Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression
Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression
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DOI：
10.1038/onc.2013.191
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发表时间：
2014-05-08
期刊：
影响因子：
8
通讯作者：
Chiarugi, P.
中科院分区：
文献类型：
--
作者：
Comito, G.;Giannoni, E.;Chiarugi, P.
炎症现在被认为是癌症的标志。癌症相关成纤维细胞（CAF）与癌细胞发生恶性串扰，最终导致上皮-间充质转化和干细胞特征的实现。在此，我们证明了间质肿瘤相关细胞的合作，有利于恶性前列腺癌（PCa）。事实上，前列腺CAF是单核细胞向肿瘤细胞募集的活性因子，主要通过基质衍生生长因子-1递送起作用，并促进它们向M2巨噬细胞表型的转分化。M2巨噬细胞和CAF之间的关系是相互的，因为M2巨噬细胞能够影响成纤维细胞的间充质-间充质转化，导致其反应性增强。另一方面，PCa细胞本身通过分泌单核细胞趋化蛋白-1参与这种相互作用，促进单核细胞募集并再次促进巨噬细胞分化和M2极化。最后，癌细胞、CAF和M2巨噬细胞之间的这种复杂的相互作用协同增加肿瘤细胞运动性，最终促进癌细胞逃离原发性肿瘤和转移性扩散，以及激活内皮细胞及其骨髓源性前体以驱动新生血管生成。与我们在体外获得的数据一致，对不同临床阶段前列腺癌患者的分析显示，M2/M1比值与临床值相关，明显增加。这些数据，再加上CAF在恶性肿瘤中引起干细胞样性状表达的作用，应该对旨在共同靶向炎性细胞和成纤维细胞以提高治疗效果的创新策略产生极大的兴趣。
Inflammation is now acknowledged as an hallmark of cancer. Cancer-associated fibroblasts (CAFs) force a malignant cross talk with cancer cells, culminating in their epithelial-mesenchymal transition and achievement of stemness traits. Herein, we demonstrate that stromal tumor-associated cells cooperate to favor malignancy of prostate carcinoma (PCa). Indeed, prostate CAFs are active factors of monocyte recruitment toward tumor cells, mainly acting through stromal-derived growth factor-1 delivery and promote their trans-differentiation toward the M2 macrophage phenotype. The relationship between M2 macrophages and CAFs is reciprocal, as M2 macrophages are able to affect mesenchymal-mesenchymal transition of fibroblasts, leading to their enhanced reactivity. On the other side, PCa cells themselves participate in this cross talk through secretion of monocyte chemotactic protein-1, facilitating monocyte recruitment and again macrophage differentiation and M2 polarization. Finally, this complex interplay among cancer cells, CAFs and M2 macrophages, cooperates in increasing tumor cell motility, ultimately fostering cancer cells escaping from primary tumor and metastatic spread, as well as in activation of endothelial cells and their bone marrow-derived precursors to drive de novo angiogenesis. In keeping with our data obtained in vitro, the analysis of patients affected by prostate cancers at different clinical stages revealed a clear increase in the M2/M1 ratio in correlation with clinical values. These data, coupled with the role of CAFs in carcinoma malignancy to elicit expression of stem-like traits, should focus great interest for innovative strategies aimed at the co-targeting of inflammatory cells and fibroblasts to improve therapeutic efficacy.