Current Molecular Medicine - Volume 9, Issue 8, 2009

Thirty-eight years ago when Judah Folkman proposed the first hypothesis of antiangiogenic cancer therapy, he and others had not fully appreciated the impact of pathological angiogenesis on contribution to the onset, development, and progression of the most common and severe human diseases. Folkman's original hypothesis, however, has revolutionized our thinking of development of novel therapeutic approaches for the treatment of multiple human disorders by targeting the pathological angiogenesis. Today, we know that nearly 100 human diseases including cardiovascular diseases, cancer, metastasis, diabetic complications, age-related macular degeneration, obesity, and chronic inflammation are involved in malformation or dysfunction of the vasculature. Angiogenesis research has become one of the most attractive, exciting, and promising areas in biomedicine for the development of new drugs against most common and lethal human diseases such as cancer and cardiovascular diseases. At the time when this was being composed (October), there were 4, 074 papers under the topic of angiogenesis published in 2008. In 2004, two anti-VEGF drugs, bevacizumab (avastin) and pegaptanib (macugen) had been approved for the treatment of metastatic colorectal cancer and age-related macular degeneration, respectively. These initial successes of antiangiogenic therapy in the clinic laid important milestones, which led to the approval of several other drugs mainly targeting the VEGF-mediated signaling pathways. For example, sunitinib and sorafenib were subsequently approved by the USA FDA for the treatment of various cancers, and lucentis was approved for the treatment of macular degeneration. Currently, there are approximately 40 different antiangiogenic agents are in phase III trials and hundreds are in phase II or phase I trials for the treatment of various cancers. The new generation of antiangiogenic agents seems to have broader targets by blocking multiple pathways as compared with the monospecific drugs such as bevacizumab. In contrast to the success of antiangiogenic therapy, delivery of proangiogenic agents to the ischemic myocardium or skeletal muscles in clinical patients has not been approved to be a valid approach for the treatment of myocardiac infarction or ischemic legs. Although the underlying mechanism of these clinical failures is not fully understood, these clinical findings suggest that promotion and remodeling of arteriogenesis or collaterogenesis involve complex interplay between various angiogenic and proangiogenic factors. Thus, combination therapy consisting of various proangiogenic and arteriogenic factors warrants further clinical evaluation. The aim of this special issue is to highlight the impact of angiogenesis and lymphangiogenesis on clinical development of novel therapeutic approaches. We are very grateful to many experts who have helped us to contribute review articles in their expertise to this issue. We hope that these review articles could further stimulate the excitement of angiogenesis research and could pave new pathways for young scientists who are pursuing their research careers in this field. It has been estimated that approximately 15, 000, 000 patients globally will benefit from antiangiogenic therapy by the end of 2009. Antiangiogenic agents have become the key composition of the front-line therapy for various solid cancers. Anti-VEGF agents have also considered as very effective drugs for the treatment of age-related macular been degeneration. From now, one can only imagine that dreams of miracle drugs for many patients will probably become true within the next 10 years. We thank Dr. Judah Folkman and many other experts who have paved this avenue for all of us to experience this angiogenic “revolution”.

Angiogenesis is a major factor in the development of benign, inflammatory, and malignant processes of the skin. Endothelial cells are the effector cells of angiogenesis, and understanding their response to growth factors and inhibitors is critical to understanding the pathogenesis and treatment of skin disease. Hemangiomas, benign tumors of endothelial cells, represent the most common tumor of childhood. In our previous studies, we have found that tumor vasculature in human solid tumors expresses similarities in signaling to that of hemangiomas, making the knowledge of signaling in hemangiomas widely applicable. These similarities include expression of reactive oxygen, NFkB and akt in tumor vasculature. Furthermore, we have studied malignant vascular tumors, including hemangioendothelioma and angiosarcoma and have shown distinct signaling abnormalities in these tumors. The incidence of these tumors is expected to rise due to environmental insults, such as radiation and lumpectomy for breast cancer, dietary and industrial carcinogens (hepatic angiosarcoma), and chronic ultraviolet exposure and potential Agent Orange exposure. I hypothesize that hemangiomas, angiosarcomas, and vascular malformations represent the extremes of signaling abnormalities seen in pathogenic angiogenesis.

