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

整合素 α-V β-6 依赖性基质失调如何控制 α-V β-6 依赖性转移？

• 批准号: MR/W02537X/1
• 负责人: John Marshall
• 金额: $ 66.55万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW02537X%2F1
• 关键词: How; does; integrin; alpha; beta

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.

我们的实验室发表了许多报告，表明一种名为α-vβ-6(Avb6)的分子出现在癌细胞表面，但通常不在正常细胞上，它与许多类型癌症的生长能力和癌症患者的寿命缩短有关。我们现在已经证明，avb6缩短癌症患者寿命的主要原因是它导致癌症扩散到全身，而正是这些继发性肿瘤的形成是大多数癌症威胁生命的方面。然而，avb6是如何导致癌症转移的还不清楚。最近，我们发现avb6做了一些不寻常的事情。我们检查了在携带avb6基因的癌症中发生变化的所有基因，发现变化最大的一组基因涉及到癌细胞周围空间中的蛋白质，即所谓的间质。有5个基因发生了特别的变化，脂联素、Tenascin X和Podocan基因减少，SPOCK1和Endocan基因增加。这些脂联素、Tenascin X和Podocan可以由间质中称为脂肪细胞的脂肪细胞产生，SPOCK1和Endocan可以由间质中的成纤维细胞产生。结果似乎表明，脂联素、Tenascin X和Podocan的存在以及SPOCK1和Endocan的缺失似乎阻止了癌症对生命的威胁。当我们在实验室将脂联素、Tenascin 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，含有脂联素、Tenascin X和Podocan，但没有SPOCK1和Endocan，可以减缓癌症并延长总体生存时间。问题是，如果癌症有avb6，那么这种分子就会以某种方式改变脂肪细胞和成纤维细胞的行为，并逆转这些蛋白质的自然外观：因此脂联素、Tenascin X和Podocan消失，而SPOCK1和Endocan出现。我们需要了解avb6是如何做到这一点的。这项研究确切地调查了avb6如何改变脂肪细胞和成纤维细胞，成为癌症生长和扩散的助手，但也调查了这5种蛋白质如何减少癌细胞的危险行为，以便我们可能找到可以复制它们的效果的药物。