Role of IGFs in the transformation of several cancer cells is by now well established. Both IGFs (IGF-I and IGF-II) are potent mitogenic agents for several normal and neoplastic cells. IGF binding proteins (IGF-BPs), on the other hand are believed to modulate the mitogenic effects of IGFs. Within the past two years we and others have established that primary human colon cancers and established colon cancer cell lines express and secrete the mitogen, IGF-II, and the modulating proteins, IGF-BPs. It is, however, not known if IGFs and IGF-BPs play a major role in the growth and differentiation of colon cancer cells. It is speculated that the mitogenic potential of a colon cancer cell line will depend upon the relative expression of the mitogen and the modulator. The major hypothesis of this grant proposal therefore is that the relative expression and secretion of IGF-II and IGF-BPs dictates the growth differentiation potential of colon cancer cells. Our major strategy is to investigate the individual role of IGF-II and IGF-BPs in the growth and differentiation of colon cancers. Towards this goal we will use stable and inducible transfectants that either express the sense or the antisense form of the mitogen/modulatory proteins to confirm the relative role of IGFs and IGF-BPs in initiating or supporting the proliferative/differentiated state of the cells. Alternatively, we will measure the effect of IGF peptides, specific antibodies and antisense oligonucleotides on proliferation of a representative colon cancer cell line (Colo-205) (that does not differentiate in culture), and differentiation of a representative colon cancer cell line (CaCo2 cells) (that spontaneously differentiates in culture). In a second set of studies, the proliferation of colon cancer cells will be measured in vivo in specific mouse models, in the presence or absence of IGFs, IGF-BPs and IGF-receptor antagonists. Alternatively, growth and differentiation of cancer cells, transfected with vectors expressing the sense or antisense IGFs and BPs, will be measured in nude mice. These studies will help us to define the role of circulating vs autocrine (endogenous) IGFs and IGF- BPs in the growth and differentiation of colon cancers in vivo. At the end of these studies we expect to have defined the mitogenic/differentiation potential of IGFs in the presence of modulating IGF-BPs. The results of these studies will help us to move a step closer towards our overall goal of understanding the role of the IGF system in the proliferation and differentiation of neoplastic colonic mucosal cells, and provide the basic information for developing more appropriate, clinically relevant, protocols.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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General Medicine A Subcommittee 2 (GMA)
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Spalholz, Barbara A
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University of Texas Medical Br Galveston
Anatomy/Cell Biology
Schools of Medicine
United States
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Rengifo-Cam, William; Singh, Pomila (2004) Role of progastrins and gastrins and their receptors in GI and pancreatic cancers: targets for treatment. Curr Pharm Des 10:2345-58
Singh, P; Cobb, S; Rengifo-Cam, W et al. (2004) Locomotor activity and behavior of mutant mice deleted for gastrin gene expression. J Physiol Pharmacol 55:269-78
Shen, Quiang; Singh, Pomila (2004) Identification of a novel SP3 binding site in the promoter of human IGFBP4 gene: role of SP3 and AP-1 in regulating promoter activity in CaCo2 cells. Oncogene 23:2454-64
Singh, P; Lu, X; Cobb, S et al. (2003) Progastrin1-80 stimulates growth of intestinal epithelial cells in vitro via high-affinity binding sites. Am J Physiol Gastrointest Liver Physiol 284:G328-39
Brown, D; Yallampalli, U; Owlia, A et al. (2003) pp60c-Src Kinase mediates growth effects of the full-length precursor progastrin1-80 peptide on rat intestinal epithelial cells, in vitro. Endocrinology 144:201-11
Cobb, Stephanie; Wood, Thomas; Tessarollo, Lino et al. (2002) Deletion of functional gastrin gene markedly increases colon carcinogenesis in response to azoxymethane in mice. Gastroenterology 123:516-30
Dai, B; Wu, H; Holthuizen, E et al. (2001) Identification of a novel cis element required for cell density-dependent down-regulation of insulin-like growth factor-2 P3 promoter activity in Caco2 cells. J Biol Chem 276:6937-44
Wu, H; Rao, G N; Dai, B et al. (2000) Autocrine gastrins in colon cancer cells Up-regulate cytochrome c oxidase Vb and down-regulate efflux of cytochrome c and activation of caspase-3. J Biol Chem 275:32491-8
Singh, P; Velasco, M; Given, R et al. (2000) Progastrin expression predisposes mice to colon carcinomas and adenomas in response to a chemical carcinogen. Gastroenterology 119:162-71
Singh, P; Dai, B; Given, R L et al. (1998) Differential activation of IGF-II promoters P3 and P4 in Caco-2 cells during growth and differentiation. Gastroenterology 114:1221-9

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