Research Papers

The Mechanism of the Initiation and Progression of Glioma

[+] Author and Article Information
Ishwar K. Puri

N. Waldo Harrison Professor
Fellow ASME
Department of Engineering Sciences
and Mechanics,
Virginia Tech.,
Blacksburg, VA 24061

Subbiah Elankumaran

Assistant Professor
Department of Biomedical Sciences
and Pathobiology,
Virginia Tech.,
Blacksburg, VA 24061

Moanaro Biswas

Postdoctoral Associate
Institute for Critical Technology
and Applied Science,
Virginia Tech.,
Blacksburg, VA 24061

Liwu Li

Department of Biological Sciences,
Virginia Tech.,
Blacksburg, VA 24061

1Corresponding author.

Manuscript received March 22, 2012; final manuscript received December 15, 2012; accepted manuscript posted January 22, 2013; published online July 19, 2013. Assoc. Editor: Martin Ostoja-Starzewski.

J. Appl. Mech 80(5), 050901 (Jul 19, 2013) (7 pages) Paper No: JAM-12-1112; doi: 10.1115/1.4023472 History: Received March 22, 2012; Revised December 15, 2012; Accepted January 22, 2013

The fate of malignant glioma (MG) is governed by a multifaceted and dynamic circuit that involves the surrounding cellular and molecular tumor microenvironment. Despite extensive experimental studies, a complete understanding of the complex interactions among the constituents of this microenvironment remains elusive. To clarify this, we introduce a biologically based mathematical model that examines the dynamic modulation of glioma cancer stem cells (GSC) by different immune cell types and intracellular signaling pathways. It simulates the proliferation of glioma stem cells due to macrophage-induced inflammation, particularly involving two microglia phenotypes. The model can be used to regulate therapies by monitoring the GSC self-renewal rates that determine tumor progression. We observe that the GSC population is most sensitive to its own proliferation rate and the relative levels of the activating natural killer (NK) cell stimulatory receptors (NKG2D) versus killer inhibitory receptors (KIR) on NK cells that influence the proliferation or demise of the GSC population. Thus, the two most important factors involved in tumorigenesis or tumor regression are (1) GSC proliferation and (2) the functional status of NK cells. Therefore, strategies aimed at blocking proliferation and enhancing NKG2D and KIR signals should have a potentially beneficial impact for treating malignant gliomas.

