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’Switched-Off’ genes put first chink in colon cell’s anti-tumor armor


Johns Hopkins Kimmel Cancer Center scientists have identified a switched-off family of genes that may prove to be a significant and early dent in a colon cell’s anti-cancer armor. The inactivated genes, called SFRPs - for secreted frizzled-related protein - put the brake on a pathway of cell-growth genes that is an early step en route to cancer. Because the way SFRP genes are altered-through the attachment of so-called methyl groups-is reversible, the findings, reported in the March 14 advance online edition of Nature Genetics, also suggest potential anti-cancer value in green tea and other compounds that affect methylation. "SFRP could be a great target for preventing cancer," says Stephen Baylin, M.D., Ludwig Professor of Oncology and director for basic research at the Johns Hopkins Kimmel Cancer Center. A cancer cell stops the SFRP gene’s brake on cell growth by attaching a methyl group to a specific portion of the gene in a process called hypermethylation. Green tea and other compounds are thought to block enzymes that control methylation.

SFRP genes encode proteins that, when secreted on the cell’s surface, stop a chain reaction of cell growth directed by the WNT gene. WNT stands for "wingless type," which, along with SFRP genes, gets its name from characteristics of fruit flies with mutations in these genes. The WNT gene pathway has long been linked to colon cancer by scientists at the Kimmel Cancer Center and elsewhere.

"Previously, we thought that mutations downstream of the WNT gene were enough to trigger the cell to stay alive, keep growing and develop into a tumor. Our key finding is that the cell also may need to shut off SFRP genes to become cancerous," says Baylin. When Baylin’s team put SFRPs back into colon cancer cells with inactivated SFRP genes and mutations in the WNT pathway, the cells stopped growing uncontrollably and died.

The research team also found that inactivation of SFRP genes occurs in the earliest form of lesion, called an atypical crypt foci (earlier than polyps or cancer). Approximately 5 percent of these lesions become colon cancers. "The colon cancer process may start by shutting off SFRP genes, which allows the WNT pathway to stay on, and these colon cells grow into atypical crypt foci," Baylin explains. "Then, some of these early lesions may acquire mutations in the WNT pathway that push the cell into growth overdrive, failure to die properly, and development into polyps and, finally, cancer."

In addition to studying natural compounds, the scientists will be investigating the prevention properties of aspirin, non-steroidal anti-inflammatory drugs, and other drugs that block methylation to determine their effect on SFRP genes.

This research was funded by the National Institute of Environmental Health Services.

Other participants in the research are Hiromu Suzuki, D.Neil Watkins, Kam-Wing Jair, Kornel E. Schuebel, Yoshimitsu Akiyama, Bin Yang, and James G. Herman from the Johns Hopkins Kimmel Cancer Center; Sanford D. Markowitz from the Howard Hughes Medical Institute and Case Western Reserve University, Teresa P. Pretlow and Wei-Dong Chen from Case Western Reserve, Manon van Engeland from the University of Maastricht, the Netherlands, Minoru Toyota, Takashi Tokino and Kohzoh Imai from Sapporo Medical University, and Yuji Hinoda of the Yamaguchi University School of Medicine, Japan.

The license to the MSP technique used in this research belong to OncoMethylome. Drs. Baylin and Herman serve as consultants to OncoMethylome and are entitled to royalties from any commercial use of this procedure. The terms of this arrangement are being managed by the Johns Hopkins University according to its conflict of interest policies.

Vanessa Wasta | EurekAlert!
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