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Leukemia inhibitory factor functions in parallel with interleukin-6 to promote ovarian cancer growth

Oncogene volume 38, pages 1576–1584 (2019)Cite this article

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Abstract

Ovarian carcinoma-associated mesenchymal stem cells (CA-MSC) produce not only high levels of interleukin-6 (IL6) but also the related cytokine leukemia inhibitory factor (LIF). IL6-mediated activation of STAT3 is implicated as a critical therapeutic target for cancer therapy. Less is known about the role of LIF, which can similarly activate STAT3, in ovarian cancer. We therefore sought to evaluate the tumorigenic effects of CA-MSC paracrine LIF signaling and the redundancy of IL6 and LIF in activating ovarian cancer STAT3 mediated cancer growth. As expected, we found that both IL6 and LIF induce STAT3 phosphorylation in tumor cells. In addition, both IL6 and LIF increased the percentage of ALDH+ ovarian cancer stem-like cells (CSC). Supporting redundancy of function by the two cytokines, CA-MSC induced STAT3 phosphorylation and increased cancer cell “stemness”. This effect was not inhibited by LIF or IL6 blocking antibodies alone, but was prevented by dual IL6/LIF blockade or JAK2 inhibition. Similarly, small hairpin RNA (shRNA)-mediated reduction of IL6 or LIF in CA-MSC partially decreased but could not completely abrograte the ability of CA-MSC to induce STAT3 phosphorylation and stemness. Importantly, the in vivo pro-tumorigenic effect of CA-MSC is abrogated by dual blockade with the JAK2 inhibitor ruxolitinib to a much greater extent than treatment with anti-IL6 or anti-LIF antibody alone. Ruxolitinib treatment also improves survival in the immunocompetent ovarian cancer mouse model system with ID8 tumor cells plus MSC. Ruxolitinib-treated tumors in both the immunocompromised and immunocompetent animal models demonstrate decreased phospho-STAT3, indicating on-target activity. In conclusion, CA-MSC activate ovarian cancer cell STAT3 signaling via IL6 and LIF and increase tumor cell stemness. This functional redundancy suggests that therapeutic targeting of a single cytokine may be less effective than strategies such as dual inhibitor therapy or targeting shared downstream factors of the JAK/STAT pathway.

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Acknowledgements

The authors would like to thank Yusong Gong for her technical assistance in the beginning stages of this project. Funding for this work has been provided in part by the Women’s Reproductive Health Research (WRHR) Career Development Program Award to KM (National Institutes of Health, K12 HD065257), the Department of Defense Ovarian Cancer Academy Early-Career Investigator Award to KM (DOD W81XWH-15-0194), and the generous support of the Goldberg Family.

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Authors and Affiliations

  1. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan Medical Center, Ann Arbor, MI, USA

    Karen McLean, Lijun Tan & Danielle E. Bolland

  2. Magee-Womens Research Institute University of Pittsburgh School of Medicine, Pittsburg, PA, USA

    Lan G. Coffman & Ronald J. Buckanovich

  3. Division of Hematology Oncology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA

    Luke F. Peterson & Moshe Talpaz

  4. Department of Medicinal Chemistry, College of Pharmacy North Campus Research Complex, Ann Arbor, MI, USA

    Nouri Neamati

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  1. Karen McLean
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Correspondence to Karen McLean.

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McLean, K., Tan, L., Bolland, D.E. et al. Leukemia inhibitory factor functions in parallel with interleukin-6 to promote ovarian cancer growth. Oncogene 38, 1576–1584 (2019). https://doi.org/10.1038/s41388-018-0523-6

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