Integrin receptors within hyaluronan-rich extracellular matrix complexes (Integrin-HA ECM complex)

Integrins are a family of heterodimeric transmembrane receptors that mediate cell-matrix and cell-cell interactions, playing a pivotal role in sensing the physical and chemical properties of the extracellular matrix (ECM) (Hynes, R. O., 2002, Cell). In many pathological states, particularly in solid tumors and chronic inflammation, the ECM becomes enriched with hyaluronan (HA), a large glycosaminoglycan that forms a dense, hydrated scaffold (Pedron, S., et al., 2013, Biomaterials). Within these HA-rich complexes, integrins such as alpha-v-beta-3 and alpha-5-beta-1 cooperate with HA receptors like CD44 to promote cell survival, proliferation, and invasive migration (Kim, S. H., et al., 2011, Journal of Biological Chemistry). This synergy facilitates mechanotransduction, where the physical stiffness of the HA-rich matrix triggers intracellular signaling pathways like the PI3K/Akt and MAPK cascades (Paszek, M. J., et al., 2005, Cancer Cell). Therapeutically, targeting integrins within this specific context aims to disrupt the pro-survival signals provided by the tumor microenvironment and enhance the delivery of chemotherapeutic agents by reducing interstitial fluid pressure (Ley, K., et al., 2016, Nature Reviews Drug Discovery). Current drug development focuses on monoclonal antibodies and small molecule inhibitors that block integrin binding to ECM ligands or disrupt the assembly of these multi-protein signaling hubs.

Other names

Integrin-hyaluronan signaling axisHA-ECM-integrin complexPericellular hyaluronan-integrin clustersIntegrin-CD44-HA complex

Competitive inhibition of ligand binding to the integrin extracellular domain, disruption of integrin clustering within the hyaluronan-rich glycocalyx, and inhibition of downstream focal adhesion kinase (FAK) signaling.