Current Angiogenesis (Discontinued) - Volume 1, Issue 2, 2012

Histidine-rich glycoprotein (HRG) is a heparin-binding plasma protein that is produced specifically in the liver. It circulates in the plasma at high levels both as a free protein and in platelets. HRG has an unusual structure with a very high content of histidine and proline residues arranged in pentapeptide repeats. The histidine residues in the repeats bind divalent cations such as Zn2+, which is required for most if not all of the biological effects of HRG. HRG binds a number of molecules with high affinity, such as heparin/heparan sulfate, heparanase, plasminogen, fibrinogen, thrombospondin, immunoglobulin G, FcγRs and certain complement proteins. Due to its many binding partners, HRG has been implicated in the regulation of a range of biological processes including hemostasis, the immune response and pathological angiogenesis. The mechanisms whereby HRG exerts these effects are still unclear, but direct effects of HRG in vitro and ex vivo on endothelial cells and macrophages have been described. Even though there are candidates for potential receptors for HRG, the molecular mechanisms essential for HRG in vivo biology remain to be described. To identify the in vivo target cell and the mechanisms of HRG’s effect on this cell type is a prerequisite for the exploitation of HRG in clinical medicine, such as in cancer treatment.

Tumor immune surveillance is the process by which the immune system recognizes and destroys tumor cells, without which cancer would be more frequent among humans. Tumor immune surveillance has long been known to consist of a direct tumor cell lysis component, dependent on the adaptive immune system. New evidence demonstrates that in addition to a direct effect on tumor cells, the immune system regulates tumor growth via regulation of angiogenesis. Many of the cell types of both the innate and adaptive immune system have either pro or anti-angiogenic functions. In this review, we discuss key data for the angiogenesis regulatory role of each of the major immune cell types.

The idea that tumors recruit blood vessels to survive, grow, and metastasize was proposed more than 40 years ago by Dr. Judah Folkman. Since then, studies have been conducted to identify factors able to stimulate endothelial cell functions and to inhibit their pro-angiogenic activity in pathological conditions, such as tumor-associated angiogenesis. The process of angiogenesis requires three major steps, namely endothelial cell proliferation, migration and tubulogenesis. Although release of growth factors, cytokines, and proteases is critical for the regulation of endothelial cell functions, interactions of endothelial cells with the surrounding extracellular matrix initiate intracellular signaling that result in proand/ or anti-angiogenic cues. Interactions of cells with the extracellular matrix are made possible by the transmembrane receptors integrins. Upon ligand activation, these receptors can activate various intracellular signaling, thus regulating processes such as adhesion, migration, proliferation and survival. The finding that these receptors are expressed on vascular endothelial cells and they can either promote or inhibit endothelial cell functions, has initiated studies to determine their role in physiological and pathological angiogenesis. In this review, we will focus on the role of integrins, with emphasis on the collagen binding and the alpha v containing integrins, in angiogenesis and highlight hope and tribulations of targeting these receptors for anti-angiogenic therapy. This review is dedicated to Dr. Judah Folkman who introduced us to the concept of ‘malignant’ angiogenesis.

Judah Folkman’s concept of targeting angiogenesis to regulate tumor growth and metastasis resulted in a series of scientific discoveries in vascular biology that led to the development of anti-angiogenic molecules to neutralize vascular endothelial growth factor (VEGF). The concomitant development in understanding the role of VEGF in neovascular age-related macular degeneration (NVAMD) led to a dramatic change in the treatment of NVAMD and significant improvement in its prognosis. This review will provide a brief history of angiogenesis research from its development in the world of cancer biology to its eventual application in retinal medicine and NVAMD. We will then present an overview of the therapeutic interventions for NVAMD, which highlights how a deeper understanding of the molecular mechanisms of NVAMD and angiogenesis eventually led to a paradigm shift in its management. Finally, we will discuss future interventions for NVAMD designed to circumvent the clinical and financial burdens placed on physicians and patients as a consequence of chronic anti-angiogenic therapy.

A new era of precision medicine is mandating that drug discovery and development in the field of oncology proceed in parallel with biomarker discovery that will allow patient populations to be stratified for response. This is of particular importance in the field of anti-angiogenic drug development. New therapeutic targets are being explored, and each new target will require a more complete understanding of the biology in order for predictive biomarkers to be identified, and validated, leading to more efficient clinical trials. This article reviews the current state of the art regarding potential biomarkers for anti-angiogenic therapy, including such biomarkers as hypertension, imaging parameters that measure blood flow in a tumor, as well as circulating growth factors and circulating endothelial cells. The limitations of these current biomarkers within the larger context of tumor vasculature heterogeneity are discussed.

