Current Pharmaceutical Design, 2006, 12, 3101-3115 3101 1381-6128/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd. Cytokines and Chemokines as Regulators of Angiogenesis in Health and Disease R. Benelli 1 , G. Lorusso 1,2 , A. Albini 1, * , D.M. Noonan 2 1 Molecular Oncology Laboratory, Istituto Nazionale per la Ricerca sul Cancro, Genova and 2 Department of Clinical and Biological Sciences, Università degli studi dell’Insubria, Varese, Italy Abstract: The intricate interplay between the endothelium and immune cells has been well recognized in the context of immune responses. However, the fact that this inter-relation extends well beyond immune regulation is becoming in- creasingly recognized, with particular regards to the influence of the immune system on the essential endothelial process of angiogenesis, where the contribution of cytokines drives the angiogenic process. As angiogenesis is an important com- ponent of numerous pathological states, among these chronic inflammatory conditions and cancer, understanding the role of cytokines and chemokines in guiding new vessel formation provides key insight into novel therapeutic modalities. Here we review the actions of principal cytokines and chemokines on the angiogenic process and discuss how both can be con- sidered potential pharmaceutical targets or pharmaceuticals themselves for modulation of angiogenesis in chronic inflam- mation associated with cancer, rheumatoid arthritis and other inflammatory diseases. Key Words: neutrophil, monocyte, macrophage, angiogenesis, chemokine, cytokine. INTRODUCTION The Angiogenic Response in Inflammation: Positive and Negative Regulation by Immune Modulators Angiogenesis is classically defined as the formation of new capillaries from pre-existing blood vessels, while vas- culogenesis is the process of vessel differentiation from pre- cursors generally observed in early development [1, 2]. However, recently the involvement of both processes has been recognized to occur in normal and pathological condi- tions even in adults [3]. Almost all tissues develop a vascular network that provides cells with nutrients and oxygen, once formed, the vascular network is a stable system that regener- ates slowly. In normal physiological conditions angiogenesis and vasculogenesis occur primarily during embryogenesis and embryo development, in adult organisms they are largely limited to processes in wound healing and in response to ovulation. In fact, the relatively slow turnover of normal endothelial cells, as compared to the rapid turnover observed in some pathological conditions, has led to the concept that angiogenesis can be a pharmacological target [4, 5]. The angiogenic process involves several cell types and mediators, such as growth factors, cytokines and chemoki- nes, which interact to establish a specific microenvironment suitable for new vessel formation. Systemic influences can mobilize vascular precursor cells, where local microenvi- ronment alterations may favor their insertion into newly forming vasculature, thereby enhancing angiogenesis. Angi- ogenesis is a biological event that is essential not only in physiological but also in numerous pathological processes. “Pathological” angiogenesis can be divided into two separate *Address correspondence to this author at the Molecular Oncology Laboratory, Istituto Nazionale per la Ricerca sul Cancro, Genova. Largo Rosanna Benzi n.10, 16132 Genova, Italy; Tel: +39-010 5737406; Fax: +39- 010-5737231; E-mail: adriana.albini@istge.it overall groups: those pathologies that are characterized by excessive angiogenesis, either as a primary condition such as diabetic retinopathy or age-related macular degeneration, or as a secondary condition as in rheumatoid arthritis, psoriasis and cancer. On the other side there are those pathologies where angiogenesis is insufficient; for example tissue ische- mia and delayed wound healing. In these cases the pathology arises due to inadequate restoration of vascularization and proper circulation, leading to the tissue death. Coronary ar- tery disease could be considered on both sides; while angio- genesis can help atherosclerotic plaques grow, it can also reopen them as well as create collateral circulation to reper- fuse ischemic tissues [6, 7]. Particular attention in the area of angiogenesis and its control has been paid to the concept of blocking angiogene- sis as a therapy for cancer. Preneoplastic to neoplastic trans- formation, tumor growth, invasion and metastases are all closely associated with aberrant angiogenesis, and depend on establishment of a proangiogenic environment. In cancer the tight regulatory mechanisms are corrupted, traditionally the ability of tumor cells to constitutively synthesize angiogenic growth factors and other positive regulators is blamed. How- ever, tumor cells also produce factors that effect the host cells to favor an angiogenic environment, recently the role of tumor inflammation as both an initiator and promoter of the pro-tumor environment has become increasingly recognized [8, 9]. During the angiogenic response, the normally quiescent endothelial cells are activated to change their phenotype to one characterized by degradation of their basement mem- brane and proximal extracellular matrix, directional migra- tion, cell division and organization into functional new cap- illaries invested by a basal lamina. The newly formed capil- laries are then wrapped by pericytes that stabilize and main- tain the necessary vessels, while eventual capillaries in ex- cess are left to die off. All these processes are potential