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Angiogenesis is a biological process by which new capillaries are formed from preexisting vessels. It occurs in physiological and pathological conditions, such as tumors, where a specific turning point is the transition from the avascular to the vascular phase. Tumor angiogenesis depends mainly on the release by neoplastic calls of growth factors specific for endothelial cells able to stimulate the growth of the host's blood vessels. This article summarizes the knowledge about the role of angiogenesis in the most common forms of pediatric malignant and non-malignant tumors. A major goal is the determination of whether inhibition of angiogenesis is a realistic way of inhibiting tumor cell dissemination and formation of metastasis in pediatric tumors. [ABSTRACT FROM AUTHOR]

Angiogenesis, the process of new blood vessel development from the pre-existing vasculature, is vital for tumor growth and subsequent metastasis and has become an important target for novel anticancer therapeutics. One major difficulty in the development of these antiangiogenic agents is the lack of a robust biomarker of target inhibition that will enable establishment of an optimal biological dose (OBD). Recently, several non-invasive imaging modalities have been adopted to try and address this problem, and these will be discussed in this chapter. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been most extensively investigated, and published guidelines are available detailing best practice. Emerging data indicate that changes in DCE-MRI measurements of tumor perfusion on treatment with antiangiogenic agents may correlate with clinical outcome. However, reproducibility, in particular between centers makes intertrial comparisons difficult and the problem of tumor heterogeneity, needs to be fully addressed. [ABSTRACT FROM AUTHOR]

Agents targeting angiogenesis have proven efficacy and an expanding role in cancer therapy. Preclinical development has been rapid, in part because assays exist to determine biologicall activity. In early clinical trails, the modest single agent efficacy in phase I trails requires surrogate or tumor assays to determine proof of mechanism and early proof of efficacy. Many theoretically attractive assays have been dissapointing in clinical practice. New assays have been introduced or are about to be introduced into clinical development. Experience with existing agents provides bencmarks to evaluate these proposed assays. [ABSTRACT FROM AUTHOR]

The identification of prognostic factors and the appropriate selection of the patients more likely to benefit of anti-angiogenic therapies is a major area of research. Early experience with other molecular targeted drugs, such as imatinib and/or trastuzumab, has generated the perception that pre-treatment target assessment is a pre-requisite for therapy. However, emerging evidence suggests that presently we have no predictive biomarkers for anti-angiogenic agents. Despite considerable evidence for the association of intratumoral and/or plasma vascular endothelial growth factor (VEGF) levels with tumor progression and/or poor prognosis, pre-treatment VEGF levels are not predictive of response to angiogenesis inhibitors. This may possibly be due to the complexity of the angiogenic pathways and the limitations associated with current methods of VEGF detection and quantification; e.g. low assay sensitivity and lack of standardized methods could prevent detection of very small increases in VEGF, which may be clinically important. In addition to a general lack of agreement as to the relative clinical relevance of circulating versus tumor VEGF levels, the absence of a gold standard' VEGF detection assay and the lack of a predefined, clinically relevant cut-off values pose a significant hindrance to the clinical utility of VEGF measurements for therapy selection. Several retrospective studies showed a promising important role of microvessel density and other pro-angiogenic factors (e.g. basic fibroblast growth factor, VEGF, thymidine phosphorylase, etc.) as indipendent prognostic markers in solid tumors, but these data have to be validated in prospective trials. [ABSTRACT FROM AUTHOR]

Imaging of angiogenesis is clinically relevant for tissue characterization, early detection of tumor and assessing tumor response to targeted therapies. Current imaging techniques with CT and MRI provide opportunity to assess tumor blood flow, blood volume and permeability. The kinetic models employed for estimation of these parameters are not yet standardized, however, the methods were found to be reliable and reproducible. Imaging techniques such as contrast-enhanced ultrasound, PET and optical imaging are still under research. This chapter provides a review of various methods for imaging the angiogenesis, their advantages, disadvantages and potential role in the current practice. [ABSTRACT FROM AUTHOR]

