- Email: [email protected]
Understanding Glioma Invasion: A Necessity for Effective Therapy
Perspectives Commentary on: The Role of Nrf2 in Migration and Invasion of Human Glioma Cell U251 by Pan et al. pp. 363-370.
E. Antonio Chiocca, M.D., Ph.D. Professor of Surgery, Harvard Medical School Neurosurgeon-in-Chief and Chairman, Department of Neurosurgery Co-Director, Institute for the Neurosciences at the Brigham and Women’s/Faulkner Hospital Surgical Director, Center for Neuro-oncology Dana-Farber Cancer Institute
Understanding Glioma Invasion: A Necessity for Effective Therapy Pierpaolo Peruzzi1 and E. Antonio Chiocca2
All solid malignancies have a tendency to invade other cells, resulting from a combination of cancer cell motility, loss of contact inhibition, and ability to produce factors that can disintegrate components of the extracellular matrix. For the majority of cancers, this process is the basis of metastatic spread; for gliomas, particularly glioblastoma multiforme (GBM), the equivalent of metastatic spread is diffuse and progressive brain invasion, evidenced by the characteristic intermingling of tumor cells with normal tissue. Scientifically, the majority of discoveries with the subsequent finding of therapeutic targets have been focused on the biology of glioma and tumor cell proliferation. However, greater focus is being redirected to trying to discover how tumor cells move, why they do it, and, most importantly, what can be done to prevent it. An understanding of molecular processes leading to the invasive behavior of glioblastoma and, consequently, any therapies that can derive from this knowledge would likely bring the next quantum leap in the treatment of this tumor. With the exception of surgical resection, the currently available armamentarium (radiation therapy and chemotherapy) exclusively targets the proliferative aspect of glioblastomas. Recent evidence suggests that this might have a paradoxical and counterproductive effect by stimulating cancer cells to literally “escape.” For example, it is known that sublethal irradiation promotes the invasiveness of glioma cells (19), likely by stimulating the production of histolytic proteases (18). Similarly, chemotherapy has been shown in preclinical studies to enhance cellular migration: by decreasing blood supply, antivascular endothelial growth factor treatments lead to a decrease in oxygen and energy levels within the tumor, inducing cells to migrate and create small satellite tumors near the primary mass (10). Indeed,
Key words 䡲 Glioma 䡲 Invasion 䡲 Matrix metalloproteinase-9 䡲 Migration 䡲 NF-E2⫺related factor 2
Abbreviations and Acronyms GBM: Glioblastoma multiforme MMP-9: Multiple metalloproteinase 9
some patients treated with bevacizumab, a monoclonal antibody against vascular endothelial growth factor, have experienced a significant increase in the volume of infiltrative tumor relative to the gadolinium-enhancing tumor (6). It is now accepted that cellular proliferation and migration are tightly linked. The “go or grow” hypothesis, suggesting a dichotomy between cellular proliferation and motility, was first described in 1996 and is now supported by the authors of several in vitro studies as well as mathematical models (7, 9). As a default mode, tumor cells tend to proliferate, but when conditions become unfavorable (acidic pH, decreased nutrient availability, decreased oxygen level), they opt to migrate away in search of better conditions. During this migration, their proliferative rate remains very low (17). The molecular mechanisms regulating this decision are still for the most part unknown, although some insights have begun to unravel. It has recently been shown that miR-451, a small noncoding microRNA that is down-regulated in migrating glioma cells, functions as a switch between proliferative phenotype versus migratory phenotype: miR-451 is up-regulated in presence of high levels of glucose, so that when energy is abundant miR-451 is highly expressed and in turns it down-regulates proteins involved with cell migration. Viceversa, in low-energy conditions, miR-451 levels decreases, and this releases the brakes on cell motility (8). Also, hypoxia-inducible factor 1, the master regulator of cellular response to hypoxia, has been largely validated as a key component in the induction of the migratory/invasive phenotype (5). Once the cell decides to move, a series of molecular rearrangements happen, including 1) reassortment of integrins and cadherins at the plasma membrane surface, allowing cells to dynamically