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CBTRUS, 2010, “CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States, 2004–2006,” Central Brain Tumor Registry of the United States, Hinsdale, IL.
Stupp, R., and Roila, F., 2009, “Malignant Glioma: ESMO Clinical Recommendations for Diagnosis, Treatment and Follow-Up,” Ann. Oncol., 20(Suppl 4), pp. 126–128. [CrossRef]
Prados, M. D., and Levin, V., 2000, “Biology and Treatment of Malignant Glioma,” Semin. Oncol., 27(3), pp. S1–S10.
Mirimanoff, R. O., Gorlia, T., Mason, W., Van den Bent, M. J., Kortman, R. D., Fisher, B., Reni, M., Brandes, A. A., Curschmann, J., Villa, S., Cairncross, G., Allgeier, A., Lacombe, D., and Stupp, R., 2006, “Radiotherapy and Temozolomide for Newly Diagnosed Glioblastoma: Recursive Partitioning Analysis of the EORTC 26981/22981-NCIC CE3 Phase III Randomized Trial,” J. Clin. Oncol., 24(16), pp. 2563–2569. [CrossRef]
Noushmehr, H., Weisenberger, D. J., Diefes, K., Phillips, H. S., Pujara, K., Berman, B. P., Pan, F., Pelloski, C. E., Sulman, E. P., Bhat, K. P., Verhaak, R. G., Hoadley, K. A., Hayes, D. N., Perou, C. M., Schmidt, H. K., Ding, L., Wilson, R. K., Van Den Berg, D., Shen, H., Bengtsson, H., Neuvial, P., Cope, L. M., Buckley, J., Herman, J. G., Baylin, S. B., Laird, P. W., and Aldape, K., 2010, “Identification of a CpG Island Methylator Phenotype That Defines a Distinct Subgroup of Glioma,” Cancer Cell, 17(5), pp. 510–522. [CrossRef]
Stiles, C. D., and Rowitch, D. H., 2008, “Glioma Stem Cells: A Midterm Exam,” Neuron, 58(6), pp. 832–846. [CrossRef]
Lindner, I., Hemdan, N. Y., Buchold, M., Huse, K., Bigl, M., Oerlecke, I., Ricken, A., Gaunitz, F., Sack, U., Naumann, A., Hollborn, M., Thal, D., Gebhardt, R., and Birkenmeier, G., 2010, “α2-Macroglobulin Inhibits the Malignant Properties of Astrocytoma Cells by Impeding β-Catenin Signaling,” Cancer Res., 70(1), pp. 277–287. [CrossRef]
Clarke, M. F., and Fuller, M., 2006, “Stem Cells and Cancer: Two Faces of Eve,” Cell, 124(6), pp. 1111–1115. [CrossRef]
Ganguly, R., and Puri, I. K., 2006, “Mathematical Model for the Cancer Stem Cell Hypothesis,” Cell Prolif., 39(1), pp. 3–14. [CrossRef]
Clarke, M. F., 2004, “Neurobiology: At the Root of Brain Cancer,” Nature, 432(7015), pp. 281–282. [CrossRef]
Calabrese, C., Poppleton, H., Kocak, M., Hogg, T. L., Fuller, C., Hamner, B., Oh, E. Y., Gaber, M. W., Finklestein, D., Allen, M., Frank, A., Bayazitov, I. T., Zakharenko, S. S., Gajjar, A., Davidoff, A., and Gilbertson, R. J., 2007, “A Perivascular Niche for Brain Tumor Stem Cells,” Cancer Cell, 11(1), pp. 69–82. [CrossRef]
Gilbertson, R. J., and Rich, J. N., 2007, “Making a Tumour's Bed: Glioblastoma Stem Cells and the Vascular Niche,” Nat. Rev. Cancer, 7(10), pp. 733–736. [CrossRef]
Xia, D., Wang, D., Kim, S.-H., Katoh, H., and DuBois, R. N., 2012, “Prostaglandin E2 Promotes Intestinal Tumor Growth via DNA Methylation,” Nat. Med., 18, pp. 224–226. [CrossRef]
Balkwill, F., and Mantovani, A., 2001, “Inflammation and Cancer: Back to Virchow?,” Lancet, 357(9255), pp. 539–545, available at http://www.ncbi.nlm.nih.gov/pmc/articles/pmc1994795/ [CrossRef]
Rakoff-Nahoum, S., 2006, “Cancer Issue: Why Cancer and Inflammation?,” Yale J. Biol. Med., 79(3–4), pp. 123–130.
Coussens, L. M., and Werb, Z., 2002, “Inflammation and Cancer,” Nature, 420(6917), pp. 860–867. [CrossRef]
Riquelme, P. A., Drapeau, E., and Doetsch, F., 2008, “Brain Micro-Ecologies: Neural Stem Cell Niches in the Adult Mammalian Brain,” Philos. Trans. R. Soc. London, Ser. B, 363(1489), pp. 123–137. [CrossRef]
Hjelmeland, A. B., Wu, Q., Heddleston, J. M., Choudhary, G. S., MacSwords, J., Lathia, J. D., McLendon, R., Lindner, D., Sloan, A., and Rich, J. N., 2011, “Acidic Stress Promotes a Glioma Stem Cell Phenotype,” Cell Death Differ., 18(5), pp. 829–840. [CrossRef]
Bao, S., Wu, Q., Sathornsumetee, S., Hao, Y., Li, Z., Hjelmeland, A. B., Shi, Q., McLendon, R. E., Bigner, D. D., and Rich, J. N., 2006, “Stem Cell–Like Glioma Cells Promote Tumor Angiogenesis Through Vascular Endothelial Growth Factor,” Cancer Res., 66(16), pp. 7843–7848. [CrossRef]
Scadden, D. T., 2006, “The Stem-Cell Niche as an Entity of Action,” Nature, 441(7097), pp. 1075–1079. [CrossRef]
