Stromal Fibroblasts in Cancer: A Novel Tumor-Promoting Cell Type

Abstract

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.

Prostate Cancer Increases Hyaluronan in Surrounding Nonmalignant Stroma, and This Response Is Associated with Tumor Growth and an Unfavorable Outcome

“…19,20 Adaptions in the surrounding stroma, in part mediated by macrophages recruited to the tissue around tumors, 20 such as growth of the supporting vasculature and tissue remodulation are probably necessary for subsequent tumor growth and metastasis. 19 -21 Such responses in tumor-adjacent nonmalignant tissues are morphologically similar to those seen around wounds, 8,51 and the gene expression in the normal rat prostate tissue surrounding an implanted AT-1 prostate cancer is similar to that in wounding and inflammation (Adamo et al, unpublished data). Tumors apparently are able to stimulate HA synthesis, either directly or through recruiting inflammatory cells, in surrounding cells and as the tumor expands previously nonmalignant stroma becomes integrated into the tumor stroma, probably explaining why the tumor stroma and nonmalignant tissue stroma show similar changes in HA staining.…”

A role for the podosome/invadopodia scaffold protein Tks5 in tumor growth in vivo

“…This not only fulfills a spatial requirement for tumor growth, but also allows the tumor to attract various cells from the microenvironment that provide favorable conditions for tumor growth, such as endothelial cells, fibroblasts and macrophages (Bingle et al, 2002;Orimo and Weinberg, 2006). Previously it has been shown that various types of human cancer cells form invadopodia.…”

CXCR4 signaling in the regulation of stem cell migration and development

“…Clearly it is important to identify the factors that help to enhance the growth and "health" of tumors and also contribute to their further distribution. Considerable evidence now suggests that chemokine signaling, and CXCR4 signaling in particular, can contribute to both of these phenomena (Kucia et al, 2005a;Orimo et al, 2005;Orimo and Weinberg, 2006). First SDF-1 is produced by many tumors where it can have autocrine growth promoting effects on the developing tumor and also enhance the growth of blood vessels that are important for further tumor growth and development indicating a key role for CXCR4 (or possibly CXCR7).…”