From the 1Department of Neurological Surgery, The Ohio State University Medical Center and James Cancer Hospital, Columbus, Ohio; and the 2 Department of Neurosurgery, Harvard Medical School, Institute for the Neurosciences at the Brigham and Women’s/Faulkner Hospital, and Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA To whom correspondence should be addressed: Antonio Chiocca, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2013) 80, 3/4:281-283. http://dx.doi.org/10.1016/j.wneu.2011.10.003
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www.WORLDNEUROSURGERY.org
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PERSPECTIVES
interact with the extracellular matrix (2); 2) cytoskeleton polarization by the Rho/Rac pathway, which orients the cells towards a target; and 3) microtubule and microfilament polymerization/depolimerization, allowing the formation of pseudopodia and lamellipodia, which ultimately pull the cell forward (1). Cancer cells are also endowed with a formidable set of enzymes whose function is to degrade the surrounding extracellular matrix (in the brain mainly made by collagen IV, laminin and fibronectin). Multiple metalloproteinase 9 (MMP-9) is only one of the many proteases that have been found to be involved in glioma cell migration. In fact, although MMP-2 and -9 are the two metalloproteinases (of more than 20) mainly expressed in gliomas (3) and whose level directly correlates with histological grade, other proteases, including plasminogen activators, and cathepsins have been shown to play an important role in glioma invasion (12). The growing interest in anti-invasive therapies has not been heavily translated into the clinics yet: to date, inhibition of MMPs has not resulted in any survival benefit (4). Pharmacologic inactivation of MMPs was investigated in a multicentric clinical trial in which the authors enrolled patients with newly diagnosed GBM. Treatment failed to improve overall survival or progression-free survival compared with placebo, confirming the disappointing results obtained with other cancer types (4, 11) and suggesting that metalloproteinases are only one of the players involved in cancer cell invasion and possibly not the most important ones. Cilengitide, a peptide that binds to and inactivates integrins ␣v3 and ␣v5, expressed on endothelial and tumor cells, has shown some promising results when added to radiation and temozolomide for newly diagnosed GBM, yielding a 2-year overall survival of 35% (compared with 26.5% in historical controls) (16). The paucity of clinical data available to date should not be too discouraging, particularly in light of the relative novelty of the field. In fact, there is plentiful of recent preclinical studies showing interesting results. In some cases, authors have opted for a “pragmatic approach,” that is, studying the effects of certain chemical compounds with the purpose, after the appropriate validation, to move quickly to clinical applications. This is the case, for example, of lithium, a simple element used for years in the treatment of bipolar disorder, which has been shown to inhibit migration of GBM cells in vitro and invasion in vivo (14),
REFERENCES 1. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P: The cytoskeleton. In: Alberts B, ed. The Molecular Biology of the Cell. 5th ed. New York: Garland Science; 2008:965-1052. 2. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P: Cell junctions, cell adhesion, and the extracellular matrix. In: Alberts B, ed. The Molecular Biology of the Cell. 5th ed. New York: Garland Science; 2008:1131-1178. 3. Binder DK, Berger MS: Proteases and the biology of glioma invasion. J Neurooncol 56:149-158, 2002. 4. Chu QS, Forouzesh B, Syed S, Mita M, Schwartz G, Cooper J, Curtright J, Rowinsky EK: A phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomas. Invest New Drugs 25: 359-367, 2007.
