Molecular Targets for Colon Cancer
Div Cellular & Molecular Science, Dept Oncology, University London School Medicine, St Georges Hospital, London, England, United Kingdom
Colon cancer was used as a model by Vogelstein and colleagues to demonstrate the multiple hit 'hypothesis' required for a normal cell to develop into an aggressive cancer cell. A number of recognised defects were required to occur (such as the K-ras and p53 mutations) in order for a normal cell to progress through to a cancer cell by first becoming a dysplastic lesion, then an adenoma and finally a cancer. The number of accumulated mutations rather than the chronological order in which they occur appears to be the most important association, although this may not be the case in all models. Nevertheless, a large number of defects may contribute to carcinogenesis, such as thousands of documented different mutations of the p53 gene, as well as other p53 independent pathways, which include the TGF Beta pathway associated with genetic instability and microsatellite mutator phenotype. The hereditary causes of colon cancer, such as familial adenomatous polyposis (FAP) and hereditary non polyposis colorectal cancer (HNPCC) exemplify the importance of suppressor gene inaction of the APC gene as well as the importance of the mismatched repair genes (MMR), such as hMLH-1 and MSH-2, in the development of the cancer process. More recently, the role of inflammatory genes such as COX-2 have been recognised as relevant targets with regard to colorectal cancer. COX-2 expression interacts with both the cell mediated immune response (causing immune suppression) as well as with angiogenesis by stimulating angiogenic growth factors VEGF, bFGF, and TGF-β. In addition, a COX-2 expression enhances the effect of other molecular pathways, such as p53 and IGF by induction of growth factor, angiogenesis and immune suppression. The importance of the role of other anti inflammatory agents in colorectal cancer is suggested by activity in non COX-2 dependant pathways. Molecular targets expressed by colorectal cancer cells, such as EpCAM and CD55 can also be used as immuno-therapeutic targets, either by monoclonal antibodies (panorex for EpCAM) or vaccines. In spite of the numerous mechanisms whereby suppressor genes may be inactivated and oncogenic and signalling pathways activated, there appears to be a consistency in some core pathways that should allow new therapeutic strategies to be developed using specific molecular targets for both prevention and treatment.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 1001 (Intervention strategies).