Current Angiogenesis (Discontinued) - Volume 3, Issue 4, 2014

Angiogenesis plays a vital role in ovarian carcinogenesis and has become an important therapeutic target of ovarian cancer. Insights into the genomic complexity of ovarian cancer and modest single-agent activity of targeted agents have led to testing of biologic agent combinations in order to leverage modulation of potentially interactive targets. Many studies have added angiogenesis inhibitors to chemotherapy in ovarian cancer, with progression-free survival improvements only. Novel angiogenesis inhibitor combinations that reflect the science of ovarian cancer are needed. An exciting new direction is the interaction between angiogenesis and DNA damage repair pathways, as both pathways are active therapeutic targets in ovarian cancer. Preclinical studies demonstrate an interaction between hypoxia and inhibition of DNA damage repair. γH2AX, a marker of DNA damage response activation, is necessary for endothelial cell proliferation under hypoxia and in hypoxia-driven neovascularization in vivo. The successful combination of a vascular endothelial growth factor receptor inhibitor and a poly (ADP-ribose) polymerase inhibitor in recent clinical trials has suggested this direction can be an important advance. Further clinical combination strategies of angiogenesis inhibition and other pathways including DNA damage repair pathways are currently in development for treatment of recurrent ovarian cancer.

Epithelial ovarian cancer (EOC) is the most frequent cause of death from all gynecological malignancies with the majority of women being diagnosed with advanced stage disease. It is considered a chemosensitive cancer with a high initial response rate to first-line platinum and taxane-based chemotherapy. However, a majority of patients will relapse with subsequent resistance to treatment and ultimately succumb to their disease. This emphasizes the need for the development of new therapeutic approaches to improve outcomes. Angiogenesis has been recognized as an important mechanism promoting EOC growth and metastasis with angiogenesis inhibitors being developed and tested for over a decade. Bevacizumab, a humanized monoclonal antibody, that targets vascular endothelial growth factor A (VEGF-A), has been the most well evaluated molecular targeted drug in the treatment of advanced and recurrent EOC with proven clinical efficacy. However, anti-VEGF therapies are often associated with serious toxicities and drug resistance ultimately develops. Hence, new therapeutic approaches are needed. Targeting the angiopoietin-Tie-2 complex pathway (VEGF independent) has gained interest over the last few years as an alternative strategy to overcome anti-VEGF therapy resistance and toxicity. Trebananib (formerly known as AMG 386; Amgen, Thousand Oaks, CA, USA) is a novel first-inclass angiopoietin antagonist, which inhibits angiopoietin-1 and angiopoietin-2 interaction with the Tie-2 tyrosine kinase receptor and hence, disrupts tumor angiogenesis. In preclinical models trebananib has shown antiangiogenesis and antitumor activity. It also has shown antitumor activity as a monotherapy with an acceptable toxicity profile in recurrent EOC. It prolonged progression-free survival in a recently published randomized Phase III clinical trial in the recurrent setting (TRINOVA-1). However, overall survival was unchanged.

Angiogenesis describes the sprouting of new blood vessels from preexisting vascular networks. A tightly regulated balance between pro- and antiangiogenic factors regulates this process, which can be disrupted under pathological conditions. Tumor development is characterized by an “angiogenic switch”, which results in an increase in expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and concomitant repression of angiogenesis inhibitors such as thrombospondin- 1 (TSP-1). Overexpression of pro-angiogenic factors promotes the rapid formation of tumor vasculature, which typically is hyperpermeable, convoluted, and lacks normal perivascular cell interactions. This disorganized vasculature results in reduced tumor perfusion, which can significantly impair drug delivery to the tumor. Ovarian cancer is typically not detected until late stage and can present a therapeutic challenge, due to the presence of a large, poorly-vascularized tumor. The prevalence of chemoresistance in ovarian cancer has spurred recent research into alternative therapeutic targets for this disease. Various anti-angiogenic approaches have been studied, including targeting VEGF expression and restoring expression of anti-angiogenic factors such as TSP-1. Studies using anti-angiogenic treatments have demonstrated the preferential destruction of immature, dysfunctional blood vessels, with the preservation of healthy, parental vasculature. The vessel normalization induced by anti-angiogenic therapy has been found to improve tumor perfusion, facilitate uptake of chemotherapeutic compounds and is associated with tumor regression even in advanced stage ovarian cancer. The purpose of this review is to examine the pathological angiogenic processes that characterize tumor growth, evaluate the efficacy of anti-angiogenic therapies, and discuss the process and therapeutic implications of vessel normalization in the context of antiangiogenic therapies for advanced stage ovarian cancer.

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies in developed countries. Despite advances in chemotherapy leading to improved outcomes in EOC, mortality rates have marginally decreased, because most patients will develop resistance to standard chemotherapy. New anti-tumor agents with novel mechanisms of action are needed. Angiogenesis is one of the regulated processes that are crucial for tumor growth, invasion, and metastasis. Preclinical studies demonstrated an effect of anti-angiogenesis drugs on ovarian cancer models, which led to the development of various classes of anti-angiogenic drugs against VEGF, platelet derived growth factor (PDGF), angiopoietin, and fibroblast growth factor (FGF) signaling pathways. The vascular endothelial growth factor (VEGF) and its associated receptors have emerged as major therapeutic targets. Bevacizumab, a recombinant humanized monoclonal antibody targeting VEGF, has been studied in randomized trials and has shown activity in patients with platinum-sensitive and -resistant EOC. This article will provide an overview of the basic research and translational research mechanisms focusing on angiogenesis in EOC, review the current clinical trials, and perform a pooled analysis for determining the impact of anti-angiogenesis on this disease.

Vascular endothelial growth factor receptor 2 (VEGFR2) is a tyrosine kinase receptor for the angiogenic growth factor, VEGF. VEGFR2 is typically found in hematopoietic stem cells and endothelial cells. We report the expression of VEGFR2 on highly metastatic human prostate cancer cells. Using real-time RTPCR, immunoprecipitation, western blotting, ELISA, and radioligand crosslinking, we demonstrate the expression and activation of VEGFR2 in malignant prostate tumor cells. Functionally, VEGF induced the proliferation of PC3MLN4 cells and VEGFR2 kinase inhibitors attenuated their growth. PC3MLN4 orthotopic prostate tumors in immunodeficient mice were larger, more vascular, and showed increased metastasis to lymph nodes compared to parental PC3M tumors. PC3M cells transfected with VEGFR2 show increased migration toward VEGF. Taken together, our data suggest that VEGF may act as an autocrine growth factor in aggressive prostate cancer cells. Therapies targeting VEGFR2 may directly and indirectly (by affecting angiogenesis) inhibit prostate cancer progression.

Quantitative Pathology is engaged with the determination of morphological characteristics of tissues. One important field of measurement is the estimation of angiogenesis in malignant neoplasms. The parameters of angiogenesis that are determined include: microvascular density (MVD), total vascular area (TVA) and vessel’s major axis length, minor axis length, area, perimeter, compactness, shape factor and Feret diameter [1-3]. The statistical correlations of the above mentioned parameters with prognosis or clinicopathological characteristics result in conclusions about the malignant potential and aggressiveness of different malignant tumors. In the present review article, we identify basic morphometric parameters used to characterize angiogenesis and describe the method of quantization by the appropriate image analysis software.