282
www.SCIENCEDIRECT.com
and indirubin, the active principle found in a Chinese herbal remedy for chronic pain, which was recently shown to block migration not only of glioma cells but of endothelial cells, thus reducing tumor-associated angiogenesis (20). Alternatively, with a more “molecular” approach, aimed at a mechanistic understanding of the invasive process rather than immediate practical applications, the function of specific genes has been defined, for example leading to characterize the role of hypoxiainducible factor 1, signal transducer and activator of transcription 3, and the SLIT/Robo interaction (12, 13, 15). This is the case of the study reported by Pan et al. in this issue of WORLD NEUROSURGERY. The authors propose a relationship between Nrf2, a transcription factor activated in response to cellular oxidative stress, and MMP-9, in determining an invasive phenotype in glioma cell line U251. Although not clearly stated by the authors, the hypothesis that a physiologic mechanism whose function is to protect the cell from stress can also trigger a physical “escape” by activating the migration/invasion mechanism is fascinating and completely in agreement with the “go or grow” hypothesis. However, there are some limitations in their report. The most obvious is that results were obtained with a single cell line. The use of multiple cell lines derived from fresh or recent operative specimens would have been much more in line with current standards of glioma research. Furthermore, the authors imply that there is a causal relationship between MMP-9 and Nrf2 expression, but this is based on their observation of parallel expression, which is not evidence for causality. Finally, without evidence that Nrf2 is up-regulated in glioblastoma compared with normal brain, there is a concern that Nrf2 expression might be relevant to the human U251 glioma cell line biology but not be relevant to glioblastoma biology. Despite these limitations, the report’s main findings provide a preliminary observation of this molecule (Nrf2) that should urge the authors and others to further experiments to test its relevance in glioma invasion. In the next few years, we should see increased scientific and therapeutic interest in studies that focus on glioma invasion. This is the next great frontier in glioma therapeutics and success here is likely to provide enormous benefit to the survival of patients.
5. Colin C, Voutsinos-Porche B, Nanni I, Fina F, Metellus P, Intagliata D, Baeza N, Bouvier C, Delfino C, Loundou A, Chinot O, Lah T, Kos J, Martin PM, Ouafik L, Figarella-Branger D: High expression of cathepsin B and plasminogen activator inhibitor type-1 are strong predictors of survival in glioblastomas. Acta Neuropathol 118:745-754, 2009. 6. de Groot JF, Fuller G, Kumar AJ, Piao Y, Eterovic K, Ji Y, Conrad CA: Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol 12:233-242, 2010. 7. Giese A, Loo MA, Tran N, Haskett D, Coons SW, Berens ME: Dichotomy of astrocytoma migration and proliferation. Int J Cancer 67:275-282, 1996. 8. Godlewski J, Nowicki MO, Bronisz A, Nuovo G, Palatini J, De Lay M, Van Brocklyn J, Ostrowski MC, Chiocca EA, Lawler SE: MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to
metabolic stress in glioma cells. Mol Cell 37: 620-632, 2010. 9. Hatzikirou H, Basanta D, Simon M, Schaller K, Deutsch A: ‘Go or Grow’: the key to the emergence of invasion in tumour progression? Math Med Biol 29:49-65, 2012. 10. Keunen O, Johansson M, Oudin A, Sanzey M, Rahim SA, Fack F, Thorsen F, Taxt T, Bartos M, Jirik R, Miletic H, Wang J, Stieber D, Stuhr L, Moen I, Rygh CB, Bjerkvig R, Niclou SP: Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci U S A 108: 3749-3754, 2011. 11. Levin VA, Phuphanich S, Yung WK, Forsyth PA, Maestro RD, Perry JR, Fuller GN, Baillet M: Randomized, double-blind, placebo-controlled trial of marimastat in glioblastoma multiforme patients following surgery and irradiation. J Neurooncol 78:295-302, 2006.
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2011.10.003
PERSPECTIVES
12. Méndez O, Zavadil J, Esencay M, Lukyanov Y, Santovasi D, Wang SC, Newcomb EW, Zagzag D: Knock down of HIF-1alpha in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres. Mol Cancer 9:133-142, 2010. 13. Mertsch S, Schmitz N, Jeibmann A, Geng JG, Paulus W, Senner V: Slit2 involvement in glioma cell migration is mediated by Robo1 receptor. J Neurooncol 87:1-7, 2008. 14. Nowicki MO, Dmitrieva N, Stein AM, Cutter JL, Godlewski J, Saeki Y, Nita M, Berens ME, Sander LM, Newton HB, Chiocca EA, Lawler S: Lithium inhibits invasion of glioma cells; possible involvement of glycogen synthase kinase-3. Neuro Oncol 10:690699, 2008.
