Researchers at Imperial College London in England looked at cells from people with an inherited condition called von Hippel-Lindau (VHL) syndrome, in which one copy of the VHL gene is altered.

The VHL gene normally safeguards cells against cancer, suppressing tumor growth. The research team found that when cells are deprived of the VHL protein, they behave as if they have too little oxygen - but how this contributes to the chain of events which can lead to them becoming cancerous has not been clear.

Experts said the discovery, detailed in the journal Cancer Research, could help pave the way for new treatments. Over 6,600 people in the UK and 36,000 people in the United States are diagnosed with kidney cancer each year. In the general population the average age of onset of symptoms from kidney cancer is age 62; among people with a familial syndrome like VHL, symptoms occur on average by age 42.

Lack of oxygen

Until now, it has not been clear how flaws in the VHL gene can lead to the development of kidney cancer. But the researchers found that kidney cells with flawed VHL had much less of a normal protein molecule, called e-cadherin, which contributes to normal cell behavior.

They found that the cells behaved as if they were receiving much less oxygen than they really were.

To combat this perceived lack of oxygen, the cells raised a chemical signal called HIF (hypoxia-inducible factor). HIF causes the kidney cells to switch off e-cadherin. Normally, the e-cadherin protein molecule plays an important role in helping cells to stick together to form healthy tissues.

The loss of this molecule results in a breakdown in communication between neighboring cells. Cells then acquire important features of cancer, such as the ability to invade other tissues and spread.

The scientists say their finding could also have implications for other types of cancer, as low oxygen levels are common in tumors. E-cadherin is also lost in several forms of cancer, including breast cancer.

Mechanism

The opportunity to study kidney cancer in people with VHL was invaluable to this work. Professor Patrick Maxwell, who led the research, said: “It is very powerful scientifically to be able to study cells before they become cancerous, as it helps us to understand how tumors develop.

“In the general population, kidney cancer is usually detected late, when the only available treatment option is radical surgery. Investigating cells before they develop into tumors could help us to find a way to detect and treat kidney cancer earlier.”

But he added: “We don’t think loss of e-cadherin is the only thing responsible for the development of kidney cancer. In fact there are probably many more factors involved, and our next task is to find out what these are, and work out the best way to prevent this disease from forming in the first place.”

Professor John Toy, Medical Director of Cancer Research UK, said: “By examining the relationship between oxygen levels and e-cadherin, the research group has discovered a potential mechanism by which mutant VHL could contribute to tumor development.

"This is extremely interesting research as it could pave the way for new treatments and offer hope to patients with VHL syndrome.”

The work was funded by Cancer Research UK, the Medical Research Council and the Wellcome Trust.

This article was based on an article in BBC News, April 2, 2006, reporting the publication of Esteban, Maxwell et al., Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res. 2006 Apr 1;66(7):3567-75.

As printed in the VHL Family Forum 14:1, April/May 2006. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.