Researchers at NYU Langone Medical Center and its Laura and Isaac Perlmutter Cancer Center, Princess Margaret Cancer Center, the University of Toronto, Harvard Medical School and Oxford University have identified a new signaling pathway that helps cancer cells cope with the lack of oxygen found inside tumors. These are the results of a study published in Nature Cell Biology on June 20, 2016.
Oxygen is important for the proper function of all human cells, but cancer cells thrive even when deprived of it. Rapid, abnormal cell growth seen in many solid tumors causes them to outgrow their blood supply and leave some cells with less oxygen. In the face of this “hypoxia,” cancer cells change their gene expression to turn off all but the most vital oxygen-using processes.
[Our]... new understanding of cancer cell response to hypoxia, [may] enable the design of future treatments that drive such cells into low-oxygen environments and then take away their ability to survive ...
“Our results, by yielding a new understanding of cancer cell response to hypoxia, hopefully will enable the design of future treatments that drive such cells into low-oxygen environments and then take away their ability to survive these conditions,” says Benjamin Neel, MD, PhD, director of the Perlmutter Cancer Center.
In the new research, led by Robert Banh, a graduate student in Neel’s lab, the investigators found that signals sent by the enzyme protein-tyrosine phosphatase 1B or PTP1B work in a previously unknown way to shut down oxygen-using processes in breast cancer cells deprived of oxygen, thereby enhancing their survival.
Diabetes to Cancer to Moyamoya Disease
Neel and colleagues first identified the gene for protein-tyrosine phosphatase 1B (PTP1B) as part of search for molecules that suppress tumor growth in the early 1990s. PTP1B is the hallmark member of a group of enzymes that take a phosphate group away from biomolecules to turn processes like cell growth on or off.
Neel and colleagues, as well as the group of Michel Tremblay at McGill University, found in earlier studies of mice that PTP1B function was required for the growth in certain cancers. These included breast cancers caused by the Her2 oncogene (HER2+ breast cancer cells), which is implicated in 20% of human breast cancers. In more recent work, Banh, Neel and colleagues found that human HER2+ breast cancer cells lacking PTP1B grew normally under standard culture conditions, but died much more rapidly in low oxygen.
Adapting to hypoxia
Furthermore, researchers found that the three signaling pathways by which cancer cells were known to adapt to hypoxia worked fine in PTP1B-deficient HER2+ breast cancer cells. These included the well-known hypoxia-inducible factor pathway, which shifts the way cells use oxygen from oxidative phosphorylation in cellular “machines” called mitochondria to glycolysis, which does not require oxygen. Instead they found that other non-mitochondrial sources of oxygen consumption were not dialed down appropriately in PTP1B-deficient breast cancer cells.
The team further found that PTP1B controls the response of tumors in hypoxia by regulating the protein RNF213, which in in turn suppresses oxygen consumption by enzymes called α-ketoglutarate-dependent dioxygenases (α-KGDDs). These enzymes use oxygen, vitamin C (ascorbic acid) and iron to catalyze myriad reactions.
As the team began to fill in details concerning PTP1B pathway, they realized from the literature that RNF213 was also important in a rare condition called Moyamoya Disease, a rare, progressive cerebrovascular disorder caused by blocked arteries at the base of the brain in an area called the basal ganglia. To compensate for the blockage patients experience abnormal blood vessel growth in the brain that can lead to blocked arteries and seizures.
Conceivably, Neel noted, Moyamoya disease symptoms could reflect an abnormal response to hypoxia in vascular cells, and his lab is working to understand the condition’s molecular basis.
“We have seen many times in the cancer field that studies of rare syndromes can be being important in explaining mechanisms by which cells respond to stresses,” says Neel. “We hope our new study will provide insights into Moyamoya disease that then feed back into our work in cancer biology.”
This work was supported by National Institutes of Health and by the Canadian Institutes of Health Research, the Terry Fox New Frontiers Research Program, Cancer Research‐UK and the Wellcome Trust, Kiban Kenkyu, the Princess Margaret Cancer Foundation, the Ontario Ministry of Health and Long Term Care, and the Canadian Breast Cancer Foundation.
Banh RS,Iorio C, Marcotte R, Xu Y, Cojocari D, Rahman AA, Pawling J, Zhang W, et al. PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia. Nature Cell Biology June 20, 2016 / doi:10.1038/ncb3376 [Link]
 What is Moyamoya Disease? Moyamoya Disease Information Page.nNational Institute of Neurological Disorders and Stroke/National Institutes of Health. Online. Last accessed June 20, 2016.
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