and invasive potential of human glioblastoma cells. J Neurooncol 101:393-403, 2011. 16. Stupp R, Hegi ME, Neyns B, Goldbrunner R, Schlegel U, Clement PM, Grabenbauer GG, Ochsenbein AF, Simon M, Dietrich PY, Pietsch T, Hicking C, Tonn JC, Diserens AC, Pica A, Hermisson M, Krueger S, Picard M, Weller M: Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol 28:2712-2718, 2010. 17. Tamaki M, McDonald W, Amberger VR, Moore E, Del Maestro RF: Implantation of C6 astrocytoma spheroid into collagen type I gels: invasive, proliferative, and enzymatic characterizations. J Neurosurg 87:602-609, 1997.
19. Wild-Bode C, Weller M, Rimner A, Dichgans J, Wick W: Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma. Cancer Res 61: 2744-2750, 2011.
20. Williams SP, Nowicki MO, Liu F, Press R, Godlewski J, Abdel-Rasoul M, Kaur B, Fernandez SA, Chiocca EA, Lawler SE: Indirubins decrease glioma invasion by blocking migratory phenotypes in both the tumor and stromal endothelial cell compartments. Cancer Res 71:5374-5380, 2011. Citation: World Neurosurg. (2013) 80, 3/4:281-283. http://dx.doi.org/10.1016/j.wneu.2011.10.003 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com
15. Senft C, Priester M, Polacin M, Schröder K, Seifert V, Kögel D, Weissenberger J: Inhibition of the JAK-2/ STAT3 signaling pathway impedes the migratory
18. Wang JL, Sun Y, Wu S: Gamma-irradiation induces matrix metalloproteinase II expression in a p53-dependent manner. Mol Carcinog 27:252-258, 2000.
WORLD NEUROSURGERY 80 [3/4]: 281-283, SEPTEMBER/OCTOBER 2013
1878-8750/$ - see front matter © 2013 Elsevier Inc. All rights reserved.
www.WORLDNEUROSURGERY.org
283
E. Antonio Chiocca, M.D., Ph.D. Professor of Surgery, Harvard Medical School Neurosurgeon-in-Chief and Chairman, Department of Neurosurgery Co-Director, Institute for the Neurosciences at the Brigham and Women’s/Faulkner Hospital Surgical Director, Center for Neuro-oncology Dana-Farber Cancer Institute
Understanding Glioma Invasion: A Necessity for Effective Therapy Pierpaolo Peruzzi1 and E. Antonio Chiocca2
All solid malignancies have a tendency to invade other cells, resulting from a combination of cancer cell motility, loss of contact inhibition, and ability to produce factors that can disintegrate components of the extracellular matrix. For the majority of cancers, this process is the basis of metastatic spread; for gliomas, particularly glioblastoma multiforme (GBM), the equivalent of metastatic spread is diffuse and progressive brain invasion, evidenced by the characteristic intermingling of tumor cells with normal tissue. Scientifically, the majority of discoveries with the subsequent finding of therapeutic targets have been focused on the biology of glioma and tumor cell proliferation. However, greater focus is being redirected to trying to discover how tumor cells move, why they do it, and, most importantly, what can be done to prevent it. An understanding of molecular processes leading to the invasive behavior of glioblastoma and, consequently, any therapies that can derive from this knowledge would likely bring the next quantum leap in the treatment of this tumor. With the exception of surgical resection, the currently available armamentarium (radiation therapy and chemotherapy) exclusively targets the proliferative aspect of glioblastomas. Recent evidence suggests that this might have a paradoxical and counterproductive effect by stimulating cancer cells to literally “escape.” For example, it is known that sublethal irradiation promotes the invasiveness of glioma cells (19), likely by stimulating the production of histolytic proteases (18). Similarly, chemotherapy has been shown in preclinical studies to enhance cellular migration: by decreasing blood supply, antivascular endothelial growth factor treatments lead to a decrease in oxygen and energy levels within the tumor, inducing cells to migrate and create small satellite tumors near the primary mass (10). Indeed,
Key words 䡲 Glioma 䡲 Invasion 䡲 Matrix metalloproteinase-9 䡲 Migration 䡲 NF-E2⫺related factor 2
Abbreviations and Acronyms GBM: Glioblastoma multiforme MMP-9: Multiple metalloproteinase 9
