Hypoxia signaling and oxygen metabolism in cardio-oncology

Cardio-oncology is a rapidly growing field in cardiology that focuses on the management of cardiovascular toxicities associated with cancer-directed therapies. Tumor hypoxia is a central driver of pathologic tumor growth, metastasis, and chemo-resistance. In addition, conditions that mimic hypoxia (pseudo-hypoxia) play a causal role in the pathogenesis of numerous types of cancer, including renal cell carcinoma. Therefore, therapies targeted at hypoxia signaling pathways have emerged over the past several years. Though efficacious, these therapies are associated with significant cardiovascular toxicities, ranging from hypertension to cardiomyopathy. This review focuses on oxygen metabolism in tumorigenesis, the role of targeting hypoxia signaling in cancer therapy, and the relevance of oxygen metabolism in cardio-oncology. This review will specifically focus on hypoxia signaling mediated by hypoxia-inducible factors and the prolyl hydroxylase oxygen-sensing enzymes, the cardiovascular effects of specific cancer targeted therapies mediated on VEGF and HIF signaling, hypoxic signaling in cardiovascular disease, and the role of oxygen in anthracycline cardiotoxicity. The implications of these therapies on myocardial biology and cardiac function are discussed, underlining the fine balance of hypoxia signaling in cardiac homeostasis. Understanding these cardiovascular toxicities will be important to optimize treatment for cancer patients while mitigating potentially severe cardiovascular side effects.