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

我们的实验室已经发表了许多报告，表明出现在癌细胞表面但通常不在正常细胞表面的称为α-v β-6（avb 6）的分子负责许多类型癌症的生长能力，并减少癌症患者的寿命。我们现在已经证明，avb 6缩短癌症患者寿命的主要原因是它导致癌症扩散到全身，而这些继发性肿瘤的形成是大多数癌症危及生命的方面。然而，avb 6究竟是如何导致癌症转移的还不清楚。最近我们发现avb 6做了一些不寻常的事情。我们检查了所有在携带avb 6的癌症中发生变化的基因，发现变化最大的基因组与癌细胞周围的蛋白质有关，即所谓的基质。有5个基因发生了变化，称为脂联素，腱生蛋白X和podocan减少，SPOCK 1和endocan增加。这些脂联素、腱生蛋白X和足蛋白聚糖可以由基质中称为脂肪细胞的脂肪细胞产生，而SPOCK 1和内皮聚糖可以由基质中的成纤维细胞产生。结果似乎表明，脂联素、腱生蛋白X和podocan的存在以及SPOCK 1和endocan的缺失似乎可以防止癌症如此危及生命。当我们在实验室中将脂联素，腱生蛋白X和podocan放在癌细胞上时，它们的生长和侵袭能力实际上大大降低了。因此，有脂联素，腱生蛋白X和podocan，但没有SPOCK 1和endocan可以减缓癌症并延长总体生存期。问题是，如果癌症有avb 6，那么这种分子以某种方式改变了脂肪细胞和成纤维细胞的行为，并逆转了这些蛋白质的自然外观：因此脂联素，腱生蛋白X和podocan消失，SPOCK 1和endocan出现。我们需要了解avb 6是如何做到这一点的，这项研究调查了avb 6是如何改变脂肪细胞和成纤维细胞，使其成为癌症生长和扩散的帮手，同时也调查了这5种蛋白质是如何减少癌细胞的危险行为的，这样我们就可以找到可以复制它们作用的药物。

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.