Cancer stem cells in neuroblastoma therapy resistance

Aravindan, Natarajan; Jain, Drishti; Somasundaram, Dinesh Babu; Herman, Terence S.; Aravindan, Sheeja

doi:10.20517/cdr.2019.72

Cited by 26 publications

(27 citation statements)

References 191 publications

(256 reference statements)

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“…Particularly, miR‐34 and let‐7 regulate prosurvival pathways used by tumor cells to evade the cytotoxic effects of anticancer agents and their replenishment can sensitize cancer cells to chemotherapy and/or radiotherapy, [ 68 ] holding potential benefits in the treatment of drug‐resistant tumors. [ 69 ] Indeed, miR‐34a targets crucial players of therapy resistance, including MYCN, which is known to be a mediator of drug resistance or sensitivity in NB. [ 55 ] The sensitivity to cisplatin, used also for NB treatment, is modulated via reactivation of p53/miR‐34a/MYCN axis [ 70 ] in NSCLC cells, suggesting the involvement of the same pathway in NB (Figures S9 and S10, Supporting Information).…”

Section: Discussionmentioning

confidence: 99%

Combined Replenishment of miR‐34a and let‐7b by Targeted Nanoparticles Inhibits Tumor Growth in Neuroblastoma Preclinical Models

Paolo

Pastorino

Brignole

et al. 2020

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Neuroblastoma (NB) tumor substantially contributes to childhood cancer mortality. The design of novel drugs targeted to specific molecular alterations becomes mandatory, especially for high-risk patients burdened by chemoresistant relapse. The dysregulated expression of MYCN, ALK, and LIN28B and the diminished levels of miR-34a and let-7b are oncogenic in NB. Due to the ability of miRNA-mimics to recover the tumor suppression functions of miRNAs underexpressed into cancer cells, safe and efficient nanocarriers selectively targeted to NB cells and tested in clinically relevant mouse models are developed. The technology exploits the nucleic acids negative charges to build coated-cationic liposomes, then functionalized with antibodies against GD 2 receptor. The replenishment of miR-34a and let-7b by NB-targeted nanoparticles, individually and more powerfully in combination, significantly reduces cell division, proliferation, neoangiogenesis, tumor growth and burden, and induces apoptosis in orthotopic xenografts and improves mice survival in pseudometastatic models. These functional effects highlight a cooperative down-modulation of MYCN and its down-stream targets, ALK and LIN28B, exerted by miR-34a and let-7b that reactivate regulatory networks leading to a favorable therapeutic response. These findings demonstrate a promising therapeutic efficacy of miR-34a and let-7b combined replacement and support its clinical application as adjuvant therapy for highrisk NB patients.

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Section: Discussionmentioning

confidence: 99%

Combined Replenishment of miR‐34a and let‐7b by Targeted Nanoparticles Inhibits Tumor Growth in Neuroblastoma Preclinical Models

Paolo

Pastorino

Brignole

et al. 2020

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“…Additionally, NB CSCs overexpressing CD133 and SOX2 are reported to be therapy resistant. A histone deacetylase drug Vorinostat achieves improvement in chemo-sensitivity of NB, inhibition of NB CSC's tumor-formation ability and reduction in invasive capacity [27]. Therefore, exosomal SOX2 sequences derived from SH-SY5Y and CD133 + GBM were analyzed against NSC derived exosomal SOX2 sequences as control, using the Basic Local Alignment Tool (BLAST).…”

Section: Resultsmentioning

confidence: 99%

Differential sequences and single nucleotide polymorphism of exosomal SOX2 DNA in cancer

