Angiogenesis and cancer: A cross-talk between basic science and clinical trials (the "do ut des" paradigm)

Angiogenesis plays a crucial role in facilitating tumor growth and the metastatic process, and it is the result of a dynamic balance between pro-angiogenic factors, like vascular endothelial growth factor (VEGF) and platelet-derived growth factor, and antiangiogenic factors, like thrombospondin-1 and angiostatin. Many drugs that target human tumors, like bevacizumab and some VEGF-receptor tyrosine-kinase inhibitors (e.g., BAY 43-9006, SU11248 and PTK787/ZK222584) have been studied in clinical trials, with favorable toxicity reports and encouraging results in advanced colorectal cancer, renal cell cancer, breast cancer and non-squamous non-small cell lung cancer, either combined with chemotherapy, or in monotherapy. Another potential approach to inhibiting angiogenesis is through metronomic chemotherapy (low doses of chemotherapy for long periods of time). This review describes the mechanisms of the angiogenic process and evaluates the recent data about antiangiogenic therapies in clinical trials.     

Cardio-oncology: Understanding the different mechanisms of cardiovascular toxicity

Due to the success of finding treatments for various types of cancer, overall cancer survival has increased substantially in recent decades. Ironically, the clinical success of antineoplastic therapy is attenuated by the comorbidity of cardiovascular diseases, which appear to be the main complications of intense cancer treatment and are the second main cause of long-term morbidity and mortality among cancer survivors.Cardio-oncology is the new area of cardiology that aims to treat the specific cardiologic status of cancer patients.Most antineoplastic therapies are associated with some degree of cardiovascular toxicity, ranging from asymptomatic and transient cardiac events to clinically significant and long-lasting events.Antineoplastic agents are responsible for different cardiovascular injuries, which can be reversible or permanent. All anatomical structures of the heart can, however, be affected by transthoracic radiotherapy.Cardiotoxicity mechanisms are recognized according to the presence or absence of structural anomalies and their reversibility, being classified into Type I and Type II, aiming to distinguish the drugs that induce irreversible damage (Type I) from the drugs that predominantly induce reversible left ventricular dysfunction (Type II).While anthracyclines and anti-HER2 agents form the two major groups of cardiotoxic drugs, other antineoplastic agents, such as other monoclonal antibodies, certain tyrosine kinase inhibitors and antiangiogenic drugs can also be cardiotoxic via different mechanisms.This article presents the different pathophysiological mechanisms of cardiovascular toxicity according to the treatment regimen used.     

Hypertension Due to Antiangiogenic Cancer Therapy With Vascular Endothelial Growth Factor Inhibitors: Understanding and Managing a New Syndrome

Novel antiangiogenic cancer therapies, particularly agents that block vascular endothelial growth factor (VEGF) signalling, have improved outcomes in patients with cancers and are now used as first-line therapies for some tumours. However, with VEGF inhibitors (VEGFIs) are new complications, particularly hypertension. VEGFI-induced hypertension is a dose-dependent phenomenon due to on-target effects rather than off-target effects. Increased blood pressure occurs in almost 100% of patients who take VEGFIs, with a subset who develop severe hypertension. Molecular mechanisms underlying VEGFI-induced hypertension are unclear, but endothelial dysfunction and increased vascular resistance, due to impaired nitric oxide signalling, reduced prostacyclin production, endothelin-1 (ET-1) upregulation, oxidative stress, and rarefaction have been implicated. Treatment of hypertension should be aimed at reducing the risk of short-term morbidity associated with hypertension while maintaining effective dosing of antiangiogenic therapy for optimal cancer treatment. Although specific guidelines are not yet available for the management of VEGFI-induced hypertension, angiotensin-converting enzyme inhibitors and dihydropyridine calcium channel blockers are commonly used. Severe hypertension might require reduction of VEGFI dosing, or in some cases, interruption of treatment. As more potent VEGFIs are developed and as more cancer patients are treated with VEGFIs, the burden of hypertension toxicity will increase. This will be further compounded as the use of antiangiogenic drugs broadens to include older patients and those with pre-existing cardiovascular disease. Here we focus on VEGF as a target for antiangiogenesis and how this affects increased blood pressure. Putative mechanisms underlying VEGFI-induced hypertension are highlighted and therapeutic strategies to manage such hypertension are discussed.     

