Review Genetic dissection of tumor angiogenesis: are PlGF and VEGFR-1 novel anti-cancer targets? Aernout Luttun, Monica Autiero, Marc Tjwa, Peter Carmeliet * The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KULeuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium Received 23 June 2003; received in revised form 19 September 2003; accepted 19 September 2003 Abstract Many proliferative diseases, most typically cancer, are driven by uncontrolled blood vessel growth. Genetic studies have been very helpful in unraveling the cellular and molecular players in pathological blood vessel formation and have provided opportunities to reduce tumor growth and metastasis. The fact that tumor vessels and normal blood vessels have distinct properties may help in designing more specific—and therefore safer—anti-angiogenic strategies. Such strategies may interfere with angiogenesis at the cellular or molecular level. Possible molecular targets include angiogenic growth factors and their receptors, proteinases, coagulation factors, junctional/adhesion molecules and extracellular matrix (ECM) components. Some anti-angiogenic drugs, i.e., vascular endothelial growth factor (VEGF) antibodies and VEGF receptor-2 (VEGFR-2) inhibitors, have progressed into clinical cancer trials. While the results of these trials support the potential of anti-angiogenic therapy to treat cancer, they also demonstrate the need for more effective and safer alternatives. Targeting placental growth factor (PlGF) or VEGFR-1 may constitute such an alternative since animal studies have proven their pleiotropic working mechanism and attractive safety profile. Together, these insights may bring anti-angiogenic drugs closer from bench to bedside. D 2004 Elsevier B.V. All rights reserved. Keywords: Angiogenesis; Tumor; Metastasis; VEGF; PlGF; VEGF receptor; Anti-angiogenesis 1. Introduction Blood vessels are present in every organ of the body where they deliver oxygen and nutrients necessary for the cells to survive and function. When these vessels become blocked or dysfunctional, severe organ damage and life- threatening diseases may occur. Similarly, excess blood vessel formation (angiogenesis) has a major impact on our health and contributes to the pathogenesis of many disor- ders—some even quite unexpected so (for an overview, see Ref. [1]). Historically, the best-known angiogenesis-driven disease is cancer. The association between angiogenesis and tumor formation was already recognized a century ago [2], but cancer researchers became much more interested in angiogenesis, when the first hints emerged that tumors might release diffusible angiogenic substances to foster their own progression [3,4]. Therefore, the concept was launched that starving tumors of their blood supply, by blocking such ‘tumor angiogenesis factors’ might be a means to combat cancer [5]. Later, it was posed that blocking these factors could even slow down the spread of the cancer to distant organs (metastasis), as cancer cells must enter blood vessels to travel to other parts of the body (reviewed in Ref. [6]). Subsequently, it has become clear that metastasis often involves another vessel network in the body, the lymphatic vasculature, which is connected to the blood vessel circuit and which normally serves to recirculate immune cells and absorb excess tissue fluid (reviewed in Refs. [7,8]). Thus, targeting tumor blood (or lymphatic) vessels has become an attractive, much attempted and also debated strategy to conquer cancer growth and spread. The first section of this review focuses on the molecules and cells, generally in- volved in tumor angiogenesis and growth/metastasis as revealed by genetic intervention or inhibitor studies. The second section highlights the recent elucidation of the molecular properties and functional relevance of the angio- genic growth factor placental growth factor (PlGF) and its receptor, vascular endothelial growth factor receptor-1 (VEGFR-1, also known as fms-like tyrosine kinase, Flt1), 0304-419X/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbcan.2003.09.002 * Correspondence author. Tel.: +32-16-34-57-72; fax: +32-16-34-59- 90. E-mail address: peter.carmeliet@med.kuleuven.ac.be (P. Carmeliet). www.bba-direct.com Biochimica et Biophysica Acta 1654 (2004) 79 – 94