Multiparity activates interferon pathways in peritoneal adipose tissue and decreases susceptibility to ovarian cancer metastasis in a murine allograft model

Abstract

Ovarian cancer is the fifth leading cause of cancer deaths in U.S. women and the deadliest gynecologic malignancy. This lethality is largely due to the fact that most cases are diagnosed at metastatic stages of the disease when the prognosis is poor. Epidemiologic studies consistently demonstrate that parous women have a reduced risk of developing ovarian cancer, with a greater number of births affording greater protection; however little is known about the impact of parity on ovarian cancer metastasis. Here we report that multiparous mice are less susceptible to ovarian cancer metastasis in an age-matched syngeneic murine allograft model. Interferon pathways were found to be upregulated in healthy adipose tissue of multiparous mice, suggesting a possible mechanism for the multiparous-related protective effect against metastasis. This protective effect was found to be lost with age. Based on this work, future studies exploring therapeutic strategies which harness the multiparity-associated protective effect demonstrated here are warranted.

Aging Increases Susceptibility to Ovarian Cancer Metastasis in Murine Allograft Models and Alters Immune Composition of Peritoneal Adipose Tissue

“…RNAseq analysis of gonadal adipose tissue was used to explore factors potentially contributing to metastatic success in aged vs young animals [37] . Over 1500 genes were significantly differentially expressed ( P < .05) to varying degrees, ranging from log 2 (fold change) -4.86 to 4.35 in the aged animals.…”

Host Mesothelin Expression Increases Ovarian Cancer Metastasis in the Peritoneal Microenvironment

“…To recapitulate advanced stage OvCa with peritoneal metastasis and ascites accumulation, we utilized a syngeneic immunocompetent mouse model of advanced-stage ovarian cancer metastasis, to investigate the role of host MSLN expression on ovarian cancer metastasis [47][48][49][50]. Overall abdominal tumor burden was significantly decreased in MSLN KO mice, most notably impacting metastatic colonization of omental, ovary and liver tissues, suggesting host MSLN expression is important in the metastatic success of ovarian tumor cells and in the progression of the disease.…”

“…The mouse ovarian surface epithelial ID8 ovarian cancer cell line, syngeneic to immunocompetent C57BL/6 mice tagged with red fluorescent protein designated (ID8-RFP) were maintained as previously described [47][48][49][50]62,63]. Briefly, cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 4% fetal bovine serum (FBS), 1% penicillin/streptomycin, 5 µg/mL Insulin, 5 µg/mL transferrin and 5 ng/mL sodium selenite at 37 • C, 5% CO 2 in humid air.…”

“…The mouse ovarian surface epithelial ID8 ovarian cancer cell line, syngeneic to immunocompetent C57BL/6 mice (MSLN WT and MSLN KO ), used in allograft tumor studies, were tagged with red fluorescent protein (RFP) and maintained as previously described [47][48][49][50]62,63]. To model the propagation and colonization events of ovarian cancer metastasis, ID8 RFP-tagged cells (7 × 10 6 ) were i.p.…”