Glioblastoma Multiforme: A Look Inside Its Heterogeneous Nature

Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM), the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape.

[1]  M. Greaves.  Cancer stem cells: back to Darwin? , 2010, Seminars in cancer biology.

[2]  R. Scienza,et al.  Intratumoral Hypoxic Gradient Drives Stem Cells Distribution and MGMT Expression in Glioblastoma , 2010, Stem cells.

[3]  S. Kobayashi,et al.  Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. , 2009, Clinical lung cancer.

[4]  Rebecca A Betensky,et al.  Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. , 2007, Clinical cancer research : an official journal of the American Association for Cancer Research.

[5]  Y. Iwasa,et al.  Evolutionary Dynamics of Intratumor Heterogeneity , 2011, PloS one.

[6]  K. Polyak,et al.  Tumor heterogeneity: causes and consequences. , 2010, Biochimica et biophysica acta.

[7]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.

[8]  P. Black,et al.  αvβ3 and αvβ5 Integrin Expression in Glioma Periphery , 2001 .

[9]  Sean J Morrison,et al.  Cancer stem cells: impact, heterogeneity, and uncertainty. , 2012, Cancer cell.

[10]  V. P. Collins,et al.  Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics , 2013, Proceedings of the National Academy of Sciences.

[11]  A. Børresen-Dale,et al.  The Life History of 21 Breast Cancers , 2012, Cell.

[12]  A. Órfão,et al.  Intratumoral patterns of clonal evolution in gliomas , 2010, neurogenetics.

[13]  Yoshitaka Narita,et al.  Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. , 2010, Genes & development.

[14]  L. Chin,et al.  Targeting EGFR Induced Oxidative Stress by PARP1 Inhibition in Glioblastoma Therapy , 2010, PloS one.

[15]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[16]  J. Moringlane,et al.  Evidence of focal genetic microheterogeneity in glioblastoma multiforme by area-specific CGH on microdissected tumor cells. , 1999, Journal of neuropathology and experimental neurology.

[17]  Mary R. Myerscough,et al.  Clonal diversity in carcinomas: its implications for tumour progression and the contribution made to it by epithelial-mesenchymal transitions , 2007, Clinical & Experimental Metastasis.

[18]  Stephen Yip,et al.  MSH6 Mutations Arise in Glioblastomas during Temozolomide Therapy and Mediate Temozolomide Resistance , 2009, Clinical Cancer Research.

[19]  S. Vandenberg,et al.  EGFRvIII promotes glioma angiogenesis and growth through the NF-κB, interleukin-8 pathway , 2012, Oncogene.

[20]  W. Cavenee,et al.  Heterogeneity maintenance in glioblastoma: a social network. , 2011, Cancer research.

[21]  K. Sasaki,et al.  Intratumoral cytogenetic heterogeneity detected by comparative genomic hybridization and laser scanning cytometry in human gliomas. , 1998, Cancer research.

[22]  T. Suda,et al.  Role for Angiogenesis Expression of Angiopoietin-2 in Human Glioma Cells and Its Updated Version , 2001 .

[23]  Charles Swanton,et al.  Intratumor Heterogeneity: Seeing the Wood for the Trees , 2012, Science Translational Medicine.

[24]  D. Bigner,et al.  Demonstration of complex antigenic heterogeneity in a human glioma cell line and eight derived clones by specific monoclonal antibodies. , 1983, Cancer research.

[25]  J. Troge,et al.  Tumour evolution inferred by single-cell sequencing , 2011, Nature.

[26]  P. Nowell.  The clonal evolution of tumor cell populations. , 1976, Science.

[27]  Barbara S. Paugh,et al.  Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  R. Hill.  Identifying cancer stem cells in solid tumors: case not proven. , 2006, Cancer research.

[29]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

[30]  M. Adams,et al.  Characterizing Mutational Heterogeneity in a Glioblastoma Patient with Double Recurrence , 2012, PloS one.

[31]  Debyani Chakravarty,et al.  Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response , 2012, Proceedings of the National Academy of Sciences.

[32]  J. Huse,et al.  Genetically Engineered Mouse Models of Brain Cancer and the Promise of Preclinical Testing , 2008, Brain pathology.

[33]  H. Wiley,et al.  The Enhanced Tumorigenic Activity of a Mutant Epidermal Growth Factor Receptor Common in Human Cancers Is Mediated by Threshold Levels of Constitutive Tyrosine Phosphorylation and Unattenuated Signaling* , 1997, The Journal of Biological Chemistry.

[34]  L. Chin,et al.  Malignant astrocytic glioma: genetics, biology, and paths to treatment. , 2007, Genes & development.

[35]  R. Henkelman,et al.  Identification of human brain tumour initiating cells , 2004, Nature.

[36]  S. Al-Sarraj,et al.  Receptor tyrosine kinase genes amplified in glioblastoma exhibit a mutual exclusivity in variable proportions reflective of individual tumor heterogeneity. , 2012, Cancer research.

[37]  W. Cavenee,et al.  Immunohistochemical analysis of the mutant epidermal growth factor, ΔEGFR, in glioblastoma , 2006, Brain Tumor Pathology.

[38]  Erwin G. Van Meir,et al.  Cells with TP53 mutations in low grade astrocytic tumors evolve clonally to malignancy and are an unfavorable prognostic factor , 1999, Oncogene.

[39]  W. Shapiro,et al.  Isolation, karyotype, and clonal growth of heterogeneous subpopulations of human malignant gliomas. , 1981, Cancer research.

[40]  S. Morrison,et al.  Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. , 2010, Cancer cell.

[41]  M. Shen,et al.  The roots of cancer: stem cells and the basis for tumor heterogeneity. , 2013, Bioessays.

[42]  Franziska Michor,et al.  Intratumor Heterogeneity in Evolutionary Models of Tumor Progression , 2011, Genetics.

[43]  J. Herman,et al.  Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  Rebecca A Betensky,et al.  Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. , 2011, Cancer cell.

[45]  Catherine L Nutt,et al.  Selection pressures of TP53 mutation and microenvironmental location influence epidermal growth factor receptor gene amplification in human glioblastomas. , 2003, Cancer research.

[46]  Hong Wu,et al.  A microfluidic platform for systems pathology: multiparameter single-cell signaling measurements of clinical brain tumor specimens. , 2010, Cancer research.

[47]  Kikuya Kato,et al.  Intratumor heterogeneity of epidermal growth factor receptor mutations in lung cancer and its correlation to the response to gefitinib , 2008, Cancer science.

[48]  J. Baselga,et al.  TGF-β Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma. , 2010, Cancer cell.

[49]  D. Haussler,et al.  The Somatic Genomic Landscape of Glioblastoma , 2013, Cell.

[50]  P. Benos,et al.  Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3 , 2013, Proceedings of the National Academy of Sciences.

[51]  B. Burguera,et al.  Quantitative analysis of matrix metalloproteinase-2 mRNA expression in central and peripheral regions of gliomas , 2011, Brain Tumor Pathology.

[52]  P. Sorger,et al.  Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis , 2009, Nature.

[53]  E. Fee,et al.  Rudolf Carl Virchow: medical scientist, social reformer, role model. , 2006, American journal of public health.

[54]  Thomas D. Wu,et al.  Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. , 2006, Cancer cell.