Abstract
Integrin activity and function is classically related to the bi-directional regulation of cell-extracellular matrix (ECM) contacts that regulate a number of cell pathways linked to cell adhesion, cell detachment from ECM, cell migration, and anoikis. Interestingly, emerging data continue to uncover new roles for integrins in cancer-relevant pathways, particularly concerning the regulation of immune cell activity in the tumor niche, like myeloid cell differentiation and function and, very recently, the regulation of metastatic processes by exosomes. Exosomes are deeply involved in cell-cell communication processes and several studies have shown that integrins found in tumor-associated exosomes can promote cancer progression by two novel cooperative mechanisms: horizontal transfer of integrin transcripts as vescicle cargo, and selection of target tissues to form new tumor niches during metastatic spread by integrins carried on the exosome’s surface. In this review we will discuss mounting evidence that contribute to the development of a new picture for integrins in cancer, highlighting the role of integrins in the processes that leads to tumor niche formation. In particular, the role of the periostin pathway in the recruitment of tumor-associated macrophages, and the proposed contribution of exosome-derived integrins in the metastatic spread will be discussed. Finally, in light of the above considerations, an evaluation of integrins as possible therapeutic targets will be conducted.
Highlights
Integrin activity and function is classically related to the bi-directional regulation of cell-extracellular matrix (ECM) contacts that regulate a number of cell pathways linked to cell adhesion, cell detachment from ECM, cell migration, and anoikis
ECM ligands binding to integrins leads to integrin clustering and the subsequent activation of a downstream non-receptor tyrosine kinase, focal adhesion kinase (FAK), which initiates a series of signaling pathways
Other evidence shows that the different expression of exosomal integrins can direct metastatic niche formation and, eventually, organ-specific metastasis spread
Summary
The physiological role of integrin receptors in the life of a cell is complex, involving cellular pathways that are interconnected and contribute to cell migration and cell survival; as a consequence, the role of integrins in numerous pathologies appears to be very relevant. ECM ligands binding to integrins leads to integrin clustering and the subsequent activation of a downstream non-receptor tyrosine kinase, focal adhesion kinase (FAK), which initiates a series of signaling pathways. FAK signaling, via the IP3 pathway, leads to Akt activation and inhibition of pro-apoptotic pathways. Taken together, these studies highlight two features regulated by integrins that turn to be essential to cancer cell survival and cancer progression: regulation of cell adhesion and cell migration mechanisms and regulation of survival signals. Have emphasized the role of integrins in the development and progression of this tumor type, prompting the use of Cilengitide, the first integrin antagonist to be synthesized, in clinical trials in association with chemotherapeutic drugs. The finding that αvβ, α5β1, and αvβ integrins have been found in lung cancer lymph node metastasis, together with the observation that bone metastatic cells in advanced prostate cancer express αvβ integrin, led to the proposal that specific integrin expression could represent a reliable prognostic marker of overall survival in some cancer types [4,5,6]
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