The role of angiogenesis in the development and progression of solid tumors has been well established over the 1980s and 1990s. Through more recent investigations, it has become increasingly clear that neovascularization within the bone marrow of patients with hematologic malignancies is of primary importance in the development and progression of these disorders. Evidence of malignant angiogenesis in myeloid malignancies includes increased microvascularity and vascular density within the bone marrow cavity, elevated serum or urine levels of soluble angiogenic peptides, and cellular over-expression of angiogenic molecules and their cognate receptors. Autocrine and paracrine secretion of angiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiogenin contributes not only to medullary vasculogenesis but also to the proliferation of myeloid precursors and alteration of their microenvironment. Pro-angiogenic molecules have been linked to prognosis and implicated in the progression of hematologic malignancies. Therapeutic strategies intended to inhibit angiogenesis in myeloid malignancies have reached maturity over the 1990s. Lenalidomide is the first such antiangiogenic agent to receive Food and Drug Administration (FDA) approval for the treatment of myelodysplastic syndrome (MDS) based on hematologic and cytogenetic responses. Other investigational agents in the treatment of myeloid disorders, such as thalidomide, arsenic trioxide (ATO), and bevacizumab, have shown promise as single agents or in combination with chemotherapy in the treatment of leukemia and MDS. Novel small-molecule tyrosine kinase inhibitors (TKIs) with activity against a spectrum of angiogenic receptors have completed early-phase clinical trials showing modest clinical activity. Further investigation of the contribution of angiogenic molecules to the development and progression of myeloid malignancies before this new class of therapeutics can be further integrated into standard practice. [ABSTRACT FROM AUTHOR]

This chapter addresses the epidemiology, pathogenesis and current therapeautic strategy for common gynecologic mailgnancies; angiogenesis as a mechanism of disease progression; pre-clinical knowledge on angiogenesis-specfic therapeutic targets; and the status of clinical trails incorporating antiangiogenic agents. [ABSTRACT FROM AUTHOR]

The use of antiangiogenic therapy for the treatment of renal cell cancer (RCC) has revolutionized the treatment of a disease, which for the better part of the last generation lacked a highly effective therapy. Prior standard options such as interferon-alpha (IFN-α) or IFN-β were not much better than placebo and were associated with toxicities that worsened the quality of life of many patients. Interleukin-2 (IL-2), while able to induce complete responses in a small percentage of patients, was limited to those subjects who were young enough and healthy enough to tolerate this intensive hospital-based therapy. Appreciating the pathophysiologic role that angiogenesis plays in RCC, numerous investigations have been carried out with a variety of antiangiogenic agents. Superiority of these new drugs to the time-tested standards has been defined, which has resulted in the establishment of effective standard treatments that prolong life for patients with RCC. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer is the leading cause of cancer-related mortality in the United States. In these patients, chemotherapy improves survival compared to supportive care, however, even with modern regimens the median survival is less than one year. As is true for other solid malignancies, vascular density has been demonstrated to be an important prognostic factor in lung cancer, and the extent of tumor vascularization has been linked to expression of proangiogenic molecules and oncogenic mutations. Because an adequate vascular supply is necessary for tumor growth and metastatic spread, much effort has been directed toward the development of therapies targeting the vascular component of lung cancer. In recent studies, the addition of antiangiogenic agents to either chemotherapy or other targeted agents has yielded promising results. This chapter highlights novel antiangiogenic agents and reviews emerging data from lung cancer clinical studies. [ABSTRACT FROM AUTHOR]

Malignant tumors of the central nervous system (CNS) are difficult to cure, despite advances made in the fields of neurosurgery and radiation oncology. These tumors are generally resistant to standard chemotherapeutic agents, and new strategies are needed to overcome these tumors. Tumors of the CNS system demonstrate various features of angiogenesis. Correlation has been made between the degree of increased vascularity and outcome, making these tumors enticing targets for antiangiogenic agents. Although initial clinical trials of angiogenic inhibitors have been disappointing with regard to improved patient outcome, important advances in utilizing antiangiogenic agents as an additional therapeutic modality for patients with CNS tumors have been identified. Rapid developments in understanding the molecular basis of angiogenesis and brain tumors have been made over the past decade, and application of this knowledge is currently being brought to the clinic. This chapter reviews the current knowledge of angiogenesis as it relates to brain tumors and recent advances that have been made in translating this knowledge into the treatment of patients with CNS tumors. [ABSTRACT FROM AUTHOR]

