Abstract
Morphine is an opioid analgesic drug commonly used for pain relief in cancer patients. Here, we report that morphine enhances the mammosphere forming capacity and increases the expression of stemness-related transcription factors Oct4, Sox2 and Nanog. Treatment with morphine leads to enrichment of a side population fraction in MCF-7 cells and the CD44+/CD24(-/low) population in BT549 cells. Consistently, morphine activates Wnt/β-catenin signaling to induce epithelial to mesenchymal transition and promotes metastasis. Moreover, morphine decreases the sensitivity of traditional anti-cancer drugs in breast cancer cells. Nalmefene, an antagonist of morphine, reverses morphine-induced cancer stem cell properties and chemoresistance in breast cancer. In addition, nalmefene abolishes morphine enhancing tumorigenesis in a NOD/SCID mouse model. In conclusion, our findings demonstrate that morphine contributes to chemoresistance via expanding the population of cancer stem cells and promotes tumor growth, thereby revealing a novel role of morphine and providing some new guides in clinical use of morphine.
Highlights
IntroductionBreast cancer contains a subpopulation of self-renewing cells that resemble mammary stem cells
Breast cancer is the most common cancer in women worldwide [1]
Since CD44+/CD24– were widely used as a cell surface marker of Cancer stem cells (CSCs), we detected the expression of CD44+/CD24– in breast cancer cells treated with morphine (10 μM) and found that the CD44+/ CD24– proportion were increased from 47.87 ± 1.01% to 68.8 ± 2.68% in BT549 cells (Figure 1E)
Summary
Breast cancer contains a subpopulation of self-renewing cells that resemble mammary stem cells. Breast cancer stem cells (BCSCs) first isolated by surface marker CD44+/CD24−/low possess the characteristic of unlimited self-renewal and are able to generate differentiated descendants [2]. Inoculation of small numbers of CD44+/CD24−/low breast cancer cells in NOD/ SCID mice can recapitulate the phenotypic heterogeneity of the parent tumor, whereas cells lacking the CD44+/ CD24−/low marker have a greatly reduced tumor-forming capacity [3]. The chemoresistance of BCSCs is tightly regulated by the following mechanisms: 1. The differentiation ability of CSCs to regenerate heterogeneous cancer cells [6, 7]; 3. Targeting CSCs is the current challenge for the development of anticancer treatment. The molecular mechanisms by which CSCs contribute to drug resistance remain to be determined
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