Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts

Abstract

Much interest is currently focused on the emerging role of tumorstroma interactions essential for supporting tumor progression. Carcinoma-associated fibroblasts (CAFs), frequently present in the stroma of human breast carcinomas, include a large number of myofibroblasts, a hallmark of activated fibroblasts. These fibroblasts have an ability to substantially promote tumorigenesis. However, the precise cellular origins of CAFs and the molecular mechanisms by which these cells evolve into tumor-promoting myofibroblasts remain unclear. Using a coimplantation breast tumor xenograft model, we show that resident human mammary fibroblasts progressively convert into CAF myofibroblasts during the course of tumor progression. These cells increasingly acquire two autocrine signaling loops, mediated by TGF-β and SDF-1 cytokines, which both act in autostimulatory and cross-communicating fashions. These autocrine-signaling loops initiate and maintain the differentiation of fibroblasts into myofibroblasts and the concurrent tumor-promoting phenotype. Collectively, these findings indicate that the establishment of the self-sustaining TGF-β and SDF-1 autocrine signaling gives rise to tumor-promoting CAF myofibroblasts during tumor progression. This autocrine-signaling mechanism may prove to be an attractive therapeutic target to block the evolution of tumor-promoting CAFs.CXCR4 | Smad | tumor microenvironment | alpha-smooth muscle actin M yofibroblasts are often observed in the stroma of various human carcinomas that include those of the breast (1). The presence of these cells in large numbers is also associated with higher-grade malignancy and poor prognosis in patients (2-4). Myofibroblasts express α-smooth muscle actin (α-SMA) that distinguishes these cells from fibroblasts and represents a hallmark of activated fibroblasts (5-10). The activated myofibroblast state of stromal fibroblasts also correlates with their ability to promote tumor growth (11)(12)(13)(14). Although different types of mesenchymal cells and epithelial cells are proposed to be precursors of the myofibroblasts present in tumors (15-20), their precise cellular origins and functional contributions to tumor growth still remain unclear.In recent years, the tumor-promoting roles of stromal fibroblasts and α-SMA-positive myofibroblasts, collectively termed carcinoma-associated fibroblasts (CAFs), have been studied (21). CAFs, when inoculated with carcinoma cells, have potently promoted the in vivo proliferation of carcinoma cells and tumor growth in mouse xenograft models (14,(21)(22)(23)(24)(25). We previously demonstrated that CAFs, prepared directly from invasive human mammary carcinomas, contain substantial numbers of myofibroblasts that secrete elevated levels of the proangiogenic chemokine, stromal cell-derived factor-1 (SDF-1, also called CXCL12) (14). SDF-1 signaling via its cognate receptor CXCR4, expressed on the surface of carcinoma cells, directly boosts the proliferation of these cells and can stimulate neoangiogenesis by recruiting circulating endot...

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…While it is conceivable that such paracrine signalling mechanisms that activate fibroblasts in vivo could be derived from immune cells, there is also evidence indicating direct regulation by neoplastic cells: co-culture of fibroblasts with either melanoma cells or oral squamous cell carcinoma cells induces pro-inflammatory gene expression in fibroblasts that includes CXCL1 and CXCL2 [59,60]. Activation of CAFs can also be accelerated by autocrine signalling: Kojima et al reported that autocrine TGF-β and SDF-1α/CXCL12 chemokine signalling result in activation of mammary CAFs, but the in vivo molecular signals that trigger these inflammatory pathways in CAFs remain unknown [61]. TGF-β and SDF-1α/CXCL12 may have an additional role in the recruitment of pro-inflammatory CAFs from bone marrow: In a model of induced gastric cancer, Quante et al reported that CAFs recruited into gastric tumours from bone marrow express a pro-inflammatory gene signature that includes CXCL1, CCL5, OPN, IL-6, IL-1β, CXCL12, and TNF-α [40].…”

TGFβ1 regulates HGF‐induced cell migration and hepatocyte growth factor receptor MET expression via C‐ets‐1 and miR‐128‐3p in basal‐like breast cancer

“…In breast cancer, TGFβ1 is upregulated compared to its adjacent nonmalignant tissue and it impacts on various cells of the tumor microenvironment. In the tumor stroma, TGFβ1 gets secreted by tumor‐associated macrophages and CAFs (Kojima et al ., 2010; Yu et al ., 2014). It has been shown that TGFβ1 directly acts on the basal‐like breast tumor cell line MDA‐MB‐231 and that this drives metastatic processes of breast cancer cells by its binding to TGFBR2 (Willis et al ., 2015).…”

CAF-like state in primary skin fibroblasts with constitutional BRCA1 epimutation sheds new light on tumor suppressor deficiency-related changes in healthy tissue

“…19 A huge variety of cell types such as epithelial cells, mesenchymal stem cells, resident fibroblasts or endothelial cells have been reported to be able to transdifferentiate into CAFs through epithelial-mesenchymal transition (EMT), mesothelial-to-mesenchymal transition (MMT), or endothelial-mesenchymal transition (EndMT). [20][21][22][23][24] All these models for CAF development assume exogenous stimuli that initiate transformation and, in most cases, are thought to be sent from adjacent cancer cells in form of growth factors, such as TGF-ß and CXCL12. 23 There is experimental evidence that the CAF phenotype can also be initiated by intrinsic factors.…”

“…[20][21][22][23][24] All these models for CAF development assume exogenous stimuli that initiate transformation and, in most cases, are thought to be sent from adjacent cancer cells in form of growth factors, such as TGF-ß and CXCL12. 23 There is experimental evidence that the CAF phenotype can also be initiated by intrinsic factors. In particular depletion of tumor suppressor genes was reported to convert normal fibroblasts to CAFs.…”