목적: Tumor microenvironment reportedly plays critical roles in drug resistance and proliferation of CSCs; however, the functional role of CSC-secreted factors has not been clarified.
방법: We isolated cancer stem cells (CSCs) through sphere culture of A2780 epithelial ovarian cancer (EOC) cells and primary human EOC cells, and identified lysophosphatidic acid (LPA) as a CSC-derived autocrine factor using mass spectrometry.
결과: LPA treatment stimulated CSC-like properties, including drug resistance and high tumorigenic potential. CSCs were enriched in aldehyde dehydrogenase- high subpopulation, in which autotaxin, an LPA-producing enzyme, was highly expressed. LPA signaling was mediated through LPA receptor 1-dependent activation of the PI3K-AKT pathway. Abrogation of autotaxin-LPA-LPA receptor 1-AKT signaling axis significantly suppressed CSC characteristics, which provides a potential target for CSC treatment. EOC shows high mortality due to development of resistance to chemotherapy and relapse.
결론: CSCs have been implicated in drug resistance and relapse of ovarian cancer. Our findings suggested that ATX-LPA-LPAR1-AKT1 signaling axis is critical for maintenance of cancer stem-like characteristics in an ovarian CSC subpopulation through an autocrine loop. Inhibiting ATX-LPALPAR1- AKT1 signaling axis by chemical inhibitor or knockdown of gene expression increased the sensitivity of CSCs to chemotherapeutic reagents. Our findings provide therapeutic opportunities for development of relapse-free treatment of EOC.