Angiogenesis Process in Osteosarcoma: An Updated Perspective of Pathophysiology and Therapeutics

In this review, we discuss the pathologic mechanism of the angiogenesis process in osteosarcoma (OS) and the therapeutic use of angiogenesis inhibitors in OS treatment. The activation of endothelial cells by angiogenic factors leads to the production of proteolytic enzymes, which degrade the extracellular matrix. The degradation of the underlying basement membrane enables endothelial cells to proliferate and migrate to the surrounding tissue to form new vessels. These new vessels provide cancer cells with oxygen and nutrition and play an important role in cancer cell survival and metastasis. Thus, antiangiogenic therapies might be an interesting approach in OS therapeutics.     

Cardiac Side Effects of Anticancer Treatments: New Mechanistic Insights

Damage to heart cells leading to heart failure is a known complication of well-established cancer therapies including anthracycline antibiotics and radiation therapy, and the cardiovascular complications of these therapies has been controlled in large part through dose limitations and modifications of delivery methods. Recent research into the cellular and molecular mechanisms for the cardiovascular effects of these therapies may lead to other cardioprotective strategies that improve effectiveness of cancer treatments. Newer cancer therapies that have been developed based upon specifically targeting oncogene signaling also have been associated with heart failure. Rapid development of a detailed understanding of how these agents cause cardiac dysfunction promises to improve outcomes in cancer patients, as well as stimulate concepts of cardiovascular homeostasis that will likely accelerate development of cardiovascular therapies.     

Que doit savoir un cardiologue sur le suivi et la prise en charge d'une femme atteinte de cancer du sein ?

Over the last decade, cancer mortality has decreased considerably, particularly in breast cancer thanks to better screening techniques and better therapeutic management. The significant increase in patient survival has led to the appearance of a certain number of events due to the side effects of the therapies used. Cardiovascular disease is the most frequently observed side effect in breast cancer, due to the direct toxicity of anti-cancer therapies but also due to traditional cardiovascular risk factors common to both of diseases. Anthracyclines, anti-HER2 therapies, chest radiotherapy and hormone therapy are the main causes of cardiotoxicity in breast cancer. It is important to know the rate of follow-up for cardiotoxicity screening and management.     

Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy

The recent approval of a prostate cancer vaccine has renewed hope for anticancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they often are used at high doses in the clinic to prune tumor vessels and paradoxically may compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower vascular-normalizing doses, but not high antivascular/antiangiogenic doses, of an anti-VEGF receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses in polarizing tumor-associated macrophages from an immune inhibitory M2-like phenotype toward an immune stimulatory M1-like phenotype and in facilitating CD4⁺ and CD8⁺ T-cell tumor infiltration. Based on this mechanism, scheduling lower-dose anti-VEGFR2 therapy with T-cell activation induced by a whole cancer cell vaccine therapy enhanced anticancer efficacy in a CD8⁺ T-cell–dependent manner in both immune-tolerant and immunogenic murine breast cancer models. These findings indicate that vascular-normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a strategy to use antiangiogenic agents in breast cancer more effectively with active immunotherapy and potentially other anticancer therapies.     

Challenges in the current antiangiogenic treatment paradigm for patients with non-small cell lung cancer

Patients with non-small cell lung cancer (NSCLC) often present with advanced disease and cure rates are dismal with currently available treatment. Novel therapies including small molecule tyrosine kinase inhibitors and monoclonal antibodies are being developed to target angiogenesis, an essential step in tumorigenesis and metastasis. The only antiangiogenic agent currently approved for treatment of NSCLC is bevacizumab, although numerous other antiangiogenic inhibitors (e.g., sorafenib, sunitinib, cediranib, motesanib, BIBF 1120) are in clinical trials. Individualized treatment algorithms may improve patient outcomes and new evidence suggests that biomarkers may guide treatment decisions. We present an overview of the molecular pathways involved in angiogenesis, discuss clinical trials of bevacizumab and developmental antiangiogenic agents, and address the challenges of developing individualized treatment paradigms for NSCLC, particularly the use of biomarkers.     

