Abstract
Abstract Background: Although several types of cells in the brain are able to migrate during development or even in adulthood, only cells of high grade malignancies exhibit an invasive phenotype. The present study aims to characterize the differences between infiltrating tumor cells and their cells of origin using a model of genetically-induced glioblastoma-initiating cells (GICs) in the syngeneic mouse adult brain. Methods: Neural stem cells/ multipotent progenitor cells (NSCs/NPCs) were isolated from the subventricular zone of adult C57BL/6 mice with a homozygous deletion of the Ink4a/ARF locus and cultured as neurospheres. GICs were established by overexpression of H-RasV12 in the NSCs/NPCs. Tumor cells were isolated from the tumors formed by orthotopic implantation of the GICs into 6-week-old wild type mice and propagated as tumorspheres (TS). The motility of each type of cells and their response to various chemoattractants was assessed using in vitro migration assays. Their preference for anatomical structures and their ability to infiltrate the surrounding normal brain was analyzed by tracking the cells in cultured coronal brain slices established from stereotactically-implanted mice. Results: In vitro, both tumor cells and NSCs exhibited a similar degree of motility, but consistently varied in their response to a panel of chemoattractants. Compared to NSCs, GICs and TS responded only slightly to single growth factors or cytokines, but showed significant responses to combinations of chemoattractants. The most marked increase in migration was triggered by the supernatant of cultured tumor cells. Supernatants obtained from GICs, TS or human glioma cell lines induced migration to a similar degree. Timelapse microscopy confirmed motility of both normal and tumor cells, with all three groups being able to move both within the cortex and within the striatum, and both along blood vessels and fiber tracts. However, NSCs/NPCs did not leave the injection site as single cells, while GICs and TS entered and infiltrated the normal brain as solitary cells. This pattern of migration was greatly reduced by the administration of epithelial-to-mesenchymal transition (EMT) inhibitors, both in vitro and in vivo. Conclusion: Our results show that tumor invasion is multifactorial, with both autocrine secretion of several factors, as well as a mesenchymal phenotype being key regulators. Moreover, the mesenchymal phenotype in itself is a targetable attribute and should be assessed in patient samples in order to adjust anti-invasive therapy when warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 487. doi:1538-7445.AM2012-487
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