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Normal anticancer gene may also play role in blocking angiogenesis

Thomas Jefferson University

A gene better known for its anticancer protective properties might actually play an important role in blocking a tumor's ability to create blood vessels promoting its own growth, a process called angiogenesis.

Researchers at Jefferson Medical College have shown for the first time that the gene, Rb2/p130, which is a member of the retinoblastoma "tumor suppressor" gene family, may inhibit the process, thought to be crucial to the spread of cancer.

"[The gene] Rb2 is an important inhibitor of angiogenesis," says Antonio Giordano, M.D., Ph.D., associate professor of pathology, anatomy and cell biology at Jefferson Medical College of Thomas Jefferson University in Philadelphia, who led the work. The gene is believed to be a "tumor suppressor," a normal cell growth control gene that prevents cancer. He calls Rb2 "a new biological drug."

The Jefferson team and colleagues from the University of Naples, Italy, the University of Siena, Italy and Sunnybrook Health Science in Toronto, report their work January 15 in the journal Cancer Research.

Angiogenesis has received a great deal of news coverage in the last two years, particularly from The New York Times, when stunning results in animal tests indicated that antiangiogenesis drugs had great potential to treat human cancer. Now researchers are studying the mechanisms underlying angiogenesis. Dr. Giordano and his team were studying glioblastoma tumors and lung cancer tumors in mice when they noticed that the tumors appeared calcified after treatment with Rb2. Thinking this might be caused by a lack of blood flow to the tumors, they investigated further.

"We thought this was related to one of the mechanisms of tumor inhibition exerted by the Rb2/p130 tumor suppressor gene," Dr. Giordano says. But they found Rb2 was blocking tumor growth by interfering with the angiogenesis pathway. "This is a further mechanism also inhibiting the proliferation of cells and formation of tumors."

The scientists studied vascular endothelial growth factor (VEGF), a substance which promotes the growth of cells and is a marker for angiogenesis. Tumors with high growth rates have greater VEGF gene expression.

The researchers treated lung cancer and glioblastoma cell lines by injecting Rb2 along with two types of virus delivery systems, a retrovirus and an adenovirus. As the level of Rb2 rose, VEGF decreased, reducing blood flow to the tumors.

"This doesn't mean a direct mechanism, but clearly, Rb2 has a say in the relation that is occurring between VEGF and other angiogenetic factors," Dr. Giordano says. "We don't know yet if the mechanism is direct. We can kill the tumor, but we don't know if we're directly eliminating the tumor or if we're triggering a chain of events.

"The tumor uses VEGF to have the host cell produce vessels to feed it. We showed we could inhibit 10 times the number of vessels that would form normally in the control tumor."

"This may be an extra mechanism by which Rb2 can inhibit a tumor from growing," notes Pier Paolo Claudio, M.D., Ph.D. instructor in the Department of Pathology, Anatomy and Cell Biology at Jefferson Medical College. "We can't tell if its separate mechanism or not or if one precedes the other. Basically it's inhibiting the cell cycle in its tumor suppressor role and also the angiogenetic pathway."

"The finding is surprising," Dr. Giordano says. "Rb2 has been shown to be one of the few molecules that could strongly inhibit the growth of tumor cells in animal tests, suggesting that it could be a new biological drug," says Dr. Giordano.

"We are making our biological drugs smarter, and we are learning how this biological drug is affecting the growth of the tumor and learning also to build a more sophisticated delivery system that will be able to inhibit tumor cells," Dr. Claudio says.

"Our goal is still to seek FDA approval and to bring this entire system to patient trials," he says. "Eventually, especially for lung cancer, we want to develop an easier way of delivering Rb2, perhaps by aerosol. We're in the process of designing small molecules to more efficiently deliver the small portion of Rb2 necessary to inhibit tumor growth."

Rb2 therapy may also be used as an additional treatment for some patients, whether before or after surgery, the researchers say.

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The research was supported in part by the National Cancer Institute.

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