Tumor Microenvironment

The tumor microenvironment (TME) refers to the area of interaction between malignant and non-transformed cells, and can contain cells of the immune system, tumor vasculature and lymphatics, fibroblasts, pericytes and sometimes adipocytes. The TME is regulated by intercellular communication via a diverse network of cytokines, chemokines, growth factors, inflammatory enzymes and matrix remodeling enzymes. Although the exact composition of the TME varies across different forms of cancer, many features are common and as such, targeting of either the cells of the TME or the mediators of cellular communication, could have therapeutic applications across a range of cancer types.

Cancer-associated fibroblasts

Cancer-associated fibroblasts (CAFs) play various roles in the TME; remodeling the extracellular matrix (ECM), inducing angiogenesis, recruiting inflammatory cells and directly stimulating cancer cell proliferation through secretion of growth factors and immunosuppressive cytokines. For example, chemokine (CXC) ligand 12 (CXCL12) from CAFs promotes the growth and survival of malignant cells.

Extracellular Matrix

The ECM is not only a physical scaffold but also plays a role in the evolution and spread of cancers. It contains key growth factors, angiogenic factors and cytokines that interact with cell surface receptors on cells of the TME. CAFs and tumor-associated macrophages (TAMs) secrete matrix metalloproteases (MMPs) that degrade ECM proteins, releasing chemokines, as well as angiogenic and growth factors.

Immune cells

Multiple cells of the immune system can be found in the TME. Although tumor associated antigens may stimulate an immune response to clear the tumor, cancers can also evade immune responses by recruiting immunosuppressive cells. For example, regulatory T-cells exert an immunosuppressive function, inhibiting the recognition and clearance of tumor cells. Similarly, TAMs are pro-tumorigenic, as well as being a major contributor to tumor angiogenesis.

Tumor vasculature

Many factors within the TME stimulate endothelial cells and neovascularization within cancer, including vascular endothelial growth factors (VEGFs), fibroblast growth factor and chemokines. VEGF-A is the predominant angiogenic factor in the TME and is produced by malignant cells and lymphocytes.