Stemness and anti-cancer drug resistance in ATP-binding cassette subfamily G member 2 highly expressed pancreatic cancer is induced in 3D culture conditions.

Abstract

The expression of ATP‐binding cassette subfamily G member 2 (ABCG2) is related to tumorigenic cancer stem cells (CSC) 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 fluorouracil, 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. In contrast, epithelial‐mesenchymal transition ability between ABCG2− and ABCG2+ cells was comparable. In 3D culture conditions, 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.