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.

Selective delivery of PLXDC1 small interfering RNA to endothelial cells for anti-angiogenesis tumor therapy using CD44-targeted chitosan nanoparticles for epithelial ovarian cancer

“…Anti-tumor angiogenesis therapy has been studied to prevent tumor metastasis and inhibit tumor growth, which is one of the effective strategies for eradicating tumor growth (Lu et al., 2012 ; Sennino et al., 2012 ). Recently, anti-angiogenic therapy using inhibitors have attracted much attention as novel therapies, and several studies have shown clinical studies (Ma et al., 2018 ). However, these approaches were known to be limited and had side effects (Ma et al., 2018 ).…”

Potential Therapeutic Strategies for Lung and Breast Cancers through Understanding the Anti-Angiogenesis Resistance Mechanisms

“…Several studies have revealed that VM is associated with aggressive breast and lung cancer types [71,74,75]. As with angiogenesis, growth factors and hypoxia-related factors, such as VEGF-A, vascular endothelial cadherin (VE-cadherin), platelet EC adhesion molecule (PECAM) and HIF-1 α, regulate VM [76]. When a tumor exhibits hypoxia, HIF-1 α is stabilized and promotes the transcription of angiogenesis-related genes such as the VEGF-A [20].…”

“…Invasion contributes to resistance through the upregulation of extracellular matrix (ECM)-related factors such as matrix metalloproteinase (MMP) [76,90,91]. MMPs contribute to the invasion process of the tumor cells through the degradation of the ECM [92].…”

Exogenous sickle erythrocytes combined with vascular disruption trigger disseminated tumor vaso-occlusion and lung tumor regression

“…The failure of conventional treatment has prompted a universal search for conceptually new tools and strategies to eradicate these treatment-resistant hypoxic tumor cell subpopulations. Antiangiogenic agents that limit the tumor blood supply to these niches by targeting receptors on embryonic blood vessels usually lead to tumor regrowth by activating alternate synthetic pathways, hypoxia-inducible factors, or tumor cells that evade the effect of therapy (7)(8)(9). Likewise, polymeric nanocarriers occlude only a fraction of mature tumor blood vessels and in the absence of hypoxia-sensing systems fail to access oxygen-deprived regions (10,11).…”