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Proteomics of Colon Cancer

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Proteomics of Colon Cancer
Our study of colon cancer began with Dr. Al Knudson, inventor of the two-hit hypothesis for cancer, agreeing to be our mentor and providing the support for building the Mass Spectrometry and Proteomics Facility and the Real-time PCR Facility for FCCC. We studied patients with Familial Adenomatous Polyposis (FAP), because they are virtually certain to develop colon cancer, and because much is known about the causative APC gene. We hypothesized that the inherited heterozygous mutation itself leads to changes in the proteome of morphologically normal crypts and the proteins that changed may represent targets for preventive and therapeutic agents. We determined the differential protein expression of morphologically normal colon crypts of FAP patients versus those of individuals without the mutation, using two-dimensional gel electrophoresis, mass spectrometry and validation by 2D gel Western blotting. Approximately 13% of 1,695 identified proteins were abnormally expressed in the morphologically normal crypts of APC mutation carriers, indicating that a colon crypt cell under the one-hit state is already abnormal. Many of the expression changes affect pathways consistent with the function of the APC protein, including apoptosis, cell adhesion, cell motility, cytoskeletal organization and biogenesis, mitosis, transcription and oxidative stress response. Thus, heterozygosity for a mutant APC tumor suppressor gene alters the proteome of normal-appearing crypt cells in a gene-specific manner, consistent with a detectable one-hit event. These changes may represent the earliest biomarkers of colorectal cancer development, potentially leading to the identification of molecular targets for cancer prevention.

Some of this work is listed in the recent publications section. We also explored the proteomic changes due to the APC mutation, in the fibroblasts that support the crypt cells, and in the extracellular matrix that mediates their interaction. The results of these studies are forthcoming. In all, we hope to provide a view of the comprehensive changes that occur in the one-hit state prior to colon cancer and to lead to new opportunities for intervention.

Created by: yeung Last Modification: Tuesday 16 of December, 2008 22:33:19 EST by yeung