May 24, 2002 LOS ANGELES, May 2002 - When faced with the challenge of treating patients with kidney cancer, doctors know that today’s chemotherapy offers little help. But a new study from the Keck School of Medicine of USC identifies a possible origin of the mysterious cancer, potentially pointing scientists toward ways to attack the disease.
Although scientists recognize that several factors seem to put people at higher risk of developing kidney cancer, no one has yet identified causes of the disease. USC preventive medicine researchers, however, propose in the April issue of Cancer Causes & Control that the root of the enigmatic cancer lies in a process called lipid peroxidation: the oxidation of fatty acids.
"The idea of lipid peroxidation as a mechanism for renal cell carcinoma unites many of the known risk factors for this cancer," explains Manuela Gago-Dominguez, M.D., Ph.D., researcher in preventive medicine at the USC/Norris Comprehensive Cancer Center and lead author of the study. "Obesity and high blood pressure, which are known to increase kidney cancer risk, are both associated with lipid disturbances—as are numerous other risk factors."
Physicians diagnosed about 30,800 new cases of kidney cancer last year in the United States, and about 12,100 people died from the disease, according to the American Cancer Society. Most kidney cancers are renal cell carcinomas. Kidney cancer cases have risen dramatically in the U.S. and Europe in the past three decades: by the mid-1990s, rates for both men and women were 50 percent higher than comparable rates in the early 1970s.
In addition to obesity and hypertension, known risk factors for kidney cancer include cigarette smoking, diabetes, male gender and, among women, oophorectomy (undergoing removal of the ovaries) and parity (giving birth to numerous children).
USC researchers analyzed more than two dozen studies, and found increased signs of lipid peroxidation in the blood of those who are obese, those with high blood pressure, smokers, diabetic patients and women who had had a hysterectomy and oophorectomy. Lipid peroxidation also increased in the kidney cells of rodents after testosterone treatment or oophorectomy.
Yet lipid peroxidation decreased in the renal cells of rodents after they were treated with antioxidants. Signs of lipid peroxidation also decreased in the blood of smokers after they consumed antioxidants.
Gago-Dominguez explains that when rodents were given a chemical that induces the tiny tubes in the kidneys to die off and then causes renal cell carcinoma, researchers saw signs of increased lipid peroxidation. However, when rodents were given a similar chemical that causes the tiny tubes to die off—but results in no cancer—researchers saw no increased lipid peroxidation. Lipid peroxidation might contribute to kidney cancer this way:
When fatty acids combine chemically with oxygen (oxidation) in the body, the process creates new chemical products. Some of these byproducts have been shown to react with DNA in kidney cells and cause DNA damage.
The body tries to repair the damaged DNA, but if the repair goes awry, that can lead to mutations in genes that can kick off cancer or genes that suppress cancer. These mutations are a critical step in the progression of normal cells to malignant cells.
"If lipid peroxidation is the fundamental mechanism behind the link between obesity and hypertension and kidney cancer," says Gago-Dominguez, "then developing therapeutics or chemopreventive agents that can decrease lipid peroxidation at the target site—and administering such drugs to cancer patients and those at high risk for the cancer—would lessen the burden of kidney cancer morbidity and mortality."
Manuela Gago-Dominguez, J. Esteban Castelao, Jian-Min Yuan, Ronald K. Ross and Mimi C. Yu. "Lipid peroxidation: a novel and unifying concept of the etiology of renal cell carcinoma." Cancer - Causes & Control, April 2002, Vol. 13, No. 3, pp. 287-293.
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