Molecular Mechanisms Governing the Stem Cell’s Fate in Brain Cancer: Factors of Stemness and Quiescence

Gulaia, Valeriia; Kumeiko, Vadim; Shved, Nikita A.; Cicinskas, Eduardas; Rybtsov, Stanislav; Ruzov, Alexey; Kagansky, Alexander

doi:10.3389/fncel.2018.00388

Cited by 33 publications

(30 citation statements)

References 186 publications

(199 reference statements)

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“…We also further characterized the CSCs by comparing different cell cycle stages of adherent cells with secondary spheres as a measure of cellular quiescence, a signature of CSCs. It is well established that CSCs are maintained in a poised, quiescent state characterized by slow cell cycling that confers them resistance to cytotoxic drugs (19,20). Supporting our hypothesis, secondary spheres showed significantly higher percentages of G 0 -G 1 population than the adherent cells ( fig.…”

Section: Smar1 Expression Is Attenuated In Cscssupporting

confidence: 82%

SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin

et al. 2020

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The high abundance of drug efflux pumps in cancer stem cells (CSCs) contributes to chemotherapy resistance. The transcriptional regulator SMAR1 suppresses CSC expansion in colorectal cancer, and increased abundance of SMAR1 is associated with better prognosis. Here, we found in breast tumors that the expression of SMAR1 was decreased in CSCs through the cooperative interaction of the pluripotency factors Oct4 and Sox2 with the histone deacetylase HDAC1. Overexpressing SMAR1 sensitized CSCs to chemotherapy through SMAR1-dependent recruitment of HDAC2 to the promoter of the gene encoding the drug efflux pump ABCG2. Treating cultured CSCs or 4T1 tumor-bearing mice with the nonsteroidal anti-inflammatory drug aspirin restored SMAR1 expression and ABCG2 repression and enhanced tumor sensitivity to doxorubicin. Our findings reveal transcriptional mechanisms regulating SMAR1 that also regulate cancer stemness and chemoresistance and suggest that, by restoring SMAR1 expression, aspirin might enhance chemotherapeutic efficacy in patients with stem-like tumors.

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Section: Smar1 Expression Is Attenuated In Cscssupporting

confidence: 82%

SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin

et al. 2020

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“…In contrast, FBS reduced the expression of stem markers (Oct3/4, SOX2, Nestin, Musashi-1, PDGFRα, Notch2, Nanog, STAT3, c-Myc and CD49f) in GSLCs. These results are consistent with retinoic-acid induced changes in differentiation and stem markers in GSLCs [ 13 ]. Among the 18 stem cell markers we tested, significant differences between GSLC and differentiated cells were observed in the expressions of Oct3/4, SOX2, Nestin, PDGFRα, Nanog and STAT3 in both no.…”

Section: Discussionsupporting

confidence: 88%

“…A previous study that investigated the impact of CD98 on stemness, proliferation and cell survival in acute myelogenous leukemia showed that loss of CD98 triggers apoptosis and depletion of acute myelogenous leukemia stem cells and CD98-mediated adhesion to vasculature promotes leukemia stem cell maintenance [ 28 ]. The vascular niche is one of the important GSCs niches that sustain stemness and resistance to chemoradiation therapy [ 12 , 13 ]. We speculate that GSCs with CD98 expression that reside in the vascular niche can take up BPA through LAT1 in a heterodimeric complex with CD98 on the plasma membrane and can be targeted by BNCT as our data show.…”

Section: Discussionmentioning

confidence: 99%

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Glioma Stem-Like Cells Can Be Targeted in Boron Neutron Capture Therapy with Boronophenylalanine