Advanced colorectal cancer was the first human malignancy in which inhibition of angiogenesis by targeting vascular endothelial growth factor (VEGF) led to a significant survival benefit in a randomized phase III trial. Since then, bevacizumab, a monoclonal antibody against VEGF, has become a standard component of palliative medical therapy in this disease. Various other angiogenesis inhibitors, in particular, inhibitors of VEGF-receptor kinases are currently undergoing testing in clinical trials, either as single agents or in combination with chemotherapy or other targeted agents. In addition, clinical research is currently focusing on the use of anti-VEGF-therapy in the adjuvant and neoadjuvant setting, as well as its usefulness as maintenance therapy to stabilize responses achieved with conventional cytotoxic chemotherapy. [ABSTRACT FROM AUTHOR]

Sarcomas are mesoderm-derived malignancies that include tumors arising from the soft tissues, skeleton, and vascular elements. These tumors share a common mesenchymal origin with the vasculature. Many of the signaling pathways involved in angiogenesis also drive sarcoma tumor cell growth. Autocrine and paracrine vascular endothelial growth factor (VEGF)- and platelet-derived growth factor (PDGF)-mediated growth plays a role in the pathogenesis of several sarcoma subtypes. Inhibition of signaling pathways common to sarcoma growth and angiogenesis has been shown to be an effective therapeutic strategy for some patients with sarcoma. [ABSTRACT FROM AUTHOR]

Starvation of tumors through eliminating their blood supply by blocking angiogenesis is an idea that is elegant in its very simplicity. In this chapter, we describe physiological and pathological angiogenesis and growth factors and microenvironmental influences that govern its initiation, promotion and inhibition. Our current understanding of the gene expression and biology of endothelial cells has led to the development of many therapeutic agents that target molecules in signal transduction pathways critical to angiogenesis in various types of cancer. It is clear that angiogenesis is a complex process which recruits multiple factors that act rapidly to produce a microvasculature in the developing tumor. As such, a multi-pronged attack against the growth factors aimed at early stages of cancer is likely to be most effective. [ABSTRACT FROM AUTHOR]

Although there are innumerable examples of studies demonstrating the efficacy of antiangiogenic therapy in preclinical models, unfortunatly the frequency and magnitude of this effect has been difficult to translate into the clinic. At the current time, with the exception of anti-VEGF therapy for renal cell carcinoma, single agent anti-angiogenic therapy has not lived up to expectations. At this stage is it important to critically evaluate potential explanations for why the success observed in preclinical studies has not translated into patient benifit. This chapter will focus on the biologic and human issues that have led to this apparent discrepancy. [ABSTRACT FROM AUTHOR]

Recent preclinical studies have suggested that radiotherapy in combination with antiangiogenic/vasculature-targeting agents enhances the therapeutic ratio of ionizing radiation. Because radiotherapy is one of the most widely used treatments for cancer, it is important to understand how best to use these two modalities to aid in the design of rational patient protocols. The mechanisms of interaction between antiangiogenic/vasculature-targeting agents and ionizing radiation are complex and involve interactions between the tumor stroma and vasculature and the tumor cells themselves. These agents can decrease overall tumor resistance to radiation by affecting both tumor cells and tumor vasculature, thereby breaking the codependent cycle of tumor growth and angiogenesis. Because the mechanisms of interaction between ionizing radiation and antiangiogenic/vascular targeting agents are not fully understood, the ideal way to use this potentially powerful combination for tumor cure has yet to be determined. We have described a number of possible mechanisms of interaction between antiangiogenic agents and radiation. [ABSTRACT FROM AUTHOR]

It is now widely accepted that for any tumor to grow to macroscopic size, a change to a proangiogenic phenotype leading to the formation of new blood vessels is required. This recognition has led to the development and clinical advancement of novel antiangiogenic therapeutics in cancer management. An alternative approach to targeting the neovasculature associated with tumors is not to interfere with new vessel formation but rather to disrupt the function of the tumor vasculature after it has already been formed. Vascular disrupting agents (VDAs) are designed to cause a rapid and selective vascular shutdown in tumors. The resulting ischemia produces rapid and extensive tumor cell kill. Treatment with VDAs has been shown to lead to extensive tumor necrosis in a wide variety of tumor models. VDAs also synergize with conventional anticancer treatments including radiotherapy and chemotherapy, and recent evidence indicates that VDA treatments are complimentary to antiangiogenic therapeutics. Lead VDAs have now entered clinical trials. This chapter focuses on the background and current state of development of VDAs and emphasizes their therapeutic potential when used in combination with conventional anticancer therapies and antiangiogenic agents. [ABSTRACT FROM AUTHOR]

