This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brat, D. J. Articles by Van Meir, E. G. Search for Related Content PubMed PubMed Citation Articles by Brat, D. J. Articles by Van Meir, E. G.

Pseudopalisades in Glioblastoma Are Hypoxic, Express Extracellular Matrix Proteases, and Are Formed by an Actively Migrating Cell Population

Departments of ¹ Pathology and Laboratory Medicine and ² Neurosurgery and Hematology/Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, and ³ Department of Pathology, LDS Hospital, Salt Lake City, Utah

Necrosis and vascular proliferation are the pathologic features that distinguish the most malignant infiltrative astrocytoma, glioblastoma (GBM), from those of lower grades. In GBM, hypercellular zones called pseudopalisades typically surround necrotic foci. Although these cells are known to secrete high levels of proangiogenic factors that promote tumor growth, their origins are ill defined. We propose that pseudopalisades represent differing stages and histologic samplings of astrocytoma cells migrating away from a hypoxic/anoxic focus, often triggered by a central vaso-occlusive event. This proposition is based on our findings that pseudopalisading cells are 5–50% less proliferative and 6–20 times more apoptotic than adjacent astrocytoma, indicating that cell accumulation does not result from increased proliferation or resistance to apoptosis. Coexisting inflammatory cells account for <2% of pseudopalisading cells and cannot account for hypercellularity. Pseudopalisading cells show nuclear expression of hypoxia-inducible factor 1, consistent with their hypoxic nature, and hypoxia induces a 20–60% increase in glioma cell migration in vitro. Hypoxic cells in vitro and pseudopalisades in GBM specimens show enhanced gelatinase activity, typical of an invasive phenotype. These results suggest that pseudopalisading cells are migrating at the periphery of a hypoxic center. To uncover a potential source of hypoxia and sequence of structural events leading to pseudopalisade formation, we performed a morphometric analysis of 234 pseudopalisades from 85 pretreatment GBMs. We found distorted, degenerating, or thrombosed blood vessels within the center of more than half the pseudopalisades, suggesting that at least a subset of pseudopalisades are two-dimensional histologic representations of tumor cells migrating away from a vaso-occlusive event.

This article has been cited by other articles:

				J. Micallef, M. Taccone, J. Mukherjee, S. Croul, J. Busby, M. F. Moran, and A. Guha Epidermal Growth Factor Receptor Variant III-Induced Glioma Invasion Is Mediated through Myristoylated Alanine-Rich Protein Kinase C Substrate Overexpression Cancer Res., October 1, 2009; 69(19): 7548 - 7556. [Abstract] [Full Text] [PDF]

				G. Stoica, G. Lungu, H. Martini-Stoica, S. Waghela, J. Levine, and R. Smith Identification of Cancer Stem Cells in Dog Glioblastoma Vet. Pathol., May 1, 2009; 46(3): 391 - 406. [Abstract] [Full Text] [PDF]

				Y. Rong, V. E. Belozerov, C. Tucker-Burden, G. Chen, D. L. Durden, J. J. Olson, E. G. Van Meir, N. Mackman, and D. J. Brat Epidermal Growth Factor Receptor and PTEN Modulate Tissue Factor Expression in Glioblastoma through JunD/Activator Protein-1 Transcriptional Activity Cancer Res., March 15, 2009; 69(6): 2540 - 2549. [Abstract] [Full Text] [PDF]

				B. Kaur, S. M. Cork, E. M. Sandberg, N. S. Devi, Z. Zhang, P. A. Klenotic, M. Febbraio, H. Shim, H. Mao, C. Tucker-Burden, et al. Vasculostatin Inhibits Intracranial Glioma Growth and Negatively Regulates In vivo Angiogenesis through a CD36-Dependent Mechanism Cancer Res., February 1, 2009; 69(3): 1212 - 1220. [Abstract] [Full Text] [PDF]

				D. Zagzag, M. Esencay, O. Mendez, H. Yee, I. Smirnova, Y. Huang, L. Chiriboga, E. Lukyanov, M. Liu, and E. W. Newcomb Hypoxia- and Vascular Endothelial Growth Factor-Induced Stromal Cell-Derived Factor-1{alpha}/CXCR4 Expression in Glioblastomas: One Plausible Explanation of Scherer's Structures Am. J. Pathol., August 1, 2008; 173(2): 545 - 560. [Abstract] [Full Text] [PDF]

