Role of indoleamine 2,3 dioxygenase (IDO) in the process of epithelial-mesenchymal transition(EMT) mediated by TGF-beta in human urogenital carcinoma

Abstract

The urogenital cancers represent a significant public health problem when the morbid-mortality is observed. One of the mechanisms involved in the pathogenesis of these cancers is the epithelial-mesenchymal transition (EMT), which correlates positively with tumor growth and metastasis, leading to a worse clinical outcome. One of the factors classically known as inducer of EMT is the TGF-beta, which acts in the EMT process triggering intracellular signaling pathways such as PI3K pathway. The indoleamine 2,3-dioxygenase (IDO) is an enzyme produced in the maternal-fetal interface and is related to fetal protection against maternal immune system. Interestingly, many tumors produce IDO, leading to the hypothesis that IDO confers tumor protection via immunomodulation, ensuing its growth and dissemination. However, it is likely that IDO participates of the EMT, since the TGF-beta induces IDO expression in dendritic cells, a mechanism not yet described in the tumoral EMT.The aim of the study is to analyze the role of IDO in the process of EMT presents in urogenital carcinoma. Thus, the study will be divided into three phases: The first corresponds to the analysis of TGF-beta and IDO expression in penile carcinoma biopsies by immunohistochemistry. Samples of 151 patients with penile carcinoma and 14 healthy men (control) will be analyzed. The second phase corresponds to a in vitro study using cellular lineage of urinary bladder carcinoma (T24), in which EMT will be assessed post-TGF-beta stimulus, analyzing the involvement of the PI3K pathway and IDO (enzymatic activity and structural function). The third phase is an in vivo study with the use of immunodeficient mice (BALB/c mice), analyzing the tumor growth and the metastatic ability of the T24 cells after inoculation, evaluating the influence of IDO in this process. (AU)