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

Date Published: October 1, 2017

Publisher: JKL International LLC

Author(s): Ulises Urzua, Carlos Chacon, Luis Lizama, Sebastián Sarmiento, Pía Villalobos, Belén Kroxato, Katherine Marcelain, María-Julieta Gonzalez.


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.

Partial Text

Natural ovarian decline is associated with hormone and inflammatory changes that overlap with those occurring as a consequence of aging in women. In addition, as suggested from epidemiological data in various populations, periods of suppressed ovulation plus P4 (or progestin) exposure over woman´s fertility span are major determinants of OC risk later in menopause [23]. We have approached this subject by using a syngeneic immunocompetent OC mouse model maintained under divergent host reproductive conditions (virgin and multiparous) until the peri-estropausal age. Using mouse to study age-associated cancer immunomodulation is supported by recent findings suggesting that the age-dependent evolution (adult, mature, old and long lived) of immune functions such as chemotaxis, phagocytosis, natural killer activity and lymphoproliferation is similar between humans and mice of equivalent chronological ages [32]. Estrous cycle lengthening and increased serum levels of the gonadotropins FSH and LH observed by ≥ 15 months-old in aged mice, were indicative of ovarian senescence and a declining control of the HPG axis. Since gonadotropins in aged animals were higher than in young, but lower than in ovariectomized mice (data not shown), mice of the age range studied in the present work would be equivalent to a human in late menopausal transition or early post-menopause [33].




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