Integrins as therapeutic targets in the organ-specific metastasis of human malignant melanoma

Abstract

Integrins are a large family of adhesion molecules that mediate cell-cell and cell-extracellular matrix interactions. Among the 24 integrin isoforms, many have been found to be associated with tumor angiogenesis, tumor cell migration and proliferation, and metastasis. Integrins, especially αvβ3, αvβ5 and α5β1, participate in mediating tumor angiogenesis by interacting with the vascular endothelial growth factor and angiopoietin-Tie signaling pathways. Melanoma patients have a poor prognosis when the primary tumor has generated distant metastases, and the melanoma metastatic site is an independent predictor of the survival of these patients. Different integrins on the melanoma cell surface preferentially direct circulating melanoma cells to different organs and promote the development of metastases at specific organ sites. For instance, melanoma cells expressing integrin β3 tend to metastasize to the lungs, whereas those expressing integrin β1 preferentially generate lymph node metastases. Moreover, tumor cell-derived exosomes which contain different integrins may prepare a pre-metastatic niche in specific organs and promote organ-specific metastases. Because of the important role that integrins play in tumor angiogenesis and metastasis, they have become promising targets for the treatment of advanced cancer. In this paper, we review the integrin isoforms responsible for angiogenesis and organ-specific metastasis in malignant melanoma and the inhibitors that have been considered for the future treatment of metastatic disease.

The role of integrins in melanoma: a review

“…Although the biology and behavior of tumor cells at the primary site have been studied extensively, an interesting area of upcoming research focuses on the cellular events in the metastatic niche. As recently discussed by Huang and Rofstad, 44 it is now well known that the site of distant metastasis is not random. A complex interaction between the mediators released by the primary tumor and changes at the metastatic niche determine the site of metastasis.…”

“…In addition to their role in primary tumor growth, integrins are also important mediators of metastasis 28 . They are involved in multiple steps that help in tumor spread: (i) degradation of the basement membrane barrier for tumor cells, 29‐35 (ii) angiogenesis for tumor survival at the primary site, 36‐39 (iii) as integral components of exosomes (small extracellular molecules detached from the primary tumor into the circulation), 40‐43 (iv) intravasation of tumor cells into the circulation, 36 and (v) implantation at the metastatic niche 44,45 …”

Recent progress in biomedical applications of RGD‐based ligand: From precise cancer theranostics to biomaterial engineering: A systematic review

“…Several CTPs have identified using biological strategy such as arginine-glycine-aspartic acid (RGD) peptide-a motif of extracellular proteins (e.g., vitronectin and fibronectin) which interact with integrin receptors (Bellis, 2011) and substance P (SP)-a natural ligand peptide with a specific receptor which interact with neurokinin 1 receptors (Covenas & Munoz, 2014). αvβ3 receptor, which is overexpressed on the surface of some cancerous cells and activated endothelial cells of tumor neovasculature, is used as a target to deliver therapeutic or diagnostic agents specifically into cancerous cells (Huang & Rofstad, 2018). Among the integrin receptors, αvβ3 and αIIbβ3 integrins are the ones which overexpressed on the surface of cancerous cells and platelets, respectively.…”

“…Among the integrin receptors, αvβ3 and αIIbβ3 integrins are the ones which overexpressed on the surface of cancerous cells and platelets, respectively. αvβ3 receptor, which is overexpressed on the surface of some cancerous cells and activated endothelial cells of tumor neovasculature, is used as a target to deliver therapeutic or diagnostic agents specifically into cancerous cells (Huang & Rofstad, 2018). Figure 1 shows the interaction between RGD peptide with αvβ3 receptor (Yu et al, 2014).…”

Novel Pure αVβ3 Integrin Antagonists That Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis at Low Concentrations

“…On the other hand, TDI-4161 and TDI-3761 were less effective at inhibiting angiogenesis than cilengitide, with only TDI-3761 demonstrating significant inhibition at 1 µM. This may be due to cilengitide's inhibition of αVβ5 in addition to αVβ3 since αVβ5 has also been implicated in contributing to angiogenesis; 77 TDI-4161 and TDI-3761 are more specific for αVβ3. Thus, whether TDI-4161 and TDI-3761's differences in inducing and inhibiting angiogenesis from cilengitide will translate into improved therapy of malignancy remains to be established in additional animal models and human studies.…”