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81 - Signal transduction in tumor angiogenesis
- from Part 4 - Pharmacologic targeting of oncogenic pathways
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- By Timothy Hla, Center of Vascular Biology, Department of Pathology and Laboratory Medicine,Weill Medical College of Cornell University, New York, NY, USA, Nasser Altorki, Department of Cardiothoracic Surgery and Neuberger Berman Lung Cancer Research Center,Weill Medical College of Cornell University, New York, NY, USA, Vivek Mittal, Department of Cardiothoracic Surgery and Neuberger Berman Lung Cancer Research Center, and Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY, USA
- Edited by Edward P. Gelmann, Columbia University, New York, Charles L. Sawyers, Memorial Sloan-Kettering Cancer Center, New York, Frank J. Rauscher, III
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- Book:
- Molecular Oncology
- Published online:
- 05 February 2015
- Print publication:
- 19 December 2013, pp 861-871
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Summary
Angiogenesis is the formation of nascent blood vessels from existing vasculature. It is a crucial step in physiological conditions such as normal growth, embryonic development, female estrous cycle, and wound healing, as well as in pathological scenarios such as tumor growth, diabetic retinopathy, and rheumatoid arthritis (1). During cancer progression, the angiogenic vasculature is needed for the supply of oxygen and nutrients that sustain tumor growth, and eventually acts as a conduit for metastatic dissemination of tumor cells to distant organs (2,3). Accordingly, tumor angiogenesis remains an important area of cancer research, and understanding its mechanistic basis is critical for the development of effective anti-angiogenic therapy.
Under normal physiological conditions, angiogenesis is well controlled by pro- and anti-angiogenic factors. However, in cancer, this balance of pro- and anti-angiogenic factors is perturbed, resulting in the so-called “angiogenic switch.” Multiple signals trigger the angiogenic switch, including genetic mutations, metabolic and mechanical stresses, and inflammatory responses (4–9; Figure 81.1). Growing tumors progressively become hypoxic, leading to stabilization of the hypoxia inducible factor 1α (HIF-1α) which, in turn, stimulates production of key angiogenic growth factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), placental growth factor (PLGF), granulocyte colony-stimulating factor (G-CSF), interleukin 8 (IL8), and hepatocyte growth factor (HGF). VEGF-A has been heralded as the most potent endothelial-specific angiogenic factor, which recognizes cognate tyrosine-kinase receptors such as VEGFR-2 and -3 on the endothelial cells, resulting in downstream activation of signal-transduction cascades (10), which induce endothelial cell activation and sprouting of new capillaries. In addition to the pro-angiogenic factors, there are various endogenous angiogenesis-inhibitor proteins including endostatin, angiostatin, thrombospondin-1 (Tsp-1), tumstatin, platelet factor 4, and certain interleukins, including IL-12. De novo blood-vessel formation results from a complex interplay of pro- and anti-angiogenic regulators, and dysregulation of the balance between these factors is the hallmark of tumor angiogenesis. In addition to the participation of vascular endothelial-derived vessels, the generation of new lymphatic vessels by a process referred to as lymphangiogenesis has also been implicated in tumor progression and metastasis (11,12).
45 - Sphingolipids and the Endothelium
- from PART II - ENDOTHELIAL CELL AS INPUT-OUTPUT DEVICE
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- By Timothy Hla, Center for Vascular Biology, University of Connecticut Health Center, Farmington
- Edited by William C. Aird, Harvard University, Massachusetts
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- Book:
- Endothelial Biomedicine
- Published online:
- 04 May 2010
- Print publication:
- 03 September 2007, pp 403-409
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Summary
Structural diversity in the membrane lipids is essential for proper function of eukaryotic membranes. Sphingolipids, named after the mythical Sphinx due to their enigmatic physicochemical properties, are critical for specialized membrane microdomains such as rafts and caveolae. In higher organisms, sphingolipid metabolites, such as sphingosine, sphingosine 1-phosphate (S1P), and ceramide are utilized in intracellular metabolism, signaling, and extracellular cell–cell communication events. Sphingolipids are particularly important for the mammalian vascular system, in which plasma levels of S1P are several orders of magnitude higher than tissue levels, thereby constituting a vascular S1P gradient. S1P is a major regulator of vital endothelial cell (EC) functions including vascular permeability, vascular stabilization/maturation, angiogenesis, vascular tone control, nitric oxide (NO) synthesis, and survival. The endothelium produces and responds to S1P. Indeed S1P receptors in ECs are dynamically induced and regulated. Thus, sphingolipids (sphingomyelin [SM], sphingosine, ceramide, S1P, as well as numerous glycosphingolipid [GSL] species) constitute a major class of molecules involved in the structure and function of the endothelium (Table 45–1). Further knowledge in this area promises to provide novel therapeutic approaches in the restoration of endothelial health, a vital phenomenon compromised in many human maladies.
SPHINGOLIPID METABOLISM
Sphingolipids, which are built from the sphingosine base, are major structural components of the biological membranes of all eukaryotes. Both GSLs and SM belong to this class of lipids. Sphingolipids are localized on specialized domains of the membranes (1). For example, SM and GSL are essential constituents of membrane rafts. SM contains the sphingosine backbone, a fatty-acid side chain that is linked via the amide bond, and the amphipathic phosphocholine headgroup. Most SM species contain saturated or trans monounsaturated fatty acids with 16 to 24 carbons.