D A Cheresh

University of California, San Diego, San Diego, California, United States

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Publications (267)2767.4 Total impact

  • Glen R Nemerow, David A Cheresh
    Nature Cell Biology 05/2002; 4(4):E69-71. DOI:10.1038/ncb0402-e69 · 20.06 Impact Factor
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    ABSTRACT: alpha(v)-Integrin antagonists block neovascularization in various species, whereas 20% of alpha(v)-integrin null mice are born with many normal looking blood vessels. Given that blockade of alpha(v)-integrins during angiogenesis induces p53 activity, we utilized p53 null mice to elucidate whether loss of p53 can compensate for alpha(v)-integrin function in neovascularization of the retina. Murine retinal vascularization was inhibited by systemic administration of an alpha(v)-integrin antagonist. In contrast, mice lacking p53 were refractory to this treatment, indicating that neovascularization in normal mice depends on alpha(v)-integrin-mediated suppression of p53. Blockade of alpha(v)-integrins during neovascularization resulted in an induction of p21(CIP1) in wild type and, surprisingly, in p53 null retinas, indicating that alpha(v)-integrin ligation regulates p21(CIP1) levels in a p53-independent manner. In conclusion, we demonstrate for the first time an in vivo intracellular mechanism for compensation of integrin function and that p53 and alpha(v)-integrins act in concert during retinal neovascularization.
    Journal of Biological Chemistry 05/2002; 277(16):13371-4. DOI:10.1074/jbc.C200044200 · 4.60 Impact Factor
  • David A Cheresh, Dwayne G Stupack
    Nature Medicine 04/2002; 8(3):193-4. DOI:10.1038/nm0302-193 · 28.05 Impact Factor
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    Dwayne G Stupack, David A Cheresh
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    ABSTRACT: The process of angiogenesis is a dynamic one. Vascular endothelial cells are changing at the same time the extracellular matrix is being remodeled. Stupack and Cheresh discuss how remodeling of the extracellular matrix (ECM) and changes in the endothelial cell protein production and integrin expression contribute to the complex process of new blood vessel growth from an existing vascular bed.
    Science s STKE 03/2002; 2002(119):pe7. DOI:10.1126/stke.2002.119.pe7
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    John D Hood, David A Cheresh
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    ABSTRACT: As cancer cells undergo metastasis--invasion and migration of a new tissue--they penetrate and attach to the target tissue's basal matrix. This allows the cancer cell to pull itself forward into the tissue. The attachment is mediated by cell-surface receptors known as integrins, which bind to components of the extracellular matrix. Integrins are crucial for cell invasion and migration, not only for physically tethering cells to the matrix, but also for sending and receiving molecular signals that regulate these processes.
    Nature reviews. Cancer 03/2002; 2(2):91-100. DOI:10.1038/nrc727 · 37.91 Impact Factor
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    ABSTRACT: Modulation of the balance between pro- and antiangiogenic factors holds great promise for the treatment of a broad spectrum of human disease ranging from ischemic heart disease to cancer. This requires both the identification of angiogenic regulators and their efficient delivery to target organs. Here, we demonstrate the use of a noncatalytic fragment of matrix metalloproteinase 2 (termed PEX) delivered by lentiviral vectors in different angiogenesis models. Transduction of human endothelial cells with PEX virus suppressed endothelial invasion and formation of capillary-like structures without affecting chemotaxis in vitro. Lentiviral delivery of PEX blocked basic fibroblast growth factor-induced matrix metalloproteinase 2 activation and angiogenesis on chicken chorioallantoic membranes. PEX expression also inhibited tumor-induced angiogenesis and tumor growth in a nude mouse model. Thus, our study shows that lentiviral vectors can deliver sufficient quantities of antiangiogenic substances to achieve therapeutic effects in vivo.
