Focal Adhesion Assembly in Myofibroblasts Fosters a Microenvironment that Promotes Tumor Growth
Focal Adhesion Assembly in Myofibroblasts Fosters a Microenvironment that Promotes Tumor Growth
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DOI：
10.2353/ajpath.2010.100187
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发表时间：
2010-10-01
影响因子：
6
通讯作者：
Shah, Vijay
中科院分区：
文献类型：
--
作者：
Kang, Ningling;Yaqoob, Usman;Shah, Vijay
肿瘤微环境中的细胞通过多种机制影响肿瘤生长。周细胞如肝星状细胞是肿瘤微环境中的重要细胞；它们向高运动性肌成纤维细胞的转化导致血管生成、基质细胞募集、基质沉积和随后的肿瘤生长。因此，需要更好地了解调节周细胞运动的机制。局灶黏附（FM）在细胞外环境和肌动蛋白细胞骨架之间形成了物理联系，这是细胞运动的必要步骤。FM含有一系列蛋白质，包括Ena/VASP家族成员，血管扩张剂刺激磷酸化蛋白（VASP）；然而，VASP在FA发展中的作用一直难以捉摸。通过综合siRNA敲低方法和多种VASP突变体以及互补的细胞成像方法，我们证明了在表达高水平内源性VASP的LX2肝肌成纤维细胞中，VASP对FM的最佳发育和细胞扩散是必需的。VASP的结合伙伴Rac1与VASP协同作用调控FM。在体内，对肿瘤肌成纤维前体细胞中Ena/VASP功能的干扰显著减少了周细胞向肿瘤血管系统的募集、肌成纤维细胞转化、肿瘤血管生成和肿瘤生长，为这些发现提供了体内病理学相关性。综上所述，我们的研究结果表明，在肿瘤微环境中，Ena/VASP通过调节FA动力学和随后的周细胞/肌成纤维细胞功能，是肿瘤生长的重要调节剂。（美国病理学杂志，2010,177:1888-1900;DOI: 10.2353/ajpath.2010.100187）
Cells within the tumor microenvironment influence tumor growth through multiple mechanisms. Pericytes such as hepatic stellate cells are an important cell within the tumor microenvironment; their transformation into highly motile myofibroblasts leads to angiogenesis, stromal cell recruitment, matrix deposition, and ensuing tumor growth. Thus, a better understanding of mechanisms that regulate motility of pericytes is required. Focal adhesions (FM) form a physical link between the extracellular environment and the actin cytoskeleton, a requisite step for cell motility. FM contain a collection of proteins including the Ena/VASP family member, vasodilator-stimulated phosphoprotein (VASP); however, a role for VASP in FA development has been elusive. Using a comprehensive siRNA knockdown approach and a variety of VASP mutants coupled with complementary cell imaging methodologies, we demonstrate a requirement of VASP for optimal development of FM and cell spreading in LX2 liver myofibroblasts, which express high levels of endogenous VASP. Rac1, a binding partner of VASP, acts in tandem with VASP to regulate FM. In vivo, perturbation of Ena/VASP function in tumor myofibroblast precursor cells significantly reduces pericyte recruitment to tumor vasculature, myofibroblastic transformation, tumor angiogenesis, and tumor growth, providing in vivo pathobiologic relevance to these findings. Taken together, our results identify Ena/VASP as a significant modifier of tumor growth through regulation of FA dynamics and ensuing pericyte/myofibroblast function within the tumor microenvironment. (Am J Pathol 2010, 177:1888-1900; DOI: 10.2353/ajpath.2010.100187)