Candece Gladson , M.D.
Professor of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
Department of Cancer Biology
Regulation of angiogenesis in malignant gliomas, therapeutic targets on the neovasculature in malignant gliomas, and cell signaling regulating autophagy in glioma cells.
1976, University of California at Davis, CA; B.S. in Biochemistry
1980, Loyola University, Stritch School of Medicine, Chicago, IL; M.D.
1980-1981, Loyola University, Foster G. McGraw Hospital, Chicago, IL; internship in Pathology
1981-1984, University of California at Los Angeles, CA; residency in Pathology
1984-1991, Scripps Research Institute, La Jolla, CA; post-doctoral research
1989-1990, University of California at San Diego, CA; post-doctoral fellowship in Neuropathology
1981-84 Pathology Resident, Assistant Laboratory Instructor, Department of Pathology, University of California Los Angeles, Center for the Health Sciences, Los Angeles, California
1984-87 Post-Doctoral Research Fellow, Scripps Clinic and Research Foundation, La Jolla, CA
1987-91 Fellow and Physician-Scientist Awardee, Scripps Clinic and Research Foundation, La Jolla, CA and University of California San Diego
1989-90 Neuropathology Fellow, University of California San Diego
Nov. 1991 Assistant Professor of Pathology, Div.Neuropathology, University of Alabama at Birmingham,
Oct. 1996 Associate Professor of Pathology, Div. of Neuropathology, University of Alabama at Birmingham
Oct. 2003 Professor of Pathology, Div. of Neuropathology, University of Alabama at Birmingham
Feb. 2009 Member/Staff, Lerner Research Institute, Cancer Biology, Cleveland Clinic, Cleveland, OH
One project in my laboratory focuses on the regulation of angiogenesis in malignant glioma tumors, and specifically the endogenous inhibitors of angiogenesis that are found in glioma tumors and the normal brain. A potential mechanism to inhibit angiogenesis in these tumors is to administer a recombinant endogenous inhibitor of angiogenesis as a therapeutic approach, or to administer a small molecule derived from such an inhibitor. We have shown previously that thrombospondin-1&2 induce apoptosis of brain microvessel endothelial cells in a mechanism that requires the death receptor TNF-R1. Furthermore, we found that a small peptide derived from thrombospondin-1 also induces apoptosis of tumor-associated endothelial cells in two orthotopic mouse models of malignant glioma, and inhibits tumor growth. Also, we have recently shown that the recombinant fifth kringle domain of plasminogen can induce apoptosis of brain microvessel endothelial cells in a mechanism that requires the heat shock protein GRP78 and the scavenger receptor LRP1. Utilizing animal models and in vitro mechanistic studies of endothelial cells in culture, we are pursuing the mechanism by which LRP1 signals for apoptosis and determining whether TNF-R1 could be activated on tumor-associated endothelial cells as a therapeutic maneuver to inhibit angiogenesis in malignant glioma tumors.
Another project in my laboratory focuses on the regulation of apoptosis and autophagy in glioma cells. We recently showed that FIP200 can act to inhibit apoptosis of malignant glioma cells and endothelial cells by inhibiting Pyk2 activation. We are now studying the mechanisms that regulate FIP200 function in malignant glioma tumors. Also, we are studying the role of cellular Src family members in regulating apoptosis and autophagy in malignant glioma tumors.
