Extracellular matrix and its therapeutic potential for cancer treatment

Abstract

The extracellular matrix (ECM) is one of the major components of tumors that plays multiple crucial roles, including mechanical support, modulation of the microenvironment, and a source of signaling molecules. The quantity and cross-linking status of ECM components are major factors determining tissue stiffness. During tumorigenesis, the interplay between cancer cells and the tumor microenvironment (TME) often results in the stiffness of the ECM, leading to aberrant mechanotransduction and further malignant transformation. Therefore, a comprehensive understanding of ECM dysregulation in the TME would contribute to the discovery of promising therapeutic targets for cancer treatment. Herein, we summarized the knowledge concerning the following: (1) major ECM constituents and their functions in both normal and malignant conditions; (2) the interplay between cancer cells and the ECM in the TME; (3) key receptors for mechanotransduction and their alteration during carcinogenesis; and (4) the current therapeutic strategies targeting aberrant ECM for cancer treatment.

Fig. 1

Schematic illustration of ECM components in normal tissue (left) and the TME (right). Matrix stiffness is mainly related to excessive collagen and HA within TME. Both cancer cells and fibroblasts contribute to the remodeling of the ECM during its stiffness, fundamentally influencing many critical biological processes during the development of cancer

Fig. 2

The signaling loop formed by cancer cells, macrophages and fibroblasts contributes to ECM stiffness, in which TGF-β plays a central role

Fig. 3

Intracellular signaling network triggered by TGF-β and CXCL12, two critical factors inducing ECM stiffness

Fig. 4

Crucial biological processes affected by ECM stiffness for cancer

Fig. 5

Schematic summary of key membrane receptors recognizing ECM components and their downstream signaling networks