BioWorld International Correspondent

LONDON - New insights into the chain of molecular events that leads to kidney cancer are bringing scientists closer to understanding fundamental aspects of cancer in general.

Researchers in the UK have discovered that most kidney cancer cells act as though they do not have enough oxygen, which causes them to change their nature, making them more likely to move and spread.

Patrick Maxwell, professor of nephrology at Imperial College London, based at the Hammersmith Hospital in West London, told BioWorld International: "There is a lot of interest in the cancer field in making treatments that block the pathways that cells activate when oxygen is low, and our work provides yet another strong argument that these strategies are logical ways to attack cancer. In fact, rather than attacking only part of the problem, these strategies are aimed at a 'master aspect' of cancer."

Maxwell and his colleagues published an account of their work in a paper in the April 3, 2006, Cancer Research, titled "Regulation of E-cadherin expression by VHL and hypoxia-inducible factor (HIF)."

The study focused on a type of kidney cancer that develops in people with the inherited cancer syndrome called von Hippel-Lindau (VHL) disease. People in such families have a 50 percent chance of inheriting the faulty VHL gene, and those who do inherit it have a 70 percent chance of developing kidney cancer during their lifetime.

It turns out that the VHL gene also is responsible for many cases of sporadic (non-inherited) kidney cancer. Mutations in that gene occur in most cases of clear cell renal cell cancer, which is the most common type of kidney cancer in adults.

When the VHL gene first was identified in 1993, no one had any idea what its function was. Then, in 1999, Maxwell's group showed that the protein encoded by the VHL gene plays a role in helping cells to sense how much oxygen is available. Kidney cancer cells with a faulty VHL gene behave as though there is no oxygen present. They start making a chemical signal called hypoxia-inducible factor (HIF).

Maxwell said: "Cells that are low on oxygen make lots of signals for blood vessel growth, and this makes sense for cancer cells, which don't have their own blood supply. Our finding explained aspects of how kidney cancer behaves because this cancer is very rich in blood vessels - but it did not tell us how making HIF leads to cancer, nor why it leads to kidney cancer and not other types of cancer."

As reported in the Cancer Research paper, further investigations showed that HIF causes kidney cells from people with VHL syndrome to switch off manufacture of a protein called e-cadherin. E-cadherin molecules are normally found in the cell's membrane, projecting into the cytoplasm on one side and out into the extracellular environment on the other side. Outside the cell, they interact with e-cadherin molecules on other cells, helping the cells stick together and form normal tissue.

Without e-cadherin, the cell loses the normal stimulus to stay where it is and not divide. "We think this is likely to be a pivotal step on the way to cancer," said Maxwell. "This finding also has implications for other types of cancer."

In cancers as a whole, he added, people have known that the e-cadherin signalling system is turned off, but it has not been clear how or why that happens. Normally, if cancer cells need to turn off such a pathway, they will tend to develop mutations that will have that effect.

"But cancer cells don't seem to make mutations in cadherins, and this study probably tells us why not," Maxwell explained. "As cancer cells grow, the oxygen level gets lower, and the HIF signaling system is turned on. Our study suggests that this automatically turns off manufacture of e-cadherin, which results in the cells dissolving their contacts with other cells, so that they begin to move around and become more invasive and less like normal epithelial cells."

A future goal for the team is to identify what molecules are involved in mediating the effect of HIF on e-cadherin. Maxwell said, "Although the idea of antagonizing HIF is quite attractive, it plays such an important role in normal cell behavior that it might be better to attack the next step downstream, whatever that is."

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