Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer

Abstract

The extracellular matrix (ECM) provides structural and biochemical signals that regulate cell function. A well-controlled balance between cells and surroundings (i.e., dynamic reciprocity) is crucial for regulating ECM architecture. During cancer progression, epithelial cells undergo genetic alterations which, together with stromal changes including ECM remodeling, disturb the homeostatic dynamics of the epithelium. A parallel organization of stromal ECM fibrils is associated with tumorigenic responses. In an emerging paradigm, continuous and progressive regulation via mechanical forces and aberrant signaling are believed to be responsible for tumor-associated ECM remodeling. In this review we discuss the discrete biomechanical and biochemical mechanisms that underlie these architectural changes and highlight their particular relevance to the regulation of the alignment of ECM in the mesenchymal stroma.

Keywords: Rho–ROCK; biomechanical and biochemical cues; cell–ECM dynamic reciprocity; desmoplasia; extracellular matrix; integrins.

Box 1-Fig I

Stromal ECM fiber remodeling stages. (A) Schematic diagram representing progressive remodeling within collagen fibers of ECM during tumorigenesis. (B) Micrographs acquired using multiphoton laser scanning microscopy illustrating TACS in Wnt-1 mouse breast cancer model. Reproduced and modified from open access available [13]. (C) Representative reconstituted confocal images obtained from in vitro fibroblast-derived ECM associated with murine squamous cell carcinoma. Reproduced and modified with permission from [17].

Box 2-Fig. I

Schematic diagram illustrating the “Dynamic Reciprocity” leading, maintaining and further expanding desmoplastic ECM alignment.