“Tumor hypoxia and HIF’s affect most of the cancer hallmarks … and contribute to chemo- and radiotherapy resistance.” In their review from 2016, Wigerup, Pahlman and Bexell of Lund University in Sweden discuss how hypoxia inducible factors HIF’s regulate the hypoxic microenvironment in cancer, and the therapeutic strategies that are being developed to improve patients’ prognosis. Dr. Sven Pahlman’s lab has been using the H35 HypOxystation for more than 5 years now, to research SCLC and neuroblastoma, and their data is contributing to the understanding of the role of oxygen levels in the progression of cancer.
Hypoxia and HIF-1α and 2α expression in cancer usually signify a worse prognosis, but most hypoxia-induced transcriptional, translational, and epigenetic changes are cell-type specific. Many effects engendered by hypoxia are mediated directly or indirectly via HIF pathways, and most are causative of the iconic “Hallmarks of Cancer” that Hanahan and Weinberg introduced in 2000 and expanded in 2011. Hypoxia induces increased autophagy, apoptosis, and aberrant cell proliferation; neoangiogenesis mediated by VEGF and PDGF-β; proliferation of cancer stem cells; metabolic reprogramming to satisfy energy and synthetic requirements in proliferating cells; modulation of inflammation and immune responses; genomic instability through increased mutagenesis and diminished DNA repair; and metastasis as hypoxia induces epithelial-to-mesenchymal transition and degradation of the extracellular matrix. Assaying the relationship between hypoxia and the Hallmarks of Cancer benefits significantly from the physiological atmosphere mimicked in the HypOxystation, a closed-culture hypoxia workstation controlling gasses, temperature and humidity.
In their review, Wigerup and Pahlman describe the role tumor hypoxia plays for cancer therapy and treatment resistance, as oxygen levels, production of reactive oxygen species ROS, and HIF activity are intertwined actors in the cancer battle. Any and all effects of hypoxia are cell-type specific; however, numerous studies indicate that HIF’s mediate chemoresistance, suggesting that HIF-1 and 2 inhibitors can effectively support cancer therapy. The authors state that “since hypoxia is a hallmark of solid tumors and mediates aggressive, metastatic, and resistant disease, it is arguably one of the most attractive therapeutic targets in cancer.” Strategies selectively targeting hypoxia for cancer therapy include hypoxia-activated prodrugs; inhibitors of HIF mRNA and protein expression; and inhibitors of downstream HIF signaling pathways such as VEGF. Effective drug research relies on authentic replication of the hypoxic environment for cell culture: the HypOxystation used in the Pahlman lab is able to accommodate long-term assays with sterile steam humidification and HEPA clean air. The HypOxystation concept “Choose your Atmosphere – Define your Environment” is the best way to ensure cell culture reflects physiology in cancer research and therapy.
Hypoxia is at the heart of the Hallmarks of Cancer, and results such as these from the Pahlman lab make the cancer research community hopeful that “HIF inhibition is likely to be a powerful therapeutic approach” to eradicate cancer.