Tumor-associated stromal cells as key contributors to the tumor microenvironment

Abstract

The tumor microenvironment is a heterogeneous population of cells consisting of the tumor bulk plus supporting cells. It is becoming increasingly evident that these supporting cells are recruited by cancer cells from nearby endogenous host stroma and promote events such as tumor angiogenesis, proliferation, invasion, and metastasis, as well as mediate mechanisms of therapeutic resistance. In addition, recruited stromal cells range in type and include vascular endothelial cells, pericytes, adipocytes, fibroblasts, and bone-marrow mesenchymal stromal cells. During normal wound healing and inflammatory processes, local stromal cells change their phenotype to become that of reactive stroma. Under certain conditions, however, tumor cells can co-opt these reactive stromal cells and further transition them into tumor-associated stromal cells (TASCs). These TASCs express higher levels of proteins, including alpha-smooth muscle actin, fibroblast activating protein, and matrix metalloproteinases, compared with their normal, non-reactive counterparts. TASCs are also known to secrete many pro-tumorigenic factors, including IL-6, IL-8, stromal-derived factor-1 alpha, vascular endothelial growth factor, tenascin-C, and matrix metalloproteinases, among others, which recruit additional tumor and pro-tumorigenic cells to the developing microenvironment. Here, we review the current literature pertaining to the origins of recruited host stroma, contributions toward tumor progression, tumor-associated stromal cells, and mechanisms of crosstalk between endogenous host stroma and tumor cells.

Keywords: Alpha-smooth muscle actin; Cancer-associated fibroblast; Exosome; IL-6; MCP-1; Mesenchymal stem cell; Myofibroblast; Stroma; Tumor microenvironment; Tumor-associated fibroblast; Tumor-associated stroma; microRNA.

Fig. 1

Tumor-associated stromal cells arise from distinct cellular sources. Tumor-associated stromal cells (TASC) have been found to arise from at least six distinct cellular origins: fibroblasts, pericytes, bone marrow MSCs, adipocytes, endothelial cells that have undergone an endothelial mesenchymal transition (EndMT), or tumor cells that have undergone a epithelial to mesenchymal transition (EMT). Transition of these cells occurs via soluble factors (SF), microRNAs (miR), exosomes (Exo), EMT, or EndMT and results in the formation of the TASC subtypes: tumor-associated fibroblasts (TAF), cancer-associated adipocytes (CAA), or cancer-associated endothelial cells (CAEC)

Fig. 2

Continuum of tumor-associated stromal cell phenotypes. We propose the existence of at least five tumor-associated fibroblast subtypes as distinguished by specific markers during the course of tumor progression: MSC-like is the least aggressive as evidenced by lack of remodeling of the extracellular tumor matrix and expression of MSC markers CD105, CD90, CD73, and CD44; Endothelial-like cells, which express CD31; Myofibroblast-like, which are more aggressive “activated” stroma and express alpha-smooth muscle actin (alpha SMA) and tenascin C (TnC); Pericyte-like, which express NG2 and platelet-derived growth factor receptor (PDGFr); and Matrix-remodeling, which are the most aggressive subtype indicated by extensive tumor matrix remodeling, increased expression of FAP and FSP1, and decreased expression of alpha-SMA