In addition to its role in the physiological regulation of acid secretion, another biological property attributed to gastrin is its trophic effect on gastrointestinal (Gl) mucosa. Numerous studies have shown that gastrin peptides stimulate not only the growth of normal Gl epithelial cells, but also malignant cancer cell lines of colorectal (CRC), gastric, and pancreatic etiology. Moreover, a recent epidemiologic study involving ~130,000 subjects found that prolonged hypergastrinemia comprises a major risk factor for the development of CRC. These studies suggest a potential role for gastrin in the pathogenesis of these malignancies, whereby both elevated levels of circulating gastrin, as well as tumor-derived nonamidated gastrin, could provide a stimulus for the growth of such tumors. Despite abundant evidence that gastrin peptides plays an integral role in promoting colorectal tumor growth, the precise mechanisms by which gastrin mediates its trophic properties have not been elucidated. Specifically, the aims of this project are to: (1) systematically examine the in vivo effects of hypergastrinemia and gastrin inhibition on CRC growth in 2 animal models: (a) the APC knockout mouse; and (b) the nude mouse with transplantable DLD-1 cells, a human CRC cell line that possesses gastrin receptors. Cells will be injected either subcutaneously or into the splenic subcapsule, and mice will be rendered hypergastrinemic by potent acid suppression or by gastrin peptide infusion; and (2) characterize the in vitro effects of gastrin on cell growth, apoptosis, and morphology. DLD-1 cells will be cultured under various conditions, including those in which gastrin transcription is either overexpressed or inhibited, and the effects of gastrin stimulation and inhibition on the expression of potential target genes will be determined. The prospect that gastrin constitutes a major factor for promoting tumor growth has important clinical significance. CRC is second only to lung cancer as a cause of death from malignant disease in the U.S., with ~50% of patients incurable at their presentation. Because gastrin stimulates the growth of CRC, by inhibiting antral gastrin biosynthesis and by suppressing abnormal expression of the gastrin gene in neoplastic cells, it may be possible to suppress tumor growth, as well as the progression of adenomatous polyps to invasive cancer. The answers to these provocative hypotheses can only be achieved by gaining a thorough understanding of the molecular mechanisms by which gastrin exerts its trophic properties. ? ?
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