M. Celeste Simon, PhD, discusses connections between abnormal hypoxia levels and cancer, as well as her research on hypoxia-inducible factor transcription factors, which mediate responses to hypoxic stress.
What role does low cellular oxygen play in tumor growth and metastasis?
Abnormally low cellular oxygen levels can occur in a variety of medical conditions, “but when tumors grow rapidly, they frequently develop very pronounced oxygen gradients,” says M. Celeste Simon, PhD, a professor of cell and developmental biology at the University of Pennsylvania School of Medicine and scientific director of its Abramson Family Cancer Research Institute in Philadelphia.
A Howard Hughes Medical Institute investigator, Simon spoke with Cancer Discovery's Suzanne Rose about the connection between hypoxia and cancer, and her research on hypoxia-inducible factor (HIF) transcription factors, which mediate responses to hypoxic stress.
Does hypoxia cause cancer, or is it a byproduct of cancer?
Changes in genes that have evolved to respond to hypoxia have been found to be predisposing factors for some cancers—for example, renal cancer and paraganglioma. There's also the notion that so-called cancer stem cells—whether cells of origin or the cells that simply propagate the tumor—may tend to naturally reside in hypoxic regions.
However, most people consider hypoxia a frequent byproduct of cancer development, when a tumor goes from being a slow grower to a rapid grower. If a tumor is avascular, once it reaches a certain size, it will recruit blood vessels to be less hypoxic. If the tumor is reasonably vascular in the early stages, as it acquires mutations that result in rampant cell proliferation, it will develop hypoxic domains. The vasculature will respond by becoming more extensive, but then the tumor takes off. This cat-and-mouse game happens over and over again.
How do HIFs affect cancer metabolism?
HIFs respond to reduced oxygen availability; the 2 best characterized and understood HIFs are HIF-1α and HIF-2α. Over the long term, they promote changes in blood vessel growth, blood vessel phenotype, and cell motility.
In addition, they very quickly induce changes in metabolic enzymes that allow the cell to withstand hypoxia by promoting glycolytic ATP production, instead of mitochondrial oxidative phosphorylation.
This dovetails very nicely with what people are studying in cancer metabolism. One of the common features of solid tumors is that they take up glucose and are highly glycolytic, and we believe that HIFs are one of the factors that contribute to that.
Also, HIFs respond differently in cancer cells than they do in cells with other conditions. They have cross-talk with oncogenes like Myc and with tumor suppressors like p53, so slightly different target genes are engaged.
Do HIFs promote or prevent metastasis?
There's a growing consensus that one of the main things that HIFs do is promote local invasion and metastasis at distant sites. That might seem counterintuitive because cells need to expend energy to move, but we have to remember that cancer is a long-term disease with acute and more gradual responses to hypoxia. Acutely, it tries to deal with the stress by making metabolic changes. But if the cells experience hypoxia for long periods of time and attempts to remodel the vasculature have been unsuccessful, what's the alternative? Move. HIFs regulate enzymes that change the extracellular matrix, allowing the cells to be more motile, get into the bloodstream, and go where there's more oxygen. It's interesting to see that these metastases often end up in welloxygenated tissues like the lungs.
Are HIF inhibitors being tested in patients?
Because they are transcription factors, HIFs have been difficult to drug. However, as technology improves, it is becoming increasingly possible to selectively target them.
A few FDA-approved drugs inhibit HIF activity, and they're making their way through clinical trials. The problem is that they're not really selective, so I think there's some cause for concern. Hopefully, the drugs won't have toxicity issues, but we need to make sure that any benefit is because we're affecting HIF, not because other things are going on.
I should point out that although we want to inhibit HIF activity in cancer, we actually want to promote HIF activity in conditions like severe tissue ischemia or renal failure. However, you've got to be careful. You could be aiding a tumor that hasn't been detected.
HIFs remain an attractive therapeutic target, but only at certain stages of disease and for certain kinds of cancer. I think some cancers will be dependent on HIF-1α and others will be dependent on HIF-2α. We'd better know which HIF to target at the right time for the right cancer.
What's the direction of future research?
We need to answer 3 significant questions: How do HIFs affect cancer metabolism and the many cancer phenotypes? Can we selectively and effectively inhibit one particular HIF, depending on the cancer? Finally, if we promote HIF activity to treat patients with renal failure, for example, can we do it in a way that doesn't put them at risk for advanced cancer progression?
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