    Annals of Hematology 02/2002; 81 Suppl 2:S69-70. · 2.40 Impact Factor
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    ABSTRACT: Pathological angiogenesis contributes directly to profound loss of vision associated with many diseases of the eye. Recent work suggests that human tyrosyl- and tryptophanyl-tRNA synthetases (TrpRS) link protein synthesis to signal transduction pathways including angiogenesis. In this study, we show that a recombinant form of a COOH-terminal fragment of TrpRS is a potent antagonist of vascular endothelial growth factor-induced angiogenesis in a mouse model and of naturally occurring retinal angiogenesis in the neonatal mouse. The angiostatic activity is dose-dependent in both systems. The recombinant fragment is similar in size to one generated naturally by alternative splicing and can be produced by proteolysis of the full-length protein. In contrast, the full-length protein is inactive as an antagonist of angiogenesis. These results suggest that fragments of TrpRS, as naturally occurring and potentially nonimmunogenic anti-angiogenics, can be used for the treatment of neovascular eye diseases.
    Proceedings of the National Academy of Sciences 02/2002; 99(1):178-83. DOI:10.1073/pnas.012601899 · 9.81 Impact Factor
  • J D Hood, DA Cheresh
    Cold Spring Harbor Symposia on Quantitative Biology 02/2002; 67:285-91. DOI:10.1101/sqb.2002.67.285
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    ABSTRACT: Aminoacyl-tRNA synthetases catalyze the first step of protein synthesis. It was shown recently that human tyrosyl-tRNA synthetase (TyrRS) can be split into two fragments having distinct cytokine activities, thereby linking protein synthesis to cytokine signaling pathways. Tryptophanyl-tRNA synthetase (TrpRS) is a close homologue of TyrRS. A natural fragment, herein designated as mini TrpRS, was shown by others to be produced by alternative splicing. Production of this fragment is reported to be stimulated by IFN-gamma, a cytokine that also stimulates production of angiostatic factors. Mini TrpRS is shown here to be angiostatic in a mammalian cell culture system, the chicken embryo, and two independent angiogenesis assays in the mouse. The full-length enzyme is inactive in the same assays. Thus, protein synthesis may be linked to the regulation of angiogenesis by a natural fragment of TrpRS.
    Proceedings of the National Academy of Sciences 02/2002; 99(1):173-7. DOI:10.1073/pnas.012602099 · 9.81 Impact Factor
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    ABSTRACT: Integrin-mediated adhesion promotes cell survival in vitro, whereas integrin antagonists induce apoptosis of adherent cells in vivo. Here, we demonstrate that cells adherent within a three-dimensional extracellular matrix undergo apoptosis due to expression of unligated integrins, the beta subunit cytoplasmic domain, or its membrane proximal sequence KLLITIHDRKEF. Integrin-mediated death requires initiator, but not stress, caspase activity and is distinct from anoikis, which is caused by the loss of adhesion per se. Surprisingly, unligated integrin or beta integrin tails recruit caspase-8 to the membrane, where it becomes activated in a death receptor-independent manner. Integrin ligation disrupts this integrin-caspase containing complex and increases survival, revealing an unexpected role for integrins in the regulation of apoptosis and tissue remodeling.
    The Journal of Cell Biology 11/2001; 155(3):459-70. DOI:10.1083/jcb.200106070 · 9.69 Impact Factor
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    Brian P Eliceiri, David A Cheresh
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    ABSTRACT: Recent work from several laboratories indicates that the coordination of endothelial cell adhesion events with growth factor receptor inputs regulates endothelial cell responses during angiogenesis. Analyses of the signaling pathways downstream of integrins, cadherins and growth-factor receptors are providing an insight into the molecular basis of known anti-angiogenic strategies, as well as into the design of novel therapies.
