Abstract
Human malignant astrocytic tumors are the most common primary brain malignancies. Human gliomas are classified according to the extent of anaplasia or ‘de-differentiation’ appearance. Although this type of histological classification is widely accepted, the extensive heterogeneity of astrocytic tumors has made their pathological classification rather difficult. New genome-scale high throughput technologies for gene expression profiling, such as DNA microarrays, are emerging as new tools to allow a more accurate identification and characterization of different tumor degrees by discovering new specific markers and pathways of each stage. Present work reports interesting results that might be useful to differentiate between tumor grades. Data presented here provides new evidences about the molecular basis underlying different tumor stages. In this sense, we identified key metabolic pathways, crucial for tumor progression, as being differentially regulated in different tumor stages. On the other hand, remarkable findings regarding Notch pathway are reported, as some members of this receptor family were found to be differentially expressed depending on the malignancy degree. Our results clearly point out important molecular differences between different tumor stages and suggest that more studies are needed to understand specific molecular events characteristic of each stage. These types of studies represent a first step to deepen into the tumor physiology, which may potentially help for better and a more precise diagnosis of gliomas.
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Allenspach, E. J., Maillard, I., Aster, J. C., & Pear, W. S. (2002). Notch signaling in cancer. Cancer Biology & Therapy, 1, 466–476.
Al-Shahrour, F., Diaz-Uriarte, R., & Dopazo, J. (2004). FatiGO: A web tool for finding significant associations of Gene Ontology terms with groups of genes. Bioinformatics, 20, 578–580.
Al-Shahrour, F., Diaz-Uriarte, R., & Dopazo, J. (2005). Discovering molecular functions significantly related to phenotypes by combining gene expression data and biological information. Bioinformatics, 21, 2988–2993.
Al-Shahrour, F., Minguez, P., Tarraga, J., Montaner, D., Alloza, E., Vaquerizas, J. M., et al. (2006). BABELOMICS: A systems biology perspective in the functional annotation of genome-scale experiments. Nucleic Acids Research, 34, W472-W476.
Brat, D. J., Bellail, A. C., & Van Meir, E. G. (2005). The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neurooncology, 7, 122–133.
Chang, C. Y., Li, M. C., Liao, S. L., Huang, Y. L., Shen, C. C., & Pan, H. C. (2005). Prognostic and clinical implication of IL-6 expression in gliblastoma multiforme. Journal of Clinical Neuroscience, 12, 930–933.
Charalambous, C., Pen, L. B., Su, Y. S., Milan, J., Chen, T. C., & Hofman, F. M. (2005). Interleukin-8 differentially regulates migration of tumor-associated and normal human brain endothelial cells. Cancer Research, 65, 10347–10354.
Fan, X., Mikolaenko, I., Elhassan, I., Ni, X., Wang, Y., Ball, D., et al. (2004). Notch1 and notch2 have opposite effects on embryonal brain tumor growth. Cancer Research, 64, 7787–7793.
Fuller, G. N., Rhee, C. H., Hess, K. R., Caskey, L. S., Wang, R., Bruner, J. M., et al. (1999). Reactivation of insulin-like growth factor binding protein 2 expression in glioblastoma multiforme: A revelation by parallel gene expression profiling. Cancer Research, 59, 4228–4232.
Gaiano, N., & Fishell, G. (2002). The role of notch in promoting glial and neural stem cell fates. Annual Review of Neuroscience, 25, 471–490.
Godard, S., Getz, G., Delorenzi, M., Farmer, P., Kobayashi, H., Desbaillets, I., et al. (2003). Classification of human astrocytic gliomas on the basis of gene expression: A correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes. Cancer Research, 63, 6613–6625.
Griguer, C. E., Oliva, C. R., & Gillespie, G. Y. (2005). Glucose metabolism heterogeneity in human and mouse malignant glioma cell lines. Journal of Neuro-oncology, 74, 123–133.
Hallahan, A. R., Pritchard, J. I., Hansen, S., Benson, M., Stoeck, J., Hatton, B. A., et al. (2004). The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Research, 64, 7794–7800.
Hoelzinger, D. B., Mariani, L., Weis, J., Woyke, T., Berens, T. J., McDonough, W. S., et al. (2005). Gene expression profile of glioblastoma multiforme invasive phenotype points to new therapeutic targets. Neoplasia, 7, 7–16.
Huang, H., Colella, S., Kurrer, M., Yonekawa, Y., Kleihues, P., & Ohgaki, H. (2000). Gene expression profiling of low-grade diffuse astrocytomas by cDNA arrays. Cancer Research, 60, 6868–6874.
Kato, K., Ogura, T., Kishimoto, A., Minegishi, Y., Nakajima, N., Miyazaki, M., et al. (2002). Critical roles of AMP-activated protein kinase in constitutive tolerance of cancer cells to nutrient deprivation and tumor formation. Oncogene, 21, 6082–6090.