Bleau, A. M., Huse, J. T., and Holland, E. C., 2009, “The ABCG2 Resistance Network of Glioblastoma,” Cell Cycle, 8(18), pp. 2936–2944. [CrossRef]
Bleau, A. M., and Holland, E. C., 2009, “Chemotherapeutic Treatment of Gliomas Increases the Amount of Cancer Stem-Like Cells,” Med. Sci. (Paris), 25(10), pp. 775–777. [CrossRef]
Hoa, N., Ge, L., Kuznetsov, Y., McPherson, A., Cornforth, A. N., Pham, J. T., Myers, M. P., Ahmed, N., Salsman, V. S., Lamb, L. S., Jr., Bowersock, J. E., Hu, Y., Zhou, Y. H., and Jadus, M. R., 2010, “Glioma Cells Display Complex Cell Surface Topographies That Resist the Actions of Cytolytic Effector Lymphocytes,” J. Immunol., 185(8), pp. 4793–4803. [CrossRef]
Insug, O., Ku, G., Ertl, H. C., and Blaszczyk-Thurin, M., 2002, “A Dendritic Cell Vaccine Induces Protective Immunity to Intracranial Growth of Glioma,” Anticancer Res., 22(2A), pp. 613–621, available at http://europepmc.org/abstract/MED/12014629
Kobayashi, K., Noguchi, M., Itoh, K., and Harada, M., 2003, “Identification of a Prostate-Specific Membrane Antigen-Derived Peptide Capable of Eliciting Both Cellular and Humoral Immune Responses in HLA-A24+ Prostate Cancer Patients,” Cancer Sci., 94(7), pp. 622–627. [CrossRef]
Kruse, C. A., Cepeda, L., Owens, B., Johnson, S. D., Stears, J., and Lillehei, K. O., 1997, “Treatment of Recurrent Glioma With Intracavitary Alloreactive Cytotoxic T Lymphocytes and Interleukin-2,” Cancer Immunol. Immunother., 45(2), pp. 77–87. [CrossRef]
Liau, L. M., Prins, R. M., Kiertscher, S. M., Odesa, S. K., Kremen, T. J., Giovannone, A. J., Lin, J. W., Chute, D. J., Mischel, P. S., Cloughesy, T. F., and Roth, M. D., 2005, “Dendritic Cell Vaccination in Glioblastoma Patients Induces Systemic and Intracranial T-Cell Responses Modulated by the Local Central Nervous System Tumor Microenvironment,” Clin. Cancer Res., 11(15), pp. 5515–5525. [CrossRef]
Prins, R. M., Soto, H., Konkankit, V., Odesa, S. K., Eskin, A., Yong, W. H., Nelson, S. F., and Liau, L. M., 2010, “Gene Expression Profile Correlates With T Cell Infiltration and Survival in Glioblastoma Patients Vaccinated With Dendritic Cell Immunotherapy,” Clin. Cancer Res., 17(6), pp. 1603–1615. [CrossRef]
Liu, L., Persson, J. K., Svensson, M., and Aldskogius, H., 1998, “Glial Cell Responses, Complement, and Clusterin in the Central Nervous System Following Dorsal Root Transection,” Glia, 23(3), pp. 221–238. [CrossRef]
Streit, W. J., and Kreutzberg, G. W., 1988, “Response of Endogenous Glial Cells to Motor Neuron Degeneration Induced by Toxic Ricin,” J. Comp. Neurol., 268(2), pp. 248–263. [CrossRef]
Kostianovsky, A. M., Maier, L. M., Anderson, R. C., Bruce, J. N., and Anderson, D. E., 2008, “Astrocytic Regulation of Human Monocytic/Microglial Activation,” J. Immunol., 181(8), pp. 5425–5432, available at http://www.jimmunol.org/content/181/8/5425.full.pdf
van Rossum, D., and Hanisch, U. K., 2004, “Microglia,” Metab. Brain Dis., 19(3–4), pp. 393–411. [CrossRef]
Brault, M. S., and Kurt, R. A., 2005, “Impact of Tumor-Derived CCL2 on Macrophage Effector Function,” J. Biomed. Biotechnol., 2005(1), pp. 37–43. [CrossRef]
Lin, E. Y., Nguyen, A. V., Russell, R. G., and Pollard, J. W., 2001, “Colony-Stimulating Factor 1 Promotes Progression of Mammary Tumors to Malignancy,” J. Exp. Med., 193(6), pp. 727–740. [CrossRef]
Mantovani, A., Bottazzi, B., Colotta, F., Sozzani, S., and Ruco, L., 1992, “The Origin and Function of Tumor-Associated Macrophages,” Immunol. Today, 13(7), pp. 265–270. [CrossRef]
Pollard, J. W., 2004, “Tumour-Educated Macrophages Promote Tumour Progression and Metastasis,” Nat. Rev. Cancer, 4(1), pp. 71–78. [CrossRef]
Okada, M., Saio, M., Kito, Y., Ohe, N., Yano, H., Yoshimura, S., Iwama, T., and Takami, T., 2009, “Tumor-Associated Macrophage/Microglia Infiltration in Human Gliomas is Correlated With MCP-3, but not MCP-1,” Int. J. Oncol., 34(6), pp. 1621–1627. [CrossRef]
Lamagna, C., Aurrand-Lions, M., and Imhof, B. A., 2006, “Dual Role of Macrophages in Tumor Growth and Angiogenesis,” J. Leukoc. Biol., 80(4), pp. 705–713. [CrossRef]
