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Medicine Lodge, United States

Dunleavey J.M.,University of North Carolina at Chapel Hill | Dudley A.C.,University of North Carolina at Chapel Hill | Dudley A.C.,Lineberger Comprehensive Cancer Center | Dudley A.C.,McAllister Heart Institute
Current Angiogenesis | Year: 2012

As in normal tissues, solid tumors depend on vascular networks to supply blood, oxygen, and nutrients. Tumor blood vessels are formed by common processes of neovascularization for example endothelial sprouting. However, some tumors have alternative and unexpected mechanisms of neovascularization at their disposal. In a process termed vascularmimicry, tumors create their own, tumor cell-lined channels for fluid transport independent of typical modes of angiogenesis. These tumor cell-lined conduits may express endothelial-selective markers and anti-coagulant factors which allow for anastamosis with host endothelium. In this review, we explore the current status of vascular mimicry research, highlighting recent evidence which strengthens the hypothesis for this unusual ability of tumor cells. Furthermore, we address the theoretical possibility that vascular mimicry provides a mechanism whereby tumors could escape antiangiogenic therapies. © 2012 Bentham Science Publishers.

Peirce S.M.,University of Virginia | Gabhann F.M.,Johns Hopkins University | Bautch V.L.,University of North Carolina at Chapel Hill | Bautch V.L.,McAllister Heart Institute
Current Opinion in Hematology | Year: 2012

Purpose of Review: We summarize recent experimental and computational studies that investigate molecular and cellular mechanisms of sprouting angiogenesis. We discuss how experimental tools have unveiled new opportunities for computational modeling by providing detailed phenomenological descriptions and conceptual models of cell-level behaviors underpinned by high-quality molecular data. Using recent examples, we show how new understanding results from bridging computational and experimental approaches. Recent Findings: Experimental data extends beyond the tip cell vs. stalk cell paradigm, and involves numerous molecular inputs such as vascular endothelial growth factor and Notch. This data is being used to generate and validate computational models, which can then be used to predict the results of hypothetical experiments that are difficult to perform in the laboratory, and to generate new hypotheses that account for system-wide interactions. As a result of this integration, descriptions of critical gradients of growth factor-receptor complexes have been generated, and new modulators of cell behavior have been described. Summary: We suggest that the recent emphasis on the different stages of sprouting angiogenesis, and integration of experimental and computational approaches, should provide a way to manage the complexity of this process and help identify new regulatory paradigms and therapeutic targets. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Dudley A.C.,University of North Carolina at Chapel Hill | Dudley A.C.,Lineberger Comprehensive Cancer Center | Dudley A.C.,McAllister Heart Institute
Cold Spring Harbor Perspectives in Medicine | Year: 2012

The vascular endothelium is a dynamic cellular "organ" that controls passage of nutrients into tissues, maintains the flow of blood, and regulates the trafficking of leukocytes. In tumors, factors such as hypoxia and chronic growth factor stimulation result in endothelial dysfunction. For example, tumor blood vessels have irregular diameters; they are fragile, leaky, and blood flow is abnormal. There is now good evidence that these abnormalities in the tumor endothelium contribute to tumor growth and metastasis. Thus, determining the biological basis underlying these abnormalities is critical for understanding the pathophysiology of tumor progression and facilitating the design and delivery of effective antiangiogenic therapies. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.

Kushner E.J.,University of North Carolina at Chapel Hill | Bautch V.L.,University of North Carolina at Chapel Hill | Bautch V.L.,McAllister Heart Institute | Bautch V.L.,Lineberger Comprehensive Cancer Center
Current Opinion in Hematology | Year: 2013

Purpose of Review: This review will examine developmental angiogenesis and tumor-related changes to endothelial cells. Recent Findings: Processes that govern developmental angiogenesis become dysfunctional in the tumor environment, leading to abnormal tumor endothelial cells and blood vessels. Recent findings suggest that tumor endothelial cells are permanently modified compared with normal counterparts. Summary: Coordination of numerous intracellular and extracellular programs promotes the formation of new blood vessels that are necessary for both development and certain diseases. Developmental angiogenesis uses canonical signaling modalities to effectively assemble endothelial cells into predictable vessel structures, and disruption of critical signaling factors has dramatic effects on blood vessel development. Solid tumors co-opt developmental cues to promote formation of tumor vessels that sustain their growth, but these angiogenic signals are not well regulated and produce endothelial cell dysfunction. Aberrant growth factor signaling contributes to phenotypic changes and acquired irreversible intracellular signaling, cytoskeletal and genetic modifications in endothelial cells of tumor vessels. Permanently altered tumor endothelial cells may represent a significant population. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Willis M.S.,McAllister Heart Institute | Willis M.S.,Laboratory Medicine | Townley-Tilson W.H.D.,Cell and Developmental Biology | Kang E.Y.,McAllister Heart Institute | And 4 more authors.
Circulation Research | Year: 2010

The ubiquitin proteasome system (UPS) plays a crucial role in biological processes integral to the development of the cardiovascular system and cardiovascular diseases. The UPS prototypically recognizes specific protein substrates and places polyubiquitin chains on them for subsequent destruction by the proteasome. This system is in place to degrade not only misfolded and damaged proteins, but is essential also in regulating a host of cell signaling pathways involved in proliferation, adaptation to stress, regulation of cell size, and cell death. During the development of the cardiovascular system, the UPS regulates cell signaling by modifying transcription factors, receptors, and structural proteins. Later, in the event of cardiovascular diseases as diverse as atherosclerosis, cardiac hypertrophy, and ischemia/reperfusion injury, ubiquitin ligases and the proteasome are implicated in protecting and exacerbating clinical outcomes. However, when misfolded and damaged proteins are ubiquitinated by the UPS, their destruction by the proteasome is not always possible because of their aggregated confirmations. Recent studies have discovered how these ubiquitinated misfolded proteins can be destroyed by alternative "specific" mechanisms. The cytosolic receptors p62, NBR, and histone deacetylase 6 recognize aggregated ubiquitinated proteins and target them for autophagy in the process of "selective autophagy." Even the ubiquitination of multiple proteins within whole organelles that drive the more general macro-autophagy may be due, in part, to similar ubiquitin-driven mechanisms. In summary, the crosstalk between the UPS and autophagy highlight the pivotal and diverse roles the UPS plays in maintaining protein quality control and regulating cardiovascular development and disease. © 2010 American Heart Association, Inc.

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