Extracellular matrix in cancer progression and therapy

Abstract

The tumor ecosystem with heterogeneous cellular compositions and the tumor microenvironment has increasingly become the focus of cancer research in recent years. The extracellular matrix (ECM), the major component of the tumor microenvironment, and its interactions with the tumor cells and stromal cells have also enjoyed tremendously increased attention. Like the other components of the tumor microenvironment, the ECM in solid tumors differs significantly from that in normal organs and tissues. We review recent studies of the complex roles the tumor ECM plays in cancer progression, from tumor initiation, growth to angiogenesis and invasion. We highlight that the biomolecular, biophysical, and mechanochemical interactions between the ECM and cells not only regulate the steps of cancer progression, but also affect the efficacy of systemic cancer treatment. We further discuss the strategies to target and modify the tumor ECM to improve cancer therapy.

Keywords: cancer invasion; cancer metabolism; cancer progression; cancer therapy; cell-ECM interaction; extracellular matrix; metastasis.

Figure 1:

The ECM as a regulator of tumor progression and therapy. (1) Adhesion to the ECM through the receptors (e.g., via integrin or discoidin domain receptor) promotes signaling that supports cancer cell survival. To supply metabolic pathways, cancer cells can use the ECM (laminin and fibronectin), internalized with an integrin. (2) Growth factors that are released upon cleavage by ECM proteases (mainly MMPs) can regulate cancer cells and other cells of the TME. Biologically active ECM fragments (peptides) released upon proteolysis can promote cell signaling in the TME and spread with the blood flow. (3) Recruitment of activated fibroblasts stimulates ECM production, alignment, and cross‐linking (e.g., by LOX) of collagen fibrils resulting in fibrosis. Changes in mechanical properties can prompt cancer cells to adapt their signaling, gene expression, and cytoskeleton polarization, acquiring invasive phenotype (EMT). (4) Dense and rigid ECM creates a barrier to drug and T-cell penetration. Targeted cancer cells and fibroblasts can increase their resistance by promoting ECM production and deposition. Changes in the tumor ECM are associated with the formation of a tumor‐permissive immune profile (Figure reproduced with permission [42]).

Figure 2:

Four ways the ECM affects the efficacy of systemic treatment and immunotherapy. (A) The abundant, rigid, and dense ECM is a diffusion barrier for drug molecules, thus shielding the tumor from the tumor therapy agents and T cells. (B) The ECM also reduces the diffusion of nutrients and oxygen, resulting in a hypoxic and stressful TME. Tumor cells increase the expression of drug efflux pumps, impair apoptosis and senescence, and activate and activate immunosuppressive signaling, rendering drugs that reach the cells less effective. (C) The cell-ECM contact mediated by integrin and FAK signaling inhibits the cytotoxic stress response that avoids cell cycle arrest. (D) Similarly, integrin, FAK, and hyaluronan-induced CD44/HMMR signals can lead to EMT. The mesenchymal state is less proliferative and more chemoresistant. The EMT further increases collagen production and crosslinking (Adapted from Henke et al. [41] with permission).