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.

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

“…4,5 Understanding which factors promote stemness and treatment resistance of glioma cells is of intense interest in developing new therapies in glioma. A large number of studies over the past decade have established that there is considerable plasticity in glioblastoma cell phenotypes, [6][7][8][9][10][11] that stem cell characteristics can be acquired by non-stem-like cells, 8,9,[12][13][14][15] and that microenvironmental cues such as hypoxia, 16 extracellular matrix proteins, [17][18][19][20][21][22][23][24][25] or growth factors secreted by stromal cells [26][27][28] may be sufficient to induce tumor cell stemness and therapeutic resistance. The role of the microenvironment in regulating tumor stemness is further supported by the finding that stem-like tumor cells are enriched in specific tumor niches; in GBM, primarily the perivascular niche (PVN) and hypoxic compartments.…”

Repaglinide Silences the FOXO3/Lumican Axis and Represses the Associated Metastatic Potential of Neuronal Cancer Cells

“…In colon cancer, LUM triggers cytoskeletal remodeling and elevates the cellular migration capacity [21], and, in bladder cancer, LUM expression promotes cell proliferation and migration [22]. In glioblastoma and NB, LUM expression is associated with the maintenance of a quiescent, drug-resistant, stem-cell-like phenotype [23]. Here, we report for the first time that LUM is a FOXO3-regulated gene involved in the cellular migration of neuronal tumor cells.By screening the Prestwick Chemical Library ® , containing 1120 FDA-approved drugs, we recently identified and characterized carbenoxolone (CBX) as the first FOXO3 inhibitor that overcomes FOXO3-mediated chemoprotection in high-stage NB [24].…”

“…In NB, high LUM expression is associated with lower overall survival ( Figure S2). Of note, Farace et al reported that LUM expression is associated with the maintenance of a quiescent, drug-resistant, stem-cell-like phenotype in NB and glioblastoma cells [23]. However, the impact of LUM on neuronal tumor cell migration has not been investigated to date.…”

Cancer stem cells in neuroblastoma therapy resistance

“…Expressional deregulation of many other proteins are also causally linked to the dedifferentiation of nonstem cancer cells and formation of iCSCs [118,[145][146][147] . For instance, Lamin A/C, the type V intermediate filaments of nuclear lamina, is often reduced or absent in proliferative cells of various tumors [148,149] .…”

“…Further, treatment with Ruxolitinib (JAK2/STAT3 inhibitor) or Trametinib (MEK/ERK1/2 inhibitor) significantly enhanced the response of NB tumors to etoposide [166] . The ECM small leucine-rich proteoglycans (SLRPs), including decorin (DCN) and lumican (LUM), exhibited acquired upmodulation during NB-CSC enrichment [146] . Further, these small leucine rich proteoglycans (SLRP)-positive NB-CSCs were highly resistant to temozolomide (TMZ), demonstrating that (1) CSCs promote huge quantities of DCN and LUM; and (2) increased SLRPs promote acquired TMZ resistance, cellular heterogeneity, and a quiescent phenotype.…”