Racemase: A New Marker for Cancer, and More
Have you ever seen an operator's switchboard? If it's "prime time" and many people are talking on the telephone at once, it can be a dazzling array of lights; after hours, the lights may be few and far between. This is the general concept of a gene chip, except the "lights," or lack of them, are really fluorescent-dyed copies of RNA, the switchboard is a glass slide that's half the size of a credit card, and the super-fast operator can handle more than 10,000 calls-in this case, each dyed- RNA dot represents a separate gene-at a time. All the information is then read on a scanner about the size of a laser printer.
The microarray technology was a gift from the Peter Sharp Foundation, and Brady molecular geneticist William Isaacs, Ph.D., and colleagues are using it to troll through the human genome, looking to see which genes are expressed differently in men with prostate cancer. (Note: This is different from Isaacs' other search for genes linked to inherited prostate cancer; read story). With Jeffrey Trent, Ph.D., and colleagues at the National Institutes of Health, Jun Luo, Ph.D., a Brady research scientist, and technician Tom Dun, Isaacs set up the microarray-like a telemarketer making random "cold calls" to look for "hits," genes that are expressed differently in normal and cancerous prostate cells.
And bingo-out of these studies came a gene from nowhere, one nobody even thought of in connection with prostate cancer, called a methylacyl CoA racemase (AMACR, or racemase for short). Next Isaacs turned to pathologist Angelo De Marzo, M.D., Ph.D., who also has expertise in molecular genetics, to figure out what racemase may have to do with prostate cancer.
In an elegant series of studies, De Marzo demonstrated that production of racemase is turned up in both prostate cancer and in high-grade PIN (abnormal cells that are not yet cancerous, but considered a pre-curser to cancer)-but not in normal prostate tissue. As a result of this work, De Marzo says, "we think we have a new marker for prostate cancer. This is one of the most consistently upregulated genes in prostate cancer. It gets turned up early in the process of cancer formation, and it stays up even in men who are failing hormonal therapy. This might be something we could start using right away, to help us diagnose prostate cancer in difficult cases." He is working with pathologist Jonathan Epstein, M.D., to see whether looking for higher-than-normal levels of racemase can improve the diagnosis of prostate cancer on a needle biopsy.
"We have every indication that this is going to work," says Isaacs. "There is going to be a gene expression profile which correlates with high Gleason grade." He and De Marzo also are working to create a "molecular definition" that will help predict what a man's cancer will do. For example, says Isaacs, "with men who have a Gleason 6 or 7 prostate cancer, some are going to progress, and some aren't."
Racemase and Diet
Racemase itself is not a "new" gene; scientists have known for years that it plays a key role in the body's metabolism of fatty acids. It makes an enzyme that "takes branch-chain fatty acids, which are found in dairy products and red meat, and converts them to a form that we can burn as energy," says De Marzo. But the fatty acids in question are very specific, adds Isaacs. "You don't need this enzyme for most fatty acids. However, you do need it to metabolize a type of fatty acid that's particularly prominent in dairy products." This acid, called phytanic acid, comes from phytol, which in turn is derived from chlorophyll. Which means, Isaacs explains, "that animals that eat a lot of grass end up incorporating a lot of phytanic acid into their milk and meat." Think cows, and think-as De Marzo and Isaacs are thinking, with growing excitement-of the known links between red meat and dairy products and prostate cancer.
Scientists have known for several years that men who consume large amounts of dairy products or red meat are more likely to develop metastatic prostate cancer, and to die of the disease.
What De Marzo, Isaacs, and colleagues are learning about racemase may help explain why. Racemase is expressed nine times higher in prostate cancer than in normal tissue. This means that when men with prostate cancer eat red meat or dairy products, the cancer cells have the potential to gain and use more energy from these foods than normal cells can. And something else happens, too: When the body metabolizes phytanic acid, it makes a toxic byproduct-hydrogen peroxide. "Right now it's complete speculation, but this may turn out to increase oxidative stress in the cell," says Isaacs. Oxidative damage is incremental harm, caused over many years, as free radicals-a harmful result of everyday metabolism- attack the DNA in cells, causing mutations that lead to cancer, or cause it to progress.
For years, there has been increasing scientific speculation on the role diet may play in preventing progression of prostate cancer. Says Urologist-in-chief Patrick C. Walsh, M.D.: "This may be the best scientific evidence to support the concept that dietary factors influence the growth of prostate cancer. I am impressed enough by these data to use them in making recommendations to patients. I tell men who are considering watchful waiting, or who have PSA progression after surgery or radiation therapy that they should markedly limit their intake of red meat and dairy products." (Fat-free milk is fine, Walsh adds.)
And the microarrays launched it all. "Here's a gene that we never would have thought about ordinarily," says Isaacs. "We were not even aware of this pathway, or phytanic acid, or what any of these things were, and here's this gene that comes screaming up on our arrays. This not only gives us a new marker for prostate cancer it may give us some insight into the mechanisms by which normal prostate cells convert to cancer cells. And perhaps it could prove this idea that reducing dairy products in the diet may be an important way to prevent or slow the progression of prostate cancer."