some patients treated with bevacizumab, a monoclonal antibody against vascular endothelial growth factor, have experienced a significant increase in the volume of infiltrative tumor relative to the gadolinium-enhancing tumor (6). It is now accepted that cellular proliferation and migration are tightly linked. The “go or grow” hypothesis, suggesting a dichotomy between cellular proliferation and motility, was first described in 1996 and is now supported by the authors of several in vitro studies as well as mathematical models (7, 9). As a default mode, tumor cells tend to proliferate, but when conditions become unfavorable (acidic pH, decreased nutrient availability, decreased oxygen level), they opt to migrate away in search of better conditions. During this migration, their proliferative rate remains very low (17). The molecular mechanisms regulating this decision are still for the most part unknown, although some insights have begun to unravel. It has recently been shown that miR-451, a small noncoding microRNA that is down-regulated in migrating glioma cells, functions as a switch between proliferative phenotype versus migratory phenotype: miR-451 is up-regulated in presence of high levels of glucose, so that when energy is abundant miR-451 is highly expressed and in turns it down-regulates proteins involved with cell migration. Viceversa, in low-energy conditions, miR-451 levels decreases, and this releases the brakes on cell motility (8). Also, hypoxia-inducible factor 1, the master regulator of cellular response to hypoxia, has been largely validated as a key component in the induction of the migratory/invasive phenotype (5). Once the cell decides to move, a series of molecular rearrangements happen, including 1) reassortment of integrins and cadherins at the plasma membrane surface, allowing cells to dynamically
From the 1Department of Neurological Surgery, The Ohio State University Medical Center and James Cancer Hospital, Columbus, Ohio; and the 2 Department of Neurosurgery, Harvard Medical School, Institute for the Neurosciences at the Brigham and Women’s/Faulkner Hospital, and Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA To whom correspondence should be addressed: Antonio Chiocca, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2013) 80, 3/4:281-283. http://dx.doi.org/10.1016/j.wneu.2011.10.003
WORLD NEUROSURGERY 80 [3/4]: 281-283, SEPTEMBER/OCTOBER 2013
www.WORLDNEUROSURGERY.org
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PERSPECTIVES
interact with the extracellular matrix (2); 2) cytoskeleton polarization by the Rho/Rac pathway, which orients the cells towards a target; and 3) microtubule and microfilament polymerization/depolimerization, allowing the formation of pseudopodia and lamellipodia, which ultimately pull the cell forward (1). Cancer cells are also endowed with a formidable set of enzymes whose function is to degrade the surrounding extracellular matrix (in the brain mainly made by collagen IV, laminin and fibronectin). Multiple metalloproteinase 9 (MMP-9) is only one of the many proteases that have been found to be involved in glioma cell migration. In fact, although MMP-2 and -9 are the two metalloproteinases (of more than 20) mainly expressed in gliomas (3) and whose level directly correlates with histological grade, other proteases, including plasminogen activators, and cathepsins have been shown to play an important role in glioma invasion (12). The growing interest in anti-invasive therapies has not been heavily translated into the clinics yet: to date, inhibition of MMPs has not resulted in any survival benefit (4). Pharmacologic inactivation of MMPs was investigated in a multicentric clinical trial in which the authors enrolled patients with newly diagnosed GBM. Treatment failed to improve overall survival or progression-free survival compared with placebo, confirming the disappointing results obtained with other cancer types (4, 11) and suggesting that metalloproteinases are only one of the players involved in cancer cell invasion and possibly not