CD40 pathway activation reveals dual function for macrophages in human endometrial cancer cell survival and invasion
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ORIGINAL ARTICLE
CD40 pathway activation reveals dual function for macrophages in human endometrial cancer cell survival and invasion Genevie`ve Dumas • Mathieu Dufresne • E´ric Asselin • Julie Girouard • Christian Carrier Carlos Reyes-Moreno
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Received: 8 May 2012 / Accepted: 31 July 2012 / Published online: 18 August 2012 Ó Springer-Verlag 2012
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 (M/-1) and anti-inflammatory type-2 (M/-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 M/-1 greatly reduced, while CD40-activated M/-2 increased tumor size when compared to control isotype-activated M/-1 and M/-2, Genevie`ve Dumas and Mathieu Dufresne contributed equally to this work.
Electronic supplementary material The online version of this article (doi:10.1007/s00262-012-1333-2) contains supplementary material, which is available to authorized users. G. Dumas M. Dufresne E´. Asselin J. Girouard C. Reyes-Moreno Research Group in Molecular Oncology and Endocrinology, University of Quebec at Trois-Rivieres, Trois-Rivie`res, PQ G9A 5H7, Canada C. Carrier Haemato-oncologic Service, Regional Hospital of Trois-Rivieres, Trois-Rivie`res, PQ G8Z 3R9, Canada C. Reyes-Moreno (&) Department of Chemistry-Biology, University of Quebec at Trois-Rivieres, 3351 boul. des Forges, C.P. 500, Trois-Rivieres G9A 5H7, Canada e-mail: [email protected]
respectively. In vitro assays indicated that CD40-activated M/-2 increased cell viability but failed to promote cell invasion. CD40-activated M/-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-a, known to be involved in tumor promotion and metastasis. The presence of IFN-c is minimally required for CD40-activated M/-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 tumorassociated M/s might limit the therapeutic development of CD40 agonists in endometrial cancer malignancies. Keywords CD40 receptor Endometrial cancer Immunotherapy Polarized macrophages Tumor–stroma interaction
Introduction Endometrial cancer (EC) is the most common malignancy of the female genital tract in many countries with incidences increasing in
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