The central hypothesis of our proposal is that gastrin, which is known to be trophic for normal gastrointestinal (GI) tissues, is also trophic for GI cancers & that gastrin receptors (GR) mediate the trophic effects of gastrin. The intracellular mechanism of gastrin mediated trophic effects is, however, unknown. Various hormones & hormone antagonists have been observed to modulate the growth stimulatory effects of gastrin on colon cancer cells in vivo, the mechanisms of which are largely unknown. We have recently established an in vitro system to study the trophic effects of gastrin directly on colon cancer cells. One of the major objectives of the present grant proposal is to study, 1) the intracellular mechanism of action of gastrin on cancer cells (role of cyclic nucleotides, inositol phosphates, protein kinases & growth factors will be examined), & 2) to examine the cellular & intracellular mechanism by which various steroid & peptide hormones regulate the growth of GI cancer cells. The hetero- regulation of the growth of mouse colon cancer (MC-26) cells by various hormones & hormone antagonists, in relation to concentration & binding kinetics of GR on cancer cells, has been observed by us in vivo, which could be due to either a direct or indirect interaction of the hormone/hormone antagonists with the cancer cells; indirect mechanisms involved will be investigated & the nature of direct interation defined. The physico-chemical characteristics of GR on normal tissues & GI cancers will be defined in order to determine whether the molecular characteristics of GR on cancer cells are similar or different from those on normal cells. A possible autocrine role of peptides & growth factors in the growth of MC- 26 cells will be additionally examined. In clinically relevant studies, GR levels in GI cancers from patients were found to correlate with the stage & differentiation of tumors, & may become useful in predicting the survival of patients. A second major objective of this grant proposal, therefore, is to isolate & purify GR from GI cancers & prepare mono-specific antibodies against GR which can be used for localization & identification of tumors positive for GR. We will continue to quantitate GR on freshly resected GI cancers & adjacent normal tissues from patients (using membrane binding assays & autoradiographic procedures), & correlate the receptor levels with clinical parameters including survival of the patients. The above studies will help us to further understand role of hormones in the growth of colon cancers & help define the cellular & intracellular mechanisms involved.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038651-08
Application #
2089605
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1984-12-01
Project End
1996-02-29
Budget Start
1994-03-01
Budget End
1996-02-29
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Surgery
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Singh, P; Dai, B; Yallampalli, U et al. (1996) Proliferation and differentiation of a human colon cancer cell line (CaCo2) is associated with significant changes in the expression and secretion of insulin-like growth factor (IGF) IGF-II and IGF binding protein-4: role of IGF-II. Endocrinology 137:1764-74
Singh, P; Owlia, A; Espeijo, R et al. (1995) Novel gastrin receptors mediate mitogenic effects of gastrin and processing intermediates of gastrin on Swiss 3T3 fibroblasts. Absence of detectable cholecystokinin (CCK)-A and CCK-B receptors. J Biol Chem 270:8429-38
Singh, P; Dai, B; Dhruva, B et al. (1994) Episomal expression of sense and antisense insulin-like growth factor (IGF)-binding protein-4 complementary DNA alters the mitogenic response of a human colon cancer cell line (HT-29) by mechanisms that are independent of and dependent upon IGF-I. Cancer Res 54:6563-70
Singh, P; Narayan, S; Adiga, R B (1994) Phosphorylation of pp62 and pp54 src-like proteins in a rat intestinal cell line in response to gastrin. Am J Physiol 267:G235-44
Singh, P; Xu, Z; Dai, B et al. (1994) Incomplete processing of progastrin expressed by human colon cancer cells: role of noncarboxyamidated gastrins. Am J Physiol 266:G459-68
Singh, P; Dai, B; Yallampalli, C et al. (1994) Expression of IGF-II and IGF-binding proteins by colon cancer cells in relation to growth response to IGFs. Am J Physiol 267:G608-17
Xu, Z; Dai, B; Dhruva, B et al. (1994) Gastrin gene expression in human colon cancer cells measured by a simple competitive PCR method. Life Sci 54:671-8
Singh, P; Reubi, J C; Rajakumar, G et al. (1993) In vivo mitogenic effects of estradiol on colon cancers: role of gastrin and gastrin receptors. J Steroid Biochem Mol Biol 46:49-60
Singh, P; Rubin, N (1993) Insulinlike growth factors and binding proteins in colon cancer. Gastroenterology 105:1218-37
Singh, P; Guo, Y S; Kull, F C et al. (1992) A novel bombesin receptor antagonist (2258U89), potently inhibits bombesin evoked release of gastrointestinal hormones from rats and dogs, in vitro and in vivo. Regul Pept 40:75-86

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