title: Microenvironmental Modulation of Decorin and Lumican in Temozolomide-Resistant Glioblastoma and Neuroblastoma Cancer Stem-Like Cells.
abstract: The presence of cancer stem cells (CSCs) or tumor-initiating cells can lead to cancer recurrence in a permissive cell-microenvironment interplay, promoting invasion in glioblastoma (GBM) and neuroblastoma (NB). Extracellular matrix (ECM) small leucine-rich proteoglycans (SLRPs) play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM) components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs), SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue-specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN) and lumican (LUM) are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM) to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+) CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like) showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC-like from the GBM and NB neurospheres were resistant to temozolomide (TMZ) at concentrations >750 μM. Our results suggest that GBM and NB CSC-like promote the activation of huge quantities of SLRP in response to CSC enrichment, simultaneously acquiring TMZ resistance, cellular heterogeneity, and a quiescent phenotype, suggesting a novel pivotal role for SLRP in drug resistance and cell plasticity of CSC-like, allowing cell survival and ECM/niche modulation potential.
authors.affiliation: Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Farace
authors.affiliation: Institute of Biopathology and Regenerative Medicine (IBIMER), Granada, Spain.
authors.forename: Jaime Antonio
authors.initials: JA
authors.lastname: Oliver
authors.affiliation: Institute of Biopathology and Regenerative Medicine (IBIMER), Granada, Spain; Department of Anatomy and Embryology, University of Granada, Granada, Spain; Biosanitary Institute of Granada (ibs.Granada), SAS-University of Granada, Granada, Spain.
authors.forename: Consolacion
authors.initials: C
authors.lastname: Melguizo
authors.affiliation: Institute of Biopathology and Regenerative Medicine (IBIMER), Granada, Spain; Biosanitary Institute of Granada (ibs.Granada), SAS-University of Granada, Granada, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Alvarez
authors.affiliation: Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Bandiera
authors.affiliation: Institute of Biopathology and Regenerative Medicine (IBIMER), Granada, Spain; Biosanitary Institute of Granada (ibs.Granada), SAS-University of Granada, Granada, Spain; Department of Health Science, University of Jaén, Jaén, Spain.
authors.forename: Ana Rosa
authors.initials: AR
authors.lastname: Rama
authors.affiliation: Research Center "The Great Senescence", University of Catania, Catania, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Malaguarnera
authors.affiliation: Institute of Biopathology and Regenerative Medicine (IBIMER), Granada, Spain; Biosanitary Institute of Granada (ibs.Granada), SAS-University of Granada, Granada, Spain; Department of Health Science, University of Jaén, Jaén, Spain.
authors.forename: Raul
authors.initials: R
authors.lastname: Ortiz
authors.affiliation: Department of Biomedical Sciences, University of Sassari, Sassari, Italy; National Institute of Biostructures and Biosystem (INBB), Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Madeddu
authors.affiliation: Institute of Biopathology and Regenerative Medicine (IBIMER), Granada, Spain; Department of Anatomy and Embryology, University of Granada, Granada, Spain; Biosanitary Institute of Granada (ibs.Granada), SAS-University of Granada, Granada, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Prados
mesh_terms: D001932:Brain Neoplasms / Q000473:pathology*; D011508:Chondroitin Sulfate Proteoglycans / Q000502:physiology*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058575:Decorin / Q000502:physiology*; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D007632:Keratan Sulfate / Q000502:physiology*; D000071234:Lumican; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009447:Neuroblastoma / Q000473:pathology*; D000077204:Temozolomide; D059016:Tumor Microenvironment
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D058575:Decorin; C000604306:LUM protein, human; D000071234:Lumican; D003606:Dacarbazine; D007632:Keratan Sulfate; D000077204:Temozolomide