Stemness and anti-cancer drug resistance in ABCG2 highly expressed pancreatic cancer is induced on 3D-culture condition

Summary

The expression of ATP-binding cassette subfamily G member 2 (ABCG2) is related with tumorigenic cancer stem cells (CSCs) in several cancers. However, the effects of ABCG2 on CSC-related malignant characteristics in pancreatic ductal adenocarcinoma (PDAC) are not well elucidated. In this study, we compared the characteristics of low (ABCG2–) and high (ABCG2+)-ABCG2-expressing PDAC cells after cell sorting. In adherent culture condition, human PDAC cells, PANC-1, contained approximately 10% ABCG2+ cell populations, and ABCG2+ cells displayed more and longer microvilli compared with ABCG2– cells. Unexpectedly, ABCG2+ cells did not show significant drug resistance against 5-FU, gemcitabine and vincristine, and ABCG2– cells exhibited higher sphere formation ability and stemness marker expression than those of ABCG2+ cells. Cell growth and motility was greater in ABCG2– cells compared with ABCG2+ cells. On the other hand, EMT ability between ABCG2– and ABCG2+ cells was comparable. In 3D-culture condition, spheres derived from ABCG2– cells generated a large number of ABCG2+ cells, and the expression levels of stemness markers in these spheres were higher than spheres from ABCG2+ cells. Furthermore, spheres containing large populations of ABCG2+ cells exhibited high resistance against anti-cancer drugs presumably depending on ABCG2. ABCG2+ cells in PDAC in adherent culture are not correlated with stemness and malignant behaviors, but ABCG2+ cells derived from ABCG2– cells after sphere formation have stemness characteristics and anti-cancer drug resistance. These findings suggest that ABCG2– cells generate ABCG2+ cells and the malignant potential of ABCG2+ cells in PDAC varies depending on their environments.

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