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Copyright by Eunyoung Park 2007 - The University of Texas at Austin

Copyright by Eunyoung Park 2007 - The University of Texas at Austin

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consists of several processes including: (1) invasion or digestion of the basement membrane by tumor cells and migration of these cells through the basement membrane into the circulation (intravasation) and (2) migration of the cells out of the circulation and invasion into the target tissue (extravasation). Colorectal cancer is rated using Duke’s classification system that contains four stages: A to D. Duke’s stage A refers to tumors that affect only the mucosa of the bowel and not other structures of the colon. Duke’s stage B indicates the tumor has invaded into or through the muscularis propria of the colon. In Duke’s stage C the cancer has spread to the local lymph nodes. Duke’s stage D indicates that the cancer has metastasized to distant tissues and organs. Metastasis and Matrixmetalloproteinases (MMPs) Cancer cell invasion and metastasis are multistep processes that involve extracellular matrix (ECM) proteolysis and changes in adhesion molecules. Matrix metalloproteinases (MMPs) are family of proteolytic enzymes which degrade the ECM during cancer progression [For a review please see: (8,9)]. MMP overexpression has been linked with invasion and metastasis and inhibitiors of MMPs block invasive and metastatic activities of many tumor types. MMP’s are classified into four groups based on their substrate; collagenases, gelatinases, stromelysins and matrilysins. Particularly one group of MMPs, the gelatinases MMP-2 and –9, are associated with progression of colon cancer [For a review please see: (9)]. MMP-2 and -9 mRNA were elevated in colon cancer tissues as compared with normal colon tissues (10,11). Protein levels and activation of MMP-2 and -9 in colon cancer were closely related with Duke’s staging 3

(12). The protein levels of MMP-2 and -9 were increased in invasive regions of colon cancer (13). Specifically, MMP-2 was significantly overexpressed in Duke’s D stage (13,14). MMP-2 and -9 activation has also been shown to be increased in patients with metastases (15). Those data indicate that MMP-2 and -9 are involved in cancer progression. Metastasis and Phosphatidylinositol 3-kinases (PI3K) Signaling Phosphatidylinositol 3-kinases (PI3Ks) catalyze the phosphorylation of the 3-OH position of the inositol head groups of the phosphatidylinositol (PI) lipids, phosphatidylinos--itol(4)phosphate [PI(4)P], and phosphatidylinositol(4,5)bisphosphate [PI(4,5)P2] to generate PI(3)P, PI(3,4)P2 and PI(3,4,5)P3, respectively (16). PI(3,4)P2 and PI(3,4,5)P3 are generally absent from resting cells, but their intracellular concentration rises markedly upon stimulation via a variety of cell surface receptors, suggesting a second messenger function. PI3K can be classified into three main groups on the basis of their substrate and structure. The class-1 PI3K is the most studied and is a key enzyme in a intracellular signaling pathway, modulated by many growth and survival factors, which regulate cell proliferation, growth, survival and apoptosis (17,18). In addition, the class-1 PI3K is highly expressed in colon cancer cell lines (19). The class-1 PI3K is a heterodimer composed of a catalytic subunit (p110) and a regulator subunit (p85). The substrate for class I PI3K is PI(4,5)P2 which generates the second messenger PI(3,4,5)P3. The PI3K are also involved in cancer cell proliferation, survival, motility, differentiation, cytoskeletal rearrangement, and angiogenesis (20,21). 4

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