Platten, M., Kretz, A., Naumann, U., Aulwurm, S., Egashira, K., Isenmann, S., and Weller, M., 2003, “Monocyte Chemoattractant Protein-1 Increases Microglial Infiltration and Aggressiveness of Gliomas,” Ann. Neurol., 54(3), pp. 388–392. [CrossRef]
Suzuki, Y., Funakoshi, H., Machide, M., Matsumoto, K., and Nakamura, T., 2008, “Regulation of Cell Migration and Cytokine Production by HGF-Like Protein (HLP)/Macrophage Stimulating Protein (MSP) in Primary Microglia,” Biomed. Res., 29(2), pp. 77–84. [CrossRef]
Mantovani, A., Sica, A., and Locati, M., 2005, “Macrophage Polarization Comes of Age,” Immunity, 23(4), pp. 344–346. [CrossRef]
Elgert, K. D., Alleva, D. G., and Mullins, D. W., 1998, “Tumor-Induced Immune Dysfunction: The Macrophage Connection,” J. Leukoc. Biol., 64(3), pp. 275–290, available at http://www.jleukbio.org/content/64/3/275.full.pdf
Hussain, S. F., Yang, D., Suki, D., Aldape, K., Grimm, E., and Heimberger, A. B., 2006, “The Role of Human Glioma-Infiltrating Microglia/Macrophages in Mediating Antitumor Immune Responses,” Neuro-Oncol., 8(3), pp. 261–279. [CrossRef]
Savage, N. D., de Boer, T., Walburg, K. V., Joosten, S. A., van Meijgaarden, K., Geluk, A., and Ottenhoff, T. H., 2008, “Human Anti-Inflammatory Macrophages Induce Foxp3 +GITR+CD25+ Regulatory T Cells, Which Suppress via Membrane-Bound TGFβ-1,” J. Immunol., 181(3), pp. 2220–2226, available at http://www.jimmunol.org/content/181/3/2220.full.pdf
Parney, I. F., Farr-Jones, M. A., Chang, L. J., and Petruk, K. C., 2000, “Human Glioma Immunobiology In Vitro: Implications for Immunogene Therapy,” Neurosurgery, 46(5), pp. 1169–1177. [CrossRef]
Wu, A., Wei, J., Kong, L. Y., Wang, Y., Priebe, W., Qiao, W., Sawaya, R., and Heimberger, A. B., 2010, “Glioma Cancer Stem Cells Induce Immunosuppressive Macrophages/Microglia,” Neuro-Oncol., 12(11), pp. 1113–1125. [CrossRef]
Komohara, Y., Ohnishi, K., Kuratsu, J., and Takeya, M., 2008, “Possible Involvement of the M2 Anti-Inflammatory Macrophage Phenotype in Growth of Human Gliomas,” J. Pathol., 216(1), pp. 15–24. [CrossRef]
Ganguly, R., and Puri, I. K., 2007, “Mathematical Model for Chemotherapeutic Drug Efficacy in Arresting Tumour Growth Based on the Cancer Stem Cell Hypothesis,” Cell Prolif., 40(3), pp. 338–354. [CrossRef]
Puri, I. K., and Li, L., 2010, “Mathematical Modeling for the Pathogenesis of Alzheimer's Disease,” PLoS ONE, 5(12), e15176. [CrossRef]
Hanahan, D., 2000, “The Hallmarks of Cancer,” Cell, 100(1), pp. 57–70. [CrossRef]
Ghosh, S., Elankumaran, S., and Puri, I. K., 2011, “Mathematical Model of the Role of Intercellular Signaling on Intercellular Cooperation During Tumorigenesis,” Cell Prolif., 44, pp. 192–203. [CrossRef]
Tanaka, M. L., Debinski, W., and Puri, I. K., 2009, “Hybrid Mathematical Model of Glioma Progression,” Cell Prolif., 42(5), pp. 637–646. [CrossRef]
Cooper, M. D., Tanaka, M. L., and Puri, I. K., 2010, “Coupled Mathematical Model of Tumorigenesis and Angiogenesis in Vascular Tumours,” Cell Prolif., 43(6), pp. 542–552. [CrossRef]
Anderson, A. R. A., and Quaranta, V., 2008, “Integrative Mathematical Oncology,” Nat. Rev. Cancer, 8(3), pp. 227–234. [CrossRef]
Byrne, H. M., 2003, “Modelling Avascular Tumour Growth,” Cancer Modelling and Simulation, L.Preziosi, ed., Chapman and Hall, London, pp. 75–120.
Byrne, H., and Preziosi, L., 2003, “Modelling Solid Tumour Growth Using the Theory of Mixtures,” Math. Med. Biol., 20(4), pp. 341–366. [CrossRef]
Wichmann, H. E., and Loeffler, M., 1985, Mathematical Modeling of Cell Proliferation: Stem cell Regulation in Hemopoiesis, CRC Press, Boca Raton, FL.
Aggarwal, B. B., and Gehlot, P., 2009, “Inflammation and Cancer: How Friendly is the Relationship for Cancer Patients?,” Curr. Opin. Pharmacol., 9(4), pp. 351–369. [CrossRef]
Aggarwal, B. B., Shishodia, S., Sandur, S. K., Pandey, M. K., and Sethi, G., 2006, “Inflammation and Cancer: How Hot is the Link?,” Biochem. Pharmacol., 72(11), pp. 1605–1621. [CrossRef]
Virrey, J. J., Dong, D., Stiles, C., Patterson, J. B., Pen, L., Ni, M., Schonthal, A. H., Chen, T. C., Hofman, F. M., and Lee, A. S., 2008, “Stress Chaperone GRP78/BiP Confers Chemoresistance to Tumor-Associated Endothelial Cells,” Mol. Cancer Res., 6(8), pp. 1268–1275. [CrossRef]


