Alternative Vascularization Mechanisms in Tumor Resistance to Therapy

Abstract

Blood vessels in tumors are formed through a variety of different mechanisms, each generating vessels with peculiar structural, molecular, and functional properties. This heterogeneity has a major impact on tumor response or resistance to antineoplastic therapies and is now emerging as a promising target for strategies to prevent drug resistance and improve the distribution and efficacy of antineoplastic treatments. This review presents evidence of how different mechanisms of tumor vessel formation (vasculogenesis, glomeruloid proliferation, intussusceptive angiogenesis, vasculogenic mimicry, and vessel co-option) affect tumor responses to antiangiogenic and antineoplastic therapies, but also how therapies can promote alternative mechanisms of vessel formation, contributing to tumor recurrence, malignant progression, and acquired drug resistance. We discuss the possibility of tailoring treatment strategies to overcome vasculature-mediated drug resistance or to improve drug distribution and efficacy.

Keywords: antiangiogenic therapy; drug resistance; non-sprouting angiogenesis; tumor microenvironment; tumor vasculature.

Figure 1

Formation of blood vessels in a tumor through physiological mechanisms: vasculogenesis and angiogenesis. Vasculogenesis is the de novo formation of vessels from bone marrow-derived precursors recruited to the tumor site. Angiogenesis is the formation of vessels from existing ones, through the processes of sprouting angiogenesis (endothelial cell specification into tip and stalk cells generate sprouts that elongate and fuse into new functional vessels), glomeruloid microvascular proliferation (deregulated proliferation of vascular endothelial cells generating glomeruloid structures), and intussusceptive angiogenesis (longitudinal splitting of vessels caused by the formation and extension of intra-luminar tissue pillars).

Figure 2

Tumor vasculature formation through non-angiogenic cancer-specific mechanisms: vessel co-option (cancer cells use pre-existing tissue blood vessels, migrating towards and along vessels and incorporating them into the tumor mass) and vasculogenic mimicry (cancer cells acquire endothelial-like properties and organize themselves in vascular-like functional structures connected to nearby blood vessels).