Angiogenesis as a therapeutic target in arthritis: learning the lessons of the colorectal cancer experience

Abstract

The idea of a therapeutic modality aimed at 'starving' a tissue of blood vessels, and consequentially of oxygen and nutrients, was born from the concept that blood vessel formation (angiogenesis) is central to the progression and maintenance of diseases which involve tissue expansion/invasion. In the first instance, solid malignancies were the target for anti-angiogenic treatments, with colorectal cancer being the first disease for which an angiogenesis inhibitor--anti-vascular endothelial growth factor antibody bevacizumab--was approved in 2004. Our understanding of the pathogenesis of rheumatoid arthritis (RA) has lead to many parallels being drawn between this chronic inflammatory disease and solid tumours, in that both involve tissue expansion, invasion, expression of cytokines and growth factors and areas of hypoxia/hypoperfusion. As a result, angiogenesis blockade has been touted as a possible treatment for RA. The lessons learnt during the progression of eventually successful therapies such as bevacizumab should undoubtedly guide us in the future development of comparable treatments for RA.

Neutralization of ADAM8 ameliorates liver injury and accelerates liver repair in carbon tetrachloride-induced acute liver injury

“…The formation of new blood vessels is critical for normal development and tissue repair, as well as for pathological events such as retinal neovascularization, rheumatoid arthritis, and tumor growth (Friedlander et al, 2007;Bradley et al, 2007;Chen and Smith, 2007;Olsson et al, 2006;Khong et al, 2007;Sherris, 2007). During physiological angiogenesis, vascular endothelial growth factor (VEGF) expression in response to local hypoxia drives the development of new blood vessels (Ferrara, 2002;Holderfield and Hughes, 2008;Carmeliet and Jain, 2000).…”

ADAM9 Is Involved in Pathological Retinal Neovascularization

“…In addition, pathological neovascularization also has critical roles in other diseases such as cancer and rheumatoid arthritis (12,14). Although proteins with crucial functions in pathological neovascularization are considered to be important targets for the treatment of tumor growth (5), proliferative retinopathies (19), and rheumatoid arthritis (12), much remains to be learned about the identity of these molecules and the mechanisms underlying their function.…”

Shortened ALK1 regulatory fragment maintains a specific activity in arteries feeding ischemic tissues

“…On day 14, many of the injection sites had detectable tumors (n ¼ 3; 64-648 mm 3 ); however, Alk1PIB activity was detected only in a few feeding arteries, even in the mouse with the largest tumor at this stage ( Figure 4a). As tumor sizes increased on days 21 (n ¼ 3; 543-955 mm 3 ) and 28 (n ¼ 3; 939-2475 mm 3 ), Alk1PIB was clearly active in the feeding arteries of these larger tumors (Figures 4b and c). Histological sections of B16 tumors showed X-gal-stained arteries in connective tissues encapsulating tumors, but none were identified inside the tumors (data not shown).…”

“…Targeted expression of therapeutic genes to the angiogenic vasculature would provide a valuable treatment option for a number of disorders, such as ischemic heart disease, 1 diabetic retinopathy, 2 rheumatoid arthritis, 3 malignant tumors 4 and peripheral artery disease. 5 To date, a number of targeted gene-delivery strategies have been developed to express therapeutic genes in angiogenic vessels.…”