Inhibition of Pro-Inflammatory Factor, VEGFR-1, Expressed on Adult Stem and Blood Cells, Prevents Atherosclerosis and Inflammatory Conditions That Lead to Arthritis and Cancer

Jun 30, 2002

Scientists from Weill Cornell Medical College (New York City) and the Interuniversity Institute for Biotechnology at the University of Leuven (Belgium) have discovered a key role for a biologically potent growth factor receptor, known as Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1), found on adult bone-marrow-derived stem cells. In two separate papers, just published online in Nature Medicine, these researchers show that activation of VEGFR-1 results in the mobilization and incorporation of pro-inflammatory stem and blood cells into various organs, contributing to inflammation and abnormal vessel formation. This leads to the evolution of cardiovascular diseases, such as atherosclerosis, as well as to arthritic joint diseases, blood disorders, and cancer progression.

The scientists also present important preclinical animal studies that utilize blocking antibodies—developed by scientists at ImClone Systems—to demonstrate that inhibition of VEGFR-1 activity is effective in diminishing atherosclerosis, as well as in blocking inflammatory processes, thereby preventing the progression of rheumatoid arthritis and certain cancers. The studies lay the foundation for fighting disabling diseases—including heart, joint, blood, and malignant disorders—which afflict millions of individuals world-wide.

Over the past few years, evidence has accumulated to suggest that subsets of inflammatory cells can function as a double-edged sword. On the one hand, recruitment of inflammatory cells is essential for healing processes, but, on the other, these cells may contribute to heart disease, disabling joint deformities, and even tumor progression. However, until now, the exact identity of the subsets of inflammatory cells that contribute to disease processes was not known.

In the latest research, published online on July 1 in Nature Medicine, Weill Cornell's Dr. Shahin Rafii and his colleagues Drs. B. Heissig and K. Hattori demonstrate that functional VEGFR-1, which was previously thought to be expressed only on cells found lining blood vessels, is also expressed on certain types of pluripotent adult stem cells. The scientists also find that activation of VEGFR-1 is essential for the regeneration of these stem cells to form a large number of pro-inflammatory cells. These ultimately mobilize from the bone marrow to the peripheral blood, contributing to the development of various pro-inflammatory diseases.

"The finding that activation of VEGFR-1 is essential for the recruitment of pro-inflammatory stem cells lays the foundation for designing clinical strategies to treat a wide variety of disabling diseases driven by infiltration of inflammatory cells," says Dr. Rafii, who is an Associate Professor of Medicine at Weill Cornell Medical College. "These diseases include atherosclerosis, diabetes, and arthritis. The findings also point to new strategies for preventing tumor progression."

In a related paper, being published simultaneously in Nature Medicine, Drs. Peter Carmeliet, Désiré Collen, Aernout Luttun, Marc Tjwa, and co-workers from the Flanders Interuniversity Institute for Biotechnology, Leuven (Belgium), demonstrate that inhibition of VEGFR-1 effectively blocks incorporation of bone-marrow-derived VEGFR-1-positive inflammatory cells into atherosclerotic plaques. This has the effect of diminishing plaque formation in atherosclerosis-prone mice. Similarly, inhibition of VEGFR-1 is effective in blocking inflammation and abnormal vessel formation in arthritic joints, leading to significant diminution of joint damage from arthritis. Finally, interfering with VEGFR-1 activity delays tumor growth, confirming a previous finding by the Weill Cornell group that, in certain tumors, inflammatory cells are essential for tumor growth.

In a third paper, simultaneously published in the journal Nature, Drs. Napoleone Ferrara and Hanspeter Gerber, from Genentech, validate the results obtained by the Weill Cornell group and show that activation of VEGFR-1 is essential for recruitment of adult stem cells. As demonstrated in the present study by the Weill Cornell group, activation of VEGFR-1 with one of its biologically active ligands—known as placenta growth factor (PlGF)—is effective in ameliorating chemotherapeutic- and radiation-induced marrow suppression in mice, rescuing 80% of mice from lethal complications inflicted by such suppression. PlGF, which is endowed with a low toxicity profile, may in the future be used to prevent marrow suppression in patients who receive chemotherapy and radiation, thereby avoiding such life-threatening complications as bleeding and infection.

The scientists from Leuven, in collaboration with Thromb-X, a local biotechnology start-up company, have also discovered that the administration of PlGF stimulates the formation of new functional blood vessels in the ischemic heart and limbs. This is a treatment from which as many as 300 million people with ischemic heart and limb disease, due to a variety of problems (atherosclerosis, diabetes, old age, etc.), could potentially benefit. As demonstrated by the Weill Cornell and Leuven groups, one of the mechanisms whereby PlGF induces this beneficial therapeutic effect is by recruiting VEGFR-1-expressing bone marrow cells, apart from stimulating endothelial cells. Significantly, PlGF treatment improves functional performance of an ischemic limb, creating new hope that this factor might provide a novel and attractive treatment for painful and crippling circulatory conditions.

These groundbreaking findings have tremendous implications for the treatment of atherosclerosis, vascular disease, arthritis, and cancer. They lay the foundation for clinical trials to examine the efficacy of blocking VEGFR-1 in treating heart, joint, and malignant diseases. Conversely, judicious and proper activation of VEGFR-1 may lead to augmentation of blood production, thereby pointing to strategies for addressing blood deficiencies in patients who receive high doses of blood-lowering chemotherapeutic agents. Moreover, activation of VEGFR-1 may be exploited for expanding and increasing the availability of pluripotent adult transplantable stem cells that ultimately might be used for organ regeneration. Finally, PlGF may constitute a novel treatment for ischemic heart and limb disease.

"Although very preliminary, these preclinical findings are scientifically very important and represent a tremendous step toward the development of molecular medicines for the treatment of a wide array of cardiovascular, joint, and blood diseases, as well as some forms of cancer," says Dr. Carmeliet, Professor of Medicine and Adjunct Director of the Center for Transgene Technology and Gene Therapy at the University of Leuven.

The other authors of the Weill Cornell group's article in Nature Medicine are Drs. Sergio Dias, Rafael Tejada, Barbara Ferris, Neil R. Hackett, and Ronald G. Crystal (all of Weill Cornell); Drs. David Lyden and Malcolm A.S. Moore of the Sloan-Kettering Institute; Drs. Yan Wu, Daniel Hicklin, Zhenping Zhu, Peter Bohlen, and Larry Witte, all of ImClone Systems, Inc.; Dr. Jan Hendriks of New York Blood Center; and Dr. Zena Werb of the Department of Anatomy, University of California, San Francisco.

The studies conducted at Weill Cornell Medical College and the University of Leuven were made possible by the contribution of proprietary VEGFR-1 monoclonal antibodies developed by ImClone Systems Incorporated (Nasdaq: IMCL).

The Weill Cornell work was supported by grants from the National Heart, Lung, and Blood Institute, the Sandler Family Sustaining Foundation, the Doris Duke Charitable Foundation, the American Cancer Society, and the Leukemia and Lymphoma Foundation.