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IL-6 mediates platinum-induced enrichment of ovarian cancer stem cells
Yinu Wang, … , Daniela Matei, Kenneth P. Nephew
Yinu Wang, … , Daniela Matei, Kenneth P. Nephew
Published December 6, 2018
Citation Information: JCI Insight. 2018;3(23):e122360. https://doi.org/10.1172/jci.insight.122360.
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Research Article Inflammation Stem cells

IL-6 mediates platinum-induced enrichment of ovarian cancer stem cells

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Abstract

In high-grade serous ovarian cancer (OC), chemotherapy eliminates the majority of tumor cells, leaving behind residual tumors enriched in OC stem cells (OCSC). OCSC, defined as aldehyde dehydrogenase–positive (ALDH+), persist and contribute to tumor relapse. Inflammatory cytokine IL-6 is elevated in residual tumors after platinum treatment, and we hypothesized that IL-6 plays a critical role in platinum-induced OCSC enrichment. We demonstrate that IL-6 regulates stemness features of OCSC driven by ALDH1A1 expression and activity. We show that platinum induces IL-6 secretion by cancer-associated fibroblasts in the tumor microenvironment, promoting OCSC enrichment in residual tumors after chemotherapy. By activating STAT3 and upregulating ALDH1A1 expression, IL-6 treatment converted non-OCSC to OCSC. Having previously shown altered DNA methylation in OCSC, we show here that IL-6 induces DNA methyltransferase 1 (DNMT1) expression and the hypomethylating agent (HMA) guadecitabine induced differentiation of OCSC and reduced — but did not completely eradicate — OCSC. IL-6 neutralizing antibody (IL-6-Nab) combined with HMA fully eradicated OCSC, and the combination blocked IL-6/IL6-R/pSTAT3–mediated ALDH1A1 expression and eliminated OCSC in residual tumors that persisted in vivo after chemotherapy. We conclude that IL-6 signaling blockade combined with an HMA can eliminate OCSC after platinum treatment, supporting this strategy to prevent tumor recurrence after standard chemotherapy.

Authors

Yinu Wang, Xingyue Zong, Sumegha Mitra, Anirban Kumar Mitra, Daniela Matei, Kenneth P. Nephew

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Figure 1

Increased IL-6 expression after chemotherapy associated with cancer progression and poor clinical outcome.

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Increased IL-6 expression after chemotherapy associated with cancer prog...
(A) Mean of IL-6 expression (reads per kilobase of transcript, per million mapped reads; RPKM) in patients with free tumor survival duration less than 12 months and more than 12 months after initial chemotherapy. Data was drawn from TCGA ovarian cancer portal. There are 20 patients with free tumor survival duration less than 12 months and 22 patients with free tumor survival duration more than 12 months after initial chemotherapy. (B) Survival probability of patients with high-grade serous ovarian cancer correlates with IL-6 expression levels in tumors after chemotherapy (P = 0.0023).

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