the most important ones. Cilengitide, a peptide that binds to and inactivates integrins ␣v3 and ␣v5, expressed on endothelial and tumor cells, has shown some promising results when added to radiation and temozolomide for newly diagnosed GBM, yielding a 2-year overall survival of 35% (compared with 26.5% in historical controls) (16). The paucity of clinical data available to date should not be too discouraging, particularly in light of the relative novelty of the field. In fact, there is plentiful of recent preclinical studies showing interesting results. In some cases, authors have opted for a “pragmatic approach,” that is, studying the effects of certain chemical compounds with the purpose, after the appropriate validation, to move quickly to clinical applications. This is the case, for example, of lithium, a simple element used for years in the treatment of bipolar disorder, which has been shown to inhibit migration of GBM cells in vitro and invasion in vivo (14),
REFERENCES 1. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P: The cytoskeleton. In: Alberts B, ed. The Molecular Biology of the Cell. 5th ed. New York: Garland Science; 2008:965-1052. 2. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P: Cell junctions, cell adhesion, and the extracellular matrix. In: Alberts B, ed. The Molecular Biology of the Cell. 5th ed. New York: Garland Science; 2008:1131-1178. 3. Binder DK, Berger MS: Proteases and the biology of glioma invasion. J Neurooncol 56:149-158, 2002. 4. Chu QS, Forouzesh B, Syed S, Mita M, Schwartz G, Cooper J, Curtright J, Rowinsky EK: A phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomas. Invest New Drugs 25: 359-367, 2007.
282
www.SCIENCEDIRECT.com
and indirubin, the active principle found in a Chinese herbal remedy for chronic pain, which was recently shown to block migration not only of glioma cells but of endothelial cells, thus reducing tumor-associated angiogenesis (20). Alternatively, with a more “molecular” approach, aimed at a mechanistic understanding of the invasive process rather than immediate practical applications, the function of specific genes has been defined, for example leading to characterize the role of hypoxiainducible factor 1, signal transducer and activator of transcription 3, and the SLIT/Robo interaction (12, 13, 15). This is the case of the study reported by Pan et al. in this issue of WORLD NEUROSURGERY. The authors propose a relationship between Nrf2, a transcription factor activated in response to cellular oxidative stress, and MMP-9, in determining an invasive phenotype in glioma cell line U251. Although not clearly stated by the authors, the hypothesis that a physiologic mechanism whose function is to protect the cell from stress can also trigger a physical “escape” by activating the migration/invasion mechanism is fascinating and completely in agreement with the “go or grow” hypothesis. However, there are some limitations in their report. The most obvious is that results were obtained with a single cell line. The use of multiple cell lines derived from fresh or recent operative specimens would have been much more in line with current standards of glioma research. Furthermore, the authors imply that there is a causal relationship between MMP-9 and Nrf2 expression, but this is based on their observation of parallel expression, which is not evidence for causality. Finally, without evidence that Nrf2 is up-regulated in glioblastoma compared with normal brain, there is a concern that Nrf2 expression might be relevant to the human U251 glioma cell line biology but not be relevant to glioblastoma biology. Despite these limitations, the report’s main findings provide a preliminary observation of this molecule (Nrf2) that should urge the authors and others to further experiments to test its relevance in glioma invasion. In the next few years, we should see increased scientific and therapeutic interest in studies that focus on glioma invasion. This is the next great frontier in glioma therapeutics and success here is likely to provide enormous benefit to the survival of patients.
