Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice

Abstract

Aging intersects with reproductive senescence in women by promoting a systemic low-grade chronic inflammation that predisposes women to several diseases including ovarian cancer (OC). OC risk at menopause is significantly modified by parity records during prior fertile life. To date, the combined effects of age and parity on the systemic inflammation markers that are particularly relevant to OC initiation and progression at menopause remain largely unknown. Herein, we profiled a panel of circulating cytokines in multiparous versus virgin C57BL/6 female mice at peri-estropausal age and investigated how cytokine levels were modulated by intraperitoneal tumor induction in a syngeneic immunocompetent OC mouse model. Serum FSH, LH and TSH levels increased with age in both groups while prolactin (PRL) was lower in multiparous respect to virgin mice, a finding previously observed in parous women. Serum CCL2, IL-10, IL-5, IL-4, TNF-α, IL1-β and IL-12p70 levels increased with age irrespective of parity status, but were specifically reduced following OC tumor induction only in multiparous mice. Animals developed hemorrhagic ascites and tumor implants in the omental fat band and other intraperitoneal organs by 12 weeks after induction, with multiparous mice showing a significantly extended survival. We conclude that previous parity history counteracts aging-associated systemic inflammation possibly by reducing the immunosuppression that typically allows tumor spread. Results suggest a partial impairment of the M2 shift in tumor-associated macrophages as well as decreased stimulation of regulatory B-cells in aged mice. This long term, tumor-concurrent effect of parity on inflammation markers at menopause would be a contributing factor leading to decreased OC risk.

<p>Parity as a Prognostic Factor in Patients with Advanced-Stage Epithelial Ovarian Cancer</p>

“…27 It has been reported that parity has a longterm, tumor-concurrent effect on inflammation markers at menopause which might be a contributing factor in decreasing the OC risk. 28 One explanation for this finding is that child-bearing might reduce immunosuppression (which typically allows tumor spread) and thus counteract aging-associated systemic inflammation. 28 A previous study about the combined effects of age and parity on the systemic inflammation markers relevant to OC initiation revealed two mechanisms responsible for this protection.…”

“…28 One explanation for this finding is that child-bearing might reduce immunosuppression (which typically allows tumor spread) and thus counteract aging-associated systemic inflammation. 28 A previous study about the combined effects of age and parity on the systemic inflammation markers relevant to OC initiation revealed two mechanisms responsible for this protection. These mechanisms are the decreased stimulation of regulatory B-cells and the partial impairment of the M2 shift in tumor-associated macrophages observed in multiparous aged mice compared with virgin aged mice.…”

“…These mechanisms are the decreased stimulation of regulatory B-cells and the partial impairment of the M2 shift in tumor-associated macrophages observed in multiparous aged mice compared with virgin aged mice. 28 It has also been demonstrated that the preexisting parity-associated microenvironmental niche in the omental fat band of parous mice might slow the metastatic tumor seeding and outgrowth due to the greater proportion of both T and B lymphocytes. 29 The relationship between histological types and survival of EOC patients varied across studies.…”

The Ovarian Transcriptome of Reproductively Aged Multiparous Mice: Candidate Genes for Ovarian Cancer Protection

“…This study with female C57BL/6 mice was approved by the Bioethics Committee, Faculty of Medicine, University of Chile (CBA # 0536 FMUCH). The care and monitoring of the two experimental groups, virgin and multiparous, have recently been described in detail [18]. Figure 1A depicts the experimental design for the present report.…”

“…Mouse models have been used to study OC risk factors, including obesity [15], inflammation [16], age [8], and genetic inheritance [17], among others. Continuing the recent work on peritoneal tumor spread and systemic inflammation in an aged syngeneic female C57BL/6 mouse model of OC maintained in multiparous and nulliparous regimens [18], here, we studied the effect of parity history on the ovarian transcriptome in intact, uninduced animals. Increased transcript levels of several markers of oocytes and follicles concomitant with significantly higher residual follicle counts were observed in multiparous ovaries.…”