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道，表明该分子称为α-Vβ-6（AVB6），该分子出现在癌细胞表面，但通常不在正常细胞上，这是许多类型的癌症生长和降低癌症患者寿命的能力。现在，我们已经表明，AVB6缩短癌症患者寿命的主要原因是它会导致癌症散布在体内，而这是这些次要肿瘤的形成，这是大多数癌症的危及生命。但是，AVB6确切地导致癌症转移的方式未知。最近，我们发现AVB6做了不寻常的事情。我们检查了在患有AVB6的癌症中改变的所有基因，发现最变化的基因涉及您在癌细胞周围空间中发现的蛋白质，即所谓的基质。尤其是5个被称为脂联素，tenascin X和Podocan的基因降低，而Spock1和Endocan被增加了。这些脂联素，Tenascin X和Podocan可以由脂肪细胞在基质和Spock1中的脂肪细胞和内醇中产生，并且可以由基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的不存在似乎可以阻止癌症危及生命。当我们将脂联素，Tenascin X和Podocan放在实验室的癌细胞上时，实际上会大大降低其生长和入侵的能力。因此，有脂联素，田纳西蛋白X和波多坎，但没有Spock1和内核会减慢癌症的速度并延长总体生存率。问题是，如果癌症具有AVB6，则该分子在某种程度上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，Tenascin X和Podocan消失了，Spock1和Spock1和Endocan出现。我们需要了解AVB6如何做到这一点。这项研究准确地研究了AVB6如何改变脂肪细胞和成纤维细胞成为癌症生长的帮助者并宣传，但还研究了5种蛋白质如何减少癌细胞的危险行为，以便我们可以找到可以复制其作用的药物。