Angiogenesis plays an established role in the growth promotion of dormant micrometastasis, because blood vessels deliver oxygen and nutrients into the tumor microenvironment. A discrete event termed “the angiogenic switch” has been recognized as key in promoting the transition towards a clinically aggressive tumor. This concept generally describes a permanent change in the angiogenic capacity of the tumor sustained by genetic events occurring in cancer cells. Recent evidence, however, indicates that a transient angiogenic switch delivered by components of the tumor microenvironment can also convey tumorigenic properties to tumor cells. Why is the angiogenic switch so fundamental in the promotion of tumor growth? In addition to the recognized feeding function of blood vessels, there is accumulating evidence suggesting that endothelial cells - and perhaps other cellular components of the microenvironment - communicate both positive and negative signals to tumor cells. This cross-talk between heterogeneous cell types could turn out to be important in the regulation of cancer cells' behaviour. In this review, we discuss the possible implications of the angiogenic switch on our understanding of the regulation of tumor dormancy.

We have reviewed physiological significance of rhythmical spontaneous contractions of collecting lymphatics, which play an important role in lymph transport and seem to regulate lymph formation through changing the pacemaker sites of the rhythmic contractions and conractile patterns of lymphangions. Next, we reported experimental findings that the wall effective permeability of hydrophilic substances labelled with fluorescent dyes was evaluated in an isolated cannulated rat single lymphatic using a microscope system. With the experimental evidence, we have discussed physiological significance and crucial roles of the enrichment of albumin in lymph through the wall of small lymphatics in regulation of innate immunity. In addition, we have described the mode of action of recanalization of collecting lymphatics after excision of lymph node with special reference to clinical treatment for surgical removal of lymph nodes-mediated secondary lymphedema. Finally, we have addressed the possibility that primary tumor cells and/or metastatic carcinoma cells themselves release key chemical substances to develop environment suitable for micro-metastasis in sentinel lymph node.

Anti-angiogenic therapy has fundamentally landmarked the clinical new era of anti-cancer therapy. It was demonstrated that the blockade of vascular endothelial growth factor results in regression of the disease and prolongation of survival. In contrast, it was clarified that the differential sensitivity of the therapeutic impact exists. Many thought-provoking questions have been raised in this field. Herein, we focus on the clinical data and attempt to summarize some clinical trials of anti-angiogenic treatment, highlighting the sparkling articles, the differential sensitivities to these agents beyond progression continuation, and how to individualize treatment according to validated biomarkers.

The idea of delivery of proangiogenic factors to the ischemic region of myocardium or skeletal muscles was proposed more than 30 years ago and abundant preclinical data validate this concept. However, clinical experience with this approach has generally produced unfulfilled promises. Although reestablishment of functional collateral networks for improvement of blood perfusion in ischemic tissues is an undisputed concept for therapeutic intervention, the molecular mechanism underlying collaterogenesis under tissue hypoxia remains poorly understood. Critical issues including the therapeutic efficacy of monotherapy vs. combination with arteriogenic therapy, drug release, optimal dose, and time scale of delivery remain to be resolved. The aim of this review is to discuss molecular mechanisms of angiogenesis and arteriogenesis, to better design clinical trials, and to improve therapeutic efficacy of proangiogenic and arteriogenic factors for the treatment of ischemic diseases.

The leading cause of blindness in the developed world results from several disorders that have pathologic ocular neovascularization as the common pathway leading to vision loss. These disorders include exudative age related macular degeneration (AMD), diabetic retinopathy (DR), retinopathy of prematurity (ROP), retinal vein occlusions (RVO) and ocular tumors. Because neovascularization is the common pathway to blindness in these highly prevalent conditions, the recent understanding of the cascade of angiogenesis has led to clinically available molecular therapeutics that have been proven to restore and preserve vision in patients that suffer from these blinding conditions. This article will summarize the emergence of vascular endothelial growth factor (VEGF) as a validated treatment target for and current understanding of the pathophysiology of ocular neovascularization. The article will then cover promising future strategies and therapeutic targets that are aimed at enhancing the efficacy and/or duration of effect of these clinically available anti-VEGF strategies. In particular molecules that target, VEGF, PDGF, Complement, Inflammation and Integrins that are entering or are currently in clinical trials will be reviewed.

