Researchers at Mayo Clinic Jacksonville, have found that a key gene is often silenced in clear cell renal cell carcinoma, the most common type of kidney cancer, and when they restored that gene in human kidney cancer cells in culture and animal experiments, tumors stopped growing and many disappeared.
In the August 15 issue of Clinical Cancer Research, investigators report that suppression of this gene, which makes secreted Frizzled-Related Protein-1 (sFRP-1), appears to be one defining epigenetic event in the development and progression of clear cell renal carcinoma, which is responsible for at least 80 percent of kidney cancers. The researchers also found that sFRP-1 controlled 13 tumor-promoting genes along the powerful 'Wnt' signaling pathway, whose activity has been linked to a number of different cancers, of which colon cancer is best known.
"For all intents and purposes, sFRP-1 acts as a key tumor suppressor gene in clear cell renal cell carcinoma -- it puts a brake on Wnt, stopping dangerous oncogenic signaling to the cancer cell, thus blocking tumor growth and metastasis," explained the study's senior investigator, John A. Copland, Ph.D., a molecular biologist at Mayo Clinic Cancer Center. Michelle Gumz, Ph.D., a former postdoctoral researcher at Mayo Clinic, is the lead author of the study. She is now at the University of Florida.
The findings may also be relevant to other cancers, such as breast, ovarian, prostate, bladder, lung and colon cancers, in which loss of sFRP-1 function is common, Dr. Copland explained. "Through understanding the important role sFRP-1 plays, we may be able to eventually tailor human therapies to restore its function in this type of kidney cancer and in other cancers," he says.
Kidney cancer incidence and related deaths have been increasing by about 2 percent per year for the past six decades, for reasons that are not fully understood but may be related to smoking and other environmental factors. More than 50,000 new cases of the cancer are expected in 2007, with almost 13,000 deaths. Kidney cancer tumors are often found when they are advanced and extremely difficult to treat: two-year survival at that stage is only 12 percent whereas kidney cancer that has not yet spread has a five-year survival of up to 75 percent.
To aid diagnosis and treatment, Dr. Copland and a team of researchers have been developing a panel of biomolecular markers for kidney cancer. They are comparing tissue from renal cell tumors with normal kidney tissue from the same patient, searching for ,master, genes that control signaling pathways that are involved in cancer development and progression. A master gene, if altered, would shut down the cascade of cancer-causing genes that it controls. "There are likely to be a number of molecular events that lead to cancer development, so we want to find as many genes as we can that we might shut down, like Wnt, or turn back on, like sFRP1," Dr. Copland says.
To find out which genes are activated and which are silent, in normal versus cancerous kidney tissues, the research team used three independent sets of patient kidney tissue samples from Mayo Clinic College of Medicine, in Jacksonville, and from The University of Texas M. D. Anderson Cancer Center in Houston. In one sample, they found that gene expression of sFRP-1 was ,down-regulated," or turned down low or off, in 15 of 15 patients. They also found that activity of the gene decreased as much as 70 times the level seen in normal tissue.
In a second set of 33 patient samples, the researchers looked for evidence of messenger RNA (mRNA) activity; mRNA, transcribed from sFRP-1, is the blueprint that cells need to produce sFRP-1 proteins. Every stage of kidney cancer showed decreases in sFRP-1 mRNA, some as much as 140-fold.
Investigators then searched for differences between sFRP-1 protein levels in normal versus cancerous cells within another set of 39 matched patient samples. They found that 70 percent of the cancerous samples showed a total loss of sFRP-1 proteins, and the other 30 percent had very little of the vital protein in cells. "The take home message is that there was almost a complete loss of sFRP-1 protein in most of the renal cell carcinoma samples we studied," Dr. Copland says. "If no protein is being produced, the Wnt signaling pathway is free to activate other molecules that can cause cancer."