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Cancer Stem Cells Protect Non‐Stem Cells From Anoikis: Bystander Effects

Cancer stem cells (CSCs) are capable of initiation and metastasis of tumors. Therefore, understanding the biology of CSCs and the interaction between CSCs and their counterpart non‐stem cells is crucial for developing a novel cancer therapy. We used CSC‐like and non‐stem breast cancer MDA‐MB‐231 and MDA‐MB‐453 cells to investigate mammosphere formation. We investigated the role of the epithelial cadherin (E‐cadherin)‐extracellular signal‐regulated kinase (Erk) axis in anoikis. Data from E‐cadherin small hairpin RNA assay and mitogen‐activated protein kinase kinase (MEK) inhibitor study show that activation of Erk, but not modulation of E‐cadherin level, may play an important role in anoikis resistance. Next, the two cell subtypes were mixed and the interaction between them during mammosphere culture and xenograft tumor formation was investigated. Unlike CSC‐like cells, increased secretion of interleukin‐6 (IL‐6) and growth‐related oncogene (Gro) chemokines was detected during mammosphere culture in non‐stem cells. Similar results were observed in mixed cells. Interestingly, CSC‐like cells protected non‐stem cells from anoikis and promoted tumor growth. Our results suggest bystander effects between CSC‐like cells and non‐stem cells. J. Cell. Biochem. 117: 2289–2301, 2016. © 2016 Wiley Periodicals, Inc.