Dr. Patrick Maxwell of Oxford University in England showed that the VHL protein (pVHL) regulates a substance known as the hypoxia-inducible factor (HIF-1). He explained that four billion years ago there was very little oxygen in the atmosphere. As photosynthesis went on, the levels of oxygen in the atmosphere increased, and organisms needed a mechanism to protect themselves from conditions of too much or too little oxygen.

When you are at high altitudes, oxygen is low. When you are wounded, additional oxygen is needed by the wounded tissues for healing. And when a cancer tumor is growing, it needs more oxygen to support the high rate of growth of the cells.

Otto Warburg won a Nobel Prize for his demonstration of the high correlation between growth rate of the tumor and availability of oxygen. When oxygen is low, we see the levels of HIF-1 in the cell begin to rise. HIF-1 has been shown to activate a number of important genes that are important in vascularization of tumors during conditions of low oxygen.

It looks like pVHL normally targets HIF-1 for destruction so that HIF-1 will not continually activate these genes (see Figure 2.) Just as we know that VEGF is needed for tumor growth, we now know too that oxygen is necessary to support that growth. Perhaps by doing something to inactivate HIF-1 in the cell we could also constrain the growth of a new tumor. There are probably other important proteins that are regulated by pVHL which might also separately be targeted by therapies to limit tumor growth.

Additional reports from the Basic Science Day can be found on the VHL website, www.vhl.org/conf2000

As printed in the VHL Family Forum 8:3, September 2000. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.