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Scientists Inhibit Pro-Inflammatory Factor to Prevent Arthritis, Heart Disease, Cancer

  [ 44 votes ]   [ Discuss This Article ] • July 15, 2002

Scientists from Weill Cornell Medical College and the Inter-university 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, published online in the July 1st issue of Nature Medicine, 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 arthritic joint diseases, cardiovascular diseases, such as atherosclerosis, as well as blood disorders, and cancer progression.

The scientists also present important preclinical animal studies that utilize blocking antibodies to demonstrate that inhibition of VEGFR-1 activity is effective in blocking inflammatory processes, thereby preventing the progression of rheumatoid arthritis and certain cancers as well as in diminishing atherosclerosis. 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 disabling joint deformities, heart disease and even tumor progression. However, until now, the exact identity of the subsets of inflammatory cells that contribute to disease processes was not known.

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.

In a related paper, also published simultaneously in Nature Medicine, Drs. Peter Carmeliet, and co-workers from the Flanders Interuniversity Institute for Biotechnology, Leuven (Belgium), demonstrate that 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.

These groundbreaking findings have tremendous implications for the treatment of arthritis, atherosclerosis, vascular disease, 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.

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