The Mechanism of Action of Progastrins in Colorectal Cancer

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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.