Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis.
Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis.
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DOI：
10.18632/aging.101127
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发表时间：
2016-12-15
期刊：
影响因子：
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通讯作者：
Thomas GJ
中科院分区：
文献类型：
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作者：
Mellone M;Hanley CJ;Thirdborough S;Mellows T;Garcia E;Woo J;Tod J;Frampton S;Jenei V;Moutasim KA;Kabir TD;Brennan PA;Venturi G;Ford K;Herranz N;Lim KP;Clarke J;Lambert DW;Prime SS;Underwood TJ;Vijayanand P;Eliceiri KW;Woelk C;King EV;Gil J;Ottensmeier CH;Thomas GJ
癌症相关成纤维细胞（CAF）仍然是一种特征不佳的异质细胞群。在这里，我们描述了两个先前描述的肿瘤促进CAF亚型，平滑肌肌动蛋白（SMA）阳性肌成纤维细胞和衰老成纤维细胞，确定了两者之间的新联系。对离体培养的CAF的分析显示，衰老的CAF主要是SMA阳性的;这通过头颈部（HNSCC）和食管（EAC）癌中的免疫化学证实。在体外，我们发现诱导衰老的成纤维细胞发展成肌成纤维细胞典型的分子、超微结构和收缩特征，这依赖于典型的TGF-β信号传导。与TGF-β1产生的肌成纤维细胞类似，这些细胞分泌促进肿瘤细胞运动的可溶性因子。然而，RNA测序显示两个SMA阳性CAF组之间存在显著的转录组差异，特别是在与细胞外基质（ECM）沉积和组织相关的基因中，这些基因差异性地促进肿瘤细胞侵袭。值得注意的是，SMA阳性人HNSCC和EAC的二次谐波成像和生物信息学分析显示，胶原纤维组织与不良预后相关，表明SMA阳性CAF群体内的异质性对存活率有差异性影响。这些结果表明，非纤维化的SMA阳性肌成纤维细胞可以通过诱导成纤维细胞衰老直接产生，并表明衰老和肌成纤维细胞分化是密切相关的过程。
Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-β signaling. Similar to TGF-β1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes.