Vascular endothelial growth factor (VEGF, VEGF-A) is a major regulator of physiological and pathological angiogenesis. Several VEGF inhibitors have been approved by the FDA for the treatment of ...advanced cancer and neovascular age-related macular degeneration. This brief review provides a historic account of the challenges associated with the discovery of VEGF and the early steps in elucidating the role of this molecule in the regulation of angiogenesis.
Abstract FDA approval of several inhibitors of the VEGF pathway has enabled significant advances in the therapy of cancer and neovascular age-related macular degeneration. However, similar to other ...therapies, inherent/acquired resistance to anti-angiogenic drugs may occur in patients, leading to disease progression. So far the lack of predictive biomarkers has precluded identification of patients most likely to respond to such treatments. Recent suggest that both tumor and non-tumor (stromal) cell types are involved in the reduced responsiveness to the treatments. The present review examines the role of tumor- as well as stromal cell-derived pathways involved in tumor growth and in refractoriness to anti-VEGF therapies.
Vascular endothelial growth factor (VEGF, VEGF-A) is a major regulator of physiological and pathological angiogenesis. One feature of VEGF is the existence of multiple isoforms arising from ...alternative exon splicing. Our initial biochemical and biological studies indicated that such isoforms are uniquely suited to generate angiogenic gradients by virtue of their differential ability to interact with the extracellular matrix (ECM). Although ECM-bound VEGF was bioactive, processing by physiologically relevant proteases such as plasmin was identified as a key mechanism to convert ECM-bound VEGF into freely diffusible forms. This retrospective article examines the early studies and also emphasizes the subsequent progress in our understanding of these processes in health and disease.
It is almost intuitive that blood vessels have a central role in biology and medicine. Indeed, even though the concept of blood circulation was not established until a few centuries ago, mankind had ...known for millennia that blood vessels are indispensable for bringing nourishment to organs and limbs. The converse notion--that growth of blood vessels can promote or facilitate disease--is much more recent.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Angiogenesis, the development of new blood vessels, is a fundamental physiological process. In addition, angiogenesis plays a key role in the pathogenesis of several disorders, including cancer and ...eye disorders such as diabetic retinopathy and age-related macular degeneration (AMD). However, identifying the regulators of angiogenesis proved challenging. Numerous factors that stimulated angiogenesis in various bioassays were identified, but their pathophysiological role remained unclear. In 1989, we reported the isolation and cloning of vascular endothelial growth factor (VEGF, VEGF-A) as an endothelial cell-specific mitogen and angiogenic factor. The tyrosine kinases Flt-1 (VEGFR-1) and KDR (VEGFR-2) were subsequently identified as VEGF receptors. Loss of a single vegfa allele results in defective vascularization and embryonic lethality in mice, emphasizing the essential role of VEGF in the development of blood vessels. Subsequently, we reported that anti-VEGF monoclonal antibodies block growth and neovascularization in tumor models. These findings paved the way for the clinical development of a humanized anti-VEGF antibody and other VEGF inhibitors for cancer therapy. To date, several VEGF inhibitors represent standard of care for colorectal cancer and other difficult to treat malignancies. VEGF is also implicated in intraocular neovascularization associated with retinal disorders as well as neovascular AMD. Our group developed a humanized anti–VEGF-A antibody fragment (ranibizumab) for the treatment of wet AMD. Ranibizumab not only maintained but also improved visual acuity and has been approved worldwide for the treatment of wet AMD and other neovascular disorders. Other VEGF inhibitors, including bevacizumab and aflibercept, have also resulted in significant clinical benefits. Today anti-VEGF drugs represent the most effective therapy for intraocular neovascularization. Current research addresses the need to reduce the frequency of intravitreal injections as well the identification of additional pro-angiogenic pathways that could result in improving therapeutic outcomes.
The targeting of vascular endothelial growth factor A (VEGFA), a crucial regulator of both normal and pathological angiogenesis, has revealed innovative therapeutic approaches in oncology and ...ophthalmology. The first VEGFA inhibitor, bevacizumab, was approved by the US Food and Drug Administration in 2004 for the first-line treatment of metastatic colorectal cancer, and the first VEGFA inhibitors in ophthalmology, pegaptanib and ranibizumab, were approved in 2004 and 2006, respectively. To mark this tenth anniversary of anti-VEGFA therapy, we discuss the discovery of VEGFA, the successes and challenges in the development of VEGFA inhibitors and the impact of these agents on the treatment of cancers and ophthalmic diseases.
Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a major inducer of ...VEGF gene transcription. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high-affinity VEGF receptors. The role of VEGF in developmental angiogenesis is emphasized by the finding that loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF is critical also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with various VEGF inhibitors in a variety of malignancies are ongoing. Very recently, an anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.
I am honored and humbled to be one of the awardees of the 2014 A. Champalimaud Vision Award. I offer my heartfelt thanks to the Champalimaud Foundation President, Leonor Beleza, and to the Award ...Committee Members for this wonderful recognition. I feel especially fortunate to have had the opportunity to witness my scientific discoveries move from the bench to the clinic. Scientific discovery is hugely exciting, but the ability to translate that work into potentially helping someone lead a better life is even more fulfilling. This Award is dedicated to the patients.
Chronic inflammation fosters cancer development and progression and also modulates tumor responses to anticancer therapies. Neutrophils are key effector cells in innate immunity and are known to play ...a critical role in various inflammatory disorders. However, the functions of neutrophils in cancer pathogenesis have been largely neglected until recently and still remain poorly characterized compared with other immune cells in the tumor microenvironment. We highlight recent findings on the mechanisms by which tumor cells, in cooperation with tumor-associated stromal cells, induce expansion, recruitment, and polarization of neutrophils. We also review the multifaceted roles that neutrophils play in different aspects of cancer development and progression, with an emphasis on tumor angiogenesis and metastasis.
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