGFR tyrosine kinase inhibitors

ADP-ribosylation factor-1 (ARF1) est une petite GTPase principalement connue pour son rôle dans la formation de vésicules au niveau de l’appareil de Golgi. Récemment, dans des cellules de cancer du sein, nous avons démontré qu’ARF1 est aussi un médiateur important de la signalisation du récepteur du facteur de croissance épidermique (EGFR) contrôlant la prolifération, la migration et l'invasion cellulaire. Cependant, le mécanisme par lequel l’EGFR active la GTPase ainsi que le rôle de cette dernière dans la régulation de la fonction du récepteur demeure inconnue. Dans cette thèse, nous avions comme objectifs de définir le mécanisme d'activation de ARF1 dans les cellules de cancer du sein hautement invasif et démontrer que l’activation de cette isoforme de ARF joue un rôle essentiel dans la résistance de ces cellules aux inhibiteurs de l'EGFR. Nos études démontrent que les protéines d’adaptatrices Grb2 et p66Shc jouent un rôle important dans l'activation de ARF1. Alors que Grb2 favorise le recrutement d’ARF1 à l'EGFR ainsi que l'activation de cette petite GTPase, p66Shc inhibe le recrutement du complexe Grb2-ARF1 au récepteur et donc contribue à limiter l’activation d’ARF1. De plus, nous démontrons que ARF1 favorise la résistance aux inhibiteurs des tyrosines kinases dans les cellules de cancer du sein hautement invasif. En effet, une diminution de l’expression de ARF1 a augmenté la sensibilité descellules aux inhibiteurs de l'EGFR. Nous montrons également que de hauts niveaux de ARF1 contribuent à la résistance des cellules à ces médicaments en améliorant la survie et les signaux prolifératifs à travers ERK1/2, Src et AKT, tout en bloquant les voies apoptotiques (p38MAPK et JNK). Enfin, nous mettons en évidence le rôle de la protéine ARF1 dans l’apoptose en réponse aux traitements des inhibiteurs de l’EGFR. Nos résultats indiquent que la dépletion d’ARF1 promeut la mort cellulaire induite par gefitinib, en augmentant l'expression de facteurs pro-apoptotiques (p66shc, Bax), en altérant le potentiel de la membrane mitochondriale et la libération du cytochrome C. Ensemble, nos résultats délimitent un nouveau mécanisme d'activation de ARF1 dans les cellules du cancer du sein hautement invasif et impliquent l’activité d’ARF1 comme un médiateur important de la résistance aux inhibiteurs EGFR.

Breast and cervical cancer profile, Illinois, 1986-1994 /

"August 1996."

Breast and cervical cancer surveillance in Illinois /

"July 1993."

Cervical Cancer Control, Priorities and New Directions

Cervical cancer is caused by infection with a range of high risk oncogenic human papillomavirus (HPV) types, and it is now accepted that >99% of cervical cancer is initiated by HPV infection. The estimated lifetime risk of cervical cancer is nevertheless relatively low (less than I in 20 for most community based studies). Although sensitivity and specificity of the available diagnostic techniques are suboptimal, Screening for persistent HPV infection is effective in reducing the incidence of cervical cancer. Infection can be detected by molecular techniques or by cytological examination of exfoliated cervical cells. Persistent infection is the single best predictor of risk of cervical cancer.(1) The latest findings of HPV and cervical cancer research need to be widely disseminated to the scientific and medical societies that are updating screening and management protocols, public health professionals, and to women and clinicians. This report reviews current evidence, clinical implications and directions for further research in the prevention, control and management of cervical cancer. We report the conclusions of the Experts' Meeting at the EUROGIN 2003 conference. (C) 2003 Wiley-Liss, Inc.

Prevention of Cervical Cancer Through Papillomavirus Vaccination

A subset of human papillomaviruses (HPVs) promote anogenital malignancy, including cervical cancer, and prevention and treatment strategies that reflect the causal role of HPV are being developed. Vaccines based on HPV virus-like particles induce genotype-specific virus-neutralizing antibody and prevent infection with HPV1. Persistent papillomavirus infection is required for the development of papillomavirus-associated cancer and, therefore, therapeutic vaccines are being developed to eliminate established papillomavirus infection. Such vaccines test principles for the growing field of tumour-antigen-specific immunotherapy. This article reviews progress in the field and draws conclusions for the development of future prophylactic and therapeutic viral vaccines.

RNA interference against human papillomavirus oncogenes in cervical cancer cells results in increased sensitivity to cisplatin

Targeted inhibition of oncogenes in tumor cells is a rational approach toward the development of cancer therapies based on RNA interference (RNAi). Tumors caused by human papillomavirus (HPV) infection are an ideal model system for RNAi-based cancer therapies because the oncogenes that cause cervical cancer, E6 and E7, are expressed only in cancerous cells. We investigated whether targeting HPV E6 and E7 oncogenes yields cancer cells more sensitive to chemotherapy by cisplatin, the chemotherapeutic agent currently used for the treatment of advanced cervical cancer. We have designed siRNAs directed against the HPV E6 oncogene that simultaneously targets both E6 and E7, which results in an 80% reduction in E7 protein and reactivation of the p53 pathway. The loss of E6 and E7 resulted in a reduction in cellular viability concurrent with the induction of cellular senescence. Interference was specific in that no effect on HPV-negative cells was observed. We demonstrate that RNAi against E6 and E7 oncogenes enhances the chemotherapeutic effect of cisplatin in HeLa cells. The IC50 for HeLa cells treated with cisplatin was 9.4 mu M, but after the addition of a lentivirus-delivered shRNA against E6, the IC50 was reduced almost 4-fold to 2.4 mu M. We also observed a decrease in E7 expression with a concurrent increase in p53 protein levels upon cotreatment with shRNA and cisplatin over that seen with individual treatment alone. Our results provide strong evidence that loss of E6 and E7 results in increased sensitivity to cisplatin, probably because of increased p53 levels.