Beyond proteases: Basement membrane mechanics and cancer invasion

Abstract

In epithelial cancers, cells must invade through basement membranes (BMs) to metastasize. The BM, a thin layer of extracellular matrix underlying epithelial and endothelial tissues, is primarily composed of laminin and collagen IV and serves as a structural barrier to cancer cell invasion, intravasation, and extravasation. BM invasion has been thought to require protease degradation since cells, which are typically on the order of 10 µm in size, are too large to squeeze through the nanometer-scale pores of the BM. However, recent studies point toward a more complex picture, with physical forces generated by cancer cells facilitating protease-independent BM invasion. Moreover, collective cell interactions, proliferation, cancer-associated fibroblasts, myoepithelial cells, and immune cells are all implicated in regulating BM invasion through physical forces. A comprehensive understanding of BM structure and mechanics and diverse modes of BM invasion may yield new strategies for blocking cancer progression and metastasis.

Chemically defined human vascular laminins for biologically relevant culture of hiPSC-derived brain microvascular endothelial cells

“…Laminins, of which there are at least 16 isoforms that exhibit tissue and developmental stage specificity [19], are major players in physiological endothelial-BM interactions. While the laminin network closely interacts with the receptors on the cell surface and is the only required component for BM assembly and formation [20], the type IV collagen network stabilizes the BM and protects it from mechanical stress [21,22]. Interestingly, the BM composition of the BBB and the expression of integrins on the BMECs change during development.…”

Plasticity of cancer cell invasion: Patterns and mechanisms

“…In contrast to amoeboid movement, mesenchymal migration depends on the proteolytic degradation of ECM [ 28 , 36 ]. Cells recruit surface proteases to an anterior adhesion site at the leading edge, which is an active zone for removing the ECM structures and barriers [ 37 ]. Matrix metalloproteinases (MMPs) and other proteases proteolytically digest the ECM molecules and generate cell migration tracks for disseminated cancer cells [ 28 , 36 ].…”

Framing cancer progression: influence of the organ‐ and tumour‐specific matrisome

“…1 kPa in breast tumours and is most prominent in pancreatic tumours (ca. 10 kPa) . Solid stress leads to compression of blood vessels and, consequently, to hypoxia.…”

“…Another change accompanying carcinomas growth is a disintegration of the underlying basement membrane due to the secretion of MMPs by invading cancer cells , which serves as a poor prognosis marker in several cancer types (e.g., breast, colorectal, prostate) .…”