Chemotherapy induces adaptive drug resistance and metastatic potentials via phenotypic CXCR4-expressing cell state transition in ovarian cancerReport as inadecuate




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Ovarian cancer OVC patients who receive chemotherapy often acquire drug resistance within one year. This can lead to tumor reoccurrence and metastasis, the major causes of mortality. We report a transient increase of a small distinctive CXCR4High-CD24Low cancer stem cell population CXCR4High in A2780 and SKOV-3 OVC cell lines in response to cisplatin, doxorubicin, and paclitaxel, treatments. The withdrawal of the drug challenges reversed this cell-state transition. CXCR4High exhibits dormancy in drug resistance and mesenchymal-like invasion, migration, colonization, and tumor formation properties. The removal of this cell population from a doxorubicin-resistant A2780 lineage A2780-ADR recovered the sensitivity to drug treatments. A cytotoxic peptide CXCR4-KLA that can selectively target cell-surface CXCR4 receptor was further synthesized to investigate the therapeutic merits of targeting CXCR4High. This peptide was more potent than the conventional CXCR4 antagonists AMD3100 and CTCE-9908 in eradicating the cancer stem cells. When used together with cytotoxic agents such as doxorubicin and cisplatin, the combined drug-peptide regimens exhibited a synergistic cell-killing effect on A2780, A2780-ADR, and SKOV-3. Our data suggested that chemotherapy could establish drug-resistant and tumor-initiating properties of OVC via reversible CXCR4 cell state transition. Therapeutic strategies designed to eradicate rather than antagonize CXCR4High might offer a far-reaching potential as supportive chemotherapy.



Author: Hyun Hee Lee, Vanessa Bellat, Benedict Law

Source: http://plos.srce.hr/



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