    Current Opinion in Cell Biology 11/2001; 13(5):563-8. DOI:10.1016/S0955-0674(00)00252-0 · 8.74 Impact Factor
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    ABSTRACT: This study analyzed the expression of integrins alpha(v)beta3 and alpha(v)beta5 in glioma tissue and focused on the periphery of high-grade gliomas. The analysis was performed with Western blot, immunohistochemistry, and immunofluorescence, by use of two monoclonal antibodies able to recognize the functional integrin heterodimer. The expression of integrin-related ligands and growth factors also was studied. Sections from the tumor periphery were classified as either tumor periphery (light tumor infiltrate or scant visible cells) or peritumor (heavy tumor infiltration). Our data on glioma tissues demonstrated that both integrins were expressed in glioma cells and vasculature and their expression correlated with the histological grade. Alpha(v)beta3 expression was prominent in astrocytic tumors. Both integrins were markers of tumor vasculature, particularly of endothelial proliferation. A high-grade glioma periphery demonstrated a prominent expression of integrin alpha(v)beta3. Cells demonstrating alpha(v)beta3 positivity were identified as tumor astrocytes and endothelial cells by double imaging. The same cells were surrounded by some alpha(v)beta3 ligands and co-localized fibroblast growth factor 2. Matrix metalloproteinase 2 also was found to be co-localized with alpha(v)beta3 in the same cells. Alpha(v)beta3 expression was more relevant in tumor astrocytes. Alpha(v)beta3 integrin and vascular endothelial growth factor expression increased from the periphery to the tumor center. Our data support the role of integrins alpha(v)beta3 and alpha(v)beta5 in glioma-associated angiogenesis. In addition, they suggest a role for integrin alpha(v)beta3 in neoangiogenesis and cell migration in high-grade glioma periphery.
    Neurosurgery 09/2001; 49(2):380-9; discussion 390. · 3.03 Impact Factor
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    ABSTRACT: The human embryonic kidney (HEK293) cell line, commonly used for recombinant adenovirus (Ad) propagation, does not express the Ad coreceptor alpha(v)beta3 or alpha(v)beta5 integrins, yet these cells are efficiently infected by Ad vectors. Here we demonstrate that Ad binds to HEK293 cells via the fiber receptor CAR and is subsequently internalized via interaction with integrin alpha(v)beta1. Function-blocking antibodies directed against alpha(v) or beta1, but not beta3, beta5, or alpha5, integrin subunits block Ad infection and viral endocytosis. Therefore, alpha(v)beta1 serves as a coreceptor for Ad infection, and the lack of beta3 and/or beta5 but the relatively high expression of alpha(v)beta1 integrins on certain tumor cell types may explain why these cells are readily transduced by Ad vectors.
    Journal of Virology 07/2001; 75(11):5405-9. DOI:10.1128/JVI.75.11.5405-5409.2001 · 4.65 Impact Factor
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    ABSTRACT: Viral vectors based on lentiviruses, such as the human immunodeficiency virus, are able to transduce a broad spectrum of nondividing cells in vivo. This ability of lentiviral vectors makes them an attractive vehicle for gene transfer into the liver. In order to determine the requirements for efficient lentiviral gene transfer, we used a fluorescence imaging system, which allows the detection of cells and tissues that express fluorescent reporter genes (e.g., green fluorescence protein) in the living animal. We show that the latest generation of lentiviral vectors efficiently transduces the murine liver. Further analysis demonstrated that neither cell-cycle activation nor division of liver cells is a prerequisite for lentiviral gene transfer in vivo.
    Molecular Therapy 04/2001; 3(3):319-22. DOI:10.1006/mthe.2001.0276 · 6.43 Impact Factor
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    ABSTRACT: The process of new blood vessel growth from existing vasculature, known as angiogenesis, is critical to several pathological conditions, most notably cancer. Both MMP2, which degrades the extracellular matrix (ECM), and integrin alpha(V)beta(3), which contributes to endothelial cell attachment to the ECM, are critically involved in this process. Recent findings have shown that MMP2 is localized in an active form on the surface of invasive endothelial cells based on its ability to directly bind integrin alpha(V)beta(3), suggesting that disrupting this protein--protein interaction may represent a new target for the development of angiogenesis inhibitors. The screening of small molecule libraries led to the identification of compounds which disrupt the MMP2--alpha(V)beta(3) interaction in an in vitro binding assay. A prototypical inhibitor was further found to prevent the degradation of the protein matrix without directly inhibiting MMP2 activity or disrupting the binding of alpha(V)beta(3) to its classical ECM ligand, vitronectin. The synthesis and screening of analogues and substructures of this lead compound allowed the identification of requisite structural features for inhibition of MMP2 binding to alpha(V)beta(3). This led to the synthesis of a more water-soluble derivative which maintains the in vitro biological properties and has potent antiangiogenic and antitumor activity in vivo, validating the target as one useful for therapeutic intervention.
