We discuss recent discoveries in hypoxic cellular pathophysiology and explore the interplay between hypoxic malignant cells and other stromal elements. This review will provide an update on the effects of hypoxia on cancer outcomes and therapeutic resistance.
Hypoxia has been discovered to be a key driver for tumor progression, both because of impacts on tumor cells and separately on the wider tumor microenvironment. The latter effects occur via epithelial mesenchymal transition, autophagy and metabolic switching. Through epithelial mesenchymal transition, hypoxia both drives metastasis and renders key target tissues receptive to metastasis. Autophagy is a double-edged sword which requires greater understanding to ascertain when it is a threat. Metabolic switching allows tumor cells to access hypoxic survival mechanisms even under normoxic conditions.
Every element of the malignant stroma contributes to hypoxia-driven progression. Exosomal transfer of molecules from hypoxic tumor cells to target stromal cell types and the importance of microRNAs in intercellular communication have emerged as key themes.
Antiangiogenic resistance can be caused by hypoxia-driven vasculogenic mimicry. Beyond this, hypoxia contributes to resistance to virtually all oncological treatment modalities.
Recent advances have moved us closer to being able to exploit hypoxic mechanisms to overcome hypoxia-driven progression and therapy failure.
aSchool of Medicine, The University of Western Australia, Perth
bDepartment of Medical Oncology, Fiona Stanley Hospital, Murdoch, Western Australia
cInstitute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane
dTranslational Research Institute, Woolloongabba, Australia
Correspondence to Andrew Redfern, School of Medicine, University of Western Australia; Harry Perkins Institute Building, Fiona Stanley Hospital Campus, 5 Robin Warren Drive, Murdoch 6150, Western Australia, Australia . Tel: +08 61511411; e-mail: Andrew.Redfern@uwa.edu.au