Kondo

Hara

Nakada

et al. 2020

Cancers

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As glioma stem cells are chemo- and radio-resistant, they could be the origins of recurrent malignant glioma. Boron neutron capture therapy (BNCT) is a tumor-selective particle radiation therapy. 10B(n,α)7Li capture reaction produces alpha particles whose short paths (5–9 µm) lead to selective killing of tumor cells. P-boronophenylalanine (BPA) is a chemical compound used in clinical trials for BNCT. Here, we used mass cytometry (Cytof) to investigate whether glioma stem-like cells (GSLCs) take up BPA or not. We used GSLCs, and cells differentiated from GSLCs (DCs) by fetal bovine serum. After exposure to BPA for 24 h at 25 ppm in 5% CO2 incubator, we immune-stained them with twenty stem cell markers, anti-Ki-67, anti-BPA and anti-CD98 (heterodimer that forms the large BPA transporter) antibodies and analyzed them with Cytof. The percentage of BPA+ or CD98+ cells with stem cell markers (Oct3/4, Nestin, SOX2, Musashi-1, PDGFRα, Notch2, Nanog, STAT3 and C-myc, among others) was 2–4 times larger among GSLCs than among DCs. Analyses of in vivo orthotopic tumor also indicated that 100% of SOX2+ or Nestin+ GSLCs were BPA+, whereas only 36.9% of glial fibrillary acidic protein (GFAP)+ DCs were BPA+. Therefore, GSLCs may take up BPA and could be targeted by BNCT.

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“…[7][22][23] Some have interpreted glioma recurrence as evidence that quiescent "glioma stem cells" persist in a quiescent state after chemoradiation prior to ultimately re-initiating tumor recurrence. [24] Other evidence in glioma and other tumors supports induction of a senescent-like state, after cytotoxic therapy. If indeed quiescent glioma stem cells and senescent cells both exist in glioma after standard therapy, do they both actively coexist in parallel at all points following therapy, or could initially senescent cells escape senescence to revitalize the tumor as quiescent stem cells?…”

Section: Discussionmentioning

confidence: 98%

Selective Vulnerability of Senescent Glioblastoma Cells to Bcl-XL Inhibition

Rahman

Olson

Mansour

et al. 2020

Preprint

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Despite decades of research and numerous basic science advances, there have only marginal gains in improving glioblastoma multiforme survival. Therefore, new ideas and approaches for treating this aggressive disease are essential to drive progress forward. Conventional therapies, such as radiation and Temozolomide (TMZ), function to cause oxidative stress and DNA damage yielding a senescent-like state of replicative arrest in susceptible cells. However, increasing evidence demonstrates malignant cells can escape senescence leading to tumor recurrence. Ablation of non-replicating senescent tumor cells after radiation and chemotherapy may be an avenue to reduce the rates of tumor recurrence. Senolytic agents have been developed that selectively target senescent cells, but it remains unknown whether senolytics might be utilized against senescent-like glioma cells. We employed radiation or TMZ to induce a functionally senescent state in human glioblastoma cells. Viable cells that survive these treatments were then utilized to screen candidate senolytic drugs, to identify those selectively effective at ablating senescent-like cells over naïve non-tumor and proliferative cells. Among 10 candidate senolytic drugs evaluated, only Bcl-XL inhibitors demonstrated reproducible senolytic activity in radiated or TMZ-treated glioma across the majority of GBM cell lines evaluated. Conversely, Bcl-2 inhibitors and other established senolytic drugs failed to show any consistent senolytic activity. In agreement with these data, Bcl-XL knockdown selectively reduced the viability of senescent-like GBM cells, whereas knockdown of Bcl-2 or Bcl-W yielded no senolytic effect. These findings demonstrate the potential to harness radiation-induced biology to ablate latent surviving cells and highlight Bcl-XL dependency as a potential vulnerability of surviving GBM cells after exposure to radiation or TMZ. SA--Gal stainingSenescence-associated β-galactosidase staining Kit (Cell Signaling Technology #9860) was used as an indicator of relative senescence after radiation as per the manufacturer's directions. Briefly, cells were fixed for 10 min in β-galactosidase fixative Solution (10% 100x Fixative

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Molecular Mechanisms Governing the Stem Cell’s Fate in Brain Cancer: Factors of Stemness and Quiescence

Cited by 33 publications

References 186 publications

SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin

SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin

Glioma Stem-Like Cells Can Be Targeted in Boron Neutron Capture Therapy with Boronophenylalanine

Selective Vulnerability of Senescent Glioblastoma Cells to Bcl-XL Inhibition

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