The molecular mechanism of human anal squamous cell carcinoma (ASCC) is

The molecular mechanism of human anal squamous cell carcinoma (ASCC) is unclear and the accumulating evidence TPCA-1 indicate association of ASCC with the activation of the Akt/mTOR pathway. 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. Introduction Anal cancer is an uncommon malignancy located in the anal canal and perianal area with an annual incidence of 1 1.5 per 100 0 in the general population [1] [2]. The incidence of anal cancer in the United States has been rising over the past three decades especially in some subpopulations; for example homosexual men are at a higher risk for anal cancer [1] [2]. The 5-12 months survival rate for those suffering from anal cancer has remained consistently low and nearly unchanged at approximately 60% over the past 30 years [1]. Etiologically anal cancer seems to be more similar to genital cancers than to gastrointestinal tract cancers. Like cervical cancer the human papillomavirus (HPV) contamination is considered to be an important etiological factor in the development of ASCC due to the high rate of HPV contamination in patients with anal cancer [3?5]. However 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 increased phosphorylated-Akt Mouse monoclonal to CD21.transduction complex containing CD19, CD81and other molecules as regulator of complement activation. may be due to increased copy numbers of the PIK3CA locus and some coding sequence mutations or HPV contamination [7] [8]. PTEN is usually a potent tumor suppressor gene and a negative regulator of the PI3K/Akt pathway [9]. TGF-β belongs to a superfamily of multifunctional cytokines that regulate cell apoptosis differentiation and migration thereby influencing the key physiological processes such as embryonic development immune function and carcinogenesis [10]. The three mammalian TGF-β isoforms TGF-β1 -β2 and -β3 exert their TPCA-1 functions through a cell-surface receptor complex composed of type I (TGFBR1) and type II (TGFBR2) serine/threonine kinase receptors [11]. We previously reported that this deletion of the TGF-β 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 loss TPCA-1 of Pten alone in the squamous epithelia can initiate the mouse squamous cell tumorigenesis with about 10% penetration [13]. In order to better understand the mechanism of anal cancer and to identify novel therapeutic approaches for preventing and/or treating the malignancy laboratory animal models for anal cancer were established to provide an experimental platform. Lambert’s lab developed a murine anal cancer model using HPV E6/E7 transgenic mice in which the E6 and E7 genes are linked to the K14 promoter targeting their expression to stratified epithelium [6] [14]. This model greatly promotes our understanding of the molecular mechanism of anal cancer and provides a preclinical platform to test the effects of the novel drug in anal cancer treatment [6] [14]. However these HPV transgenic mice do not spontaneously develop anal cancer and must be treated with carcinogen dimethylbenzanthracene (DMBA) or 12-O- tetradecanoylphorbol-13-acetate (TPA). We previously developed conditional knockout mice with Neurofilament-H- TPCA-1 Cre which develop anal cancer over a long period of about 4-6 months [15]. Our previous study also suggested that there may be a negative cross TPCA-1 talk between the TGF-β tumor suppressor and the PI3K/Akt pathways [12]. Here we report that double conditional knockout mice spontaneously develop anal cancer in a short period of time with activation of the Akt/mTOR pathway and without carcinogen induction. We have also have identified therapeutic effects of rapamycin a putative mTOR inhibitor which can inhibit tumorigenesis of ASCC in this mouse model. Materials and Methods Mice Generation of 2cKO (K14-CreERtam; cKO mice (K14-CreERtam; cKO (K14-CreERtam; 2cKO mice and their controls (2cKO anal SCC samples (n?=?5) as compared with 2cKO anal skin (n?=?5) anal skin (n?=?5) and rapamycin treated 2cKO anal skin (n?=?3) were stained with the antibody by immunohistochemistry using.