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Aging and Disease    2017, Vol. 8 Issue (5) : 546-557     DOI: 10.14336/AD.2017.0110
Original Article |
Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice
Ulises Urzua1,4,5,*,Carlos Chacon1,Luis Lizama2,Sebastián Sarmiento1,Pía Villalobos1,Belén Kroxato1,Katherine Marcelain3,5,María-Julieta Gonzalez4
1Laboratorio de Genómica Aplicada, Facultad de Medicina, Universidad de Chile
2Programa de Virología, ICBM
3Programa de Genética Humana, ICBM
4Programa de Biología Celular y Molecular, ICBM
5Departamento de Oncología Básica y Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
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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.

Keywords age      parity      ovarian cancer      menopause      cytokine      inflammation      mouse model     
Corresponding Authors: Ulises Urzua   
Just Accepted Date: 25 January 2017   Issue Date: 26 September 2017
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Ulises Urzua
Carlos Chacon
Luis Lizama
Sebastián Sarmiento
Pía Villalobos
Belén Kroxato
Katherine Marcelain
María-Julieta Gonzalez
Cite this article:   
Ulises Urzua,Carlos Chacon,Luis Lizama, et al. Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice[J]. A&D, 2017, 8(5): 546-557.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.0110     OR     http://www.aginganddisease.org/EN/Y2017/V8/I5/546
Figure 1.  Study design and parity records

(A) Two groups of C57BL6 female mice (n=70 per group) were maintained from 3-20 months old in virgin (nulliparous) or multiparous conditions. A smaller third group, composed of young adult 4 months old virgin mice (n=6), was used as reference controls in some assays. Multiparous mice were allowed to breastfeed their pups until 21-days old. Circulating cytokines and hormones were measured once per month in 3-4 distinct, randomly taken mice aged 15-19 months old. Tumor induction was initiated at 16 months old (n=8 per condition) with cytokines and hormones measured similarly. The age scale shown is not proportional. See Methods section for additional details. (B) Chart corresponds to the total number of litters as a function of age. (C) depicts the distribution of number of litters per individual mice over the reproductive period, both data-sets for the entire multiparous group.

Figure 2.  Circulating pituitary hormones in aged mice

Serum levels of the indicated hormones were measured monthly in 4 randomly chosen female mice 15-19 months old. The reference group, was 4 months old young adults (n=6) was. Bars represent mean with SEM corresponding to the above-mentioned time period. (*) p<0.05, (**) p<0.01, (***) p<0.005, (§) 0.05<p<0.10. Further details in Methods.

Figure 3.  Circulating cytokines in control and tumor-induced aged mice

Serum levels of the indicated cytokines were measured monthly from 15-19 months old in 3-4 randomly chosen female mice per group. Cytokines in the tumor-induced conditions (dashed bars, n=8 per group) were measured from the time of injection (16 months old) until time of death (19-19.5 months old). The young adult reference group (n=6) was 4 months old. Bars represent the mean with SEM corresponding to the above-mentioned time periods. (*) p<0.05, (**) p<0.01, (***) p<0.005, (§) 0.05<p<0.10. Further details in Methods.

Figure 4.  Tumor spread and survival of host aged mice

(A) Demonstrative image of intraperitoneal tumor implants formed in a 19 months-old virgin C57BL6 female mouse injected with MOSE cells. Tumor implants in the omental fat band are shown pulled-out with clamps. (B) Survival plots of virgin and multiparous aged mice injected with IG-10 MOSE cells; day 0 corresponds to 16.1 ± 0.3 months of age for the two groups. Median survivals were 98 and 87 days for the multiparous and virgin groups, respectively. The p value of log-rank (Mantel-Cox) is shown. Both the log-rank and the Gehan-Breslow-Wilcoxon (p=0.038) tests were performed in GraphPad Prism 5 with 95% CI of 0.7638-1.489 for ratios of survival.

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