				A. M. Spence, M. Muzi, K. R. Swanson, F. O'Sullivan, J. K. Rockhill, J. G. Rajendran, T. C.H. Adamsen, J. M. Link, P. E. Swanson, K. J. Yagle, et al. Regional Hypoxia in Glioblastoma Multiforme Quantified with [18F]Fluoromisonidazole Positron Emission Tomography before Radiotherapy: Correlation with Time to Progression and Survival Clin. Cancer Res., May 1, 2008; 14(9): 2623 - 2630. [Abstract] [Full Text] [PDF]

				R. Du, C. Petritsch, K. Lu, P. Liu, A. Haller, R. Ganss, H. Song, S. Vandenberg, and G. Bergers Matrix metalloproteinase-2 regulates vascular patterning and growth affecting tumor cell survival and invasion in GBM Neuro-oncol, January 1, 2008; 10(3): 254 - 264. [Abstract] [Full Text] [PDF]

				M. Hutterer, P. Knyazev, A. Abate, M. Reschke, H. Maier, N. Stefanova, T. Knyazeva, V. Barbieri, M. Reindl, A. Muigg, et al. Axl and Growth Arrest Specific Gene 6 Are Frequently Overexpressed in Human Gliomas and Predict Poor Prognosis in Patients with Glioblastoma Multiforme Clin. Cancer Res., January 1, 2008; 14(1): 130 - 138. [Abstract] [Full Text] [PDF]

				F.J. Wippold II, M. Lammle, F. Anatelli, J. Lennerz, and A. Perry Neuropathology for the Neuroradiologist: Palisades and Pseudopalisades AJNR Am. J. Neuroradiol., November 1, 2006; 27(10): 2037 - 2041. [Abstract] [Full Text] [PDF]

				Z. F. Yang, R. T.P. Poon, Y. Liu, C. K. Lau, D. W. Ho, K. H. Tam, C. T. Lam, and S. T. Fan High doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: dual effects on cancer cell and angiogenesis. Mol. Cancer Ther., September 1, 2006; 5(9): 2261 - 2270. [Abstract] [Full Text] [PDF]

				G. Tabatabai, B. Frank, R. Mohle, M. Weller, and W. Wick Irradiation and hypoxia promote homing of haematopoietic progenitor cells towards gliomas by TGF-{beta}-dependent HIF-1{alpha}-mediated induction of CXCL12 Brain, September 1, 2006; 129(9): 2426 - 2435. [Abstract] [Full Text] [PDF]

				Y. Rong, F. Hu, R. Huang, N. Mackman, J. M. Horowitz, R. L. Jensen, D. L. Durden, E. G. Van Meir, and D. J. Brat Early Growth Response Gene-1 Regulates Hypoxia-Induced Expression of Tissue Factor in Glioblastoma Multiforme through Hypoxia-Inducible Factor-1-Independent Mechanisms. Cancer Res., July 15, 2006; 66(14): 7067 - 7074. [Abstract] [Full Text] [PDF]

				Y.-H. Zhou, K. R. Hess, L. Liu, Mark. E. Linskey, and W.K. A. Yung Modeling prognosis for patients with malignant astrocytic gliomas: Quantifying the expression of multiple genetic markers and clinical variables Neuro-oncol, October 1, 2005; 7(4): 485 - 494. [Abstract] [PDF]

				E. W. Newcomb, M. A. Ali, T. Schnee, L. Lan, Y. Lukyanov, M. Fowkes, D. C. Miller, and D. Zagzag Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1{alpha} expression in human glioma cells by a proteasome-independent pathway: Implications for in vivo therapy Neuro-oncol, July 1, 2005; 7(3): 225 - 235. [Abstract] [PDF]

				B. Kaur, F. W. Khwaja, E. A. Severson, S. L. Matheny, D. J. Brat, and E. G. Van Meir Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis Neuro-oncol, April 1, 2005; 7(2): 134 - 153. [Abstract] [PDF]

				M. Bruehlmeier, U. Roelcke, P. A. Schubiger, and S. M. Ametamey Assessment of Hypoxia and Perfusion in Human Brain Tumors Using PET with 18F-Fluoromisonidazole and 15O-H2O J. Nucl. Med., November 1, 2004; 45(11): 1851 - 1859. [Abstract] [Full Text] [PDF]