Angiogenesis research has become one of the most important areas in biomedical research. At the time of writing this review, there were approximately 3536 articles published in the year of 2008 alone on the topic of angiogenesis. The fast expansion of this research field demands development of rigorous, reliable, stable, convenient, and clinically relevant assay systems for disease diagnosis, prognosis, therapeutic evaluation, drug discovery, and mechanistic studies at the molecular level. Here, we discuss several commonly used in vivo angiogenesis models by systematically analyzing and pointing out pitfalls of each assay. Owing to existence of numerous assays and the limitation of text, it is impossible to discuss all these assays in this article. Here we select several most commonly used angiogenesis assays performed in various species including mice, chicks and zebrafish for further in-depth discussion. We hope this information will be valuable for improving current angiogenesis research.

Multiple sclerosis is a disease of the central nervous system that predmoninantly affects young adults. The pathogenic mechanisms are complex, however numerous studies indicate that the disease is initiated by an autoimmune attack on protein targets present in the central nervous system. Given that a dysfunctional immune system perpetuates the pathophysiological mechanisms that characterize this inflammatory disorder, several therapeutic approaches that target immune cells or their secreted mediators have been generated and are currently used clinically. Although these strategies have been partially beneficial to a proportion of patients, current therapies are not particularly effective at preventing disease progression. As such there is a large and unmet need for the development of more effective treatments. Owing to a number of promising results obtained in mouse models of multiple sclerosis, cell therapies implementing hematopoietic, mesenchymal and neural stem cells may provide practical vehicles for in situ immunomodulation, neuroprotection and regeneration. In concert with these approaches, gene therapy strategies are being investigated to restore antigen-specific tolerance or to deliver anti-inflammatory molecules. Furthermore targeted delivery of glial or neurotropic factors, which counteract the activity of inhibitory molecules within the neurodegenerative component of the lesion, is also being pursued. It is conceivable that these experimental approaches alone, or in combination with emerging and current treatments, may establish a rational protocol for the treatment of multiple sclerosis and potentially other autoimmune disorders.

Combining groundbreaking research and developments in cancer biomarkers, nanotechnology and molecular targeted medicine, a new realm of therapy is possible: personalized and predictive medicine. Developing a method to detect the overexpression of several tumor marker genes simultaneously, knowing that a single cell generally expresses more than one altered gene, should have a high predictive value for identifying cancer cells amidst the normal cellular background. Theoretically, a cancer's unique molecular profile can be used to predict its invasive and metastatic potential, its ability to evade immune surveillance, and its potential response to treatment. Fluorescent probes have been developed to detect the levels of expression of various biomarkers in tumor cells and tissues. Expression of biomarker messenger RNAs (mRNAs) or the presence of a specific mutation in an oncogene in cancer cells can be detected using molecular beacons (MBs) that only emit fluorescent signals after binding to its specific target mRNAs. Antibodies or ligands labeled with fluorophores or fluorescent quantum dots (QDs) have been successfully used to identify specific proteins expressed in cells. Furthermore, multiplex imaging using both MBs and antibodies labeled with a fluorescent probe on the same sample may provide important information correlating the level of mRNA expression and the subsequent level of protein production for a given biomarker. This technology will be useful in research investigating cancer biology, molecular imaging and molecular profiling. With the identification of biomarkers that are related to aggressive tumor types, we may be able to predict within certain patient populations who will develop invasive cancers, and what their prognosis will be given different treatment modalities, ultimately delivering medical care and treatment strategies that are specifically tailored to each individual patient, making personalized and predictive medicine a reality.