Metronomic (antiangiogenic) chemotherapy refers to a form of dose dense chemotherapy involving close regular, even daily, administration of conventional chemotherapy drugs at relatively low doses over long periods in the absence of prolonged drug-free periods. Anti-tumor efficacy, which in some cases can be remarkably effective in various experimental mouse models of cancer, even in the absence of toxicity, is thought to be mediated mainly by antiangiogenic effects, either locally, by direct targeting of activated/dividing endothelial cells in the angiogenic tumor neovasculature, or systemically, by effects on circulating (bone marrow derived) endothelial progenitor cells (CEPs). However, additional mechanisms may also be involved, including stimulation of the immune system by targeting regulatory T cells, and possibly also direct effects on tumor cells—which could include the tumor stem cell(-like) subpopulation. Metronomic chemotherapy, because of its relatively nontoxic nature, is ideal for combination therapy using various targeted biologic agents, especially antiangiogenic drugs. Other promising combinatorial strategies include "doublet" metronomic chemotherapy using two different chemotherapy drugs, interspersing low-dose chemotherapy with higher bolus dose (BD) injections of the same drug, or short-course maximum tolerated dose (MTD) chemotherapy followed by long-term metronomic chemotherapy combined with a targeted biologic agent. Such combinations can sometimes have striking preclinical anti-tumor effects, even in models involving large primary tumors or widespread high-volume metastatic disease. A number of clinical trials and pilot studies testing various combinatorial metronomic chemotherapy regimens have been undertaken which, in aggregate, appear to confirm encouraging clinical activity in certain advanced-stage cancers, with only modest or minimal host toxicity being observed. Larger randomized phase III trials are thus warranted, especially considering some of the potential advantages of metronomic chemotherapy. These include increased convenience when using oral chemotherapeutic drugs, reduced costs when off-patent chemotherapeutic drugs are used, and reduced severity of toxic side effects. These features make metronomic chemotherapy-type regimens ideal for adjuvant chemotherapy of early-stage cancers, an example of which is long-term, nontoxic daily oral tegafur-uracil (UFT) (a 5-FU prodrug composed of uracil and tegafur) for treatment of early-stage non-small cell lung cancer (NSCLC). [ABSTRACT FROM AUTHOR]

Solid tumors require blood vessels for growth, and many new cancer therapies are targeted against the tumor vasculature. The widely held view is that these antiangiogenic therapies destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. Indeed that is the ultimate goal of antiangiogenic therapies. However, emerging preclinical and clinical evidence support an alternative hypothesis, that judicious application of agents that block angiogenesis directly (e.g., bevacizumab and cediranib) and indirectly (e.g., trastuzumab) can also transiently "normalize" the abnormal structure and function of tumor vasculature. In addition to being more efficient for oxygen and drug delivery, the normalized vessels are fortified with pericytes, which can hinder intravasation of cancer cells, a necessary step in hematogenous metastasis. Drugs that induce vascular normalization can also normalize the tumor microenvironment—reduce hypoxia and interstitial fluid pressure—and thus increase the efficacy of many conventional therapies if both are carefully scheduled. Reduced interstitial fluid pressure can decrease tumor-associated edema as well as the probability of lymphatic dissemination. Independent of these effects, alleviation of hypoxia can decrease the selection pressure for a more malignant phenotype. Finally, the increase in proliferation of cancer cells during the "vascular normalization window" can potentially sensitize tumors to cytotoxic agents. Results from our recent phase II clinical trial of cediranib, an oral, pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (TKI) in glioblastoma patients, show that the normalization window—identified using advanced magnetic resonance imaging (MRI) techniques—can last 1-4 months, and the resulting changes in tumor vasculature correlate with blood circulating molecular and cellular biomarkers in these patients. Antiangiogenic therapies may provide benefit for cancer patients by working through different mechanisms at different points in time. Normalization may be an early consequence of antiangiogenic therapy and offers an opportunity for optimizing delivery and facilitating the cytotoxic effects of chemotherapy and radiation. However, additional consequences of antiangiogenic therapies may include vessel "pruning" and nutrient deprivation of tumors. [ABSTRACT FROM AUTHOR]