    Journal of the American Chemical Society 03/2001; 123(7):1280-8. DOI:10.1021/ja003579+ · 11.44 Impact Factor
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    ABSTRACT: Vascular endothelial growth factor (VEGF), an angiogenic factor produced in response to ischemic injury, promotes vascular permeability (VP). Evidence is provided that Src kinase regulates VEGF-mediated VP in the brain following stroke and that suppression of Src activity decreases VP thereby minimizing brain injury. Mice lacking pp60c-src are resistant to VEGF-induced VP and show decreased infarct volumes after stroke whereas mice deficient in pp59c-fyn, another Src family member, have normal VEGF-mediated VP and infarct size. Systemic application of a Src-inhibitor given up to six hours following stroke suppressed VP protecting wild-type mice from ischemia-induced brain damage without influencing VEGF expression. This was associated with reduced edema, improved cerebral perfusion and decreased infarct volume 24 hours after injury as measured by magnetic resonance imaging and histological analysis. Thus, Src represents a key intermediate and novel therapeutic target in the pathophysiology of cerebral ischemia where it appears to regulate neuronal damage by influencing VEGF-mediated VP.
    Nature Medicine 03/2001; 7(2):222-7. DOI:10.1038/84675 · 28.05 Impact Factor
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    ABSTRACT: Matrix metalloproteinase 2 (MMP2) can associate with integrin alpha(v)beta3 on the surface of endothelial cells, thereby promoting vascular invasion. Here, we describe an organic molecule (TSRI265) selected for its ability to bind to integrin alphav(v)beta3 and block alpha(v)beta3 interaction with MMP2. Although disrupting alpha(v)beta3/MMP2 complex formation, TSRI265 has no effect on alpha(v)beta3 binding to its extracellular matrix ligand vitronectin and does not influence MMP2 activation or catalytic activity directly. However, TSRI265 acts as a potent antiangiogenic agent and thereby blocks tumor growth in vivo. These findings suggest that activated MMP2 does not facilitate vascular invasion during angiogenesis unless it forms a complex with alpha(v)beta(3) on the endothelial cell surface. By disrupting endothelial cell invasion without broadly suppressing cell adhesion or MMP function, the use of compounds such as TSRI265 may provide a novel therapeutic approach for diseases associated with uncontrolled angiogenesis.
    Proceedings of the National Academy of Sciences 02/2001; 98(1):119-24. DOI:10.1073/pnas.011343298 · 9.81 Impact Factor
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    ABSTRACT: Brain tumors are highly angiogenic, and their growth and spread depend on the generation of new blood vessels. We examined the effect of the cyclic peptide antagonist pentapeptide EMD 121974, an antiangiogenic agent, on orthotopic and heterotopic brain tumor growth. The human brain tumor cell lines DAOY (medulloblastoma) and U87 MG (glioblastoma) were injected into either the forebrain (orthotopic) or the subcutis (heterotopic) of nude mice, and daily systemic treatment with the active peptide was initiated after tumors were established. All control animals with orthotopic brain tumors and that received the inactive peptide EMD 135981 daily died as a result of tumor progression within 4 to 6 weeks; tumors measured 3 to 5 mm in diameter. In contrast, mice with orthotopic tumors that were treated daily with the active peptide survived for more than 16 weeks, and histological examination of the brains after 4, 8, and 12 weeks showed either no tumors or microscopic residual tumors. The growth of these brain tumor cells injected simultaneously or separately into the subcutis of nude mice (heterotopic model) was not affected by the active peptide, suggesting that the brain environment is a critical determinant of brain tumor susceptibility to growth inhibition by this pentapeptide. The cyclic pentapeptide EMD 121974 may become a treatment option specific to brain tumors. Because of its antiangiogenic effect, its use may be especially indicated after tumors are removed surgically.
