Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Br J Cancer. 2010 Jan 19;102(2):392-402. doi: 10.1038/sj.bjc.6605469. Epub 2009 Dec 1.
Carcinoma-associated fibroblasts (CAFs) can promote the progression of tumours in many ways. They can remodel the extracellular matrix to generate an environment that enables the invasion of cancer cells. We hypothesised that compounds that prevent matrix remodelling by CAFs would block their ability to promote carcinoma cell invasion.
We designed a screen for compounds that interfere with CAF-promoted matrix remodelling. Hits from this screen were investigated in organotypic invasion models of squamous cell carcinoma (SCC).
We find that lovastatin and simvastatin reduce matrix remodelling by fibroblasts and thereby reduce SCC invasion. This class of compounds exert their effects partly through disrupting the function of Rab proteins, and we show a new role for Rab21 in promoting cancer cell invasion promoted by CAFs.
Rab21 is required for CAFs to promote the invasion of cancer cells. It enables the accumulation of integrin alpha5 at the plasma membrane and subsequent force-mediated matrix remodelling.
癌相关成纤维细胞（CAFs）可以通过多种方式促进肿瘤的进展。它们可以重塑细胞外基质，产生允许癌细胞侵袭的环境。我们假设通过 CAF 预防基质重塑的化合物将阻止它们促进癌侵袭的能力。
我们设计了一种筛选可干扰 CAF 促进基质重塑的化合物的方法。从该筛选中获得的阳性化合物在鳞状细胞癌（SCC）的器官样侵袭模型中进行了研究。
我们发现洛伐他汀和辛伐他汀可减少成纤维细胞的基质重塑，从而减少 SCC 的侵袭。这类化合物通过干扰 Rab 蛋白的功能发挥作用，我们发现 Rab21 在促进 CAF 促进的癌细胞侵袭中具有新的作用。
Rab21 是 CAF 促进癌细胞侵袭所必需的。它使整合素 alpha5 在质膜上聚集，并随后进行力介导的基质重塑。
