Hypoxia and the Hallmarks of Cancer: Metabolic Reprogramming

Hanahan and Weinberg’s seminal papers on the Hallmarks of Cancer describe how cancer cells accommodate the frenzied growth characteristic of tumours. Low oxygen is eminently characteristic of tumours, and in this hypoxic environment, metabolism is reprogrammed to satisfy energetic and synthetic needs of the cells.

 

Our series on Hypoxia and the Hallmarks of Cancer has showcased research on how hypoxia in the tumour microenvironment affects 8 of the Hallmarks, and in the fifth and final chapter, we look more closely at how researchers are using the Hypoxystation to delineate the Hallmark Metabolic Reprogramming.

The Hypoxystation creates authentic cell culture conditions with regard to oxygen, CO₂, temperature, and humidity.  Glove-less access to culture and manipulate cells under physiological atmosphere, in a HEPA-clean environment, allows cancer researchers to re-create the hypoxic tumour microenvironment. Hypoxystation user Dr Ali Tavassolli states that “We have only ever used the H35. I like the ease with which we can regulate and change the oxygen concentration”. And our user Dr. Brad Wouters at the Princess Margaret Cancer Centre in Toronto, who recently purchased his fourth Hypoxystation, says, “The continuous hypoxia we achieve in the workstation is a prerequisite for studies with hypoxia-activated drugs used in cancer therapy strategies.”

Hallmarks of Cancer

Metabolic Reprogramming

Changes in energy metabolism feature prominently in aggressive malignancy, and tumour hypoxia and the responding signalling pathways, featuring many HIF target genes, clearly interface with reprogrammed tumour metabolism. Reprogramming of conventional metabolic pathways serves to satisfy burgeoning energetic and anabolic needs of the tumour cells; many cancer cells may preferentially utilise glycolysis over oxidative phosphorylation, uncoupling mitochondrial metabolism from oxygen availability. Hypoxia-induced HIF’s attenuate mitochondrial function through diverse mechanisms, including down-regulation of enzymes in the electron transport chain and suppression of biogenesis of mitochondria. Signalling pathways involving HIF’s and many products of oncogenes and tumour suppressor genes interact to balance the energy needs of dividing cells with the requirement for bio-synthetic intermediates. Activation of lipid biosynthesis and other pathways with biosynthetic significance, such as the pentose phosphate pathway, is another metabolic consequence of hypoxia and HIF up-regulation. Reactive oxygen species ROS produced by the mitochondria stabilise HIF-1, influence redox homeostasis, and provide protective antioxidants to the cancer cells.

LITERATURE:

• Thoren et al. (2017) “Myc-induced glutaminolysis bypasses HIF-driven glycolysis in hypoxic small cell lung carcinoma cells” Oncotarget, 2017, Vol. 8, (No. 30), pp: 48983-48995
  www.ncbi.nlm.nih.gov/pubmed/28430666 Hypoxystation user
• Bulusu et al. (2017) “Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation” Cell Reports 18, 647–658
  www.sciencedirect.com/science/article/pii/S2211124716317624 Hypoxystation user
• Cheloni et al. (2017) “The Leukemic Stem Cell Niche: Adaptation to “Hypoxia” versus Oncogene Addiction” Stem Cells International Volume 2017, Article ID 4979474
  www.hindawi.com/journals/sci/2017/4979474/ Hypoxystation user
• Eales et al. (2016) “Hypoxia and metabolic adaptation of cancer cells” Oncogenesis (2016) 5
  www.nature.com/oncsis/journal/v5/n1/full/oncsis201550a.html Hypoxystation user
• Asby et al. (2016) “Triggering apoptosis in cancer cells with an analogue of cribrostatin 6 that elevates intracellular ROS” Org. Biomol. Chem., 2016,14, 9322-9330
  pubs.rsc.org/en/content/articlelanding/2016/ob/c6ob01591c#!divAbstract Hypoxystation user
• Burr et al. (2016) “Mitochondrial Protein Lipoylation and the 2-Oxoglutarate Dehydrogenase Complex Controls HIF1a Stability in Aerobic Conditions” Cell Metabolism 25, 740–752, November 8, 2016
  www.ncbi.nlm.nih.gov/pubmed/27923773 Hypoxystation user
• DeBerardinis and Chandel (2016) “Fundamentals of Cancer Metabolism” Sci. Adv. 2016; 2 :5
  advances.sciencemag.org/content/2/5/e1600200