Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
Histology and Molecular Diagnostic University Careggi Hospital, University of Florence, Florence, Italy.
Oncogene. 2014 May 8;33(19):2423-31. doi: 10.1038/onc.2013.191. Epub 2013 Jun 3.
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.
炎症现在被认为是癌症的一个标志。癌症相关成纤维细胞（CAFs）迫使癌细胞发生恶性串扰，最终导致上皮-间充质转化和获得干性特征。在此，我们证明基质肿瘤相关细胞共同促进前列腺癌（PCa）的恶性进展。事实上，前列腺 CAFs 是向肿瘤细胞募集单核细胞的活跃因子，主要通过基质衍生生长因子-1 的传递来发挥作用，并促进其向 M2 巨噬细胞表型的转分化。M2 巨噬细胞和 CAFs 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 参与这种串扰，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、CAFs 和 M2 巨噬细胞之间的这种复杂相互作用，共同增加了肿瘤细胞的迁移能力，最终促进了癌细胞从原发肿瘤和转移扩散的逃逸，以及激活内皮细胞及其骨髓来源前体以驱动新血管生成。与我们在体外获得的数据一致，对处于不同临床阶段的前列腺癌患者的分析显示，M2/M1 比值明显增加，与临床值相关。这些数据，加上 CAFs 在癌恶性中的作用，以引发干性特征的表达，应该引起人们对靶向炎症细胞和成纤维细胞的创新策略的极大兴趣，以提高治疗效果。
