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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

INTRODUCTION Colorectal

INTRODUCTION Colorectal cancer is the third most common cancer and cause of death due to cancer in the United States. Death due to colorectal cancer is generally caused by distant metastasis rather than the primary tumor itself (7). Many cancers metastasize to specific organs [For a review please see: (172)]. For example, colon cancer mainly metastasizes to the liver and lungs (172). The diet contains (1) preformed vitamin A as retinyl esters in animal-derived food sources and (2) provitamin A carotenoids in plant- derived food sources. Once absorbed, retinol is re-esterified and transported to the liver, the major site of vitamin A storage, via chylomicrons. Hepatic retinol levels increase in response to supplementation and values in excess of 90 μM have been reported (44). Therefore, dietary vitamin A supplementation can increase retinol levels in the colon and liver, potentially affecting both primary colon tumors and those that have metastasized to the liver. The retinoids, a group of compounds consisting of vitamin A (retinol), its natural metabolites and several synthetic compounds, have also been shown to inhibit metastasis in a variety of model systems. For example, dietary retinyl palmitate decreased malignant melanoma metastasis in mice (86). ATRA decreased breast cancer (105), gastric cancer (87) and colon cancer cell invasion (88) in vivo and rhabdomyosarcoma metastasis in rats (135). Also, retinol decreased hepatic metastases in a hamster model of pancreatic ductal carcinoma (173). Previously, we showed that retinol decreased the growth and invasion of ATRA-resistant human colon cancer cells via a novel RAR- independent mechanism in vitro (144,162,174). 99

Recent studies in our laboratory showed that retinol decreases MMP-2, -9 and PI3K activity to inhibit cancer cell invasion in vitro (144,174) In addition, nude mice studies bearing colon cancer cells to generate liver metastasis showed that down regulation of these proteins was associated with regression of cancer progression. For example, interferon-α administration to nude mice following intrasplenic injection with human colon cancer cells (KM12L4) showed a decrease in MMP-9 and basic fibroblast growth factor (bFGF) levels in liver metastatic tumors and reduced liver metastasis incidence (175). PI3K specific siRNA treatment suppressed the hepatic metastases of colon cancer cells injected intrasplenically (176). On the other hand, an HCT-116 mutant cell line expressing constitutively active PI3K promoted liver metastases in orthotopically implanted nude mice than when compared to nude mice implanted with wild type HCT-116 cells (24). The objectives of the present study were to determine if dietary vitamin A supplementation decreased the hepatic metastases of colon tumor cells in vivo. Liver metastases were induced by intrasplenic injection of wild type HCT-116 human colon carcinoma cells into female BALB/cAnNCr-nu/nu nude mice. Hepatic tumor incidence and multiplicity were measured to examine the effect of dietary vitamin A supplementation. MMP-2, -9 and phospho-Akt levels were also examined to determine the mechanism by which dietary vitamin A reduces liver metastasis in vivo. 100

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