VEGF inhibition causes vascular regression
VEGF inhibition causes vascular regression and tissue hypoxia in tumor tissues and their surrounding healthy adipose tissues. In this regard, tumors in steatotic livers and adjacent to adipose tissues would experience more hypoxia than non-adipose tumors. Indeed, our present experimental results support this notion, showing the existence of tissue hypoxia in adipose tumors. In both in vitro and in vivo experimental settings, we show that AAD-triggered hypoxia is the primary driving force for switching to the lipid-dependent metabolic reprogramming in tumor cells. FAO-committing crucial molecular components, including AMPK, are significantly upregulated, indicating activation of the FAO pathway in cancer Cdk2/Cyclin Inhibitory Peptide I sale in AAD-treated adipose tumors. Hypoxia might also trigger lipolysis in tumor adjacent adipose tissues that release more FFA. This interesting possibility warrants future investigation. In addition, hypoxia markedly increases expression levels of FFA uptake, transportation, and metabolism machineries in malignant cells to ensure the availability of FFA as a fuel for the FAO-committed energy production. Paradoxically, activation of FAO also requires oxygen for energy production and tissue hypoxia would be counterintuitive to this dogma. It is likely that mild and intermittent hypoxia induced by AAD still allows sufficient oxygen for fuel. We provide crucial evidence of the functional impact of FFA on cell proliferation under hypoxic conditions. Under the normoxic condition, FFA has no impact on cancer cell proliferation. Perhaps there is no need for cancer cell to utilize FFA for energy production because of the predominant glycolysis metabolic pathway (i.e., the Warburg effect). Under hypoxic conditions, however, both FFA uptake and metabolism pathways are activated and FFA is able to further stimulate cancer cell growth. Consistent with these in vitro findings, our recent work demonstrates that tumors in adipose tissues grow at exacerbated rates relative to non-adipose tissues (Lim et al., 2016). These data also imply that the FAO-committed bioenergetic pathway also significantly contributes to tumor expansion under hypoxic conditions.
Acknowledgments We thank Simcere Pharmaceuticals, Nanjing, China, for providing a rabbit anti-VEGF neutralizing monoclonal antibody. We thank Dr. Schlisio in the Ludwig Institute for Cancer Research, Karolinska Institute, for assistance with hypoxia assay. Y.C.’s laboratory is supported through research grants from the Swedish Research Council; the Swedish Cancer Foundation; the Karolinska Institute Foundation; the Karolinska Institute Distinguished Professor Award; the Torsten Soderbergs Foundation; the Tore Nilsons Foundation; the Ruth and Richard Julin Foundation; the Ogonfonden Foundation; Wera Ekströms Foundation; the Lars Hiertas Minne Foundation; National Natural Science Foundation of China (project no. 81773059); the International Research Fund for Subsidy of Kyushu University School of Medicine Alumni; the Martin Rinds Foundation; the Maud and Birger Foundation; the Alex and Eva Wallströms Foundation; the Robert Lundbergs Memorial Foundation; the Swedish Diabetes Foundation; the Swedish Children Cancer Foundation; the European Research Council (ERC) advanced grant ANGIOFAT (project no. 250021); the Knut Alice Wallenberg Foundation; and the NOVO Nordisk Foundation for the advanced grant. G.N. is supported by the Shenzhen Science and Technology Innovation Committee (project nos. JCYJ20170306091452714, GJHZ20170313172439851, and JCYJ20170413162242627).