Although the role of vascular endothelial growth factor (VEGF or VEGF-A) in angiogenesis is well studied, little is known about its role in the maintenance of quiescent vasculature. Recent observations from clinical trials using anti-VEGF therapy, as well as from the disease preeclampsia, point to a role for VEGF in the adult. This chapter explores both clinical and experimental VEGF neutralization studies and discusses the potential role of VEGF in the adult in maintaining endothelial cell (EC) survival and fenestration, as well as its action on non-ECs. Properties that may affect VEGF action in vivo are discussed. Finally, implications for use in anti- and pro-angiogenic therapy are proposed. [ABSTRACT FROM AUTHOR]

Blood vessels in general and micro-vessels in particular, must be maintained in a highly dynamic state. The ability of the circulation to alter vessel permeability during inflammation or to repeatedly grow and regress during the female reproductive cycle are but two examples of such dynamism. One consequence that stems from above considerations is that the microcirculation cannot be both flexible and completely impermeable to plasma. Thus, certain amount of plasma escapes from blood vessels into the interstitial tissue under normal conditions and this leakage is greatly increased during pathological states. The lymphatic system represents a parallel vasculature whose primary function is to return excess interstitial fluid to the circulation. The lymphatic system also acquired a secondary function as a conduit of leukocytes from the periphery to lymph nodes thus facilitating immune response to pathogens. This function is frequently subverted by cancer cells that invade tumor-associated lymphatic vessels and migrate to the regional lymph nodes. The presence of tumor cells in lymph nodes is an important clinical predictor of disease severity and prognosis. In some cancers, lymphatic invasion also represents a route of tumor dissemination to distant organs. [ABSTRACT FROM AUTHOR]

The tumor vasculature is largely induced by secreted VEGF-A and consists of a heterogeneous mixture of highly abnormal blood vessels. Recently, it has been possible to replicate many of these vessel types by introducing an adenovirus expressing VEGF-A164 (Ad-VEGF-A164) into mouse tissues. At least five different microvessels form in sequence from preexisting venules, each with distinctly different structural and functional properties. Mother vessels (MV) from first and evolve into several types of daugther vessels: bridged MV, capillaries, glomeruloid microvascular proliferations (GMP), and vascular malformations (VM). In addition to this angiogenic response, feeder arteries (FA) and draining veins (DV) develop from preexisting arteries and veins, respectively, to supply and drain the tumor microvasculature. This classification has helped to elucidate the steps and mechanisms by which tumors induce new blood vessels and hopefully will lead to the identification of new therapeutic targets that can improve anti-angiogenic tumor therapy. [ABSTRACT FROM AUTHOR]

Tie2 was identified as a receptor tyrosine kinase (RTK) expressed principally on vascular endothelium. Disrupting Tie2 function in mice resulted in embryonic lethality with defects in embryonic vasculature. Multiple ligands for Tie2, named angiopoietin (Ang), have been identified. Ang1, an agonist, stimulates Tie2 phosphorylation in endothelial cells (EC). Ang2 has been considered to be an antagonist of Tie2 that blocks Tie2 activation induced by Ang1 in EC. Disrupting the function of Ang1 or overproduction of Ang2 yielded a phenotype similar to the Tie2 knockout, confirming the importance of the Ang/Tie2 pathway during embryonic vascular development. The genetic evidence suggests that the VEGF pathway and the Tie2 pathway seem to work in a complementary and coordinated fashion during vascular development. Many clinical and animal studies show critical roles of Ang/Tie2 pathway in tumor angiogenesis. The interaction of the Ang/Tie2 pathway with the VEGF pathway has also been demonstrated. Elevated VEGF and Ang2 expressions are associated with increased tumor angiogenesis. Ang2 corresponds positively with tumor development and progression as well as with metastasis and correlates negatively with patient survival in many studies. Blocking the Ang/Tie2 pathway has been shown to inhibit tumor angiogenesis, growth, and metastasis, demonstrating the potential of future clinical therapies based on this pathway. As anti-angiogenic therapies move from the bench to a clinical setting, an understanding of the role of the Ang/Tie2 pathway is vital. [ABSTRACT FROM AUTHOR]

