Role of Gastrin in the Pathogenesis of Colorectal Cancer

描述（由申请人提供）：除了其在酸分泌的生理调节中的作用之外，归因于胃泌素的另一种生物学特性是其对胃肠（GI）粘膜的营养作用。许多研究表明，胃泌素肽不仅刺激正常GI上皮细胞的生长，而且刺激结肠直肠（CRC）、胃和胰腺病因的恶性癌细胞系的生长。此外，最近一项涉及约130，000名受试者的流行病学研究发现，长期高胃泌素血症是CRC发展的主要风险因素。这些研究表明胃泌素在这些恶性肿瘤的发病机制中的潜在作用，其中循环胃泌素水平升高以及肿瘤衍生的非酰胺化胃泌素都可以为此类肿瘤的生长提供刺激。尽管有大量证据表明胃泌素肽在促进结直肠肿瘤生长中起着不可或缺的作用，但胃泌素介导其营养特性的确切机制尚未阐明。具体而言，本项目的目的是：（1）在2种动物模型中系统地检查高胃泌素血症和胃泌素抑制对CRC生长的体内影响：（a）APC敲除小鼠;和（B）具有可移植DLD-1细胞的裸鼠，DLD-1细胞是一种具有胃泌素受体的人CRC细胞系。将细胞皮下注射或注射到脾被膜下，通过强效酸抑制或胃泌素肽输注使小鼠出现高胃泌素血症;和（2）表征胃泌素对细胞生长、细胞凋亡和形态的体外作用。将在各种条件下培养DLD-1细胞，包括其中胃泌素转录过表达或被抑制的条件，并将确定胃泌素刺激和抑制对潜在靶基因表达的影响。胃泌素成为促进肿瘤生长的主要因素的前景具有重要的临床意义。在美国，CRC是仅次于肺癌的恶性疾病死亡原因，约50%的患者在就诊时无法治愈。因为胃泌素通过抑制胃窦胃泌素生物合成和通过抑制肿瘤细胞中胃泌素基因的异常表达来刺激CRC的生长，所以可能抑制肿瘤生长以及腺瘤性息肉向浸润性癌症的进展。这些挑衅性的假设的答案只能通过获得一个彻底的了解胃泌素发挥其营养特性的分子机制来实现。

DESCRIPTION (provided by applicant): 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.