The role of tumor microenvironment in resistance to anti-angiogenic therapy

Abstract

Anti-angiogenic therapy has been demonstrated to increase progression-free survival in patients with many different solid cancers. Unfortunately, the benefit in overall survival is modest and the rapid emergence of drug resistance is a significant clinical problem. Over the last decade, several mechanisms have been identified to decipher the emergence of resistance. There is a multitude of changes within the tumor microenvironment (TME) in response to anti-angiogenic therapy that offers new therapeutic opportunities. In this review, we compile results from contemporary studies related to adaptive changes in the TME in the development of resistance to anti-angiogenic therapy. These include preclinical models of emerging resistance, dynamic changes in hypoxia signaling and stromal cells during treatment, and novel strategies to overcome resistance by targeting the TME.

Keywords: MET signaling; anti-angiogenic therapy; drug resistance; tumor microenvironment.

Figure 1.. Schematic illustration of the role of the tumor microenvironment in resistance to anti-angiogenic therapy.

Anti-angiogenic therapy inhibits tumor growth by reducing vessel density; however, the subsequent hypoxia and the responsive genes can cause resistance to such therapy. The hypoxia-related metabolic symbiosis, invasion and metastasis, vessel co-option, and vasculogenic mimicry (VM) lead to resistance to anti-angiogenic therapy. The recruitment of stromal cells also plays a critical role in resistance to anti-angiogenic therapy. Ang1/2, angiopoietin 1/2; CXCR4, C-X-C chemokine receptor type 4; EMT, epithelial-to-mesenchymal transition; EphA2, Eph receptor A2; FAK, focal adhesion kinase; FGF, fibroblast growth factor; GLUT1, glucose transporter-1; HGF, hepatocyte growth factor; HIF-1α, hypoxia-inducible factor 1α; IGF, insulin-like growth factor; LIAS, lipoic acid synthase; MCT4, monocarboxylate transporter 4; MDSC, myeloid-derived suppressor cell; MIF, macrophage migration inhibitory factor; mTOR, mammalian target of rapamycin; mtROS, mitochondria reactive oxygen species; OGDH, oxoglutarate dehydrogenase; PDGF, platelet-derived growth factor; PECAM, platelet endothelial cell adhesion molecule; SDF1, stromal cell-derived factor 1; TEM; Ties-expressing macrophage; Treg, regulatory T cell; VE-cadherin, vascular endothelial cadherin; VEGF, vascular endothelial growth factor.