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.
Highlights
Glioblastoma (GBM) and neuroblastoma (NB) are the most common and lethal nervous system malignant cancers in adult and pediatric patients, respectively
Our results suggest that GBM and NB cancer stem cells (CSCs)-like promote the activation of huge quantities of small leucine-rich proteoglycans (SLRPs) 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 extracellular matrix (ECM)/niche modulation potential
Treatment failure in cancer patients has previously been related to cancer stem cell (CSC) subpopulations, which ensure the maintenance of cancer heterogeneity, and these CSC subpopulations are more resistant to selective drugs through multiple concerted steps of selfrenewal and differentiation [7,8,9]
Summary
Glioblastoma (GBM) and neuroblastoma (NB) are the most common and lethal nervous system malignant cancers in adult and pediatric patients, respectively. Temozolomide (TMZ)–an alkylating agent which induces cell death by whole DNA alkylation/methylation in guanine residues–in combination with other drugs or radiotherapy represent a firstline treatment increasing the overall survival (OS) of patients with GBM or NB [3, 4], drug resistance and cancer progression are common. Abundant research suggests that cells stem-like cells are equipped with innate machinery that protects them from radio/chemotherapy [11, 12]. This includes stemrelated mechanisms, such as protective cell niches and changes in the expression of genes involved in the regulation of the cell cycle, DNA repair, drug metabolism, and drug efflux [13]. The drug resistance and cellular invasion potential of CSCs increase at the reversible epithelial-to-mesenchymal phenotypic transition (EMT) [14, 15], which recapitulates the EMT in normal organogenesis and development [16, 17]
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