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

Abstract

Type II endometrial carcinomas are estrogen independent, poorly differentiated tumors that behave in an aggressive manner. Since 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 endometrial carcinomas, including focal areas of papillary differentiation, protruding cytoplasm into the lumen (hobnailing) and severe nuclear atypia at 6-mo of age. Further, Cdh1d/dTrp53d/d tumors in 12-mo 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 morphologic 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 NFκB 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 endometrial carcinomas.

Essential genes of the macrophage response to Staphylococcus aureus exposure

“…STAT3 and IL-10 play a key role in driving immune dysregulation and severe immunodeficiency [ 25 ]. A recent study suggested that the absence of TP53 in endometrial cells initiates chronic inflammation, and a TP53 mutant in endometrial cancer cells induces normal macrophages to express genes that are involved in the inflammatory reaction through signal pathways [ 26 ]. In our study, after 24 h of S. aureus infection, the expression of TP53 in macrophages was down-regulated.…”

Periovulatory insulin signaling is essential for ovulation, granulosa cell differentiation, and female fertility

“…Carver Biotechnology Center at the University of Illinois for library creation and sequencing as described previously . Gene set enrichment analysis (GSEA) was used to identify genetic pathways disrupted by loss of INSR activity as we performed previously . The publically available GSEA platform (http://www.broad.mit.edu) was used with the recommended settings for gene ranking and comparison with gene sets defined as significantly enriched if the FDR q value was less than 0.2 when using Pearson metrics and 1000 permutations of gene sets.…”

Niclosamide As a Potential Nonsteroidal Therapy for Endometriosis That Preserves Reproductive Function in an Experimental Mouse Model

“…Bioinformatics analysis was performed using the database for annotation, visualization, and integrated discovery (DAVID) for a total of 199 genes (which exhibited an FDR of less than 0.1), and gene set enrichment analysis (GSEA) to identify additional genetic pathways affected by niclosamide treatment, as we previously performed [ 50 ]. Briefly, to examine genomewide expression profiles, the publicly available GSEA software package ( www.broad.mit.edu ) was used for leading edge analysis to determine whether the members of the identified gene ontology pathways were randomly distributed throughout the ranked gene list or concentrated at the top or bottom.…”