Blood Vessels Key to Giving Tumors Foothold in Body

A discovery by cancer researchers that zeroes in on the process of how tumors gather nutrients, flourish and spread holds strong implications for diagnosis and treatment.

The finding, reported in a recent issue of the journal Nature Medicine, shows how tumor growth depends on the recruitment of vessel-building cells from bone marrow. After blocking these cells in transit to tumors, scientists saw cancers shrink in mice.

“Blood vessels are important to tumors,” said Dr. David Lyden, a pediatric oncologist and the study’s lead investigator, at Memorial Sloan-Kettering Cancer Center in Manhattan.

Angiogenesis, the sequence of events tumors employ to sprout life-sustaining blood vessels, has been among the most mystifying processes in tumor biology. With blood vessels, cancers are capable of growing, gaining bulk and ultimately spreading to distant sites. Though well theorized, the actual process largely was clouded by unknowns, at least until now.

A project by Memorial Sloan-Kettering Cancer Center and Weill-Cornell Medical College of Cornell University, also in Manhattan, has found that tumor blood-vessel growth begins with insidious precursor cells in bone marrow.

These cells, as it turns out, are invited to the tumor by growth factors, molecules secreted from the cancer. It is a survival mechanism that has helped some tumors grow to tremendous size, and countless others to spread.

“Most people in the field of angiogenesis, and certainly Dr. Judah Folkman, always felt that cells contributing to angiogenesis originated in the bone marrow,” Lyden said. Now, based on animal studies, he and his colleagues know that this is, in fact, what occurs.

Folkman, a Harvard University cancer researcher and theorist, was the first to suggest that tumors grow, gain strength and thrive by virtue of having their own blood supply. Eliminate the vessels, Folkman has argued, and the tumor will cease to be. Understanding the finer points of tumor blood vessel development, nevertheless, has remained largely a conundrum.

“This whole process starts defining very early,” Lyden said. He and his colleagues found that the precursor cells, once mobilized, headed straight to the tumor.

Decoding how tumors recruit the building blocks of blood vessels holds tremendous potential as a diagnostic, Lyden explained, at the point of early cancer growth as well as metastasis. A diagnostic test based on this premise is being evaluated at Memorial Sloan-Kettering.

One hope is to block mobilized, vessel-producing cells, Lyden added, before they reach the tumor.

Much of the foundation for this new understanding was produced in the laboratory of Dr. Robert Benezra, director of cell biology and genetics at Memorial Sloan-Kettering. He demonstrated that two proteins, Id1 and Id3, are required to sustain blood vessel growth in tumors.

Scientists transplanted bone marrow cells from donor mice into Id-deficient mice. These cells were tagged with the protein beta-galatosidase, which has the capability of turning blue when stained with a dye. Here, the working idea was that vessel-building cells should turn blue, and hence their path would become easily traceable through the labyrinthine circulatory system.

Within a month, the animals were given either lymphoma cells or lung cancer cells. The transplanted mice developed metastases and were dead within 26 days.

Startlingly--but confirming the theory that cells involved in the formation of tumors are recruited from the bone marrow--blue cells were found in liberal profusion in all vessels supporting tumors in mice.

“We’ve seen the mobilization of these cells very early in angiogenesis,” Benezra said. “The hope is to monitor these cells” in patients, Benezra added, “for the presence of minimal residual disease.”

The findings are being hailed as an advance in elucidating how tumors grow and spread. “This is the first definitive proof that bone marrow contributes to the formation of functional blood vessels of certain tumors,” said Dr. Shanin Rafii, an oncologist and specialist in cancers of the blood and the team member at Weill-Cornell Medical College. His initial research helped launch the study.