By the time a newly hatched cancer has grown to a million cells (a fewcubic millimeters), it's out for blood.In order to keep on growing, a solid tumor needs to tap into thecirculation of its host's body, to supply its insatiably proliferating cellswith oxygen and nutrients.Angiogenesis is the name of cancer's game _ the ceaseless creationand spreading of capillaries, the minute blood vessels that feed atumor's frenzy of malignant expansion.Among the numerous growth factors that contribute to angiogenesis,one in particular, basic fibroblast growth factor (bfGF) stands out inbringing new blood vessels to malignancies, especially in brain andnervous system. Turning this tumor-nourishing propensity to clinicaladvantage is the theme of a paper in this week's Lancet, "Microvesselcount and cerebrospinal fluid basic fibroblast growth factor in childrenwith brain tumors."Its principal author is cancer researcher Judah Folkman, who teachespediatric surgery at Harvard Medical School. Folkman has become apioneer in putting angiogenesis on the map of cancer research since theearly 1970s.Best Blood Vessel Output Means Worst Patient Outlook"This study in Lancet," he told BioWorld Today, "shows that bfGFgoes up to very high levels, and so we can use it to try to predict theoutcome of the patient." He explained, "The tumors that are mosthighly angiogenic _ that is, the ones that induce the most bloodvessels _ have the worst outcome and prognosis. These tumors aremost likely to recur [after surgical removal] or relapse."What this is telling us," he continued, "is that if you look at the braintumor's ability to signal for new capillaries, it says that some tumorscan do it very well, others, poorly. The ones that do it well are mostlikely to be the most virulent."From this finding flows the prospect of using bfGF levels in tumortissue as markers for measuring tumor growth, and targeting treatment.The place to look for bfGF in the brain is the cerebrospinal fluid (CSF),which bathes the brain and spinal cord. Between July 1991 and October1992, Folkman and his collaborators analyzed the CSF of 26 brain-tumor patients, three to 20 years of age, for bfGF. As controls, theytook CSF from 18 children with non-solid, blood-cell tumors orhydrocephalus.They detected bfGF in the CSF of 16 of the 26 patients, (62 percent),but in none of the controls. Since this initial analysis, follow-ups of the26 patients, Lancet reported, "revealed an association of earlier tumorrecurrence with elevated bfGF and with increased microvesseldensity."The fact that three CSF samples had no bfGF, yet stimulatedendothelial-cell DNA synthesis suggested that "bfGF is not the onlyangiogenic peptide present in the CSF of brain-tumor patients." Othercandidate neovascularization molecules include acidic fibroblast GFand vascular endothelial GF.For this reason, Folkman pointed out, it would be pointless to trycurbing a tumor with a bfGF-specific monoclonal antibody. "Thetumor could be making one, two or three angiogenic factors, soattacking one wouldn't do it."Angiogenesis Inhibitors In Phase IOn the other hand, he added, seven angiogenesis-inhibiting compoundsare currently in Phase I clinical trials in Europe and the U.S. Three ofthese were developed in his laboratory, including a protein, plateletfactor 4, (PF4), found normally in the body. Repligen Corp., ofCambridge, Mass., is producing PF4, and managing its use in clinicaltrials.bfGF is a protein occurring normally in the body, where it helps tomediate such functions as wound healing, scar-tissue formation andmenstruation. "The key thing about its normal use," Folkmanemphasized, "is that bfGF is very rigorously controlled; it's turned onand off in a few days, whereas in tumors, once turned on it stays on andon and on _ almost as if its gene is over-expressing _ and it's verydangerous."However, high-level bfGF readings are not confined to cancers, as aserendipitous discovery confirmed. With his manuscript for Lancetalready in press, Folkman happened to come across a 1993 Japanesepaper titled, "The cerebrospinal fluid in patients with moyamoyadisease contains high levels of basic fibroblast growth factor."Moyamoya is a very common non-malignant disorder among childrenin Japan. It blocks blood vessels at the base of the brain, andrevascularizes them by an out-of-control outgrowth of fine vessels.Moyamoya's symptoms include convulsions, mental retardation andcerebral hemorrhage.One of Folkman's co-authors, neurosurgeon R. Michael Scott, has oneof the largest collections of moyamoya disease in the U.S., where it isexceedingly rare. Folkman now intends to follow these patients, "andsee what they look like."Neurosurgeon and oncologist Henry Brem is principal investigator inthe National Cancer Institute's Brain Tumor Vascular Biology Centerat Johns Hopkins University. Hospital, BaltimoreCSF monitoring for bfGF is a major aspect of the Center's work, Bremtold BioWorld Today. "I've been interested in the same area asFolkman," he said, "but in adults more than in children.""Folkman," Brem said, "basically discovered the field of angiogenesisresearch in the 1970s, and in the last 25 years has really nailed itdown."Brem sees two major potential payoffs in the current Lancet bfGFpaper: "One: The whole area of biomarkers is very important for braintumors, by reflecting the ability of a lesion to grow. Second: The abilityto monitor what is the best marker for angiogenesis means that we havea way of testing the effectiveness of an anti-angiogenesis treatment,once it becomes current clinical practice." n

-- David N. Leff Science Editor

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