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)
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