Wang D, Yamamoto S, Hijiya N, Benveniste E, and Gladson CL. Transcriptional regulation of the human osteopontin promoter: Functional analysis and DNA-protein interactions. Oncogene 2000;19(50):5801-09. PMCID: 11126367
Han X, Stewart JE, Jr., Bellis SL, Beneveniste EN, Ding Q, Tachibana K, Grammer JR, and Gladson CL. TGF-b1 Up-regulates paxillin protein expression in malignant astrocytoma cells: Requirement for a fibronectin substrate. Oncogene 2001;20(55):7976-86. PMCID: 11753680
Hecker TP, Grammer JR, Gillespie GY, Stewart JE, Jr., and Gladson CL. FAK enhances signaling through the Shc/Erk pathway in anaplastic astrocytoma tumor biopsy samples. Cancer Res 2002,62:2699-707. PMCID: 11980671
Ding Q, Grammer JR, Stewart JE, Jr., Prince CW, Chang P-L, Trikha M, Han X, and Gladson CL. Promotion of malignant astrocytoma cell migration by osteopontin expressed in the normal brain: Differences in integrin signaling during cell adhesion to osteopontin versus vitronectin. Cancer Res 2002, 62:5336-43. PMCID: 12235004
Haskell H, Natarajan M, Hecker T, Ding Q, Grammer JR, Stewart JE, Jr., and Gladson CL. Focal adhesion kinase is expressed in the angiogenic blood vessels of malignant astrocytic tumors in vivo and promotes capillary tube formation of brain microvascular endothelial cells. Clin Cancer Res 2003;9:2157-65. PMCID: 12796381
Rosenthal EL, Shreenivas S, Peters GE, Grizzle WE, Desmond R, and Gladson CL. Expression of extracellular matrix metalloprotease inducer in laryngeal squamous cell carcinoma. Laryngoscope 2003;113:1406-10. PMCID: 12897567
Ding Q, Stewart J, Jr, Olman MA, Klobe MR and Gladson CL. The pattern of enhancement of Src kinase activity on PDGF stimulation of glioblastoma cells is affected by the integrin engaged. J Biol Chem 2003; 278:39882-91. PMCID: 12881526
Repovic P, Fears CY, Gladson CL, and Benveniste EN. Oncostatin-M induction of vascular endothelial growth factor expression in astroglioma cells. Oncogene 2003;22:8117-24. PMCID: 14603252
Natarajan M, Hecker TP, and Gladson CL. FAK signaling in malignant astrocytomas. Cancer J 2003;9: 126-33. PMCID: 12784878
Derrick M, Luo NL, Bregman JC, Jilling T, Ji X, Fisher K, Gladson CL, Beardsley DJ, Murdoch G, Back SA, and Tan S. Preterm fetal hypoxia-ischemia causes hypertonia and motor deficits in the neonatal rabbit: A model for human cerebral palsy? J Neurosci 2004;24:24-34. PMCID: 14715934
Hecker TP, Ding Q, Rege T, Hanks S, and Gladson CL. Overexpression of FAK promotes Ras activity through the formation of a FAK/p120RasGAP complex in malignant astrocytoma cells. Oncogene 2004; 23:3962-3971. PMCID: 15077193
Fears CY, Sontheimer HW, Bullard DC, and Gladson CL. Could labeled neuronal progenitor cells be used to target glioma tumor endothelium? Cancer Biol Ther 2004;3(9):845-846. PMCID: 15467422
Ding Q, Grammer JR, Nelson MA, Guan J-L, Stewart JE Jr, and Gladson CL. P27(Kip1) and cyclin D1 are necessary for focal adhesion kinase (FAK) regulation of cell cycle progression in glioblastoma cells propagated in vitro and in vivo in the scid mouse brain. J Biol Chem 2005;280:6802-15. PMCID: 15557280
Rege TA, Fears CY, and Gladson CL. Endogenous inhibitors of angiogenesis in malignant gliomas. Neuro-Oncology 2005;7:106-121. PMCID: 15831230
Stettner MR, Wang W, Nabors LB, Bharara S, Grammer JR, Gillespie GY, and Gladson CL. Lyn kinase activity is the predominant cellular Src kinase activity in glioblastoma tumor cells. Cancer Res 2005;65:5535-35. PMCID: 15994925
Chung WJ, Lyons SA, Nelson GM, Hamza H, Gladson CL, Gillespie GL, and Sontheimer H. Inhibition of cystine uptake disrupts the growth of primary brain tumors. J Neuroscience 2005;25:7101-7110. PMCID: 16079392
Fears CY, Grammer JR, Stewart JE Jr, Annis DS, Mosher DF, Bornstein P, and Gladson CL. Low-density lipoprotein receptor-related protein contributes to the antiangiogenic activity of thrombospondin-2 in a murine glioma model. Cancer Res 2005; 65(20):9338-9346. PMCID: 16230396
Wang D, Anderson J, and Gladson CL. The Role of the Extracellular Matrix in Malignant Glioma Tumors. Brain Pathology 2005, 15(4): 318-326. PMDIC: 16389944 Natarajan M, Stewart JE Jr, Golemis EA, Pugacheva EN, Alexandropoulos K, Grammer JR, and Gladson CL. HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells. Oncogene 2006; 25(12): 1721-1732. PMCID: 1628824
Akella SN, Ding Q, Menegazzo L, Wang W, Gillespie GY, Grammer JR, *Gladson CL, and *Nabors LB. A novel technique to quantify glioma tumor invasion using serial microscopy sections. J Neuroscience Methods 2006; 153: 183 – 189. *Co-senior authors. PMCID: 16406041
Cox BD, Natarajan M, Stettner MR, and Gladson CL. New Concepts regarding focal adhesion kinase promotion of migration and proliferation. J Cell Biochem 2006; 99(1): 35 – 52. PMCID: 16823799
Fears CY, Gladson CL, and Woods A. Syndecan-2 is expressed in the microvasculature of gliomas and regulates angiogenic processes in microvascular endothelial cells. J Biol Chem. 2006; 281(21): 14533 – 14536. PMCID: 16574663
Anderson JC, Grammer RJ, Wang W, Nabors LB, Henkin J, Stewart JE Jr., and Gladson CL. ABT-510, a modified type 1 repeat peptide of thrombospondin, inhibits malignant glioma growth in vivo by inhibiting angiogenesis. Cancer Biology and Therapy 2007; 6(3): 454 – 462. PMCID: 17384534
Ding Q, Gladson CL, Wu H, Hayasaka H, Parsons JT, and Olman MA. FRNK overexpression inhibits myofibroblast differentiation through both FAK-dependent and FAK-Independent Pathways, J. Biol. Chem. 2008; 283(40): 26839-26849 PMCID: PMC2556008
Anderson JC, McFarland BC, and Gladson CL. New molecular targets in the angiogenic vessels of glioblastoma tumors. Expert Reviews in Molecular Medicine, 2008 Epub 10:e23 doi: 10.2028/S1462399408000768. PMCID: 18684337.
