The principal objective of the research is to determine the possible role of gastrin and 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 tumor cells. Our first aim is to test this hypothesis by studying the effects of gastrin on growth of a transplantable mouse colon tumor (CT26), both in vivo and in vitro. We also will test the effects of gastrin on macromolecular synthesis and cell division in human colon and stomach tumor cell lines in tissue culture. It is possible that not all colorectal and stomach tumors and cultured tumor cell lines require or are growth-responsive to gastrin. These tumors and cells may have decreased or absent GR. To study this, we will measure the GR concentration in different cultured tumor cell lines and compare this with their gastrin responsiveness. 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 tumor 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 hormones known to affect normal GI mucosal cell growth do so by altering the concentration of GR. 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 also will be measured in membranes prepared from human breast tumor biopsy specimens to determine if variations in GR concentrations occur in vivo. The experiments outlined should clarify the role of gastrin and GR in large bowel and stomach cancer and may lead to a 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.
NIH ExPorter
NIH ExPorter