Role of Gastrin in the Pathogenesis of Colorectal Cancer

描述（由申请人提供）：胃泌素除了在生理上调节酸分泌的作用外，另一个归因于胃泌素的生物学特性是其对胃肠道（Gl）粘膜的营养作用。大量研究表明，胃泌素肽不仅能刺激正常Gl上皮细胞的生长，还能刺激结直肠癌（CRC）、胃癌和胰腺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发展的主要危险因素。这些研究提示了胃泌素在这些恶性肿瘤发病机制中的潜在作用，即循环胃泌素水平的升高，以及肿瘤来源的非修饰胃泌素，都可能刺激这类肿瘤的生长。尽管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。具体来说，本项目的目的是：(1)在2种动物模型中系统地研究高胃泌素血症和胃泌素抑制对结直肠癌生长的体内影响：(a) APC敲除小鼠；(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结直肠癌细胞系。将细胞皮下注射或注入脾下囊，通过强效抑酸或胃泌素肽输注使小鼠高胃泌素血症；(2)研究胃泌素在体外对细胞生长、凋亡和形态的影响。DLD-1细胞将在各种条件下培养，包括胃泌素转录过表达或抑制的条件下，并确定胃泌素刺激和抑制对潜在靶基因表达的影响。胃泌素是促进肿瘤生长的主要因素，这一前景具有重要的临床意义。在美国，结直肠癌是仅次于肺癌的恶性疾病死亡原因，约50%的患者在发病时无法治愈。由于胃泌素刺激结直肠癌的生长，通过抑制胃窦胃泌素的生物合成和抑制肿瘤细胞中胃泌素基因的异常表达，有可能抑制肿瘤的生长，以及腺瘤性息肉向侵袭性癌的进展。这些挑衅性假设的答案只能通过获得对胃泌素发挥其营养特性的分子机制的透彻理解来实现。

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.