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Modulation of the expression of extracellular matrix components in glioblastoma and neuroblastoma-derived stem cells

A. R. Rama1*, Oliver JA1*, Madeddu R2, Farace C2, Jiménez-Luna C1, G. Perazzoli1, L. Cabeza1, I. Zafra1, M.C. Leiva1, J. Jiménez1, R. Hernandez1, Prados J1, Melguizo C1. 1Institute of Biopathology and Regenerative Medicine (IBIMER), Faculty of Medicine, University of Granada. 2Department of Biomedical Science, Faculty of Medicine, University of Sassary.

Summary: Cancer Stem Cells (CSC) are one of the causes of tumor progression in Glioblastoma (GBM) and Neuroblastoma (NB). The study of tumor microenvironment (TME) has been of special interest as it determines the transition from mesenchymal tissue to epithelial and vice versa. In this field, the most analyzed elements are the extracellular matrix components (EMC). The EMC perform several functions in cellular remodeling and homeostasis; the Decorin (DCN) and the Lumican (LUM) being the most prominent ones. These have been related to the cellular differentiation of stem cells, the migration and invasion of cancer cells, as well as to chemoresistance. Preliminary studies have shown us that DCN and LUM may have implications in the formation of 3D neurospheres in GBM and NB, a model widely accepted of CSC. In our study we subjected the lines SK-N-SH and SF-268 of GBM and NB to a CSC enrichment culture and we analyzed the ARNn expression by means of qPCR, and proteic, by means of Western-Blot, for DCN as well as NB. In addition we analyzed the invasivity by means of soft agar and the resistance to temozolomide (TMZ) by means of MTT. Our results showed: 1. Significative increase in the CSC at ARNm level as well as proteic of DCN and LUM, 2. Cell growth exclusive of the CSC in soft agar and 3. Significative resistance to TMZ only at the highest doses. Thus, we proved the relevance of the EMC in the formation of the CSC in GBM and NB and the possible implications in the chemoresistance before high doses of TMZ. We can conclude that the quiescence related to the EMC may be one of the key points of the chemoresistance and invasivity of the CSC and knowing this phenomenon better could allow the design of new therapies that improve the prognosis.

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