A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers.
A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers.
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DOI：
10.18632/oncotarget.6740
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发表时间：
2016-02-02
期刊：
影响因子：
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通讯作者：
Thomas GJ
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文献类型：
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作者：
Hanley CJ;Noble F;Ward M;Bullock M;Drifka C;Mellone M;Manousopoulou A;Johnston HE;Hayden A;Thirdborough S;Liu Y;Smith DM;Mellows T;Kao WJ;Garbis SD;Mirnezami A;Underwood TJ;Eliceiri KW;Thomas GJ
胶原结构已被证明影响乳腺癌中肿瘤细胞的侵袭、转移和临床结果。然而，目前尚不清楚它如何影响其他实体癌。在这里，我们利用多光子激光扫描显微镜和二次谐波发生来识别头颈部、食管和结直肠癌的肿瘤间质内胶原纤维结构的改变。然后应用图像分割算法来定量表征这些形态学变化，显示伸长的胶原纤维与不良临床结果显著相关（对数秩p < 0.05）。我们使用TGF-β处理来模拟成纤维细胞转化为平滑肌肌动蛋白SMA阳性癌相关成纤维细胞（CAF），并发现这些细胞在体内诱导细长胶原纤维的形成。然而，离体培养的SMA阳性CAFs的蛋白质组学/转录组学分析显示，胶原纤维组织基因本体的基因表达具有显著的异质性。值得注意的是，发现根据基质SMA阳性和胶原纤维伸长对患者进行分层与所有3种癌症类型的生存率均极显著相关（对数秩p ≤ 0.003）。总之，我们发现胶原纤维长度增加与多种肿瘤类型患者生存率低相关，并且只有SMA阳性CAF的子集可以介导这种胶原结构的形成。
Collagen structure has been shown to influence tumor cell invasion, metastasis and clinical outcome in breast cancer. However, it remains unclear how it affects other solid cancers. Here we utilized multi-photon laser scanning microscopy and Second Harmonic Generation to identify alterations to collagen fiber structure within the tumor stroma of head & neck, esophageal and colorectal cancers. Image segmentation algorithms were then applied to quantitatively characterize these morphological changes, showing that elongated collagen fibers significantly correlated with poor clinical outcome (Log Rank p < 0.05). We used TGF-β treatment to model fibroblast conversion to smooth muscle actin SMA-positive cancer associated fibroblasts (CAFs) and found that these cells induce the formation of elongated collagen fibers in vivo. However, proteomic/transcriptomic analysis of SMA-positive CAFs cultured ex-vivo showed significant heterogeneity in the expression of genes with collagen fibril organizing gene ontology. Notably, stratifying patients according to stromal SMA-positivity and collagen fiber elongation was found to provide a highly significant correlation with poor survival in all 3 cancer types (Log Rank p ≤ 0.003). In summary, we show that increased collagen fiber length correlates with poor patient survival in multiple tumor types and that only a sub-set of SMA-positive CAFs can mediate the formation of this collagen structure.