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

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 p...

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Bibliographic Details
Published in:Oncogene 2015-05, Vol.34 (19), p.2471-2482
Main Authors: Stodden, G R, Lindberg, M E, King, M L, Paquet, M, MacLean, J A, Mann, J L, DeMayo, F J, Lydon, J P, Hayashi, K
Format: Article
Language:English
Subjects:
Adipose tissue
Angiogenesis
Animals
Antigens, CD - genetics
Antigens, Differentiation, Myelomonocytic - genetics
Arginase - genetics
Carcinoma
Care and treatment
CD163 antigen
Cdh1 Proteins - genetics
Cell activation
Cell Line
Cell proliferation
Cell Proliferation - genetics
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - pathology
Cytoplasm
Diagnosis
E-cadherin
Endometrial cancer
Endometrial Neoplasms - genetics
Endometrial Neoplasms - pathology
Endometrium
Female
Gene expression
Health aspects
Humans
Inflammation
Inflammation - genetics
Inflammation - immunology
Inflammation - pathology
Intermediates
Intestine
Lymph nodes
Macrophages
Macrophages - immunology
Mesentery
Metastasis
Mice
Mice, Knockout
Mutants
Mutation
Neovascularization, Pathologic - genetics
NF-kappa B - metabolism
p53 Protein
Peritoneum
Phenotypes
Postmenopausal women
Receptors, Cell Surface - genetics
Transcription activation
Tumor Microenvironment - immunology
Tumor Suppressor Protein p53 - genetics
Tumorigenesis
Tumors
Uterine cancer
Uterus
Uterus - cytology
Uterus - pathology
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Summary: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 (Cdh1(d/d)Trp53(d/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, Cdh1(d/d)Trp53(d/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 Cdh1(d/d)Trp53(d/d) mice. Our microarray analysis found that most of the genes differentially regulated in the uteri of Cdh1(d/d)Trp53(d/d) mice were involved in inflammatory responses. CD163 and Arg1, markers for tumor-associated macrophages, were also detected and increased in the uteri of Cdh1(d/d)Trp53(d/d) mice, suggesting that an inflammatory tumor microenvironment with immune cell recruitment is augmenting tumor development in Cdh1(d/d)Trp53(d/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.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2014.193