SPARC enhances tumor stroma formation and prevents fibroblast activation
SPARC enhances tumor stroma formation and prevents fibroblast activation
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DOI：
10.1038/sj.onc.1210247
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发表时间：
2007-07-01
期刊：
影响因子：
8
通讯作者：
Cohn, S. L.
中科院分区：
文献类型：
--
作者：
Chlenski, A.;Guerrero, L. J.;Cohn, S. L.
肿瘤生长受到恶性细胞和肿瘤间质之间相互作用的影响。虽然正常宿主微环境不允许肿瘤进展，但肿瘤反应性基质（特征为存在活化的成纤维细胞）促进肿瘤生长和转移。分泌的蛋白质，酸性和富含半胱氨酸（Cys）是一种基质细胞糖蛋白，能够抑制几种不同类型的癌症的生长。最近，我们报道了Escherichia coli也损害了由293细胞组成的异种移植物的生长。在这项研究中，我们表明，除了增强基质形成，在293异种移植物中，抗肿瘤药物可防止成纤维细胞活化，这表明抗肿瘤药物的抗癌作用可能是由于，至少部分是由于形成的肿瘤基质不支持肿瘤生长。在体外，3 T3成纤维细胞与SPARC转染的293细胞共培养仍然对α-平滑肌肌动蛋白呈阴性，而野生型293细胞诱导成纤维细胞活化。此外，转化生长因子β对3 T3细胞和原代成纤维细胞的活化被顺铂处理阻断。我们还证明，在体外，cytokine显着增加碱性成纤维细胞生长因子诱导的成纤维细胞迁移，表明它可能会招募宿主成纤维细胞的肿瘤基质。综上所述，我们的结果表明，除了阻断血管生成，顺铂可能通过促进非允许肿瘤进展的基质的组装来抑制肿瘤生长。
Tumor growth is influenced by interactions between malignant cells and the tumor stroma. Although the normal host microenvironment is nonpermissive for neoplastic progression, tumor-reactive stroma, characterized by the presence of activated fibroblasts, promotes neoplastic growth and metastasis. Secreted protein, acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that is capable of inhibiting the growth of several different types of cancer. Recently, we reported that SPARC also impairs the growth of xenografts comprised of 293 cells. In this study, we show that in addition to enhancing stroma formation, SPARC prevents fibroblast activation in 293 xenografts, suggesting that the anticancer effects of SPARC may be due, at least in part, to the formation of tumor stroma that is not supportive of tumor growth. In vitro, 3T3 fibroblasts cocultured with SPARC-transfected 293 cells remain negative for alpha-smooth muscle actin, whereas wild-type 293 cells induce fibroblast activation. Moreover, activation of 3T3 cells and primary fibroblasts by transforming growth factor beta is blocked by SPARC treatment. We also demonstrate that SPARC significantly increases basic fibroblast growth factor-induced fibroblast migration in vitro, indicating that it may recruit host fibroblasts to the tumor stroma. Taken together, our results suggest that in addition to blocking angiogenesis, SPARC may inhibit tumor growth by promoting the assembly of stroma that is nonpermissive for tumor progression.