Abstract
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.
Highlights
Anal cancer is an uncommon malignancy located in the anal canal and perianal area, with an annual incidence of 1.5 per 100,000 in the general population [1,2]
We previously reported that the deletion of the TGF-b receptor I (Tgfbr1) promotes tumorigenesis of head and neck squamous cell carcinoma, mainly through the activation of the Akt pathway, but it does not initiate it [12]
The tumor originated from squamous epithelial but not from columnar epithelial (Figs 2Aand 2B), which is composed of atypical differentiated epithelial cells that grew as solid sheets or strands, a hallmark feature of squamous cell carcinoma Fig. 2B
Summary
Anal cancer is an uncommon malignancy located in the anal canal and perianal area, with an annual incidence of 1.5 per 100,000 in the general population [1,2]. The human papillomavirus (HPV) infection is considered to be an important etiological factor in the development of ASCC due to the high rate of HPV infection in patients with anal cancer [325]. The HPV oncogenes which lead to increases in cell proliferation and evasion from the apoptotic pathway are considered insufficient for causing this tumor [6]. Another important molecular change that has been reported in 66% of anal cancer cases is the cellular accumulation of phosphorylated Akt and the subsequent nuclear translocation of TP53 [7]. The loss of Pten alone in the squamous epithelia can initiate the mouse squamous cell tumorigenesis with about 10% penetration [13]
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