    Neurosurgery 02/2001; 48(1):151-7. DOI:10.1097/00006123-200101000-00026 · 3.03 Impact Factor
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    ABSTRACT: OBJECTIVE: This study analyzed the expression of integrins αvβ3 and αvβ5 in glioma tissue and focused on the periphery of high-grade gliomas. METHODS: The analysis was performed with Western blot, immunohistochemistry, and immunofluorescence, by use of two monoclonal antibodies able to recognize the functional integrin heterodimer. The expression of integrin-related ligands and growth factors also was studied. Sections from the tumor periphery were classified as either tumor periphery (light tumor infiltrate or scant visible cells) or peritumor (heavy tumor infiltration). RESULTS: Our data on glioma tissues demonstrated that both integrins were expressed in glioma cells and vasculature and their expression correlated with the histological grade. αvβ3 expression was prominent in astrocytic tumors. Both integrins were markers of tumor vasculature, particularly of endothelial proliferation. A high-grade glioma periphery demonstrated a prominent expression of integrin αvβ3. Cells demonstrating αvβ3 positivity were identified as tumor astrocytes and endothelial cells by double imaging. The same cells were surrounded by some αvβ3 ligands and co-localized fibroblast growth factor 2. Matrix metalloproteinase 2 also was found to be co-localized with αvβ3 in the same cells. αvβ3 expression was more relevant in tumor astrocytes. αvβ3 integrin and vascular endothelial growth factor expression increased from the periphery to the tumor center. CONCLUSION: Our data support the role of integrins αvβ3 and αvβ5 in glioma-associated angiogenesis. In addition, they suggest a role for integrin αvβ3 in neoangiogenesis and cell migration in high-grade glioma periphery.
    Neurosurgery 01/2001; 49(2):380-390. DOI:10.1227/00006123-200108000-00022 · 3.03 Impact Factor
  • Neurosurgery 01/2001; 49(2):380-390. DOI:10.1097/00006123-200108000-00022 · 3.03 Impact Factor

Publication Stats

35k Citations
2,767.40 Total Impact Points

Institutions

  • 1990–2015
    • University of California, San Diego
      • • Moores Cancer Center/Oncology
      • • Department of Pathology
      • • Department of Medicine
      San Diego, California, United States
    • University of Southern California
      • Department of Medicine
      Los Angeles, California, United States
  • 2011
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2009
    • National University (California)
      San Diego, California, United States
  • 1989–2009
    • The Scripps Research Institute
      • • Skaggs Institute for Chemical Biology
      • • Department of Molecular and Experimental Medicine
      La Jolla, California, United States
    • Michigan State University
      • Department of Biochemistry and Molecular Biology
      East Lansing, Michigan, United States
  • 2008
    • University of Massachusetts Medical School
      • Department of Pathology
      Worcester, MA, United States
  • 1995–2003
    • La Jolla Institute for Allergy & Immunology
      La Jolla, California, United States
    • University of Alabama at Birmingham
      • Division of Neuropathology
      Birmingham, Alabama, United States
  • 2002
    • Karolinska Institutet
      Solna, Stockholm, Sweden
    • University of Münster
      • Department of Medicine, Hematology and Oncology
      Münster, North Rhine-Westphalia, Germany
  • 2001
    • Salk Institute
      La Jolla, California, United States
  • 1998
    • Azienda Ospedaliera Bianchi-Melacrino-Morelli di Reggio Calabria
      Reggio di Calabria, Calabria, Italy
  • 1997
    • University of Illinois at Chicago
      • Department of Physiology and Biophysics (Chicago)
      Chicago, Illinois, United States
  • 1991–1993
    • Barnes Jewish Hospital
      San Luis, Missouri, United States
    • University of Washington Seattle
      Seattle, Washington, United States