Larson, D. F., & Horak, K. (2006). Macrophage migration inhibitory factor: Controller of systemic inflammation. Critical Care, 10, 138.
Lasky, J. L., & Wu, H. (2005). Notch signaling, brain development, and human disease. Pediatric Research, 57, 104R-109R.
Laurent, N., de Bouard, S., Guillamo, J. S., Christov, C., Zini, R., Jouault, H., et al. (2004). Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo. Molecular Cancer Therapeutics, 3, 129–136.
Liang, Q., Xiong, H., Gao, G., Xiong, K., Wang, X., Zhao, Z., et al. (2005a). Inhibition of basigin expression in glioblastoma cell line via antisense RNA reduces tumor cell invasion and angiogenesis. Cancer Biology & Therapy, 4, 759–762.
Liang, Y., Diehn, M., Watson, N., Bollen, A. W., Aldape, K. D., Nicholas, M. K., et al. (2005b). Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Proceedings of the National Academy of Sciences of the United States of America, 102, 5814–5819.
Mischel, P. S., Cloughesy, T. F., & Nelson, S. F. (2004). DNA-microarray analysis of brain cancer: Molecular classification for therapy. Nature Reviews. Neuroscience, 5, 782–792.
Nagashima, G., Suzuki, R., Asai, J. I., Noda, M., Fujimoto, M., & Fujimoto, T. (2003). Tissue reconstruction process in the area of peri-tumoural oedema caused by glioblastoma-immunohistochemical and graphical analysis using brain obtained at autopsy. Acta Neurochirurgica. Supplementum, 86, 507–511.
Nickoloff, B. J., Osborne, B. A., & Miele, L. (2003). Notch signaling as a therapeutic target in cancer: A new approach to the development of cell fate modifying agents. Oncogene, 22, 6598–6608.
Phillips, H. S., Kharbanda, S., Chen, R., Forrest, W. F., Soriano, R. H., Wu, T. D., et al. (2006). Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell, 9, 157–173.
Radtke, F., & Raj, K. (2003). The role of Notch in tumorigenesis: Oncogene or tumour suppressor? Nature Reviews. Cancer, 3, 756–767.
Rich, J. N., Hans, C., Jones, B., Iversen, E. S., McLendon, R. E., Rasheed, B. K., et al. (2005). Gene expression profiling and genetic markers in glioblastoma survival. Cancer Research, 65, 4051–4058.
Rickman, D. S., Bobek, M. P., Misek, D. E., Kuick, R., Blaivas, M., Kurnit, D. M., et al. (2001). Distinctive molecular profiles of high-grade and low-grade gliomas based on oligonucleotide microarray analysis. Cancer Research, 61, 6885–6891.
Rodriguez-Enriquez, S., Vital-Gonzalez, P. A., Flores-Rodriguez, F. L., Marin-Hernandez, A., Ruiz-Azuara, L., & Moreno-Sanchez, R. (2006). Control of cellular proliferation by modulation of oxidative phosphorylation in human and rodent fast-growing tumor cells. Toxicology and Applied Pharmacology, 215(2), 208–217.
Sallinen, S. L., Sallinen, P. K., Haapasalo, H. K., Helin, H. J., Helen, P. T., Schraml, P., et al. (2000). Identification of differentially expressed genes in human gliomas by DNA microarray and tissue chip techniques. Cancer Research, 60, 6617–6622.
Shai, R. M. (2006). Microarray tools for deciphering complex diseases. Frontiers in Bioscience, 11, 1414–1424.
Solecki, D. J., Liu, X. L., Tomoda, T., Fang, Y., & Hatten, M. E. (2001). Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron, 31, 557–568.
Spataro, V., Norbury, C., & Harris, A. L. (1998). The ubiquitin-proteasome pathway in cancer. British Journal of Cancer, 77, 448–455.
van den Boom, J., Wolter, M., Kuick, R., Misek, D. E., Youkilis, A. S., Wechsler, D. S., et al. (2003). Characterization of gene expression profiles associated with glioma progression using oligonucleotide-based microarray analysis and real-time reverse transcription-polymerase chain reaction. American Journal of Pathology, 163, 1033–1043.
Warburg, O. (1956). On the origin of cancer cells. Science, 123, 309–314.
Zhou, Y. H., Hess, K. R., Liu, L., Linskey, M. E., & Yung, W. K. (2005). Modeling prognosis for patients with malignant astrocytic gliomas: Quantifying the expression of multiple genetic markers and clinical variables. Neurooncology, 7, 485–494.
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Margareto, J., Larrarte, E., Leis, O. et al. Gene expression profiling of human gliomas reveals differences between GBM and LGA related to energy metabolism and notch signaling pathways. J Mol Neurosci 32, 53–63 (2007). https://doi.org/10.1007/s12031-007-0008-5
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DOI: https://doi.org/10.1007/s12031-007-0008-5