Rege TA, Stewart J Jr, Dranka B, Benveniste EN, Silverstein R, and Gladson CL. TNF-R1 Can Mediate Thrombospondin-1-induced Apoptosis of Brain Microvascular Endothelial Cells. J Cell Physiol, 2008; 218(1): 94-103. PMCID: 18726995.
Gladson CL and Welch DR. New insights into the role of CXCR4 in prostate cancer metastasis. Cancer Biol & Ther. 2008; 7(11): Epub ahead of print. PMCID: 18981717.
Zhu S, Gladson CL, White KE, Ding Q, Stewart Jr JE, Jin TH, Chapman Jr HA, Olman MA. Urokinase receptor mediates lung fibroblast attachment and migration towards provisional matrix proteins through interaction with multiple integrins. Am J Physiol Lung Cell Mol Physiol May 1, 2009. [Epub ahead of print] McFarland BC, Stewart J, Hamza A, Davidson D, Henkin J, and Gladson CL. Plasminogen kringle 5 induces apoptosis of brain microvessel endothelial cells: Sensitization by radiation and requirement for GRP78 and LRP1. Cancer Research, 2009;69(13):5537-5545.
Gladson CL, Prayson RA, and Liu MW. The Pathobiology of Gliomas. Annual Review of Pathology: Mechanisms of Disease, 2010,5:35-50.
G. Cai, A.,Zheng, Q. Tang, E.S. White, C-F. Chou, C.L. Gladson, M.A. Olman, and Q. Ding. Downregulation of FAK-Related Non-Kinase Mediates the Migratory Phenotype of Human Fibrotic Lung Fibroblasts. Experimental Cell Research, 2010;316(9):1600-1609.
M. S. Ahluwalia and C.L. Gladson Progress on Anti-Angiogenic Therapy for Patients With Malignant Glioma. Journal of Oncology, 2010;2010:689018. Epub 2010 April 6.
L.B. Nabors, J. Fiveash, J. Markert, M.S. Kehan, G.Y. Gillespie, Z. Huang, M. Johnson, S. Meleth, H. Kuo, C.L. Gladson, and H. Fathallah. A Phase I Trial of ABT-510 Concurrent with Standard Chemoradiation for Patients with Newly Diagnosed Glioblastoma Multiforme (GBM). Archives of Neurology, 2010;67(3):313-319.
Klenotic, P. Huang, J. Palomo, B. Kaur, E. Van Meir, M. Vogelbaum, M. Febbraio, C.L. Gladson, and R. Silverstein. Histidine-Rich Glycoprotein Modulates the Anti-Angiogenic Effects of Vasculostatin. American Journal of Pathology, 2010;176(4):2039-2050.
M. S. Ahlwalia,, J. de Groot, W. M. Liu, and C.L. Gladson, Targeting SRC in Glioblastoma Tumors, Cancer Letters, 2010;298(2):139-149.
D. Wang, M.A. Olman, J.E. Stewart, Jr., R. Tipps, P. Huang, P. W. Sanders, E. Toline, R. Prayson, J. Lee, R. Weil, C.A. Palmer, G.Y. Gillespie, W.M. Liu, R.Pieper, J.L.Guan, and C.L. Gladson Downregulation of FIP200 Induces Apoptosis of Glioblastoma Cells and Microvascular Endothelial Cells by Enhancing Pyk2 Activity. PLoS ONE, 2011;6(5):e19629. doi:10.137/journal.pone.0019629.