Heterogeneous glioblastoma cell cross-talk promotes phenotype alterations and enhanced drug resistance
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Helena Motaln1, Ana Koren2, Kristina Gruden3, Živa Ramšak3, Christian Schichor4, Tamara T. Lah1,5
1Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
2Laboratory for Clinical Immunology and Molecular Genetics, University Clinic Golnik, Golnik, Slovenia
3Department of Biotechnology and Systems Biology, National Institute of Biology, Ljubljana, Slovenia
4Department of Neurosurgery, Klinikum Großhadern, Ludwig-Maximilians-Universität, Munich, Germany
5Department of Biochemistry, Faculty of Chemistry and Chemical Engineering, University of Ljubljana, Ljubljana, Slovenia
Helena Motaln, e-mail: [email protected]
Keywords: glioblastoma heterogeneity, U87 cells, temozolomide resistance, cellular cross-talk, transcriptomics
Received: April 28, 2015 Accepted: September 16, 2015 Published: October 20, 2015
Glioblastoma multiforme is the most lethal of brain cancer, and it comprises a heterogeneous mixture of functionally distinct cancer cells that affect tumor progression. We examined the U87, U251, and U373 malignant cell lines as in vitro models to determine the impact of cellular cross-talk on their phenotypic alterations in co-cultures. These cells were also studied at the transcriptome level, to define the mechanisms of their observed mutually affected genomic stability, proliferation, invasion and resistance to temozolomide. This is the first direct demonstration of the neural and mesenchymal molecular fingerprints of U87 and U373 cells, respectively. U87-cell conditioned medium lowered the genomic stability of U373 (U251) cells, without affecting cell proliferation. In contrast, upon exposure of U87 cells to U373 (U251) conditioned medium, U87 cells showed increased genomic stability, decreased proliferation rates and increased invasion, due to a plethora of produced cytokines identified in the co-culture media. This cross talk altered the expression 264 genes in U87 cells that are associated with proliferation, inflammation, migration, and adhesion, and 221 genes in U373 cells that are associated with apoptosis, the cell cycle, cell differentiation and migration. Indirect and direct co-culturing of U87 and U373 cells showed mutually opposite effects on temozolomide resistance. In conclusion, definition of transcriptional alterations of distinct glioblastoma cells upon co-culturing provides better understanding of the mechanisms of glioblastoma heterogeneity, which will provide the basis for more informed glioma treatment in the future.
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