Combined Antiangiogenic and Immune Therapy of Prostate Cancer

Experimental studies of antiangiogenic or immune therapy of cancer have generated a great deal of optimism. However, the results of clinical testing of these therapies are below expectations. We hypothesized that the antitumor efficacy can be increased when immune destruction of tumor cell is combined with destruction of tumor vasculature by antiangiogenic drugs. In the present study the therapeutic efficacy of combined antiangiogenic and immune therapy has been tested against the highly aggressive, MHC class I negative murine RM1 prostate tumor. SU6668 was used as the antiangiogenic drug and recombinant murine B7.2-IgG fusion protein was used to stimulate T cell-mediated immune destruction of tumor cells. SU6668 is an inhibitor of the tyrosine kinase activity of three angiogenic receptors VEGFR2 (Flk-1/KDR), PDGFRβ and FGFR1 that play a crucial role in tumor-induced vascularization. Our studies show that B7.2-IgG treatment of mice with established RM1 prostate tumors resulted in a significant inhibition of tumor growth. Both CD4⁺ and CD8⁺ T cells were responsible for this effect. SU6668 therapy substantially inhibited tumor vascularization and tumor growth. When tumor-bearing mice were treated with SU6668 in combination with B7.2-IgG, the antitumor effects were substantially higher than in mice treated separately with SU6668 or B7.2-IgG. Prolonged treatment of mice with SU6668 did not inhibit the immunoreactivity of T lymphocytes. On the contrary, T cells from mice treated with a combination of SU6668 and B7.2-IgG showed higher proliferative responses and cytokine production following anti-CD3 stimulation than T cells of mice treated separately with these modalities. These results indicate that antiangiogenic and immune therapies using SU6668 and B7.2-IgG are compatible and manifest complementary antitumor effects. Combined antiangiogenic and immune therapy might represent a new strategy for cancer treatment.     

Comparison of the antiangiogenic effects of heparin sodium, enoxaparin sodium, and tinzaparin sodium by using chorioallantoic membrane assay

Unfractionated heparin (UFH) and low molecular weight heparins have been used as anticoagulation agents in cardiovascular clinics for decades. However, these molecules also have potent antiangiogenic effects. Whereas, angiogenesis may be the most crucial determinant of the prognosis of cardiovascular diseases, and except some special situation, antiangiogenic effect is not desirable in the most of the cardiovascular disease. In this study, we aimed to compare the antiangiogenic potency of UFH, enoxaparin, and tinzaparin. The antiangiogenic efficacies of UFH, enoxaparin, and tinzaparin were examined in vivo by using the chick chorioallantoic membrane (CAM) model. Twenty fertilized eggs were used for each studied drug. Drug solutions were prepared in 10 and 1 IU/10 μl concentrations. Decreases in the density of the capillaries were assessed and scored. All three drugs showed antiangiogenic effects on the chick CAM at the 10 IU/10 μl concentration. However, the antiangiogenic score of the UFH was significantly higher than that of enoxaparin and tinzaparin at 1 and 10 IU/10 μl concentrations. UFH had stronger and antiangiogenic potential than enoxaparin and tinzaparin. However, tinzaparin showed dose-dependent antiangiogenic effects. We think that an anticoagulant molecule with a less and dose-dependent antiangiogenic effect, as in the case of tinzaparin, may be more desirable in case of cardiovascular disease related with insufficient angiogenesis.     