Angiogenesis is the process of new blood vessel growth and is a critical biological process under both physiological and pathological conditions. Angiogenesis can occur under physiological conditions that include embryogenesis and the ovarian/menstrual cycle. In contrast, pathological angiogenesis is associated with chronic inflammation/chronic fibroproliferative disorders and tumorigenesis of cancer. Net angiogenesis is determined by a balance in the expression of angiogenic, as compared with angiostatic factors. CXC chemokines are heparin-binding proteins that display unique disparate roles in the regulation of angiogenesis. Based on their structure, CXC chemokines can be divided into two groups that either promote or inhibit angiogenesis, and they are therefore uniquely placed to regulate net angiogenesis in both physiological and pathological conditions including cancer growth. [ABSTRACT FROM AUTHOR]

The identification of cell-surface markers expressed selectively by tumor vasculature is challenging. To get as close to the human disease as possible, investigators have isolated endothelial cells from fresh human tumor specimens and subjected them to RNA-based gene-expression analysis. The data indicate that there are few proteins that distinguish tumor vasculature from normal vasculature and re-enforce the notion that the endothelium is a tissue specialized cell type. Endosialin and tumor endothelial marker 7 (TEM 7) were identified as a cell-surface TEMs. The selective expression of endosialin and TEM 7 by tumor vasculature and stroma has been confirmed. Although the function of endosialin and TEM 7 remains to be elucidated, the expression pattern for this protein may be favorable for cancer therapy. PRL-3 was also identified by SAGE (serial analysis of gene expression) as a TEM. PRL-3 is an intracellular phosphatase that is expressed not only in tumor vasculature but in aggressive disease. SAGE analysis of subpopulations of tumors has provided useful leads for new vascular targets. It remains to the basic scientists to elucidate the function of these proteins and to the "drug hunters" to determine whether these targets can be used in therapeutically meaningful ways. [ABSTRACT FROM AUTHOR]

Pericytes are morphologically, biochemically, and physiologically heterogeneous and play an essential role in angiogenesis. Pericytes interact with endothelial cells, stabilize the newly formed endothelial tubes, modulate blood flow and vascular permeability, and regulate endothelial proliferation, differentiation, migration and survival. This chapter will review the biology, physiology and pathology of pericytes, as well as their role in angiogenesis. We will also discuss the potential relevance of pericytes in anti-angiogenic therapeutic approaches. Dual targeting of both endothelial and pericytes may provide more efficacious anti-angiogenic approaches for cancer therapy. [ABSTRACT FROM AUTHOR]

The recognition that blood vessel growth is a critical process in developing tumors has led to the increased study of tumor vasculature. Originally, it was considered that only nearby host vasculature provided the necessary cellular components that comprise blood vessels, endothelial cells (EC), and pericytes. Data gathered in recent years have supported the notion that endothelial precursor cells (EPC) exist postnatal and that EPC can also contribute to both physiological and pathological angiogenic processes including wound healing and cancer. EPC possess or can acquire many of the characteristics of mature, fully differentiation EC such as the ability to form tubes, to incorporate into developing vasculature, and to express many EC markers such as vascular endothelial growth factor 2 (VEGFR2) or von Willebrand factor (vWF). The most primitive EPC exhibit properties of progenitor cells that are denoted by expression of the hematopoietic stem cell marker CD34 and typically co-expressing CD133. Experiments in genetically engineered mice have demonstrated recruitment of cells from bone marrow to tumor vasculature. Studies in humans have also proven the existence of EPC. Although EPC represent a small percentage of the EC population, these progenitor cells offer new insights into tumor biology and may reveal novel targets for drug development. [ABSTRACT FROM AUTHOR]

