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Reading cancer's road map


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Tuesday, February 14, 2006



One of cancer's enduring secrets is how it manages to burst from its origins in the breast, colon, lung or prostate and establish deadly new colonies in other organs.

New studies have revealed a few of the cunning tricks cancer uses to spread throughout the body. Cancer cells, for instance, apparently use signals from normal tissue to break away from primary tumors. Tumors also can enlist bone marrow cells to scout out new sites where cancer can set up housekeeping.

The process of metastasis amazes even scientists who have studied cancer for decades.

"It really is very bizarre," says Ira Mellman, scientific director of the Yale Cancer Center.

Yet understanding metastasis is also a crucial step in the fight against cancer. Stationary tumors don't generally kill people. Tumors that travel do.

"We really don't understand metastasis," says David Lyden, associate professor of pediatrics and cell and developmental biology at Weill Cornell Medical College. "We have really failed patients with metastatic cancer."

However, Lyden and others have begun to shed light on how cancer spreads.

Ross L. Cagan at the University of Washington in St. Louis, for instance, is focused on a simple question:

"It's never been entirely clear why cancer cells leave in the first place," said Cagan, professor of molecular biology and pharmacology.

Last month in the journal Development Cell, Cagan and post-graduate student Marcos Vidal identified one reason why cancer cells begin to migrate. Looking at tumors in living fruit flies, the scientists found that cells at the edge of a tumor, in direct contact with normal cells, elicit a molecular response from the surrounding tissue that enables the cancer cells to break free and move away.

They found that when cancer cells with a high level of the gene SRC, which is commonly found in breast cancers, come in contact with normal tissue, the cancer cells lose surface proteins called cadherins, which act as a sort of molecular glue that binds cancer cells together.

The changes occur only in cancer cells at the border of the tumor, not in the interior of the tumor mass. And the newly wandering cancer cells are aided in their escape by another enzyme secreted by the tumor that dissolves the matrix surrounding the cells.

'Kicked out'

"Normal tissue sends out a signal that says, 'Hey, you shouldn't be here,' and literally kicks the cells (at the edge of a tumor) out," Cagan said. "They just walk out of the tumor mass. Of course, that turns out to be very bad."

Scientists used to think that freed cancer cells simply wandered through the bloodstream or lymphatic system until they randomly found another home. But Lyden's work with mice suggests tumors are much more deliberate than that -- that they have already recruited other cells to find and prepare a safe haven for migrant cancer cells even before they begin their journey.

The cellular scouts are adult bone marrow stem cells that activate a gene called VEGFR1 -- one of the genes known to promote angiogenesis, or the formation of new blood vessels.

Usually present only during embryonic development, the angiogenesis process is resurrected by cancer tumors to provide nutrients to help them grow. Studies of human tissues have shown VEGFR1-positive bone marrow cells are present in higher-than-expected numbers in cancer patients.

Before migrating cancer cells land, these bone marrow cells arrive at the site of a future metastasis and build a sort of welcoming nest where cancer cells can land and proliferate.

Growth factors that the tumor secretes are believed to start the work on this welcoming nest. Those growth factors produce an adhesion molecule called fibronectin that provides a docking site for the bone marrow cells.

Scientists have long been puzzled about why primary tumor types have a tendency to metastasize to different organs -- colon to liver, breast to bone or lung, lung to brain.

Lyden and his colleagues believe that the answer may lie in part in genetic differences in the patients or in the type of growth factor secreted by primary tumors.

Lyden says that tracking bone marrow stem cells provides a "road map" for metastasis. He believes it will be possible to predict the risk of metastatic cancer -- and, therefore, how aggressively a patient's cancer should be treated -- by measuring VEGFR1-positive bone marrow cells. He also says that antibodies might be developed that would attack those cells, preventing cancer from spreading.

Cagan similarly says he believes the SRC gene could provide diagnostic and therapeutic potential.

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