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.
Showing the most recent 10 out of 43 publications
