Effect of Stromal Cells in Tumor Microenvironment on Metastasis Initiation

Abstract

The cellular environment where tumor cells reside is called the tumor microenvironment (TME), which consists of borders, blood vessels, lymph vessels, extracellular matrix (ECM), stromal cells, immune/inflammatory cells, secreted proteins, RNAs and small organelles. By dynamically interacting with tumor cells, stromal cells participate in all stages of tumor initiation, progression, metastasis, recurrence and drug response, and consequently, affect the fate of patients. During the processes of tumor evolution and metastasis initiation, stromal cells in TME also experience some changes and play roles in both the suppression and promotion of metastasis, while the overall function of stromal cells is beneficial for cancer cell survival and movement. In this review, we examine the effects of stromal cells in TME on metastasis initiation, including angiogenesis, epithelial-mesenchymal transition (EMT) and invasion. We also highlight functions of proteins, RNAs and small organelles secreted by stromal cells in their influences on multiple stages of tumor metastasis.

Keywords: Breast Cancer; Metastasis Initiation; Stromal cells; TME.

Figure 1

Cells and Molecules (Grey) in TME. (A) TME and cells in TME: CAFs, MSCs, TAMs, Lymphocytes, Endothelial cells, Pericytes, Tumor cells in epithelial status and mesenchymal status. (B) The roles of CAFs in TME: Secret cytokines to affect tumor cells' fates; Remodel ECM; Immunosuppression. (C) The roles of MSCs in TME: Differentiate into other cell types; Secrete cytokines or miRNAs directly, or through exosomes; Transfer organelles through nanotubes; Are recruited by tumor cells. (D) The roles of TAMs in TME: Are recruited by other cells; Secrete cytokines or inflammatory signals to affect tumor cells' fate; Remodel ECM; Immunosuppression. (E) ECM in TME: ECM have many molecules and is remodeled by CAFs, MSCs and TAMs, while it affects the fates of tumors through integrins and other molecules.

Figure 2

The Effects of TME on Epithelial-Mesenchymal Transition. In TME, stromal cells, like CAFs, MSCs and TAMs, secrete growth factors like TGF-β, PDGF, EGF and HGF, along with miRNAs like miR21 and miR200 family, to regulate EMT through EMT transcription factors or RAS/RAF/MEK/ERK/MAPK pathway. They also secret MMPs to degrade ECM and junctions between cells and cells with ECM to “free” tumor cells. Inflammatory signals secreted by TAMs, like TNF-α and IL-6, trigger EMT through TGF-β or NF-κB pathways. Meanwhile, hypoxia produced in TME up-regulate HIFα-1 and trigger EMT through the NF-κB pathway.

Figure 3

The Effects of TME on Intravasation. Tumor cells in mesenchymal status is leaded by Vessel Associated/Tumor Associated Macrophages and invade toward the vessel wall, tumor cells in turn, recruit macrophages. Growth factors, chemokines, proteases and inflammatory factors that are secreted by stromal or tumor cells, promote the opening of junctions between endothelial cells. Factors promoting angiogenesis enhance intravasation due to the loose junction between endothelial cells and low coverage of pericytes in newly formed blood vessels.