VEGF-A and Tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization
VEGF-A and Tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization
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DOI：
10.1073/pnas.1109493108
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发表时间：
2011-09-20
影响因子：
11.1
通讯作者：
Kalluri, Raghu
中科院分区：
文献类型：
--
作者：
O'Connell, Joyce T.;Sugimoto, Hikaru;Kalluri, Raghu
S100 A4（+）细胞数量的增加与癌症患者的预后不良有关。虽然S100 A4（+）癌细胞的转移能力已经被研究，但S100 A4（+）基质细胞在转移中的功能作用在很大程度上是未知的。为了研究S100 A4（+）基质细胞在转移中的作用，我们使用在S100 A4启动子控制下表达病毒胸苷激酶的转基因小鼠特异性地消融S100 A4（+）基质细胞。S100 A4（+）基质细胞的消耗显著减少了转移性定植，而不影响原发性肿瘤生长。多项骨髓移植研究表明，S100 A4（+）基质细胞的这些作用可归因于局部非骨髓来源的S100 A4（+）细胞，在这种情况下，这些细胞可能是成纤维细胞。由于S100 A4（+）成纤维细胞的损失导致的转移减少与几种ECM分子和生长因子（特别是生腱蛋白-C和VEGF-A）的表达的伴随减少相关。通过检查腱生蛋白-C缺失小鼠和在S100 A4启动子控制下表达Cre重组酶的转基因小鼠与携带侧接loxP位点的VEGF-A等位基因的小鼠杂交，确定了基质腱生蛋白-C和S100 A4（+）成纤维细胞衍生的VEGF-A在转移中的功能重要性，所述小鼠表现出转移性定殖的显著降低而不影响原发性肿瘤生长。特别是，S100 A4（+）成纤维细胞来源的VEGF-A在转移部位建立血管生成微环境以促进定植中起重要作用，而基质生腱蛋白-C可提供保护免于凋亡。我们的研究证明了局部S100 A4（+）成纤维细胞在为转移性定植提供允许的“土壤”方面的关键作用，这是转移级联反应中具有挑战性的一步。
Increased numbers of S100A4(+) cells are associated with poor prognosis in patients who have cancer. Although the metastatic capabilities of S100A4(+) cancer cells have been examined, the functional role of S100A4(+) stromal cells in metastasis is largely unknown. To study the contribution of S100A4(+) stromal cells in metastasis, we used transgenic mice that express viral thymidine kinase under control of the S100A4 promoter to specifically ablate S100A4(+) stromal cells. Depletion of S100A4(+) stromal cells significantly reduced metastatic colonization without affecting primary tumor growth. Multiple bone marrow transplantation studies demonstrated that these effects of S100A4(+) stromal cells are attributable to local non-bone marrow-derived S100A4(+) cells, which are likely fibroblasts in this setting. Reduction in metastasis due to the loss of S100A4(+) fibroblasts correlated with a concomitant decrease in the expression of several ECM molecules and growth factors, particularly Tenascin-C and VEGF-A. The functional importance of stromal Tenascin-C and S100A4(+) fibroblast-derived VEGF-A in metastasis was established by examining Tenascin-C null mice and transgenic mice expressing Cre recombinase under control of the S100A4 promoter crossed with mice carrying VEGF-A alleles flanked by loxP sites, which exhibited a significant decrease in metastatic colonization without effects on primary tumor growth. In particular, S100A4(+) fibroblast-derived VEGF-A plays an important role in the establishment of an angiogenic microenvironment at the metastatic site to facilitate colonization, whereas stromal Tenascin-C may provide protection from apoptosis. Our study demonstrates a crucial role for local S100A4(+) fibroblasts in providing the permissive "soil" for metastatic colonization, a challenging step in the metastatic cascade.