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CD40 pathway activation reveals dual function for macrophages in human endometrial cancer cell survival and invasion

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Abstract

Reproductive malignancies are a major cause of cancer death in women worldwide. CD40 is a TNF receptor family member, which upon activation may mediate tumor regression. However, despite the great potential of CD40 agonists, their use as a therapeutic option for reproductive cancers has never been investigated. Because CD40 ligation is a potent pathway of macrophage activation, an in vitro model of pro-inflammatory type-1 (Mϕ-1) and anti-inflammatory type-2 (Mϕ-2) macrophages was developed to determine whether and how macrophage CD40 pathway activation might influence endometrial tumor cell behavior. Analysis of tumor growth kinetic in the endometrial cancer xenograft model indicates that, when injected once into the growing tumors, CD40-activated Mϕ-1 greatly reduced, while CD40-activated Mϕ-2 increased tumor size when compared to control isotype-activated Mϕ-1 and Mϕ-2, respectively. In vitro assays indicated that CD40-activated Mϕ-2 increased cell viability but failed to promote cell invasion. CD40-activated Mϕ-1, in contrast, decreased cell survival but greatly increased cell invasion in tumor cells less susceptible to cell death by apoptosis; they also induced the expression of some pro-inflammatory genes, such as IL-6, LIF, and TNF-α, known to be involved in tumor promotion and metastasis. The presence of IFN-γ is minimally required for CD40-activated Mϕ-1 to promote tumor cell invasion, a process that is mediated in part through the activation of the PI3K/Akt2 signaling pathway in tumor cells. From these results, we speculate that some functions of CD40 in tumor-associated Mϕs might limit the therapeutic development of CD40 agonists in endometrial cancer malignancies.

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Acknowledgments

This study was financially supported by grants from The Fonds de la Recherche en Santé du Québec (FRSQ) and the Natural Science and Engineering Research Council (NSERC) of Canada to C.R.M. G.D. and was supported by the Research Awards Program of the NSERC. J.G. holds a postdoctoral fellowship from the FRSQ. E.A. is holder of the Canada research chair in Molecular Gyneco–Oncology.

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The authors declare no financial conflict of interest.

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Authors and Affiliations

  1. Research Group in Molecular Oncology and Endocrinology, University of Quebec at Trois-Rivieres, Trois-Rivières, PQ, G9A 5H7, Canada

    Geneviève Dumas, Mathieu Dufresne, Éric Asselin, Julie Girouard & Carlos Reyes-Moreno

  2. Haemato-oncologic Service, Regional Hospital of Trois-Rivieres, Trois-Rivières, PQ, G8Z 3R9, Canada

    Christian Carrier

  3. Department of Chemistry-Biology, University of Quebec at Trois-Rivieres, 3351 boul. des Forges, C.P. 500, Trois-Rivieres, G9A 5H7, Canada

    Carlos Reyes-Moreno

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  1. Geneviève Dumas
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  2. Mathieu Dufresne
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  3. Éric Asselin
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  4. Julie Girouard
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Correspondence to Carlos Reyes-Moreno.

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Geneviève Dumas and Mathieu Dufresne contributed equally to this work.

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Dumas, G., Dufresne, M., Asselin, É. et al. CD40 pathway activation reveals dual function for macrophages in human endometrial cancer cell survival and invasion. Cancer Immunol Immunother 62, 273–283 (2013). https://doi.org/10.1007/s00262-012-1333-2

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