Fibroblasts often constitute the majority of the stromal cells within a breast carcinoma, yet the functional contributions of these cells to tumorigenesis are poorly understood. Using a coimplantation tumor xenograft model, we demonstrate that carcinoma-associated fibroblasts (CAFs) extracted from human breast carcinomas promote the growth of admixed breast carcinoma cells significantly more than do normal mammary fibroblasts derived from the same patients. The CAFs, which exhibit the traits of myofibroblasts, play a central role in promoting the growth of tumor cells through their ability to secrete stromal cell-derived factor 1 (SDF-1); CAFs promote angiogenesis by recruiting endothelial progenitor cells (EPCs) into carcinomas, an effect mediated in part by SDF-1. CAF-secreted SDF-1 also stimulates tumor growth directly, acting through the cognate receptor, CXCR4, which is expressed by carcinoma cells. Our findings indicate that fibroblasts within invasive breast carcinomas contribute to tumor promotion in large part through the secretion of SDF-1.

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...

Tumors are highly complex tissues composed of neoplastic cells and, in the case of carcinomas, stromal cell compartments containing a variety of mesenchymal cells, notably fibroblasts, myofibroblasts, endothelial cells, pericytes, and a variety of inflammatory cells associated with the immune system. Fibroblasts and myofibroblasts often represent the majority of the stromal cells within various types of human carcinomas, yet the specific contributions of these cells to tumor growth are poorly understood. Recent work has demonstrated that stromal fibroblast fractions, named carcinoma-associated fibroblasts (CAFs), that have been extracted from a number of invasive human breast carcinomas are more competent to promote the growth of mammary carcinoma cells and to enhance tumor angiogenesis than are comparable cells derived from outside of these tumor masses. CAFs include large populations of myofibroblasts that secrete elevated levels of stromal cell-derived factor 1 (SDF-1), also called CXCL12, which plays a central role in the promotion of tumor growth and angiogenesis; CAF-derived SDF-1 not only stimulates carcinoma cell growth directly through the CXCR4 receptor displayed on tumor cells but also serves to recruit endothelial progenitor cells (EPCs) into tumors, thereby furthering neoangiogenesis. In this review, we highlight the importance of this SDF-1-CXCR4 signaling pathway in the tumor microenvironment and discuss the mechanisms by which stromal fibroblasts within mammary carcinomas enhance tumor growth.