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Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

Cancer Stem Cells with Overexpression of Neuronal Markers Enhance Chemoresistance and Invasion in Retinoblastoma

Author(s): Sekaran Balaji, Radhakrishnan Santhi, Usha Kim, Veerappan Muthukkaruppan, Chidambaranathan G. Priya and Ayyasamy Vanniarajan*

Volume 20, Issue 9, 2020

Page: [710 - 719] Pages: 10

DOI: 10.2174/1568009620666200504112711

Price: $65


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.

Keywords: Chemoresistance, ABC transporter, retinoblastoma, histopathology, cancer stem cell, neuronal stem cell markers.

Graphical Abstract
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