Current Angiogenesis (Discontinued) - Volume 2, Issue 1, 2013

In the last four decades the recognition of a tumor’s fundamental need of an expanding blood vessel network for successful development and growth has led to the identification of novel cancer therapeutic targets. As a consequence anti-angiogenic therapy has now become a common therapeutic modality in cancer treatment. However, patients often do not respond to the currently available anti-angiogenic agents or become resistant to them upon prolonged exposure. Thus, the full potential of anti-angiogenic therapy is yet to be realized and alternate modes of angiogenesis inhibition are needed. Recently a new target in the angiogenic process was identified. The angiopoietin/Tie axis is important in vascular development and plays a role in the maintenance or destabilization of blood vessels. Angiopoietin-1 (Ang-1) is secreted by peri-endothelial cells (e.g. smooth muscle cells and pericytes) and interacts with Tie2 receptor in a paracrine manner, promoting a quiescent vascular phenotype. Angiopoietin-2 (Ang-2) is secreted by endothelial cells during angiogenic stimulus and interacts with Tie2 in an autocrine manner, disrupting endothelial and peri-endothelial cell interactions of normal vessels. Ang-2 is commonly upregulated in tumors and in some cancer settings correlates with advanced disease and poor prognosis. As a result Ang-2 has become a desirable therapeutic target and several Ang-2 inhibiting agents are currently in preclinical or clinical development. This reviews focuses on the current status of these agents and discusses future considerations for Ang-2 targeting in cancer therapy.

ANGPTL4 is a member of the angiopoietin/angiopoietin-like gene family and encodes a glycosylated, secreted protein consisting of a signal sequence, N-terminal coiled-coil and a fibrinogen like C-terminal domain. The encoded protein has emerged as a member of dynamically expressed, extracellular matrix-associated proteins that play critical roles in regulating glucose homeostasis, lipid metabolism, and insulin sensitivity and also acts as an apoptosis survival factor for vascular endothelial cells. Recent studies have uncovered novel ANGPTL4 activities unexpected for matricellular proteins, including the ability to modulate integrin-mediated signaling and added a new facet to the cell-matrix interactions and signaling during wound repair and cancer metastasis. ANGPTL4 function primarily through direct binding to specific integrin receptors, thereby triggering signal transduction events that by modulating gene expression culminate in the regulation of cell adhesion, migration, proliferation, differentiation and survival. This review surveys the published data on molecular functions and mechanism by which ANGPTL4 exerts its effects. We also discuss use of ANGPTL4 as diagnostic or prognostic marker for wound healing process and cancer; and highlight the therapeutic potential of this ligand, as well as possible limitations to its use. We also consider the data on ANGPTL4 receptors and speculate on how to maximize therapeutic benefit.

Angiogenesis can be described as a dynamic, hypoxia - stimulated and growth factor - dependent process, and the term should be specifically referred to as the formation of new blood vessels from pre-existing ones. Literature data coming from either experimental and clinical studies have reported the occurrence of hepatic angiogenesis in conditions of chronic liver diseases (CLDs) characterized by perpetuation of cell injury and death, inflammatory response and progressive fibrogenesis. In the scenario of CLDs hepatic angiogenesis has been proposed to favour fibrogenic progression of the disease, whatever the aetiology, towards the end-point of cirrhosis and related complications. Accordingly, angiogenesis and related changes in liver vascular architecture can concur to increase vascular resistance and portal hypertension, to decrease parenchymal perfusion as well as to modulate the genesis of portal-systemic shunts and increase in splanchnic blood flow. These changes can significantly affect complications of cirrhosis and are also believed to be critical for the growth and progression of hepatocellular carcinoma (HCC). Anti-angiogenic experimental strategies have been shown to limit the progression of animal models of CLDs and anti-angiogenic therapy is currently debated as a new, potentially effective, way for pharmacological intervention in patients with advanced fibrosis and cirrhosis. Finally, recent literature has identified cellular and molecular mechanisms governing the cross talk between angiogenesis and fibrogenesis, with a specific emphasis on the crucial role of hypoxic conditions and reactive oxygen species (ROS) and a research focus on the role of hepatic myofibroblasts in their activated pro-fibrogenic phenotype.

