Resistance to neoadjuvant chemoradiation therapy (CRT) remains a critical barrier to the effective treatment of esophageal adenocarcinoma (EAC). Cancer stem-like cells (CSCs) are a distinct subpopulation of cells implicated in the resistance of tumors to anti-cancer therapy. However, their role in the resistance of EAC to CRT is largely unknown. In a recent study, using a novel in vitro isogenic model of radioresistant EAC, researchers from Trinity College Dublin demonstrate that radioresistant EAC cells have enhanced tumorigenicity in vivo, increased expression of CSC-associated markers and enhanced holoclone forming ability.

Further investigation identified a subpopulation of cells that are characterised by high aldehyde dehydrogenase (ALDH) activity, enhanced radioresistance and decreased expression of miR-17-5p.

OE33 R cells demonstrate enhanced tumorigenicity in vivo

A. OE33 P and OE33 R cells were implanted subcutaneously into NOD SCID mice (n=3). OE33 R cells demonstrated significantly enhanced tumorigenesis when compared to OE33 P cells. Data are presented as the mean ± SEM. Statistical analysis was performed using a two-tailed unpaired Student’s t-test,***p < 0.0001 B. Representative images of tumors extracted from OE33 P and OE33 R cells injected into NOD SCID mice.

In vitro, miR-17-5p was demonstrated to significantly sensitise radioresistant cells to X-ray radiation and promoted the repression of genes with miR-17-5p binding sites, such as C6orf120In vivo, miR-17-5p was significantly decreased, whilst C6orf120 was significantly increased, in pre-treatment EAC tumour samples from patients who demonstrated a poor response to neoadjuvant CRT.

This study sheds novel insights into the role of CSCs in the resistance of EAC to CRT and highlights miR-17-5p as a potential biomarker of CRT sensitivity and novel therapeutic target in treatment resistant EAC.

 

Reference
N. Lynam-Lennon, S. Heavey, J. J. O’Leary, M. F. Gallagher, J. V. Reynolds, S. G. Maher et al. (2017) MicroRNA-17 is downregulated in esophageal adenocarcinoma cancer stem-like cells and promotes a radioresistant phenotype Oncotarget 8(7) 11400-11413 doi: 10.18632/oncotarget.13940 [article]

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