There is a growing body of evidence that the Transforming growth factor-p (TGF-beta) family of peptides has critical functions in the gastrointestinal tract. In normal epithelial cells TGF-beta has a predominant growth- inhibitory effect and serves a tumor suppressor role. Neoplastic transformation results in loss of this normal growth-inhibitory response. Several lines of evidence reveal that the responses to TGF-beta may become predominantly tumor-promoting in the context of either prolonged exposure of cells to high levels of TGF-beta or after oncogenic transformation. Based on these observations, we have developed the following central hypothesis: Loss of TGF-beta tumor suppressor effects is a common consequence of neoplastic transformation, and tumor cell responses to TGF-beta promote angiogenesis and tumor growth due to a switch in signal transduction. We further hypothesize that TGF-beta causes a collaborative and synergistic induction of VEGF expression in epithelial cells that express a dominant oncogene such as Ras or cyclin D I . Our short-term goals to be pursued over the next five years are to test this hypothesis and to identify mechanisms for this switch in TGFbetaP responses. A long-term goal is to use this information to identify novel therapeutic strategies that selectively target the tumor promoting effects of TGF-BETA, while preserving the tumor-suppressive actions. Secondary hypotheses that emanate from the central hypothesis will be tested under the following specific aims.
Specific Aim 1 : Determine the mechanism for TGF-BETA regulation of VEGF gene expression, and the role of TGF-BETA-induced VEGF expression on tumor angiogenesis in colorectal cancer.
Specific Aim 2 : To examine the interaction of the Wnt/BETA-catenin signaling pathway with TGF-BETA responsiveness in colonocyte and hepatocyte cells.
Specific Aim 3 : To determine whether loss of TGF-BETA growth-inhibitory responsiveness or TGF-BETA tumor promotion contributes to hepatocellular tumorigenesis in the LFABP-cyclin D1 transgenic mice.
|Zhu, Jing; Wang, Jing; Shi, Zhiao et al. (2013) Deciphering genomic alterations in colorectal cancer through transcriptional subtype-based network analysis. PLoS One 8:e79282|
|Al-Greene, Nicole T; Means, Anna L; Lu, Pengcheng et al. (2013) Four jointed box 1 promotes angiogenesis and is associated with poor patient survival in colorectal carcinoma. PLoS One 8:e69660|
|Freeman, Tanner J; Smith, J Joshua; Chen, Xi et al. (2012) Smad4-mediated signaling inhibits intestinal neoplasia by inhibiting expression of ?-catenin. Gastroenterology 142:562-571.e2|
|Shi, Mingguang; Beauchamp, R Daniel; Zhang, Bing (2012) A network-based gene expression signature informs prognosis and treatment for colorectal cancer patients. PLoS One 7:e41292|
|Hanson, Alison J; Wallace, Heather A; Freeman, Tanner J et al. (2012) XIAP monoubiquitylates Groucho/TLE to promote canonical Wnt signaling. Mol Cell 45:619-28|
|Singh, Amar B; Sharma, Ashok; Smith, J Joshua et al. (2011) Claudin-1 up-regulates the repressor ZEB-1 to inhibit E-cadherin expression in colon cancer cells. Gastroenterology 141:2140-53|
|Rachakonda, G; Sekhar, K R; Jowhar, D et al. (2010) Increased cell migration and plasticity in Nrf2-deficient cancer cell lines. Oncogene 29:3703-14|
|Smith, J Joshua; Deane, Natasha G; Wu, Fei et al. (2010) Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer. Gastroenterology 138:958-68|
|Krishnan, M; Singh, A B; Smith, J J et al. (2010) HDAC inhibitors regulate claudin-1 expression in colon cancer cells through modulation of mRNA stability. Oncogene 29:305-12|
|Nam, Ki Taek; Lee, Hyuk-Joon; Smith, J Joshua et al. (2010) Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas. J Clin Invest 120:840-9|
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