Targeting cancer cells resistant to hypoxia and nutrient starvation to improve anti-angiogeneic therapy

Angiogenesis, formation of new blood vessels, is essential for tumor progression, invasion, and metastasis. 1 Vascular endo-thelial growth factors (VEGFs) and their receptors (VEGFRs) are primary regulators of angiogenesis, coordinating with other angiogenic factors such as fibroblast growth factors (FGFs), hepatic growth factor (HGF), angiopoietins, and Notch-Dll4. Anti-VEGF antibodies (e.g., beva-cizumab) and small molecular inhibitors of VEGFRs (e.g., sunitinib and sorafenib) were validated as the first cancer therapeutic agents targeting the tumor microenvi-ronment. 1 These anti-angiogenic therapies effectively suppress the growth of solid tumors and are widely used for the treatment of malignant colorectal cancer, some non-small cell lung cancers, hepatocellular carcinoma, kidney cancer, and neuroen-docrine tumors. Angiogenesis inhibitors suppress the formation of new tumor vas-culature and may normalize existing vas-culature, resulting in increased efficacy of combination chemotherapy. 2 However, the effectiveness of anti-angiogenic treatments is limited to certain types of cancer. In addition, they may not completely eradicate tumor growth and may elicit malignant progression by, for example, inducing resistance to chemotherapy. 3 Thus, the molecular mechanism underlying the elimination of such resistant and refrac-tory cancer cells needs to be elucidated. Following the inhibition of angiogen-esis, cancer cells can be exposed to both hypoxia and nutrient starvation, which may stimulate tumor aggressiveness. 4 We developed a simple model system to maintain cancer cells under conditions of both hypoxia and nutrient starvation, and demonstrated that long-term hypoxia and nutrient starvation induces tumor aggressiveness. 4 Therefore, the tumor microen-vironment associated with hypoxia and nutrient starvation may be important in the regulation of tumor progression. However, with the exception of known hypoxia-induced factors, the factors that regulate angiogenesis under conditions of hypoxia and nutrient starvation are unclear. Epigenetic regulation of angio-genesis may play a role, but this has not yet been fully elucidated. Previously, we reported that the histone demethylase JHDM1D is highly expressed in various cancer cells under conditions of nutrient starvation and that subsequent suppression of solid tumor growth was associated with the downregulation of several pro-angiogenic factors such as VEGF-B and angiopoietins. 5 Conversely, another histone demethylase JMJD1A stimulated tumor angiogenesis under conditions of hypoxia and nutrient starvation by upregulating the expression of several pro-angiogenic factors, such as angio-poietins, FGFs, and HGF, resulting in increased infiltration of tumor-associated macrophages. 4 Importantly, JMJD1A inhibition suppressed tumor growth when used in combination with anti-VEGF (bevacizumab) and anti-VEGFR treatment (sunitinib), possibly by sensitizing the refractory cells of the tumor to anti-angiogenic treatment. …