Angiogenesis is critical to tumor growth and metastasis and is dependent on growth factors, such as vascular endothelial growth factor (VEGF). The most characterized angiogenic factor, VEGF is an endothelial cell mitogen and permeability factor that has been found to be overexpressed in almost all human cancers. In a number of tumor model systems, antagonism of the VEGF pathway results in inhibition of angiogenesis and tumor growth. Specifically, VEGF inhibition has been shown to suppress tumor growth, decrease microvasculature, and induce apoptosis of endothelial cells. This close relationship between hypoxia, angiogenesis, and tumor growth makes VEGF and VEGF receptors attractive targets for anti-neoplastic therapies. However, in neuroblastoma, a vascular, aggressive pediatric solid tumor, VEGF therapies has demonstrated limited success, which may be due to resistance. Identifying synergistic anti-angiogenic targets may improve efficacy of VEGF treatments in neurobasltoma. In this article, we review the state of VEGF-targeted therapies, the results of recent clinical trials, as well as the future of novel anti-VEGF therapeutics. We will follow this with a review of VEGF treatment in the aggressive, pediatric malignancy, neuroblastoma, and discuss combination therapy of VEGF treatments with chemotherapy and other molecular targeted drugs.

The process of angiogenesis involves the generation of blood vessels from pre-existing vessels. Abnormal angiogenesis occurs when the balance between pro- and anti-angiogenic signals is perturbed and is a hallmark of pathological conditions such as cancer, ischemic and inflammatory diseases. MicroRNAs (miRNAs) are short non-coding RNAs, whose main function is to negatively regulate gene expression. MiRNA-mediated regulation is essential for many biological processes including development and disease. Here, we review findings in which these small RNA molecules have been increasingly recognized as key regulators of the angiogenic response, as well as potential therapeutic targets in pro and anti-angiogenic medicine.

Exosomes, a group of small vesicles (30-100 nm), originate when the inward budding of the endosomal membrane forms multivesicular bodies (MVBs). Exosomes are released into the extracellular space when the MVBs fuse with the plasma membrane. Numerous studies have indicated that exosomes play critical roles in mediating cell-to-cell communication. Also, exosomes are believed to possess a powerful capacity in regulating cell survival/death, inflammation and tumor metastasis, depending on the particular array of molecules contained within a particular population of exosomes. This mini-review will summarize dual roles of exosomes derived from different types of cells (i.e. endothelial cells, tumor cells, platelets, bone-marrow stem cells, cardiomyocytes, myocardial progenitor cells and among others) in endothelial cell proliferation, migration and tube-like formation. In particular, this review will focus on the therapeutic potential of exosomes as a natural nano-particle for delivering pro-/anti-angiogenic factors (proteins, mRNAs and microRNAs) into endothelial cells.

Histone Deacetylase enzymes (HDACs) are commonly known as epigenetic regulators of gene transcription, with indispensable roles in all biological processes. However, their activity is not limited solely to the chromatin modification but also to the deacetylation of cytoplasmic proteins and to act as signal transducers, with important implications in cell type-specific functions. This mini-review focuses on the roles of HDACs in angiogenesis, a process where a complex coordination of different cellular events, such as cell migration, survival, proliferation and differentiation, is required for the sprouting of blood vessels. Specific HDAC inhibitors have already been proved to be effective in the treatment of different tumors, indicating the importance of this family of enzymes as therapeutic targets in angiogenesis-related disorders.

Neoangiogenesis plays an essential role in colorectal carcinogenesis. Using murine models of colorectal cancer and confocal laser endomicroscopy (CLE), the aim of this study was to optimize methodology and develop a robust scoring system to distinguish vascular characteristics of neoplastic colonic tissue from normal colon. Tumors were induced in mice using standard protocols with either azoxymethane (AOM) or azoxymethane/dextran sulfate sodium (AOM/DSS). In vivo imaging studies were performed with colonoscopy to identify visible lesions followed by CLE with either fluorescein sodium to assess microarchitecture or fluorescein-isothiocyanate linked to dextran (FITC-D) to visualize blood vessels. Qualitative and quantitative morphometric measures detected by CLE were developed that included a 10-point scoring system to characterize abnormal blood vessel features. Tumor vessels differed significantly from normal vessels in loss of vessel co-planarity, vessel dilation, sprouting, irregular vessel pattern, and dye extravasation from vessels (each parameter p<0.0001). An overall score of 4 or more was significantly associated with tumor vessels compared to normal colonic blood vessels (p<0.0001). Fourier analysis of blood vessel patterns also showed striking differences between neoplastic and normal blood vessels. We propose a simple 10-point scoring system to distinguish neoplastic from normal vessels based on CLE. This methodology and scoring system could provide quantitative measures of neoplastic angiogenesis to advance our understanding of tumor biology and cancer risk assessment and monitor responses to therapy.