Cancer Stem Cells with Overexpression of Neuronal Markers Enhance Chemoresistance and Invasion in Retinoblastoma.
ATP Binding Cassette Transporter, Subfamily B
/ metabolism
Antineoplastic Agents, Phytogenic
/ pharmacology
Apoptosis
/ drug effects
Carboplatin
/ pharmacology
Cell Line, Tumor
Drug Resistance, Neoplasm
/ drug effects
Etoposide
/ pharmacology
Humans
Multidrug Resistance-Associated Proteins
/ metabolism
Nanog Homeobox Protein
/ metabolism
Neoplasm Invasiveness
Neoplastic Stem Cells
/ metabolism
Neural Stem Cells
/ metabolism
Octamer Transcription Factor-3
Retinal Neoplasms
/ drug therapy
Retinoblastoma
/ drug therapy
SOXB1 Transcription Factors
/ metabolism
Signal Transduction
ABC transporter
Chemoresistance
cancer stem cell
histopathology
neuronal stem cell markers
retinoblastoma
Journal
Current cancer drug targets
ISSN: 1873-5576
Titre abrégé: Curr Cancer Drug Targets
Pays: Netherlands
ID NLM: 101094211
Informations de publication
Date de publication:
2020
2020
Historique:
received:
01
01
2020
revised:
05
03
2020
accepted:
17
03
2020
pubmed:
5
5
2020
medline:
18
9
2021
entrez:
5
5
2020
Statut:
ppublish
Résumé
Retinoblastoma is a sight and life-threatening embryonal tumor in children. Though chemotherapy is the main mode of therapy, evolving resistance remains a major obstacle in treatment success. The presence of cancer stem cells (CSC) is frequently reported to be responsible for chemoresistance in multiple tumors. Our study aims to identify the molecular factors that facilitate the chemoresistance through cancer stem cells in retinoblastoma. We developed etoposide and carboplatin resistant retinoblastoma (Y79) cell lines by stepwise drug increment treatment, validated with MTT and TUNEL assays. Colony forming and invasive ability were studied by soft-agar colony forming and transwell assays, respectively. Similar analysis in non-responsive retinoblastoma tumors were carried out by histopathology. Finally, expression of CSC/neuronal markers and ABC transporters were examined by quantitative PCR and protein expression of neuronal stem cell markers was confirmed by Western blot. Larger colony size of resistant cells in soft-agar assay provided evidence for increased selfrenewability. Histopathology in non-responsive tumors showed poorly differentiated cells predominantly. Besides, both resistant cell lines and non-responsive tumors showed increased invasion with higher expression of neuronal stem cell markers - SOX2, NANOG, OCT4 and ABC transporters - ABCB1 and ABCC3. Increased self-renewal ability and invasion along with overexpression of stemness markers in resistant cells and tumors provide evidence for stemness driving chemoresistance and invasion in retinoblastoma. We have demonstrated Neuronal stem cell/CSC markers that facilitate the maintenance of cancer stem cells. Developing therapies targeting these factors will help in overcoming resistance and improving retinoblastoma treatment.
Sections du résumé
BACKGROUND
Retinoblastoma is a sight and life-threatening embryonal tumor in children. Though chemotherapy is the main mode of therapy, evolving resistance remains a major obstacle in treatment success. The presence of cancer stem cells (CSC) is frequently reported to be responsible for chemoresistance in multiple tumors.
OBJECTIVE
Our study aims to identify the molecular factors that facilitate the chemoresistance through cancer stem cells in retinoblastoma.
METHODS
We developed etoposide and carboplatin resistant retinoblastoma (Y79) cell lines by stepwise drug increment treatment, validated with MTT and TUNEL assays. Colony forming and invasive ability were studied by soft-agar colony forming and transwell assays, respectively. Similar analysis in non-responsive retinoblastoma tumors were carried out by histopathology. Finally, expression of CSC/neuronal markers and ABC transporters were examined by quantitative PCR and protein expression of neuronal stem cell markers was confirmed by Western blot.
RESULTS
Larger colony size of resistant cells in soft-agar assay provided evidence for increased selfrenewability. Histopathology in non-responsive tumors showed poorly differentiated cells predominantly. Besides, both resistant cell lines and non-responsive tumors showed increased invasion with higher expression of neuronal stem cell markers - SOX2, NANOG, OCT4 and ABC transporters - ABCB1 and ABCC3. Increased self-renewal ability and invasion along with overexpression of stemness markers in resistant cells and tumors provide evidence for stemness driving chemoresistance and invasion in retinoblastoma.
CONCLUSION
We have demonstrated Neuronal stem cell/CSC markers that facilitate the maintenance of cancer stem cells. Developing therapies targeting these factors will help in overcoming resistance and improving retinoblastoma treatment.
Identifiants
pubmed: 32364077
pii: CCDT-EPUB-106334
doi: 10.2174/1568009620666200504112711
doi:
Substances chimiques
ABCB1 protein, human
0
ATP Binding Cassette Transporter, Subfamily B
0
Antineoplastic Agents, Phytogenic
0
Multidrug Resistance-Associated Proteins
0
NANOG protein, human
0
Nanog Homeobox Protein
0
Octamer Transcription Factor-3
0
POU5F1 protein, human
0
SOX2 protein, human
0
SOXB1 Transcription Factors
0
multidrug resistance-associated protein 3
1YV0492L5Z
Etoposide
6PLQ3CP4P3
Carboplatin
BG3F62OND5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
710-719Informations de copyright
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.