Vaidya

Sugaya

2020

PLoS ONE

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Glioblastoma multiforme (GBM) is the most common form of brain cancer, with an average life expectancy of fewer than two years post-diagnosis. We have previously reported that cancer cell originated exosomes, including GBM, have NANOG and NANOGP8 DNA associated with them. The exosomal NANOG DNA has certain differences as compared to its normal counterpart that are of immense importance as a potential cancer biomarker. NANOG has been demonstrated to play an essential role in the maintenance of embryonic stem cells, and its pseudogene, NANOGP8, is suggested to promote the cancer stem cell phenotype. Similarly, SOX2 is another stemness gene highly expressed in cancer stem cells with an intimate involvement in GBM progression and metastasis as well as promotion of tumorigenicity in Neuroblastoma (NB). Since exosomes are critical in intercellular communication with a role in dissipating hallmark biomolecules responsible for cancer, we conducted a detailed analysis of the association of the SOX2 gene with exosomes whose sequence modulations with further research and appropriate sample size can help to identify diagnostic markers for cancer. We have detected SOX2 DNA associated with exosomes and have identified some of the SNPs and nucleotide variations in the sequences from a GBM and SH-SY5Y sample. Although a further systematic investigation of exosomal DNA from GBM and NB patient's blood is needed, finding of SOX2 DNA in exosomes in the current study may have value in clinical research. SOX2 is known to be misregulated in cancer cells by changes in miRNA function, such as SNPs in the binding sites. Our finding of cancer-specific SNPs in exosomal SOX2 DNA sequence may reflect those changes in the cancer stem cells as well as cancer cells. A series of our study on embryonic stem cell gene analysis in exosomal DNA may lead to a minimally invasive exosome-based diagnosis, and give us a key in understanding the mechanisms of cancer formation, progression, and metastasis.

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“…While lower doses of RA resulted in decreased proliferation of COA6 CD133-enriched cells, the ability of this CD133-enriched subpopulation to proliferate in the presence of high doses of RA, for example, might explain the minimal effect seen on the proliferation of bulk COA6 cells treated with RA. Seeing an effect on CD133-depleted but not CD133-enriched subpopulations with RA is where current therapies for neuroblastoma stand [ [65] , [66] , [67] ]. In contrast, treatment with UAB30 decreased proliferation and viability of both CD133-enriched and CD133-depleted cells and effectively targeted the SCLCC subpopulation that showed resistance to RA.…”

Section: Discussionmentioning

confidence: 99%

9-cis-UAB30, a novel rexinoid agonist, decreases tumorigenicity and cancer cell stemness of human neuroblastoma patient-derived xenografts

Marayati

Bownes

Stafman

et al. 2021

Translational Oncology

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Retinoic acid (RA) therapy has been utilized as maintenance therapy for high-risk neuroblastoma, but over half of patients treated with RA relapse. Neuroblastoma stem cell-like cancer cells (SCLCCs) are a subpopulation of cells characterized by the expression of the cell surface marker CD133 and are hypothesized to contribute to drug resistance and disease relapse. A novel rexinoid compound, 9- cis -UAB30 (UAB30), was developed having the same anti-tumor effects as RA but a more favorable toxicity profile. In the current study, we investigated the efficacy of UAB30 in neuroblastoma patient-derived xenografts (PDX). Two PDXs, COA3 and COA6, were utilized and alterations in the malignant phenotype were assessed following treatment with RA or UAB30. UAB30 significantly decreased proliferation, viability, and motility of both PDXs. UAB30 induced cell-cycle arrest as demonstrated by the significant increase in percentage of cells in G1 (COA6: 33.7 ± 0.7 vs. 43.3 ± 0.7%, control vs. UAB30) and decrease in percentage of cells in S phase (COA6: 44.7 ± 1.2 vs. 38.6 ± 1%, control vs. UAB30). UAB30 led to differentiation of PDX cells, as evidenced by the increase in neurite outgrowth and mRNA abundance of differentiation markers. CD133 expression was decreased by 40% in COA6 cells after UAB30. The ability to form tumorspheres and mRNA abundance of known stemness markers were also significantly decreased following treatment with UAB30, further indicating decreased cancer cell stemness. These results provide evidence that UAB30 decreased tumorigenicity and cancer cell stemness in neuroblastoma PDXs, warranting further exploration as therapy for high-risk neuroblastoma.

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Cancer stem cells in neuroblastoma therapy resistance

Cited by 26 publications

References 191 publications

Combined Replenishment of miR‐34a and let‐7b by Targeted Nanoparticles Inhibits Tumor Growth in Neuroblastoma Preclinical Models

Combined Replenishment of miR‐34a and let‐7b by Targeted Nanoparticles Inhibits Tumor Growth in Neuroblastoma Preclinical Models

Differential sequences and single nucleotide polymorphism of exosomal SOX2 DNA in cancer

9-cis-UAB30, a novel rexinoid agonist, decreases tumorigenicity and cancer cell stemness of human neuroblastoma patient-derived xenografts

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