To celebrate the 2019 Nobel Prize in Physiology or Medicine, awarded to William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza for their discoveries of how cells sense and adapt to oxygen availability, we’ve asked four researchers in the oxygen-sensing field what they see on the horizon after this momentous milestone.
The Next Horizons
Looking forward, I think these questions will fascinate oxygen biologists for decades to come:
(1) Comprehensively understanding all oxygen-dependent reactions. There are hundreds of oxygen-dependent reactions in the body. In extreme hypoxia, all these reactions fail and can serve as “oxygen sensors.” The key is to understand the downstream effects, whether adaptive or detrimental. (2) Bridging the gap between different scales of oxygen sensing. To date, researchers have focused either on cellular oxygen sensing via the HIF pathway or somewhat separately, on whole-organism responses to hypoxia. The key now is to bridge the gap between these two scales of oxygen sensing and incorporate other tightly coupled variables such as carbon dioxide and pH. (3) Hypoxia versus ischemia. Most mammalian systems can adapt relatively well to hypoxia. However, it is the combination of low oxygen and low nutrients (i.e., ischemia) that is truly pathological. It will be critical for the field to dissect the differences between hypoxia sensing and ischemia sensing. (4) Hyperoxia sensing and toxicity. We have come to appreciate that too little oxygen is detrimental. It will be exciting to now study the opposite side of the coin: Why and when is too much oxygen toxic? Are there ways the body senses hyperoxia? And how does excess oxygen contribute to diseases ranging from metabolic disorders to the aging process?
Memories of O2 in Metastatic Seeds
The breakthrough discovery of O2-sensing mechanisms allowed cancer biologists to understand the physiological relationship between primary tumor cells and their microenvironment. This led to insight into why primary tumor hypoxia can correspond to poor prognosis. However, the next step in understanding the effects of hypoxia in cancer resides in appreciating that its effects do not stop with the primary tumor. Poor prognosis is commonly due to the development of metastasis, which can appear years to decades after removal of the initial tumor. How could hypoxic signals in the primary site impact events years later? Is the poor prognosis a consequence of events taking place only at the primary site, or do disseminated cancer cells carry a phenotype-defining epigenetic “memory” of their time in varying O2 microenvironments? The most significant battle in cancer will be inhibition of dormant disseminated cancer cell survival and their expansion into metastases. Thus, revealing how an epigenetic memory of O2 tensions in the primary site, in circulation, and in secondary organs influences DCC fate might provide tools to target hypoxia-initiated programs for patients during minimal residual disease and metastatic phases.
The Less ROSy Side of Hypoxia
I consider the finding that life under low-oxygen conditions triggers the formation of reactive oxygen species (ROS) most unexpected. Wouldn’t the opposite seem much more logical? In fact, cells use ROS production under low-oxygen tension to activate HIF, which in turn mediates metabolic and transcriptional reprogramming to combat oxidative stress. Thus, hypoxic cancer cells seem to be unfortunately well adapted to high ROS-producing stress conditions. It is also now becoming increasingly evident that localized ROS production serves as a signaling mechanism that promotes cell proliferation, differentiation, and growth. As such, cancer cells use ROS production to enhance cell survival and initiate metastasis. So why then have generic antioxidant strategies repeatedly failed to treat cancer in clinical trials? Possible reasons include that effective ROS signaling is needed in healthy cells and that antioxidants counteract potential ROS-induced apoptosis events in cancer cells. As long as we are unable to target localized ROS signaling specifically in cancer cells, it seems unlikely that there will be much success in applying antioxidants in cancer treatment. However, with the development of ROS-specific probes and cell-specific targeting, we may be getting closer in using what we have learned about ROS to help combat some forms of cancer.
Hypoxia Research Nobel: Kudos!
For those of us studying cellular, tissue, and organismal responses to changes in oxygen availability, the 2019 Nobel Prize in Physiology or Medicine awarded to Drs. Kaelin, Ratcliffe, and Semenza confirms our belief in the overall importance of hypoxia research. It now seems obvious that the ability to sense and adapt to oxygen limitation is a fundamental and highly conserved characteristic integral to the survival of most forms of life on Earth. Yet, the notion that HIF proteins are modified by prolyl hydroxylations (rather than threonine or serine phosphorylations, for example) was extremely novel in 2001, and certainly took me by surprise. What will the next big surprise be? Perhaps it will come from investigating HIF-independent forms of oxygen sensation, including 2-oxoglutarate-dependent dioxygenases, epigenetics, mitochondrial signaling, ion channels, polypeptide synthesis, protein quality control, and other homeostatic processes. In the meantime, we heartily celebrate the outstanding achievements of these three recipients of the 2019 award.