Stromal cells in tumor microenvironment and breast cancer

Abstract

Cancer is a systemic disease encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion, and metastasis. In breast cancer, CAFs not only promote tumor progression but also induce therapeutic resistance. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistance. This review summarizes the current understandings of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. In addition, the effects of other stromal components such as endothelial cells, macrophages, and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to categorize patients into a specific and confirmed subtype for personalized treatment.

Figure 1. The origin of CAFs

Schematic of cells that may transit to (arrows) CAFs. Abbreviations: CAF, cancer-associated fibroblast; NAF, normal tissue derived fibroblast; MDSC, mesenchymal derived stem cell; EC, endothelial cell; EMT, epithelial mesenchymal transition; EndoMT, endocrine mesenchymal transition; ASC, adipose tissue-derived stem cells.

Figure 2. Schematic representation showing the role of stroma cells in microenvironment and breast cancer progression

The tumor microenvironment is a dynamic composite of cells broadly categorized as multiple components of no-stroma and stroma cells, where tumor cells thrive. Stroma cells promote tumor growth, invasion, and metastasis by secreting multiple cytokines, chemokines and other growth factors, et al. Moreover, tumor cells also affect the phenotype of stroma cells. Obviously, the tumor and stroma cell interactions are truly reciprocal; while stroma cells may support tumors, tumor cells in turn modulate the microenvironments within which they inside. Abbreviations: SDF-1, stroma-derived factor; TNF- α, tumor necrosis factor; TGF-β, transforming growth factor-β; NF-κB, nuclear factor κB; MMP-7,9,11 matrixmetalloproteinase-2,9; α-SMA, alpha smooth muscle actin; FAP , fibroblast activation protein; FSP-1, fibroblast specific protein; PDGFR-α/β, platelet-derived growth factor-α/β; FGF, fibroblast growth factor; Cav-1, caveolin-1; IL-1,4,6,10,13, interleukin -1,4,6,10,13; E2, estrone -E2; CCL2, 5, 18, chemokine ligand 2, 5, 18; RANKL , nuclear factor-κB (RANK) ligand; CSF-1, colony stimulating factor-1; COLVI , collagen VI; VEGF, vascular endothelial growth factor; HGF, hepatocyte growth factor.