Integrin α11β1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer.
Integrin α11β1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer.
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DOI：
10.1038/onc.2015.254
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发表时间：
2016-04-14
期刊：
影响因子：
8
通讯作者：
Tsao MS
中科院分区：
文献类型：
--
作者：
Navab R;Strumpf D;To C;Pasko E;Kim KS;Park CJ;Hai J;Liu J;Jonkman J;Barczyk M;Bandarchi B;Wang YH;Venkat K;Ibrahimov E;Pham NA;Ng C;Radulovich N;Zhu CQ;Pintilie M;Wang D;Lu A;Jurisica I;Walker GC;Gullberg D;Tsao MS
整合素α11β1是纤维状胶原的基质细胞特异性受体，在癌相关成纤维细胞（CAF）中过表达。我们通过产生整合素α11（α11）表达缺陷的严重联合免疫缺陷（SCID）小鼠来研究其在癌症进展中的直接作用。与野生型（α 11+/+）SCID小鼠相比，这些α11敲除（α11−/−）小鼠中A549肺腺癌细胞和两种患者来源的非小细胞肺癌（NSCLC）异种移植物的生长显著受阻。将自发转移性NCI-H460 SM细胞系原位植入α11−/−和α11+/+小鼠的肺中，结果显示这些细胞在α11−/−小鼠中的转移潜力显著降低。我们发现胶原交联与间质α11表达相关，肿瘤间质α11表达的缺失与胶原重组和硬度降低相关。本研究显示了整合素α11β1（纤维胶原的受体）在成纤维细胞分化为CAFs中的作用。此外，我们的数据支持α11信号通路在CAFs中的重要作用，促进NSCLC细胞的肿瘤生长和转移潜力，并与胶原交联以及纤维状胶原基质的组织和刚度密切相关。
Integrin α11β1 is a stromal cell-specific receptor for fibrillar collagens and is overexpressed in carcinoma-associated fibroblasts (CAFs). We have investigated its direct role in cancer progression by generating severe combined immune deficient (SCID) mice deficient in integrin α11 (α11) expression. The growth of A549 lung adenocarcinoma cells and two patient-derived non-small cell lung carcinoma (NSCLC) xenografts in these α11 knockout (α11−/−) mice was significantly impeded, as compared with wild-type (α11+/+) SCID mice. Orthotopic implantation of a spontaneously metastatic NCI-H460SM cell line into the lungs of α11−/− and α11+/+ mice showed significant reduction in the metastatic potential of these cells in the α11−/− mice. We identified that collagen cross-linking is associated with stromal α11 expression, and the loss of tumor stromal α11 expression was correlated with decreased collagen reorganization and stiffness. This study shows the role of integrin α11β1, a receptor for fibrillar collagen in differentiation of fibroblasts into CAFs. Furthermore, our data support an important role for α11 signaling pathway in CAFs, promoting tumor growth and metastatic potential of NSCLC cells and being closely associated with collagen cross-linking and the organization and stiffness of fibrillar collagen matrices.