Oncogenes and angiogenesis: a way to personalize anti-angiogenic therapy?
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Cellular and Molecular Life Sciences
Review
Oncogenes and angiogenesis: a way to personalize anti‑angiogenic therapy? Alessia Bottos · Alberto Bardelli
Received: 4 December 2012 / Revised: 10 March 2013 / Accepted: 25 March 2013 © Springer Basel 2013
Abstract The acquisition of oncogenic mutations and promotion of angiogenesis are key hallmarks of cancer. These features are often thought of as separate events in tumor progression and the two fields of research have frequently been considered as independent. However, as we highlight in this review, activated oncogenes and deregulated angiogenesis are tightly associated, as mutations in cancer cells can lead to perturbation of the pro- and antiangiogenic balance thereby causing aberrant angiogenesis. We propose that normalization of the vascular network by targeting oncogenes in the tumor cells might lead to more efficient and sustained therapeutic effects compared to therapies targeting tumor vessels. We discuss how pharmacological inhibition of oncogenes in tumor cells restores a functional vasculature by bystander anti-angiogenic effect. As genetic alterations are tumor-specific, targeted therapy, which potentially blocks the angiogenic program activated by individual oncogenes may lead to personalized antiangiogenic therapy. A. Bottos Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, PO Box 2543, 4058 Basel, Switzerland e-mail: [email protected] A. Bardelli (*) Department of Oncological Sciences, University of Torino, Strada prov 142, km 3.95, 10060 Candiolo, Turin, Italy e-mail: [email protected] A. Bardelli Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, Strada prov 142, km 3.95, 10060 Candiolo, Turin, Italy A. Bardelli Fondazione Italiana per la Ricerca sul Cancro Institute of Molecular Oncology, 20139 Milan, Italy
Keywords Oncogenes · Angiogenesis · Vessel normalization · Anti-angiogenic therapy · Targeted therapy
Anti‑angiogenic therapy: where are we? Angiogenesis is the biological process that drives the formation of new blood vessels from a pre-existing vasculature. Throughout embryonic development, physiological angiogenesis allows for expansion of the primitive vascular network formed by vasculogenesis, thanks to branching, remodeling, and maturation of the vascular bed [1]. During adulthood, angiogenesis normally occurs in only a few processes, such as in the female reproductive apparatus, and in pathological situations including wound healing, diabetic retinopathy, rheumatoid arthritis, and cancer [2]. More than 50 years ago, angiogenesis was described as a hallmark of tumor biology, and for the first time anti-angiogenic therapy was proposed as a cancer cure. Folkman and colleagues were pioneers in demonstrating that growing tumors need neovascularization when reaching a critical volume (around 1–2 mm3) in order to continue their expansion [3, 4]. The induction of tumor vasculature, also known as “angiogenic switch”, represents a complex and time-regulated process in cancer
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