通过胶原蛋白基质中整合素α5β1/纤连蛋白的相互作用与成纤维细胞接触的集体癌细胞侵袭,Cancer Science

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通过胶原蛋白基质中整合素α5β1/纤连蛋白的相互作用与成纤维细胞接触的集体癌细胞侵袭
Cancer Science ( IF 4.5 ) Pub Date : 2020-09-26 , DOI: 10.1111/cas.14664
Kaoru Miyazaki ₁ , Shinsaku Togo ₂ , Reiko Okamoto _{3,

4} , Alimjan Idiris ₃ , Hiromichi Kumagai ₅ , Yohei Miyagi ₁

Affiliation

癌细胞与癌症相关的成纤维细胞（CAF）的相互作用在肿瘤进展中起关键作用。最近，我们提出了一种新的肿瘤侵袭机制，其中侵袭性癌细胞分别在3D胶原基质中的CAF（CAF纤维）的细长突起上迁移。在这种机制下，癌细胞主要通过整联蛋白α5β1与装配在CAF上的纤连蛋白原纤维相互作用。在这里，我们使用两种表达E-钙粘蛋白的腺癌细胞系DLD-1（结肠）和MCF-7（乳腺癌）来测试这种机制是否适用于癌细胞的集体侵袭。当DLD-1细胞与CAF的混合球体嵌入胶原蛋白凝胶中时，DLD-1细胞会集中但非常缓慢地迁移穿过与CAFs接触的胶原蛋白基质。表皮生长因子和肿瘤坏死因子-α促进了集体侵袭，可能是通过减少E-钙黏着蛋白连接来实现的，就像通过刺激CAF的生长来转变转化生长因子-β抑制剂SB431542一样。转化生长因子β本身抑制了癌细胞的侵袭。要使DLD-1细胞有效地集体入侵，就需要大型CAF纤维或将其组装成稳定的粘附基质。功能阻断抗体和siRNA的实验证实DLD-1细胞主要通过整联蛋白α5β1粘附在CAF上的纤连蛋白原纤维上。抗E-钙粘蛋白Ab通过解离E-钙粘蛋白连接促进了DLD-1细胞的单细胞侵袭。尽管MCF-7细胞与CAF的结合亲和力低于DLD-1，但它们也以与DLD-1细胞类似的方式共同侵入胶原蛋白基质。我们的研究结果表明，与CAF以及环境细胞因子的直接相互作用，

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Collective cancer cell invasion in contact with fibroblasts through integrin‐α5β1/fibronectin interaction in collagen matrix

Interaction of cancer cells with cancer‐associated fibroblasts (CAFs) plays critical roles in tumor progression. Recently we proposed a new tumor invasion mechanism in which invasive cancer cells individually migrate on elongate protrusions of CAFs (CAF fibers) in 3‐D collagen matrix. In this mechanism, cancer cells interact with fibronectin fibrils assembled on CAFs mainly through integrin‐α5β1. Here we tested whether this mechanism is applicable to the collective invasion of cancer cells, using two E‐cadherin‐expressing adenocarcinoma cell lines, DLD‐1 (colon) and MCF‐7 (breast). When hybrid spheroids of DLD‐1 cells with CAFs were embedded into collagen gel, DLD‐1 cells collectively but very slowly migrated through the collagen matrix in contact with CAFs. Epidermal growth factor and tumor necrosis factor‐α promoted the collective invasion, possibly by reducing the E‐cadherin junction, as did the transforming growth factor‐β inhibitor SB431542 by stimulating the outgrowth of CAFs. Transforming growth factor‐β itself inhibited the cancer cell invasion. Efficient collective invasion of DLD‐1 cells required large CAF fibers or their assembly as stable adhesion substrates. Experiments with function‐blocking Abs and siRNAs confirmed that DLD‐1 cells adhered to fibronectin fibrils on CAFs mainly through integrin‐α5β1. Anti‐E‐cadherin Ab promoted the single cell invasion of DLD‐1 cells by dissociating the E‐cadherin junction. Although the binding affinity of MCF‐7 cells to CAFs was lower than DLD‐1, they also collectively invaded the collagen matrix in a similar fashion to DLD‐1 cells. Our results suggest that the direct interaction with CAFs, as well as environmental cytokines, contributes to the collective invasion of cancers.

更新日期：2020-09-26

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