Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression

Abstract

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.

Alternatively activated macrophages are associated with metastasis and poor prognosis in prostate adenocarcinoma

“…They concluded that a higher density of macrophages was associated with poor prognosis and that AAM was significantly associated with tumor extension. Furthermore, Comito et al (21) demonstrated that PCa cells participate in the differentiation process through secretion of monocyte chemotactic protein-1, facilitating monocyte recruitment, macrophage differentiation and M2 polarization. This complex interplay among cancer cells and AAMs contributes to increasing tumor cell motility, ultimately facilitating the escape of cancer cells from the primary tumor and metastatic spread; therefore, Comito et al (21) concluded that AAMs interact with cancerassociated fibroblasts during prostate carcinoma progression.…”

“…In addition, two recent studies have indicated that TAMs and AAMs participated in the progression of prostate cancer (19)(20)(21). However, the association between differentiation of macrophages and metastasis of prostate adenocarcinoma (PCa) is not well-established.…”

The Importance of Controlling the TGF-β Signaling Pathway in the Gastric Cancer Microenvironment

“…CAFs can be isolated from breast, prostate, pancreatic, cholangiocarcinoma, and gastric cancers, which are characterized by abundant fibrotic stroma. Conversely, CAFs are relatively rare in brain, renal, and ovarian cancers [44, [54][55][56][57][58][59][60][61]. A common theory of the origin of CAFs implicates resident tissue fibroblasts where TGF-β may promote the differentiation of fibroblasts to activated fibroblasts [62], which involves chloride intracellular channel 4 (CLIC4) [63].…”

β3-adrenoreceptor and tumor microenvironment: a new hub

“…The contribution of these cells to cancer progression has been assessed by several landmark papers. 2 CAFs have been associated with engagement of epithelial mesenchymal transition and achievement of stem like traits of cancer cells, as well as with the ability to supply energy rich nutrients to cancer cells. CAMs, that usually are polarized toward the protumoral M2 phenotype, are able to orchestrate de novo angiogenesis and, through a reciprocal interplay with CAFs, sustain pro-inflammatory signals favoring pro-metastatic behavior of cancer cells.…”

“…CAMs, that usually are polarized toward the protumoral M2 phenotype, are able to orchestrate de novo angiogenesis and, through a reciprocal interplay with CAFs, sustain pro-inflammatory signals favoring pro-metastatic behavior of cancer cells. 2 Experimental and clinical data underline a strong relationship between stress and tumor progression and the sympathetic nervous system is acknowledged to play a pivotal role in multiple steps of cancer progression, including tumor cell growth, migration, and angiogenesis. 3 Hypoxia, a very common feature of tumor microenvironment, known to induce neoangiogenesis, is also able to increase sympathetic release of norepinephrine (NE) and stress hormones, thereby concurring to increase intratumoral high NE levels.…”