Restoration of a gene that is frequently functionally silenced in clear cell renal carcinoma can suppress tumor growth or even eliminate tumors in vitro and in animal models, according to an article in the August 15 issue of Clinical Cancer Research.

The researchers, at Mayo Clinic Jacksonville, FL, found that suppression of the gene for secreted Frizzled-Related Protein-1 (sFRP-1) appears to be one defining epigenetic event in 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, including colon cancer.

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, 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. 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 cancer samples showed a total loss of sFRP-1 proteins and the other 30 percent had very little of the protein.

Finally, researchers used a common experimental technique to see what would happen if they reactivated sFRP-1 in tumor cells. They had discovered that, in clear cell renal carcinoma, sFRP-1 is silenced through a process known as methylation.

Restoring sFRP-1 protein expression by a technique of transfecting the sFRP1 gene into human renal cancer cells was remarkably effective. Growth of tumors decreased by at least 90 percent in sFRP1 transfected patient-derived cancer cells in the laboratory, and Wnt-regulated oncogenes such as c-myc were suppressed compared to untreated cells.

In mice, tumors in which sFRP-1 function had been restored for seven weeks were an average of 3 percent the size of tumors in untreated animals. In many animals, the tumors disappeared completely. “This was a dramatic reduction,” Gumz said. “Our report is the first to show anti-tumor activity of sFRP-1 in an animal model and to clearly implicate Wnt as an oncogenic signaling pathway in renal cell carcinoma.”

Understanding and targeting the Wnt signaling pathway with drugs has been a goal of researchers worldwide, Copland sad. “There are at least 20 known Wnt molecules and five members of the sFRP family, and we are slowly beginning to understand how they work together.” Anti-methylation agents are now being tested in various clinical trials, he added, saying, “Given results of this study, that kind of strategy might be useful. There are few effective therapeutic options for metastatic clear cell renal cell carcinoma that result in increased longevity and quality of life. Restoration of sFRP-1 function represents a possible therapeutic target.”

The findings might also be helpful in identifying which type of kidney cancer a patient has developed. The researchers found that loss of sFRP-1 is common in clear cell renal cell carcinoma as well as in the next most common form of renal cell carcinoma, the papillary subtype. But loss of this gene is not seen in chromophobe renal cell carcinoma and benign oncocytoma. “Although biopsies are not performed for renal cell carcinoma currently, creating molecular signatures unique to the subtype of renal cell carcinoma using genes such as sFRP1 and removing a small piece of tumor tissue by biopsy could save some patients from surgical removal of a benign mass,” Copland said.