Grahic Jump Location
Fig. 1

Schematic of the cellular network controlling glial stem cell (Gsc) proliferation that result by considering the mechanism of cancer. Positive as well as negative feedbacks connecting Gsc and other cells in the microenvironment are depicted. The weights associated with the molecular signaling pathways 1–9 are included in Table 1. Arrows “→” imply positive influences whereas the symbol ⊥ denotes inhibition.

Grahic Jump Location
Fig. 2

These images from experiments by our group show that GBM cells (U87MG) differentiate in the presence of serum and express (a) the embryonic stem cell marker nestin (light contrast), (b) the neuronal differentiation marker β Tubulin III (light), and (c) the glial fibrillary acidic protein (GFAP) (light). When they are grown in the absence of serum in stem cell medium as neurospheres, they enrich for (d) nestin (light) but lose the expression of (e) β tubulin III and (f) GFAP. This shows how the fate of GSCs is driven towards stemness in a stem cell microenvironment, i.e., how the TME drives this fate.

Grahic Jump Location
Fig. 4

Variations in the M2 populations over 9 months when the values of α3 and α4 are varied, i.e., α3,4 = 10−1× (lowermost), 1× (middle, baseline), and 10× (top) of their values reported in Table 1. As α3,4 increase, the population of proinflammatory M2 microglia decreases. These macrophages drive inflammation by directly and indirectly (through Th1 lineage T cells) inhibiting the influence of NK cells and thus enhance tumor progression.

Grahic Jump Location
Fig. 5

Variation in the Gsc population over 9 months as a result of decreasing αp to a tenth of its base value or when it is doubled, i.e., αp = 10−1× (lowermost, baseline), 1× (middle), and 2× (top) of the value reported in Table 1. As αp increases, so does Gsc and hence tumor progression.

Grahic Jump Location
Fig. 6

Variation in the Nk population over 9 months as a result of decreasing α6 to a tenth of its base value or when it is halved, i.e., α6 = 10−1× (top, baseline), 0.5× (middle), and 1× (lowermost) of the value reported in Table 1. As α6 increases, the Nk population falls.

Grahic Jump Location
Fig. 3

Variations in the Gsc populations over 9 months when the values of α9 are varied, i.e., αp = 10−1× (top), 1× (middle, baseline), and 10× (lowermost) of the value reported in Table 1. As α9 increases, the glial stem cell population that drives tumor progression decreases.



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