By David N. Leff

Besides growing out of control, and metastasizing out of sight, some tumors add a little-known insult to those injuries. It¿s called paraneoplastic syndrome ¿ PNS for short.

The key clue to this remote, nonmalignant cancer spin-off is that the patient¿s blood swarms with an overload of vascular endothelial growth factor ¿ VEGF. This is the powerful angiogenic molecule that promotes the growth and survival of inner endothelial cell walls lining the arteries, veins and capillaries of mammalian blood vessels. When a nascent tumor starts to feel its oats, it summons VEGF to build it a network of arterioles, venules and capillaries as pipelines freighting in the oxygen and nutrients it needs to keep growing, and ship out the waste products it can do without.

This process of angiogenesis is currently commanding intense research and investment interest as an attack ¿ anti-angiogenesis ¿ on what is perceived as a tumor¿s Achilles¿ heel. (See BioWorld Today, Oct. 20, 1998, p, 1.)

It¿s when a tumor that, for reasons still a mystery, impulsively starts pouring huge amounts of VEGF into a cancer patient¿s bloodstream that PNS symptoms kick in.

¿There have been associations reported in human patients,¿ observed melanoma geneticist Lynda Chin, ¿where poor prognosis or advanced tumors correlated with high circulating levels of VEGF detected in the blood. But a definitive causal relationship between high VEGF levels and tumor growth had not been made.¿

Chin, at the Harvard-affiliated Dana-Farber Cancer Institute in Boston, makes that correlation in the current Proceedings of the National Academy of Sciences (PNAS), dated June 19, 2001. The research article, of which she is senior author, bears the title: ¿Excessive tumor-elaborated VEGF and its neutralization define a lethal paraneoplastic syndrome.¿ A co-author, and close collaborator, is George Yancopoulos, senior vice president of research and chief science officer at Regeneron Pharmaceuticals Inc., of Tarrytown, N.Y.

Mouse Experiments Reverse VEGF Depredation

¿The main point of the finding that we reported in PNAS,¿ Chin told BioWorld Today, ¿is the observation that high circulating levels of VEGF can have deleterious effects, and may lead to development of signs and symptoms that resemble the rare human peliosis hepatus, which devastates the liver. The implication of this is that such patients are known to have what we call paraneoplastic syndrome. Correction of that condition,¿ she pointed out, ¿which is independent of the tumor burden itself, may provide cancer patients a better quality of life.¿

Chin and her co-authors ¿implanted murine melanoma and human glioma cells into mice, engineered to express VEGF. Those cells grew into big tumors. We had previously established a mouse model of melanoma by activating the ras oncogene in melanocytes, and inactivating a tumor suppressor,¿ she related. ¿And that¿s where the tumor cell line was derived. Ras,¿ she observed, ¿is an oncogene, often mutated in many different tumor types, including melanomas.

¿As the mouse model tumors grew larger,¿ Chin recounted, ¿the mice began to show signs of illness. At that point, we surgically excised the tumors, or administered a systemic antagonist of VEGF called VEGF-TRAP. Either procedure completely blocked the symptoms of the paraneoplastic syndrome, which was mainly attacking the liver.

¿In one experiment,¿ Chin went on, ¿we gave the mice only a single dose of the VEGF antagonist, and looked at their livers 24 hours later. Over this period, the melanoma tumor burden did not change, but there was a dramatic reversal of the peliosis hepatus-like symptoms. So we believe we can reverse this syndrome without really affecting the tumor.

¿That reversal factor,¿ she said, ¿is VEGF-TRAP ¿ the trademarked term the Regeneron company calls it. TRAP is basically a modified receptor body that goes around and sops up ¿ entraps ¿ all the VEGF, preventing it from binding to its actual receptor, thereby blocking the syndrome. This is the first published experimental report of TRAP,¿ she observed. ¿We could give it not every day but twice a week, and still get the good effects that we were seeing.¿

Chin made the point, ¿One of the most dramatic things the paper shows is the effect of the TRAP. From academic and clinical points of interest, it points out the potential of this VEGF-mediated syndrome in treating cancer patients. There will also be a use for anti-VEGF therapy, not just to target the tumor itself directly, but potentially for beneficial effects for cancer patients suffering from this syndrome.

¿Our mouse study would suggest,¿ Chin surmised, ¿that it¿s possible some of those patients may succumb to the side effects of high-level VEGF secreted from their tumor, rather than the tumor itself. It remains to be shown in patients that by treating those symptoms, we can improve and potentially prolong their lives.

¿In the mouse model that we studied,¿ she noted, ¿the liver was the only organ that seemed to be affected. But in the mice, our study was very short ¿ about three weeks was the longest observation time that we had. It wouldn¿t surprise me if we could look at the condition over a longer period of time ¿ say a year, five years, 10 years ¿ in a human patient with a tumor, and find the syndrome affecting other organs than the liver.¿

AIDS-Related Infection Has VEGF Link

¿So that¿s in terms of therapy for cancer,¿ Chin went on. ¿But there¿s another point that we mentioned in our PNAS article, which is Bartonella henselae infection. This is a chronic bacterial infection that induces perivascular lesions. Our study may suggest a link to excess VEGF in the mechanism of how Bartonellosis leads to development of those symptoms. If that correlation holds true, it provides a way for treating the infection. It¿s not very common,¿ Chin pointed out, ¿occurring more in certain populations, including HIV patients; it¿s not a prevalent infection like pneumonia.¿

Bartonella infection, which causes high fever, anemia and skin lesions, first surfaced in World War I, under the name of trench fever. It staged a comeback in World War II, and frequently infects AIDS patients who keep pet cats, which inflict cat-scratch fever.

Chin¿s PNAS paper concludes, ¿Our findings in the mouse have suggested an etiologic role for VEGF in [Bartonella infection], and may lead to diagnostic and therapeutic options for this debilitating condition in humans.¿