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Loss of Cdh1 and Trp53 in the uterus induces chronic inflammation with modification of tumor microenvironment

Oncogene volume 34, pages 2471–2482 (2015)Cite this article

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Abstract

Type II endometrial carcinomas (ECs) are estrogen independent, poorly differentiated tumors that behave in an aggressive manner. As TP53 mutation and CDH1 inactivation occur in 80% of human endometrial type II carcinomas, we hypothesized that mouse uteri lacking both Trp53 and Cdh1 would exhibit a phenotype indicative of neoplastic transformation. Mice with conditional ablation of Cdh1 and Trp53 (Cdh1d/dTrp53d/d) clearly demonstrate architectural features characteristic of type II ECs, including focal areas of papillary differentiation, protruding cytoplasm into the lumen (hobnailing) and severe nuclear atypia at 6 months of age. Further, Cdh1d/dTrp53d/d tumors in 12-month-old mice were highly aggressive, and metastasized to nearby and distant organs within the peritoneal cavity, such as abdominal lymph nodes, mesentery and peri-intestinal adipose tissues, demonstrating that tumorigenesis in this model proceeds through the universally recognized morphological intermediates associated with type II endometrial neoplasia. We also observed abundant cell proliferation and complex angiogenesis in the uteri of Cdh1d/dTrp53d/d mice. Our microarray analysis found that most of the genes differentially regulated in the uteri of Cdh1d/dTrp53d/d mice were involved in inflammatory responses. CD163 and Arg1, markers for tumor-associated macrophages, were also detected and increased in the uteri of Cdh1d/dTrp53d/d mice, suggesting that an inflammatory tumor microenvironment with immune cell recruitment is augmenting tumor development in Cdh1d/dTrp53d/d uteri. Further, inflammatory mediators secreted from CDH1-negative, TP53 mutant endometrial cancer cells induced normal macrophages to express inflammatory-related genes through activation of nuclear factor-κB signaling. These results indicate that absence of CDH1 and TP53 in endometrial cells initiates chronic inflammation, promotes tumor microenvironment development following the recruitment of macrophages and promotes aggressive ECs.

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Acknowledgements

We thank Jenny Zadeh at the University of Illinois at Urbana-Champaign Biotechnology Center for microarray analysis. This work was supported by NIH/NCI R15CA179214 and ACS-IL 139038 (to KH), NIH/NICHD R15HD065584 (to JAM) and NIH/NICHD U54HD007495 (to FJD and JPL).

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  1. G R Stodden and M E Lindberg: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA

    G R Stodden, M E Lindberg, M L King, J A MacLean & K Hayashi

  2. Departement de Pathologie et de Microbiologie, Université de Montreal, St-Hyacinthe, Quebec, Canada

    M Paquet

  3. Department of Pathology, Southern Illinois University School of Medicine, Springfield, IL, USA

    J L Mann

  4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    F J DeMayo & J P Lydon

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  1. G R Stodden
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Stodden, G., Lindberg, M., King, M. et al. Loss of Cdh1 and Trp53 in the uterus induces chronic inflammation with modification of tumor microenvironment. Oncogene 34, 2471–2482 (2015). https://doi.org/10.1038/onc.2014.193

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