The emerging issue of cardiac dysfunction induced by antineoplastic angiogenesis inhibitors

Left ventricular dysfunction from anticancer drugs has emerged as a relevant problem in the clinical and scientific communities. Anthracycline toxicity has always been the most relevant, but with the increasing use of biological targeted therapies in treatment protocols, with an increasing number of cancer survivors, new toxicities have been increasing in more recent years. Cardiomyopathy after ErbB2 inhibitors has been intensively studied. Another important class of biological anticancer drugs are vascular endothelial growth factor (VEGF) inhibitors. VEGF signalling is crucial for vascular growth, but it also has a major impact on myocardial function. Also, it is important to note that such angiogenesis inhibitors are multitargeted in most cases, and can produce a broad spectrum of cardiovascular side effects. Here we review the mechanisms and pathophysiology of the most significant cardiotoxic effects of antiangiogenic drugs, and particular attention is drawn to LV dysfunction, discussing the assessment and management on the basis of the most recent cardio‐oncological findings and heart failure guidelines.     

Angiogenesis and antiangiogenic cancer therapy

Physiologic angiogenesis takes place during tissue growth and repair, during the female reproductive cycle, and during fetal development. Angiogenesis is also required for tumor growth and metastasis and, therefore, represents an exciting target for cancer treatment. Angiogenesis is a complex process that is tightly regulated by pro- and antiangiogenic growth factors. Pathologic angiogenesis is characterized by either excessive (eg. cancer) or inadequate (eg. coronary artery disease) neovascularization. Avascular tumors are severely restricted in their growth potential because of the lack of a blood supply. For tumors to develop in size and metastatic potential they must make an "angiogenic switch" through perturbing the local balance of proangiogenic and antiangiogenic factors. Frequently, tumors overexpress proangiogenic factors, such as vascular endothelial growth factor, allowing them to make this angiogenic switch. Two strategies used in the development of antiangiogenic agents involve the inhibition of proangiogenic factors (eg. anti-vascular endothelial growth factor monoclonal antibodies) as well as therapy with endogenous inhibitors of angiogenesis. Emerging antiangiogenic agents currently in clinical studies are discussed in this review.     

Angiostatic peptides use plasma fibronectin to home to angiogenic vasculature

A group of angiogenesis inhibitors are derived from fragments of extracellular matrix or blood proteins. Endostatin, antithrombin, and anastellin are members of this group of substances. The plasma adhesion proteins fibronectin and vitronectin serve as cofactors for these three antiangiogenic proteins. Anginex is a synthetic 33-amino acid peptide that was originally modeled to reproduce the beta-sheet structure of antiangiogenic proteins. Here, we show that anginex initiates fibronectin polymerization and is inactive in mice that lack plasma fibronectin. Anginex shares these characteristics with anastellin. Fluorescein-labeled anginex and anastellin specifically localized in angiogenic vessels in vivo. This localization was dependent on plasma fibronectin and inhibited by an Arg-Gly-Asp peptide. Thus, anginex shares with several physiological angiogenesis inhibitors a dependence on plasma adhesion proteins. The role of the adhesion protein interaction apparently is to form integrin-binding complexes that deliver the antiangiogenic proteins to sites of angiogenesis. This functional convergence of several antiangiogenic factors has important implications for antiangiogenic therapies.     

Emerging biotechnological strategies for non-viral antiangiogenic gene therapy

Angiogenesis has emerged as a promising target of cancer treatment. With the development of biotechnology, major progress has been made in the exploring effective therapies on targeting tumor angiogenesis over the last 20?years. Gene therapy has attracted considerable interest by virtue of the capabilities of expressing sustained levels of therapeutic agents within cells of the patients. However, the major challenge of gene therapy is the efficient delivery of therapeutic gene to the target site. Compared with viral strategies, non-viral strategies were more acceptable by their widely recognized security and lower side effects. This paper reviews the basic biology of angiogenesis, the potential advantages of antiangiogenic gene therapy, the therapeutic genetic drugs developed through biotechnology, as well as the biotechnological strategies that enhancing non-viral gene therapy targeting to tumor angiogenesis in a more controlled manner, with great respect to RNA interference, ligand-directed vascular targeting strategies, vascular endothelial growth factor pathway and tumor associated macrophages targeting. In conclusion, antiangiogenic gene therapy holds great promise in advancing cancer therapy. Developing better non-viral biotechnological platforms will benefit antiangiogenic targeted cancer gene therapeutic methods, support their evaluation in human clinical trials and realize the actual utilization in the near future.     

