Abstract
BackgroundCancer stem cells (CSCs), responsible for cancer metastasis and recurrence, are generated from non-CSCs after chemo-radiation therapy. This study investigated the induction of CSC potential in non-stem breast cancer cells and the underlying molecular mechanisms in detachment culture.MethodsBulk breast cancer cells, or sorted non-CSCs and CSCs were cultured under an attached or detached condition to assess CSC numbers, ability to form tumor spheres, expression of stemness markers, and chemoresistance. Lentivirus carrying CD147 shRNA or cDNA was used to manipulate CD147 expression, while CD147 ligand recombinant cyclophilin A (CyPA) or its inhibitor was used to activate or inhibit CD147 signaling.ResultsDetachment promoted anoikis resistance, chemoresistance, sphere formation, self-renewal, and expression of stemness markers in breast cancer cells. Detachment increased functional ALDH+ or CD44highCD24–/low CSCs, and induced CSC potential in ALDH– or CD44lowCD24high non-CSCs. Upon detachment, both CD147 expression and CyPA secretion were enhanced, and CyPA-CD147 activation mediated detachment induced CSC potential in non-CSCs via STAT3 signaling. Clinically, CD147 and pSTAT3 were highly co-expressed and correlated with poor overall survival and tumor recurrence in breast cancer patients.ConclusionThis study demonstrates that detachment induces the generation of CSCs from non-stem breast cancer cells via CyPA-CD147 signaling, indicating that targeting CD147 may serve as a potential novel therapeutic strategy for lethal metastatic breast cancer by eliminating induced CSCs.
Highlights
Breast cancer is the most commonly diagnosed cancer in women and the sixth leading cause of cancer-related deaths in Chinese women (Li et al, 2016)
To detect the effect of detachment culture on induction of cancer stem cells (CSCs) potential, we first determined the ability of breast cancer cells to resist anoikis
As compared with cancer cells cultured under the attached condition, we found that cancer cells grown under the detached condition exhibited different degrees of apoptosis (Figure 1A)
Summary
Breast cancer is the most commonly diagnosed cancer in women and the sixth leading cause of cancer-related deaths in Chinese women (Li et al, 2016). It is estimated that millions of cancer cells are released from a primary tumor mass into the circulation system daily; only a few of these cells can survive and successfully form metastatic lesions This small portion of cancer cells are referred to as cancer stem cells (CSCs), which possess the ability to initiate tumor formation and growth or to initiate tumor metastasis and recurrence in patients (Batlle and Clevers, 2017; Clarke, 2019). Breast CSCs were found to have higher specific cell surface antigen CD44 expression but no or lower CD24 expression, or to have higher aldehyde dehydrogenase 1 (ALDH1) activity (CeliaTerrassa and Kang, 2016; Cortes-Hernandez et al, 2019). This study investigated the induction of CSC potential in non-stem breast cancer cells and the underlying molecular mechanisms in detachment culture
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