Alternative Vascularization Mechanisms in Tumor Resistance to Therapy

SIMPLE SUMMARY: Tumors rely on blood vessels to grow and metastasize. Malignant tumors can employ different strategies to create a functional vascular network. Tumor cells can use normal processes of vessel formation but can also employ cancer-specific mechanisms, by co-opting normal vessels present in tissues or by turning themselves into vascular cells. These different types of tumor vessels have specific molecular and functional characteristics that profoundly affect tumor behavior and response to therapies, including drugs targeting the tumor vasculature (antiangiogenic therapies). In this review, we discuss how vessels formed by different mechanisms affect the intrinsic sensitivity of tumors to therapy and, on the other hand, how therapies can affect tumor vessel formation, leading to resistance to drugs, cancer recurrence, and treatment failure. Potential strategies to avoid vessel-mediated resistance to antineoplastic therapies will be discussed. 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.