Angiogenesis and Metabolism: Entwined for Therapy Resistance

Angiogenesis and metabolism are entwined processes during tumor development, and their interface offers unprecedented opportunities for therapeutic intervention. Antiangiogenic drugs are currently used in the clinic, but therapy resistance emerges over time with disease progression. Recently, metabolic symbiosis has emerged as a new mechanism of resistance to these therapies. Metabolic symbiosis comprises tumor compartmentalization in which hypoxic regions (far from blood vessels) are highly glycolytic and generate high amounts of lactate. By contrast, normoxic regions (close to blood vessels) uptake the excess of lactate and metabolize it by aerobic mitochondrial respiration. This mutualistic balance allows tumors to evade antiangiogenic therapies and continue to grow. Targeting angiogenesis and metabolic adaptation could substantially extend the benefits of antiangiogenic therapies. Angiogenesis and metabolism are entwined processes that permit tumor growth and progression. Blood vessel supply is necessary for tumor survival not only by providing oxygen and nutrients for anabolism but also by removing waste products from cellular metabolism. On the other hand, blocking angiogenesis with antiangiogenic therapies shows clinical benefits in treating several tumor types. Nevertheless, resistance to therapy emerges over time. In this review we discuss a novel mechanism of adaptive resistance involving metabolic adaptation of tumor cells, and we also provide examples of tumor adaptation to therapy, which may represent a new mechanism of resistance in several types of cancer. Thus, targeting this metabolic tumor adaptation could be a way to avoid resistance in cancer patients. Angiogenesis and metabolism are entwined processes that permit tumor growth and progression. Blood vessel supply is necessary for tumor survival not only by providing oxygen and nutrients for anabolism but also by removing waste products from cellular metabolism. On the other hand, blocking angiogenesis with antiangiogenic therapies shows clinical benefits in treating several tumor types. Nevertheless, resistance to therapy emerges over time. In this review we discuss a novel mechanism of adaptive resistance involving metabolic adaptation of tumor cells, and we also provide examples of tumor adaptation to therapy, which may represent a new mechanism of resistance in several types of cancer. Thus, targeting this metabolic tumor adaptation could be a way to avoid resistance in cancer patients. the transformation of glucose to lactate when limited amounts of oxygen (O2) are available. the formation of new blood vessels from pre-existing vessels. a process that involves different mechanisms in the tumor that allow evasion of therapy. a class of anticancer therapies that target the tumor vasculature. form a single-cell layer that lines all blood vessels and regulates molecule exchanges between the bloodstream and surrounding tissues. the metabolic pathway that converts glucose into pyruvate. an organizing principle for rationalizing the complexities of neoplastic disease. a condition where tissues are not oxygenated adequately in tumors, usually due to an insufficient or aberrant microcirculation or deterioration of diffusion. a key regulator that plays an integral role in the tissue response to low oxygen concentrations. changes that occur in tumor cells in response to low levels of oxygen and nutrients that allow tumor cells to survive in these conditions. a mechanism of resistance where hypoxic cancer cells import glucose and export lactate, while normoxic cells import and catabolize lactate. describes the increased utilization of glycolysis instead of oxidative phosphorylation by tumor cells for their energy requirements under physiological oxygen conditions. This effect has been the basis for much speculation on the survival advantage of tumor cells, tumorigenesis, and the microenvironment of tumors.