Cell survival mechanisms associated with metastasis of human colon carcinoma

Colorectal cancer has the third highest incidence and is second highest in cancer-related death in the US. The majority of deaths are due to colorectal metastatic disease. Current treatment modalities are limited in their effectiveness in targeting metastatic disease due to the inadequate knowledge of molecular mechanisms involved in the malignant progression of colon cancer. Thus understanding the mechanisms that promote metastasis would facilitate development of more effective therapy. The hypothesis of this study is that enhanced survival signaling is associated with robust colon cancer metastatic disease. Identification of the pathways leading to metastasis would facilitate discovery of novel molecular targets and provide a rationale for the development of therapeutic targeting agents. The above hypothesis was examined by chaacterizing 3 different signaling pathways: Transforming Growth Factor-&agr; (TGF&agr;), Phosphoinositide-3 Kinase (PI3K)/AKT and Transforming Growth Factor-beta (TGFbeta) whose aberrant signaling resulted either in a gain of function (oncogenic) or a loss of function (loss of tumor suppressor) and their effect on malignant progression in a non-tumorigenic human colon cancer cell, FET. Aberrant oncogenic TGF&agr; signaling was sufficient to impart robust tumorigenicity and invasion in the FET cells but inadequate for promoting metastasis. However, oncogenic TGF&agr; signaling in conjunction with loss of TGFbeta tumor suppressor signaling enhanced cell survival signaling and resulted in robust metastatic disease in an in vivo colonic orthotopic model. Exploration of the mechanisms that underlie enhanced survival signaling in cells revealed that AKT and Survivin/XIAP proteins were involved. AKT activation was enhanced in cells with loss of TGFbeta signaling. Higher protein expression of both survivin and XIAP proteins were found to be localized in the cytoplasm of cells with metastatic function due to loss of TGFbeta signaling.;In summary, our data support the hypothesis that enhanced cell survival is associated with the malignant progression of colon cancer and metastasis. Our novel finding provides identification of potential targets, i.e. TGFalpha signaling pathway components, for therapeutic intervention.