The Mechanism of Action of Progastrins in Colorectal Cancer

现在有明确的证据表明，激素胃泌素前体与结直肠癌(CRC)的发生有关。血液中胃泌素浓度升高增加了发生结直肠癌的风险，在结直肠癌患者中，血液胃泌素浓度高于正常水平。此外，在动物身上的实验表明，胃泌素前体刺激结肠内部细胞的生长。这一领域的主要挑战是鉴定将胃泌素前体结合到结肠细胞表面的蛋白质(称为受体)，以及了解受体结合如何触发结肠中导致结直肠癌发生的变化。我们最近发现，胃泌素前体通过减少细胞间的黏附来促进细胞迁移，从结直肠癌的角度来看，这一发现特别重要，因为这种现象在癌症发展的早期阶段具有潜在的重要性。我们最近观察到胃泌素前体以高亲和力结合金属离子，进一步表明金属结合可能是受体结合所必需的，从而对生物活性也是必要的。因此，我们将研究：(1)金属离子与胃泌素前体结合是否影响生物活性，(2)受体结合所需的胃泌素前体区域，(3)将胃泌素前体与结肠细胞结合的受体的结构，(4)将受体连接到维持相邻细胞之间联系的其他细胞内蛋白质的途径，以及(5)控制黏附的途径与控制细胞生长的途径之间的差异。该项目将导致对胃泌素前体对结肠细胞生长和黏附影响的分子机制的详细了解。受体的定义和所涉及的细胞内信号机制最终可能导致包括结直肠癌在内的结肠增殖障碍的新治疗方法。

Clear evidence now links precursors of the hormone gastrin with the development of colorectal cancer (CRC). Elevated gastrin concentrations in the blood increase the risk of developing CRC, and in patients with CRC blood gastrin concentrations are higher than normal. Furthermore experiments in animals indicate that gastrin precursors stimulate growth of the cells lining the interior of the colon. The major challenges in this field are to characterise the proteins (called receptors) which bind gastrin precursors to the surface of colon cells, and to understand how receptor binding triggers changes in the colon which result in CRC development. Our recent discovery that gastrin precursors promote cell migration by reducing adhesion between cells is particularly significant from the perspective of CRC because of the potential importance of this phenomenon in the early stages of cancer development. Our recent observation that gastrin precursors bind metal ions with high affinity further suggests that metal binding may be essential for receptor binding and hence for biological activity. We will therefore investigate: (1) whether binding of metal ions to gastrin precursors effects biological activity, (2) which regions of gastrin precursors are required for receptor binding, (3) the structures of the receptors which bind gastrin precursors to colon cells, (4) the pathways which connect the receptors to other intracellular proteins that maintain contact between adjacent cells, and (5) the differences between the pathways controlling adhesion and the pathways controlling cell growth. This project should lead to a detailed understanding of the molecular mechanisms underlying the effect of gastrin precursors on colon cell growth and adhesion. Definition of the receptors and intracellular signalling mechanisms involved may ultimately lead to novel treatments for disorders of colonic proliferation including CRC.