Tumor neovascularization requires the activation of a subset of endothelial cells from normal vascular beds, the digestion of the underlying basement membrane, and the directional migration of these cells toward an avascular site. The contribution of vascular endothelial growth factor (VEGF) to each one of these steps has received large experimental support, and it has been demonstrated that pharmacological and/or genetic inactivation of this growth factor can impact the angiogenic response and consequently suppress tumor growth. Thus, understanding the mechanisms that control VEGF levels has become an important focus of investigation. Today, we have a fairly comprehensive understanding of the mechanisms that regulate VEGF transcriptional rate and half-life. In contrast, little emphasis has been placed on the regulation of VEGF biology post-secretion. In this chapter, we focus our attention on the question of how VEGF becomes released from the extracellular environment and contributes to tumor neovascularization. We discuss this point in the larger context of matrix interaction with growth factors and their modulation by matrix metalloproteinases (MMPs). [ABSTRACT FROM AUTHOR]

In the 1970's, anti-angiogenic therapy was realized as a potential strategy to shrink solid tumors. Since that time, many aspects of vascular biology have been investigated in attempts at understanding the mechanisms that regulate how blood vessels develop in health and disease. In the tumor microenvironment, factors such as hypoxia and acidosis impinge on normal endothelial cell (EC) function. Accordingly, the vascular structure in tumors is highly disorganized, vessels are of variable diameter, and there is vessel leakiness. Although these morphological changes in the tumor vasculature have been known for some time, it was only recently shown that tumor-associated EC are indeed distinct from normal EC at the molecular level. This chapter will discuss the abnormalities observed in the tumor endothelium. [ABSTRACT FROM AUTHOR]

An understanding of the mechanisms regulating endothelial cell roles in angiogenesis has led to the development of novel anti-tumor agents directed against members of the integrin family of cell adhesion proteins. Several integrins play important roles in promoting endothelial cell migration and survival during angiogenesis. Antagonists of these integrins either suppress cell migration and invasion of endothelial cells, suppress intercellular adhesion of endothelial cells and pericytes, or induce apoptosis of endothelial cells. Integrin antagonists also block tumor angiogenesis and metastasis. Currently, humanized or chimeric antibody antagonists of integrins α5β1, αvβ3 and αvβ5 and peptide inhibitors of these integrins are in clinical trials as angiogenesis-inhibiting agents for cancer therapy. [ABSTRACT FROM AUTHOR]

This chapter will present a pathophysiologic paradigm that occurs in solid tumors that is characterized by a self-propagating cycle of abnormally regulated angiogenesis, instability in perfusion, and hypoxia. Interactions between tumor and endothelial cells occur during tumor growth and in response to therapy. These interactions are of central importance in establishing codependence that contributes to promotion of tumor and endothelial cell survival, treatment resistance, enhanced invasion, and metastasis. Results indicate that concurrent targeting of both tumor and endothelial cells may be of central importance in improving treatment responses to both radiation and chemotherapy. [ABSTRACT FROM AUTHOR]

The vascular endothelial growth factors (VEGFs) are key regulators of blood and lymphatic vessel development during embryogenesis and in promoting new vascular growth during physiological and pathological processes in the adult. The VEGF family of ligands in mammals includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PlGF). These ligands bind to and activate three receptor tyrosine kinases, designated VEGFR-1, VEGFR-2, and VEGFR-3. VEGF ligands bind to these receptors with overlapping ligand-receptor specificities, and activation may be further modulated through interaction with coreceptors such as the neuropilins (NRP-1 and NRP-2), integrins, or Vascular endothelial-cadherin (VE-cadherin). Ligand activation of VEGFRs triggers a network of distinct downstream-signaling pathways in a cell-type-specific manner that promotes vascular permeability, endothelial cell growth, migration, and survival. VEGF is an important survival factor for hematopoietic stem cells (HSCs) and stimulates the mobilization of endothelial progenitor cells (EPC) from the bone marrow to distant sites of neovascularization. A large body of experimental evidence has established VEGF as an essential molecule in promoting angiogenesis during tumor growth. These findings have led to the development of therapeutic agents that selectively target various VEGF ligands and their receptors. This chapter reviews the biology of VEGF and its receptors, emphasizing their important role for cancerous growth. [ABSTRACT FROM AUTHOR]