Integrin Regulation in Immunological and Cancerous Cells and Exosomes

Abstract

Integrins represent the biologically and medically significant family of cell adhesion molecules that govern a wide range of normal physiology. The activities of integrins in cells are dynamically controlled via activation-dependent conformational changes regulated by the balance of intracellular activators, such as talin and kindlin, and inactivators, such as Shank-associated RH domain interactor (SHARPIN) and integrin cytoplasmic domain-associated protein 1 (ICAP-1). The activities of integrins are alternatively controlled by homotypic lateral association with themselves to induce integrin clustering and/or by heterotypic lateral engagement with tetraspanin and syndecan in the same cells to modulate integrin adhesiveness. It has recently emerged that integrins are expressed not only in cells but also in exosomes, important entities of extracellular vesicles secreted from cells. Exosomal integrins have received considerable attention in recent years, and they are clearly involved in determining the tissue distribution of exosomes, forming premetastatic niches, supporting internalization of exosomes by target cells and mediating exosome-mediated transfer of the membrane proteins and associated kinases to target cells. A growing body of evidence shows that tumor and immune cell exosomes have the ability to alter endothelial characteristics (proliferation, migration) and gene expression, some of these effects being facilitated by vesicle-bound integrins. As endothelial metabolism is now thought to play a key role in tumor angiogenesis, we also discuss how tumor cells and their exosomes pleiotropically modulate endothelial functions in the tumor microenvironment.

Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression

“…Inactive integrins with low affinity for the ECM ligand adopt a bent-closed conformation, whereas active integrins, capable of binding ligands with increasing affinity, adopt an extended-closed and extended-open conformation [ 268 ]. These conformations depend on activators, inactivators, and ligand interactions of the integrins [ 269 ].…”

Multifaceted roles of extracellular RNAs in different diseases

“…These overexpressed TAAs are subsequently transported to dendritic cells by EVs, accelerating CD4 + and CD8 + T-cell aggregation, infiltration, and tumor killing [ 99 ]. Conversely, during the priming of the premetastatic niche, tumor-derived exosomes have been shown to carry molecular signals important in angiogenesis and stromal remodeling for tumor cell adhesion and proliferation [ 100 ]. Exosomes hold potential in cancer therapeutics, as evident from various studies; however, further preclinical trials are necessary to consider them a viable approach [ 101 , 102 ].…”

Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers

“…We speculate that kindlin 2 may be an important molecular regulator of the tumor invasive networks to move through muscle. Recent work has highlighted emerging evidence for kindlin oligomerization and integrin clustering as mechanisms to regulate integrin function ( Bu et al, 2021 ; Soe et al, 2021 ).…”