Barretts esophagus books 2

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HPV carcinoma: Novel Mouse Model Recapitulates Human Cervical Cancer

There is currently substantial interest in developing improved treatments for cervical cancer and its preclinical lesions. In order to develop treatments, however, robust and clinically relevant preclinical models are required. Current pre-clinical models for cervical cancer have drawbacks that limit their utility in accurately evaluating novel therapies. We reasoned that an improved preclinical model for cervical cancer would 1) locally express HPV E6E7 in the reproductive tract of mice 2) have monitorable tumor progression through HSIL to squamous cell carcinoma 3) be accompanied by a mutation in the PI3K/AKT pathway, as mutations in the PI3K/AKT pathway are the most common somatic mutations found in cervical cancers, 4) be amenable for the evaluation of novel treatments for HSIL and cervical cancer, including immunotherapies, 5) and display flexibility in which HPV genotype is used for tumorigenesis as there are multiple high risk HPV types beyond HPV16. In this study, we developed a novel strategy to induce HPV16-E6E7 expressing (HPV+) cancer in the murine reproductive tract. We integrated plasmids that encoded 1) constitutively active AKT (myrAKT) as it is an oncogene in the PI3K/AKT pathway, 2) c-myc, because the upregulation of c-myc has been noted in HPV E6E7 transfected cells as well as cancer patients, where it has been found to be a negative prognostic factor for survival, and 3) HPV16-E7E6 with a luciferase reporter gene, abbreviated as AMES-16 plasmids. Using this methodology we transfected AMES-16 oncogenes into the reproductive tract of C57BL/6 mice following transient CD3+ T cell depletion, which induced HPV+ tumor outgrowth that progressed through HSIL to invasive squamous cell carcinoma (SCC). We found that this methodology induced cervicovaginal tumors that expressed relevant tumor markers and were infiltrated by immune cells and the tumors progressed from high-grade lesions to invasive carcinoma. Additionally, we isolated and characterized a HPV16+ cancer cell line, Tal3, from an intraperitoneal (IP) metastasis of a tumor induced by the AMES-16 model. In all, we have produced a novel spontaneous tumor model that better recapitulates aspect of the clinical condition, and additionally have characterized a novel Tal3 transplantable cell line, and these marked advancements hold promise to better predict clinical outcomes o novel therapeutic interventions for HPV-associated cancers. Further investigation to validate these tumor models and exploring their utility in humanized mice is warranted.

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