sirolimus and Anus-Neoplasms

The molecular mechanism of human anal squamous cell carcinoma (ASCC) is unclear, and the accumulating evidence indicate association of ASCC with the activation of the Akt/mTOR pathway. Here we describe a mouse model with spontaneous anal squamous cell cancer, wherein a combined deletion of Tgfbr1 and Pten in stratified squamous epithelia was induced using inducible K14-Cre. Histopathologic analyses confirmed that 33.3% of the mice showed increased susceptibility to ASCC and precancerous lesions. Biomarker analyses demonstrated that the activation of the Akt pathway in ASCC of the Tgfbr1 and Pten double knockout (2cKO) mouse was similar to that observed in human anal cancer. Chemopreventive experiments using mTOR inhibitor-rapamycin treatment significantly delayed the onset of the ASCC tumors and reduced the tumor burden in 2cKO mice by decreasing the phosphorylation of Akt and S6. This is the first conditional knockout mouse model used for investigating the contributions of viral and cellular factors in anal carcinogenesis without carcinogen-mediated induction, and it would provide a platform for assessing new therapeutic modalities for treating and/or preventing this type of cancer.

Topics: Animals; Anti-Bacterial Agents; Anus Neoplasms; Blotting, Western; Female; Immunohistochemistry; In Situ Nick-End Labeling; Male; Mice; Mice, Knockout; Mice, Transgenic; Phosphorylation; Protein Serine-Threonine Kinases; PTEN Phosphohydrolase; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; Sirolimus; TOR Serine-Threonine Kinases

The incidence of anal cancer is increasing especially among HIV-infected persons in the HAART era. Treatment of this cancer is based upon traditional chemoradiotherapeutic approaches, which are associated with high morbidity and of limited effectiveness for patients with high-grade disease. The mammalian target of rapamycin (mTOR) pathway has been implicated in several human cancers, and is being investigated as a potential therapeutic target. In archival human anal cancers, we observed mTOR pathway activation. To assess response of anal cancer to mTOR inhibition, we utilized two newly developed mouse models, one in which anal cancers are induced to arise in HPV16 transgenic mice and the second a human anal cancer xenograft model. Using the transgenic mouse model, we assessed the preventative effect of rapamycin on neoplastic disease. We saw significant changes in the overall incidence of tumors, and tumor growth rate was also reduced. Using both the transgenic mouse and human anal xenograft mouse models, we studied the therapeutic effect of rapamycin on preexisting anal cancer. Rapamycin was found to significantly slow, if not stop, the growth of both mouse and human anal cancers. As has been seen in other cancers, rapamycin treatment led to an activation of the MAPK pathway. These results provide us cause to pursue further the evaluation of rapamycin as a therapeutic agent in the control of anal cancer.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antibiotics, Antineoplastic; Anus Neoplasms; Blotting, Western; Carcinogens; Cell Transformation, Neoplastic; Disease Models, Animal; Female; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; Male; Mice; Mice, Nude; Mice, SCID; Mice, Transgenic; Oncogene Proteins, Viral; Papilloma; Papillomaviridae; Papillomavirus E7 Proteins; Repressor Proteins; Sirolimus