How does integrin alpha-v beta-6-dependent de-regulation of the stroma control alpha-v beta-6-dependent metastasis?

点击翻译按钮获取中文摘要

Our lab has published many reports showing that the molecule called alpha-v beta-6 (avb6) which appears on the surface of cancer cells but is not usually on normal cells, is responsible for the ability of many types of cancer to grow and to reduce the life span of cancer patients. We have now shown that the main reason why avb6 shortens the lifespan of cancer patients is that it causes the cancers to spread around the body, and it is the formation of these secondary tumours which is the life-threatening aspect of most cancers. However, exactly how avb6 causes cancers to metastasise is notknown. Recently we discovered that avb6 does something unusual. We examined all the genes that were changed in a cancer that had avb6 and found that the most changed sets of genes were involved in proteins you find in the space surrounding the cancer cells, the so-called stroma. There were 5 genes in particular that were changed called adiponectin, tenascin X and podocan that were reduced, and SPOCK1 and endocan that were increased. These adiponectin, tenascin X and podocan can be produced by fat cells called adipocytes in the stroma and SPOCK1 and endocan can be produced by fibroblasts in the stroma. The results seemed to suggest that the presence of adiponectin, tenascin X and podocan and the absence of SPOCK1 and endocan seemed to prevent cancers from being so life threatening. When we put adiponectin, tenascin X and podocan onto cancer cells in the laboratory their ability to grow and to invade was actually dramatically reduced. So having adiponectin, tenascin X and podocan, but no SPOCK1 and endocan slows cancers down and extends overall survival. The problem is that if the cancer has avb6 then this molecule somehow changes the behaviour of the adipocytes and fibroblasts and reverses the natural appearance of these proteins: so adiponectin, tenascin X and podocan disappear and SPOCK1 and endocan appear. We need to understand how avb6 can do this.This study investigates exactly how avb6 changes the adipocytes and fibroblasts to become helpers of cancer growth andspread but also investigates how the 5 proteins reduce the hazardous behaviour of the cancer cells so that we might find drugs that can copy their effects.