Role of hematopoietic growth factors in angiogenesis

In early ontogeny, hematopoiesis is closely associated with angiogenesis. This article reviews recent studies of the effect of hematopoietic growth factors on several endothelial cell functions together with recent findings about angiogenesis and antiangiogenic therapies in hematopoietic malignancies such as leukemia, lymphoma and myeloma.     

Thyroid effects and anticancer treatment

Thyroid consequences of cancer therapy are multiple, better known after radiotherapy than after chemotherapy and recently described with targeted therapies. Cervical or total body irradiation may result in thyroid insufficiency or cancer. The consequences of treatment with new antiangiogenic drugs are under evaluation; however their effect on thyroid function is already well established. Thyroid dysfunction usually occurs late, several months or years after treatment and have to be depicted. There is an improvement in the overall survival of patients suffering from cancer and endocrinologists must be aware of the endocrine effects of treatments to propose an adequate survey and an appropriate treatment to improve well-being of patients.     

Developing a Cardiology-Oncology Clinical Practice Guideline

Clinical Practice Guidelines (CPG) have become an increasingly common method to assist practitioner and patient decisions about health care for specific medical problems. CPGs generally address a single medical diagnosis or syndrome leaving practitioners and patients with little guidance when two major medical diagnoses exist such as in the case of heart disease and cancer. As cancer and heart disease are both diseases of the elderly and share many common risk factors it is likely they will coexist in many patients. Thus screening for and preventing and treating heart disease in the cancer patient assumes increasing importance as aggressive cancer therapies are applied to older patients and as a growing number of cardiovascular side effects of anti-cancer therapy are described. Careful evaluation of heart disease in the cancer patient will likely improve quality of life but may also improve mortality as the presence or development of heart disease may significantly limit life-saving cancer therapies. The rationale, potential problems, and important steps in developing a cardiology-oncology guideline are discussed.     

The Role of Exercise Interventions in Reducing the Risk for Cardiometabolic Disease in Cancer Survivors

The leading cause of death in developed countries is cancer, influenced by negative lifestyle factors including obesity, unhealthy diet, physical inactivity and addictive habits such as smoking and alcohol. These established cancer-promoting behaviors are also well-known causative factors of cardiac disease and cardiometabolic syndrome. While improved treatments have led to improved cancer-specific outcomes, many cancer survivors are now at increased risk of death from cardiovascular disease, as a result of pre-existing cardiometabolic syndrome and cardiometabolic toxicities of anti-cancer therapies. In the cardiology discipline, exercise therapy has a proven role in disease rehabilitation and risk reduction. The purpose of this review is to discuss the potential role of exercise interventions in risk reduction of cardiometabolic disease in adult cancer survivors.     

Drug insight: antiangiogenic therapies for gastrointestinal cancers--focus on monoclonal antibodies

Tumor angiogenesis is strongly induced by vascular endothelial growth factor (VEGF), which is overexpressed in most human gastrointestinal cancers. VEGF overexpression is known to be associated with poor prognosis and survival in patients with various solid tumors. The humanized monoclonal anti-VEGF antibody bevacizumab (Avastin, Genentech Inc., South San Francisco, CA) is a prototypic antiangiogenic compound, and has proven therapeutic benefit combined with conventional chemotherapy-namely, significantly improved progression-free survival in patients with metastatic colorectal cancer. Bevacizumab is the only anti-VEGF antibody that has been approved by the FDA and the European Medicines Agency for the treatment of metastatic colorectal cancer. Several ongoing clinical studies are evaluating the potential of bevacizumab therapy for other gastrointestinal cancers, in combination with chemotherapy, other targeted therapies and/or radiation. Soluble chimeric receptors, tyrosine kinase inhibitors, and monoclonal antibodies against VEGF and molecular targets in the integrin and Delta-like protein 4-Notch pathways are being developed. As tumors acquire resistance to anti-VEGF therapy, further development of antiangiogenic and vascular targets and therapy is warranted.