Pancreatic cancer cells resistant to chemoradiotherapy rich in "stem-cell-like" tumor cells.

BACKGROUND

Tumor resistance to chemoradiation therapy is partly attributed to the presence of apoptosis-resistant cancer stem cells (CSCs). Chemoradiation therapy can enrich CSCs by killing apoptosis-susceptible cancer cells.

AIM

Our preliminary study showed chemoradiation-resistant pancreatic cancer cells to have some CSC characteristics, and to undergo epithelial-mesenchymal transition (EMT); we aimed to verify that study's implication that chemoradiation-resistant subpopulations are enriched with "stem-cell-like" tumor cells, which may be linked to EMT.

METHODS

Four pancreatic cancer cell lines were cultured in gemcitabine with synchronous radiotherapy to obtain resistant subpopulations. Morphological changes were observed under microscope; migration and invasiveness were assessed by Transwell tests. Protein expression was determined by immunoblotting. Pancreatic CSC markers were studied using fluorescence-activated cell sorting analyses. Colony-formation tests, tumor sphere formation assays, and tumor xenografts in BALB/C nude mice were used to evaluate "stemness" in resistant cells.

RESULTS

Resistant cells expressed more antiapoptotic protein Bcl-2, apoptosis-inhibitory protein survivin, and stem cell markers Oct4, ABCG2, CD24, and CD133, were more tumorigenic in vitro and in vivo, and showed phenotypic and molecular changes consistent with EMT, including upregulation of vimentin and downregulation of E-cadherin. They were also more invasive and migratory.

CONCLUSIONS

We found chemoradiation-resistant pancreatic cancer cells to be similar to CSCs and to undergo EMT, suggesting that chemoradiation resistance-induced EMT is linked to CSC generation.