Angiogenesis and Prostate Cancer: Important Laboratory and Clinical Findings Michael C. Cox, PharmD, Matthew Permenter, BS, and William D. Figg, PharmD Address National Cancer Institute, 10 Center Drive, Building 10, Room 5A-01, Bethesda, MD 20892, USA. E-mail: wdfigg@helix.nih.gov Current Oncology Reports 2005, 7:215–219 Current Science Inc. ISSN 1523-3790 Copyright © 2005 by Current Science Inc. Introduction Prostate cancer is the most common malignancy in Amer- ican men and the second leading cause of cancer-related deaths (29,900 deaths estimated in 2004) [1,2]. It has been estimated that approximately 20% of men will be diagnosed with prostate cancer. In 1971, Folkman [3] proposed that angiogenesis is important for tumor progression. He has gone on to hypothesize that angio- genesis plays an important role in determining the possi- bility of metastasis and patient prognosis [4]. His group has put forward the idea of an “angiogenic switch” that is required to “turn on” angiogenesis in the tumor. Basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and tumor necrosis factor (TNF)-α are among the most important angiogenic proteins found in tumors [4]. Malignant cells can alter endogenous angiogenic pathways and retard antiangiogenic factors, thus providing an imbalance in blood vessel formation [5]. The understanding of angiogenesis and how it relates to tumor progression, as well as being a target for therapy, is rapidly becoming a reality. In this review, we highlight recent laboratory and clinical advances in angiogenesis inhibition and prostate cancer treatment. Angiogenesis and Prostate Cancer Growth, invasion, and metastasis of solid tumors requires angiogenesis in order to occur [6]. A tumor is unable to grow beyond a few cubic millimeters without the develop- ment of new vessels. With an extensive capillary network being built to provide nutrients to this growing tumor, a path for metastatic dissemination is formed. The transfor- mation of the tumor to an angiogenic phenotype depends on a net imbalance of positive and negative angiogenic factors, which is driven by the formation of new capillaries [7]. Prostate cancer development requires a number of intricate, highly orchestrated events, following a normal progression from high-grade prostatic intraepithelial neoplasia (PIN), to focal carcinoma, onward to invasive carcinoma, and lastly, metastatic disease. Data have been presented that suggest angiogenesis is a crucial step in the progression of prostate cancer from early to advanced disease [8,9]. Microvessel density is an indicator of biologic aggres- siveness and metastatic potential in many primary tumors [10]. Interruption of this process would halt the progres- sion of cancers that are dependent upon angiogenesis for advancing pathology by eliminating their potential for growth. Inhibition of angiogenesis is expected to augment the effects of other therapies, such as chemotherapy or radiation, by containing the tumor in a dormant state of low metastatic potential [11]. The dependence of prostate tumors on androgens for induction of tumor growth and metastasis is unique to this cancer [8]. Androgens have been implicated in the induction of VEGF expression, supporting the hypothesis that androgen ablation affects prostate tumors at least in part through inhibition of angiogenesis [8]. Prostate cancer is the leading cause of cancer diagnosis in men and the second leading cause of cancer-related death. Androgen ablation is effective initially, and progression of disease often occurs in many patients. Although recent reports have noted a survival benefit when patients with androgen-independent prostate cancer are treated with docetaxel, patients still have disease progression. Angiogen- esis plays a pivotal role for the growth, invasion, and metastasis of prostate cancer. Therefore, antiangiogenesis is a promising new therapeutic modality. More than 20 anti- angiogenic agents are now in various stages of clinical trials. We discuss current knowledge on controlling tumor angio- genesis and advances in the development of antiangiogenic agents with promising antitumor activity in prostate cancer.