Stromal cells and integrins: conforming to the needs of the tumor microenvironment

Abstract

The microenvironment of a tumor is constituted of a heterogenous population of stromal cells, extracellular matrix components, and secreted factors, all of which make the tumor microenvironment distinct from that of normal tissue. Unlike healthy cells, tumor cells require these unique surroundings to metastasize, spread, and form a secondary tumor at a distant site. In this review, we discuss that stromal cells such as fibroblasts and immune cells including macrophages, their secreted factors, such as vascular endothelial growth factor, transforming growth factor beta, and various chemokines, and the integrins that connect the various cell types play a particularly vital role in the survival of a growing tumor mass. Macrophages and fibroblasts are uniquely plastic cells because they are not only able to switch from tumor suppressing to tumor supporting phenotypes but also able to adopt various tumor-supporting functions based on their location within the microenvironment. Integrins serve as the backbone for all of these prometastatic operations because their function as cell-cell and cell-matrix signal transducers are important for the heterogenous components of the microenvironment to communicate.

Figure 1

Summary of the microenvironment. The tumor mass microenvironment is composed of a heterogeneous mixture of stromal cells (such as fibroblasts, endothelial cells, and immune cells such as macrophages) and ECM components. The tumor mass uses these various cell types to secrete chemokines such as CXCR4/CXCL12, growth factors such as VEGF and TGF-β, and matrix-degrading proteins (MMPs) to create a prometastatic niche that supports the tumor during invasion, angiogenesis, and extravasation. In addition, integrins and their receptors mediate cellular attachment and communication.

Figure 2

The process of metastasis. The primary tumor mass secretes growth factors, cytokines, and MMPs that allow metastatic cells to invade the circulatory system and travel to distant organs such as lungs and liver. Once they extravasate into the secondary site, the tumor cells induce normal fibroblasts to assume a CAF phenotype. CAFs, in turn, recruit protumorigenic bone marrow-derived cells (BDMCs) to the microenvironment, thereby supporting the growth, proliferation, and angiogenesis of the secondary tumor.