The principle objective of the proposed research is to determine the possible role of gastrin in its receptor (GR) in human large bowel and stomach cancer. In normal tissue, gastrin has trophic effects on the gastrointestinal (GI) mucosa. There is some evidence to suggest that gastrin may stimulate the growth of some colorectal and stomach cancer cells.
Our first aim i s to test the hypothesis by studying the effects of gastrin on growth of a transplantable mouse colon cancer (MC26), both in vivo and in vitro. We will also test the effects of gastrin on macromolecular synthesis and cell division in human colon and stomach cancer cell lines in tissue culture. It is possible that not all colorectal and stomach cancers and cultured cancer cell lines require or are growth-responsive to gastrin. These cancers and cells may have decreased or absent GR. To study this, we will measure the GR concentration in different cultured cancer cell lines, examine the optimal conditions for GR estimation, and compare GR characteristics with gastrin responsiveness of the cell lines. Regulation of GR concentration is one mechanism by which growth of the cells could be regulated. We have observed an apparent cell cycle variation in GR by LoVo cancer cells. We plan to investigate whether this type of GR regulation occurs in other cell lines and whether it is physiologically significant, i.e., does it alter the sensitivity of the cell to gastrin? We also plan to investigate whether other peptide and steroid hormones alter the binding characteristics and/or GR levels as a means of possible synergistic/antagonistic effects on gastrin action on mucosal growth. If gastrin is shown to have an effect on cell growth, then the effects of various chemotherapeutic agents on cell survival will be tested to examine the possibility of combining hormonal stimulation and drug therapy as a means of increasing cell kill. GR will also be measured in membranes prepared from GI tumor biopsy specimens to determine if variations in GR concentrations occur in vivo. Populations, binding, and structure of GR will be examined in cancerous and normal gastric and colonic mucosa from rats, mice, and humans to determine abnormal patterns in GR, if any, with neoplastic change. The experiments outlined in this proposal should clarify the role of gastrin and GR in large bowel and stomach cancer and may lead to better understanding of the factors influencing tumor growth. Ultimately, it may be possible to select patients who would benefit from endocrine manipulations. It may also be possible to increase the effectiveness of chemotherapeutic agents by combining them with hormonal treatment. (C)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038651-03
Application #
3176795
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1984-12-01
Project End
1988-04-30
Budget Start
1986-12-01
Budget End
1988-04-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
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
Narayan, S; Rajakumar, G; Prouix, H et al. (1992) Estradiol is trophic for colon cancer in mice: effect on ornithine decarboxylase and c-myc messenger RNA. Gastroenterology 103:1823-32

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