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Abstract: While the development of anti-angiogenic therapy, as it pertains to cancer treatment, may still be in its infancy relative to well-established modalities such as chemotherapy, radiation, and surgery, major strides made in the past several decades have allowed translation of basic science discoveries in this field into clinical reality. The discovery of key molecular modulators of angiogenesis, notably vascular endothelial growth factor (VEGF), has catalyzed the development of numerous neutralizing therapeutic agents. The validity of VEGF inhibition as a therapeutic strategy has been well supported in randomized clinical trials, as well as U.S. Food and Drug Administration approval of the VEGF antagonists bevacizumab, sunitinib malate, sorafenib, pegaptinib and ranibizumab. Accordingly, this review will (1) briefly review the basic molecular biology of VEGF and (2) summarize recent progress in targeting the VEGF molecular pathway as therapy for angiogenic diseases such as cancer and age-related macular degeneration. [Copyright &y& Elsevier]

The use of recombinant adenoviruses (Ad) to express secreted antagonists of growth factors represents a powerful strategy for studying physiologic functions of growth factor pathways in experimental animals. Indeed, a single adenoviral injection can produce characteristic high-level and persistent plasma expression of soluble receptor ectodomains or secreted protein antagonists, allowing highly stringent conditional inactivation of target pathways in vivo. In this review, we describe our experience using recombinant Ad to inactivate growth factor pathways in vivo and discuss their advantages and limitations. Using our studies on vascular endothelial growth factor and Wnt systems as examples, we further describe how recombinant Ad can unveil previously unknown physiological roles of signaling pathways. Finally, we discuss the potential physiological and therapeutic relevance of our findings. [ABSTRACT FROM AUTHOR]

Angiogenesis, the formation of new blood vessels from pre-existing vessels, in the central nervous system (CNS) is seen both as a normal physiological response as well as a pathological step in disease progression. Formation of the blood-brain barrier (BBB) is an essential step in physiological CNS angiogenesis. The BBB is regulated by a neurovascular unit (NVU) consisting of endothelial and perivascular cells as well as vascular astrocytes. The NVU plays a critical role in preventing entry of neurotoxic substances and regulation of blood flow in the CNS. In recent years, research on numerous acquired and hereditary disorders of the CNS has increasingly emphasized the role of angiogenesis in disease pathophysiology. Here, we discuss molecular mechanisms of CNS angiogenesis during embryogenesis as well as various pathological states including brain tumor formation, ischemic stroke, arteriovenous malformations, and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

We retrospectively analyzed hematologic parameters in 22 patients with advanced, nonsquamous, NSCLC undergoing VEGF inhibition on a phase II clinical trial of bevacizumab, carboplatin, and gemcitabine. We also examined TTP in relation to hemoglobin changes. Median hemoglobin increased significantly from a 12.9 g/dL pretreatment to 13.8 g/dL ( p ==.01) after the second cycle of maintenance bevacizumab until the first off cycle measurement. There was no difference in TTP in patients who achieved a rise in hemoglobin compared with patients who did not (median 238 days vs. 268 days, p ==.38.) Maintenance bevacizumab is associated with increased hemoglobin in advanced, nonsquamous, NSCLC patients. [ABSTRACT FROM AUTHOR]

Intronic microRNAs have been proposed to complicate the design and interpretation of mouse knockout studies. The endothelial-expressed Egfl7/miR-126 locus contains miR-126 within Egfl7 intron 7, and angiogenesis deficits have been previously ascribed to Egfl7 gene-trap and lacZ knock-in mice. Surprisingly, selectively floxed Egfl7Δ and miR-126Δ alleles revealed that Egfl7Δ/Δ mice were phenotypically normal, whereas miR-126Δ/Δ mice bearing a 289-nt microdeletion recapitulated previously described Egfl7 embryonic and postnatal retinal vascular phenotypes. Regulation of angiogenesis by miR-126 was confirmed by endothelial-specific deletion and in the adult cornea micropocket assay. Furthermore, miR-126 deletion inhibited VEGF-dependent Akt and Erk signaling by derepression of the p85β subunit of PI3 kinase and of Spred1, respectively. These studies demonstrate the regulation of angiogenesis by an endothelial miRNA, attribute previously described Egfl7 vascular phenotypes to miR-126, and document inadvertent miRNA dysregulation as a complication of mouse knockout strategies. [ABSTRACT FROM AUTHOR]