NEW YORK (Dec. 7, 2005) -- Turning a corner in the history of cancer research, a Weill Medical College of Cornell University team, led by Dr. David Lyden, has pinpointed key players in "pre-metastasis" -- cells and compounds that coalesce in tumor-specific niches before the arrival of cancer cells to create the "fertile ground" metastasis needs to spread and grow.

The research is being published in the December 8 issue of Nature.

"It's a big step forward -- these are events that are highly detectable and occur even when cancer cells remain at microscopic levels in the bloodstream. It could open up a whole new door to spotting and treating metastatic cancer before it starts," explained lead researcher Dr. Rosandra N. Kaplan, the Charles, Lillian and Betty Neuwirth Clinical Scholar in Pediatric Oncology and in the ChildrenÕs Blood Foundation Laboratories at Weill Cornell Medical College, and Special Pediatric Fellow at Memorial Sloan-Kettering Cancer Center, both in New York City.

"It should also help us classify patients based on their individual risk for metastatic disease," she added.

The paper also sets forth the intriguing theory that tumor spread may not only be dependent on the oncogenicity of the cancer cells, but also on the existence of "pre-metastatic niches" or "hot spots" in the body that are receptive to metastasis.

"It is conceivable that the number and capacity of these 'hot spots' to permit lodgment of tumor cells may be determined by the genetic make-up of any given patient," said co-author Dr. Shahin Rafii, the Arthur B. Belfer Professor in Genetic Medicine at Weill Cornell and Howard Hughes Medical Institute (HHMI) investigator. "This may explain why subsets of patients with early-stage colon cancer are more prone to liver metastasis, while others with an identical stage of cancer are cured of their disease with timely chemotherapy or surgery."

While much progress has been made in treating primary cancers (i.e., the tumor of origin), "we've made very little headway in fighting the biggest cancer killer, metastatic disease," pointed out senior researcher Dr. David Lyden, Associate Professor of Pediatrics and Cell and Developmental Biology at Weill Cornell Medical College; Director of the ChildrenÕs Blood Foundation Laboratories at Weill Cornell; and Attending Pediatrician at both NewYork-Presbyterian/Weill Cornell and Memorial Sloan-Kettering.

Most research on metastasis over the past century focused on malignant cells themselves, he said. More recently, experts at Weill Cornell and elsewhere have begun to examine the "microenvironment" of the metastatic site -- the enzymes, proteins, and growth factors that encourage cancer's spread.

"In this paper, however, we've gone beyond that, identifying a third party to this process -- a type of stem/progenitor cell originating in the bone marrow," Dr. Rafii explained.

Like most adult stem cells, these "vascular endothelial growth factor 1+" (VEGFR1+) cells are found in extremely small numbers in the bone marrow. They usually remain dormant until "awakened" by specific chemicals called growth factors.

"In the case of VEGFR1+ cells, we noticed that growth factors released by primary cancers triggered this awakening," Dr. Kaplan explained.

In their experiments with mice, the Weill Cornell team injected human lung cancer cells under the rodents' skin. Those cells soon formed tumors, which began to emit growth factors particular to this form of lung cancer.

"We then used a fluorescent molecular tracker to follow the movements of VEGFR1+ cells as they exited the bone marrow," Dr. Lyden said.

What they found was intriguing: As tumor-exuded growth factors circulated in the bloodstream, VEGFR1+ cells began to cluster together, moving out of the marrow and settling in specific sites within the lung.

"These were exactly the sites you'd expect lung cancer to spread once it left the primary tumor," Dr. Lyden said.

But would VEGFR1+ act differently in the presence of other cancers?

In their second experiment, the Weill Cornell team injected melanoma cells under the rodents' skin. Again, a primary tumor formed.

"However, unlike lung cancer, melanoma tends to spread to sites all over the body," Dr. Kaplan said. "We wondered if VEGFR1+ would mimic that process."

It did: "VEGFR1+ migrated to disparate sites -- just as we would have expected in the presence of a primary melanoma tumor," Dr. Rafii said. "So, it appears that these cells pave the way for different cancers in distinct ways, based on the cancer type."

"We went one step further, however," Dr. Kaplan said. "We wanted to figure out what held the VEGFR1+ cell to the intended site, once it found it."

In their experiments, Dr. Kaplan's team discovered that fibronectin -- a protein secreted naturally by cells called fibroblasts -- acts as a kind of "glue," helping VEGFR1+ cells settle in the "pre-metastatic niche."

"In fact, the same tumor growth factors that pull VEGFR1+ out into the bloodstream also increase the production of fibronectin, whenever a VEGFR1+ cell comes near," explained medical student co-researcher Rebecca Riba. "That's because a molecule found on the cell's surface, called VLA4, acts as a kind of binding agent, linking VEGFR1+ and fibronectin together," she said.

The bottom line? "This partnership of cells and proteins creates the ideal environment for migrating cancer cells, in exactly the location they are seeking depending on their specific cancer type," Dr. Lyden said.

The Weill Cornell team also analyzed non-malignant tissues from patients with primary cancers of the breast, lung, and throat, to see if this process was replicated in humans.

"As expected, we found clusters of VEGFR1+ cells already present in tissues taken from sites that were the usual targets of the cancers in question. VEGFR1+ was there before the cancer cells had arrived," Dr. Lyden said.

"It's really amazing," Dr. Kaplan said. "We've been able to illuminate a whole new series of steps that makes metastatic disease possible. And all of this happens prior to cancer cells colonizing the site themselves."

Theoretically, that means that drugs or other therapies that interrupt the movement of VEGFR1+ cells out of the bone marrow or stop their binding with fibronectin might prevent metastatic cancer from finding the fallow ground it needs to grow.

"What's more, monitoring this 'pre-metastatic' activity should help us stratify patients according to their individual risk for recurrence," Dr. Kaplan said.

Patients with high levels of VEGFR1+-related activity may need preventive therapies to cut their chance of metastatic disease, she explained, while patients with lower levels might be spared these treatments.

"This is just the beginning," Dr. Lyden added. "Preventing primary cancers from getting a toehold elsewhere in the body could be just the weapon patients need to prevent and fight metastatic disease."

The work was funded by grants from the National Cancer Institute, The Doris Duke Charitable Foundation, the Children's Blood Foundation, the Emerald Foundation, the Theodore A. Rapp Foundation, the American Hellenic Educational Progressive Association 5th District, and the LTC Foundation.

Co-researchers include Dr. Stergios Zacharoulis, of Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center, New York; Dr. Elisa Port of Memorial Sloan-Kettering; Zhenping Zhu, Daniel Hicklin, and Yan Wu of Imclone Systems Incorporated, New York; Davide Ruggero of Fox Chase Cancer Center, Philadelphia; as well as Anna H. Bramley, Loic Vincent, Carla Costa, Daniel D. MacDonald, Dr. David K. Jin, Dr. Koji Shido, Scott A. Kerns, Dr. Jeffrey L. Port, Dr. Nasser Altorki, Dr. Sergey V. Shmelkov, and Dr. Kristian K. Jensen -- all of Weill Cornell.

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