5. Colin C, Voutsinos-Porche B, Nanni I, Fina F, Metellus P, Intagliata D, Baeza N, Bouvier C, Delfino C, Loundou A, Chinot O, Lah T, Kos J, Martin PM, Ouafik L, Figarella-Branger D: High expression of cathepsin B and plasminogen activator inhibitor type-1 are strong predictors of survival in glioblastomas. Acta Neuropathol 118:745-754, 2009. 6. de Groot JF, Fuller G, Kumar AJ, Piao Y, Eterovic K, Ji Y, Conrad CA: Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol 12:233-242, 2010. 7. Giese A, Loo MA, Tran N, Haskett D, Coons SW, Berens ME: Dichotomy of astrocytoma migration and proliferation. Int J Cancer 67:275-282, 1996. 8. Godlewski J, Nowicki MO, Bronisz A, Nuovo G, Palatini J, De Lay M, Van Brocklyn J, Ostrowski MC, Chiocca EA, Lawler SE: MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to
metabolic stress in glioma cells. Mol Cell 37: 620-632, 2010. 9. Hatzikirou H, Basanta D, Simon M, Schaller K, Deutsch A: ‘Go or Grow’: the key to the emergence of invasion in tumour progression? Math Med Biol 29:49-65, 2012. 10. Keunen O, Johansson M, Oudin A, Sanzey M, Rahim SA, Fack F, Thorsen F, Taxt T, Bartos M, Jirik R, Miletic H, Wang J, Stieber D, Stuhr L, Moen I, Rygh CB, Bjerkvig R, Niclou SP: Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci U S A 108: 3749-3754, 2011. 11. Levin VA, Phuphanich S, Yung WK, Forsyth PA, Maestro RD, Perry JR, Fuller GN, Baillet M: Randomized, double-blind, placebo-controlled trial of marimastat in glioblastoma multiforme patients following surgery and irradiation. J Neurooncol 78:295-302, 2006.
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2011.10.003
PERSPECTIVES
12. Méndez O, Zavadil J, Esencay M, Lukyanov Y, Santovasi D, Wang SC, Newcomb EW, Zagzag D: Knock down of HIF-1alpha in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres. Mol Cancer 9:133-142, 2010. 13. Mertsch S, Schmitz N, Jeibmann A, Geng JG, Paulus W, Senner V: Slit2 involvement in glioma cell migration is mediated by Robo1 receptor. J Neurooncol 87:1-7, 2008. 14. Nowicki MO, Dmitrieva N, Stein AM, Cutter JL, Godlewski J, Saeki Y, Nita M, Berens ME, Sander LM, Newton HB, Chiocca EA, Lawler S: Lithium inhibits invasion of glioma cells; possible involvement of glycogen synthase kinase-3. Neuro Oncol 10:690699, 2008.
and invasive potential of human glioblastoma cells. J Neurooncol 101:393-403, 2011. 16. Stupp R, Hegi ME, Neyns B, Goldbrunner R, Schlegel U, Clement PM, Grabenbauer GG, Ochsenbein AF, Simon M, Dietrich PY, Pietsch T, Hicking C, Tonn JC, Diserens AC, Pica A, Hermisson M, Krueger S, Picard M, Weller M: Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol 28:2712-2718, 2010. 17. Tamaki M, McDonald W, Amberger VR, Moore E, Del Maestro RF: Implantation of C6 astrocytoma spheroid into collagen type I gels: invasive, proliferative, and enzymatic characterizations. J Neurosurg 87:602-609, 1997.
19. Wild-Bode C, Weller M, Rimner A, Dichgans J, Wick W: Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma. Cancer Res 61: 2744-2750, 2011.
20. Williams SP, Nowicki MO, Liu F, Press R, Godlewski J, Abdel-Rasoul M, Kaur B, Fernandez SA, Chiocca EA, Lawler SE: Indirubins decrease glioma invasion by blocking migratory phenotypes in both the tumor and stromal endothelial cell compartments. Cancer Res 71:5374-5380, 2011. Citation: World Neurosurg. (2013) 80, 3/4:281-283. http://dx.doi.org/10.1016/j.wneu.2011.10.003 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com
15. Senft C, Priester M, Polacin M, Schröder K, Seifert V, Kögel D, Weissenberger J: Inhibition of the JAK-2/ STAT3 signaling pathway impedes the migratory
18. Wang JL, Sun Y, Wu S: Gamma-irradiation induces matrix metalloproteinase II expression in a p53-dependent manner. Mol Carcinog 27:252-258, 2000.
WORLD NEUROSURGERY 80 [3/4]: 281-283, SEPTEMBER/OCTOBER 2013
1878-8750/$ - see front matter © 2013 Elsevier Inc. All rights reserved.
www.WORLDNEUROSURGERY.org
283