The creation of functional blood vessel circuits is a critical step during embryonic development to support organ growth and differentiation. In the adult, angiogenesis occurs naturally in the female reproductive system, during exercise- induced muscle growth and in wound healing. However, adult angiogenesis also promotes tumour growth and contributes to many other diseases with tissue ischemia. The transmembrane protein neuropilin 1 (NRP1) is an isoformselective receptor for the most potent vascular growth and permeability factor, VEGF-A. NRP1 also functions as a receptor for an archetypical neural guidance cue called SEMA3A that inhibits tumour angiogenesis. In the adult vasculature, both VEGF-A and SEMA3A increase vascular permeability and thereby promote the formation of tissue oedema. Here, we review current knowledge about NRP1 function during blood vessel growth and vascular pathology.

As in normal tissues, solid tumors depend on vascular networks to supply blood, oxygen, and nutrients. Tumor blood vessels are formed by common processes of neovascularization for example endothelial sprouting. However, some tumors have alternative and unexpected mechanisms of neovascularization at their disposal. In a process termed "vascular mimicry," tumors create their own, tumor cell-lined channels for fluid transport independent of typical modes of angiogenesis. These tumor cell-lined conduits may express endothelial-selective markers and anti-coagulant factors which allow for anastamosis with host endothelium. In this review, we explore the current status of vascular mimicry research, highlighting recent evidence which strengthens the hypothesis for this unusual ability of tumor cells. Furthermore, we address the theoretical possibility that vascular mimicry provides a mechanism whereby tumors could escape antiangiogenic therapies.

Growth of solid tumors and cancer metastases is accompanied by inflammation-assisted remodeling of the tissue microenvironment that resembles the physiological process of wound healing. As a consequence, the non-malignant tumor stroma constitutes up to 85% of the tumor volume and is simply not just a passive bystander, but regulates tumor survival, growth and metastatic spread. The importance of the tumor vasculature was first recognized in 1971, when Judah Folkman suggested that neovascularization allows a tumor to exceed its dormant stage and grow beyond a size of 2 mm. This hypothesis was not fully appreciated until three decades later when the outbreak of angiogenesis research was followed by the first clinical applications of antiangiogenic drugs. Even though the antiangiogenesis paradigm is broadly accepted, the clinical success of new drugs is limited. Different mechanisms of resistance to antiangiogenesis treatments have been proposed, like compensatory action of blood vessel growth factors, lower sensitivity of normalized vessels to the therapy or vessel growth by alternative modes of angiogenesis. In this review we will analyze the known mechanisms of neovascularization, including postnatal vasculogenesis, sprouting angiogenesis, intussusceptive angiogenesis, and looping angiogenesis and their potential effects on tumor vascularization. We will also discuss how the current basic knowledge of angiogenic mechanisms translate into limited success of clinical trials utilizing antiangiogenic drugs.

Dr. Judah Folkman first introduced the concept of anti-angiogenic therapy almost four decades ago. This novel idea has subsequently been supported by extensive research in the multistep process of tumor-associated angiogenesis. As new blood vessels are formed, angiogenesis is switched on within the tumor microenvironment and the physiological balance between endogenous pro-angiogenic and anti-angiogenic factors is disrupted. Since then, angiogenesis inhibitors have been developed as drugs and administered in the clinic as part of anti-cancer therapy. Tissue inhibitor of metalloproteinase 2 (TIMP-2) is an endogenous inhibitor of angiogenesis that was initially discovered through the ability to inhibit matrix metalloproteinase (MMP) activity. Subsequently, TIMP-2 was shown to suppress endothelial cell proliferation and migration through MMP dependent and independent mechanisms. Moreover, recent studies indicate that TIMP-2- mediated inhibition of tumor growth may occur, at least in part, via mechanisms that are distinct from its ability to inhibit MMP activity. TIMP-2 is an essential element of the normal tissue microenvironment in the presence of low levels of MMP expression. However, in tumor tissue TIMP-2 levels are reduced. Recent experiments demonstrate that reconstitution of TIMP-2 expression in tumors not only inhibits tumor angiogenesis, but also acts directly on tumor cells to modulate interactions between the tumor cells and the microenvironment. These recent research findings support the idea that TIMP-2 is an excellent candidate for preclinical development as a novel biological agent for cancer therapy.

Radiation, chemotherapy, and surgery share roles in modern cancer therapy targeting neoplastic tumor cells. Greater understanding of the importance of angiogenesis and tumor neovascularization in oncology has led to development of another therapeutic modality, angiogenesis inhibitors, which specifically target the tumor vasculature. Antiangiogenic agents have been shown to act synergistically with traditional cytotoxic treatments, including radiation, against a variety of tumor histologies. Their selective incorporation in multimodality therapy based on tumor type, angiogenic profile, and individual patient response offers the potential for greater disease control. In this review we summarize studies evaluating angiogenesis inhibitors combined with radiation in cancer therapy, and progress made towards optimally incorporating these agents into established treatment regimens.