Metformin Abrogates Age-Associated Ovarian Fibrosis

Abstract

◥Purpose: The ovarian cancer risk factors of age and ovulation are curious because ovarian cancer incidence increases in postmenopausal women, long after ovulations have ceased. To determine how age and ovulation underlie ovarian cancer risk, we assessed the effects of these risk factors on the ovarian microenvironment.Experimental Design: Aged C57/lcrfa mice (0-33 months old) were generated to assess the aged ovarian microenvironment. To expand our findings into human aging, we assembled a cohort of normal human ovaries (n ¼ 18, 21-71 years old). To validate our findings, an independent cohort of normal human ovaries was assembled (n ¼ 9, 41-82 years old).Results: We first validated the presence of age-associated murine ovarian fibrosis. Using interdisciplinary methodologies, we provide novel evidence that ovarian fibrosis also develops in human postmenopausal ovaries across two independent cohorts (n ¼ 27). Fibrotic ovaries have an increasedConclusions: These data support a novel hypothesis that unifies the primary nonhereditary ovarian cancer risk factors through the development of ovarian fibrosis and the formation of a premetastatic niche, and suggests a potential use for metformin in ovarian cancer prophylaxis.

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“…In addition, the presence of age-associated fibrosis, which had been previously demonstrated in mice [ 32 ], was recently confirmed by McCloskey and colleagues in a cohort of human samples [ 31 ]. This age-associated fibrosis may explain the pro-tumor niche of the ovary that supports the growth and spread of tumor cells originating from the fallopian tubes [ 31 ].…”

“…Furthermore, CAFs are the primary source of extracellular matrix components, such as collagen. Fibrosis is likely an important mediator of ovarian tumorigenesis, which is supported by recent research showing that use of metformin, which treats and prevents fibrosis, is associated with an 88% reduction in ovarian cancer incidence in women taking it for the treatment of type II diabetes [ 31 ]. In addition, the presence of age-associated fibrosis, which had been previously demonstrated in mice [ 32 ], was recently confirmed by McCloskey and colleagues in a cohort of human samples [ 31 ].…”

“…Fibrosis is likely an important mediator of ovarian tumorigenesis, which is supported by recent research showing that use of metformin, which treats and prevents fibrosis, is associated with an 88% reduction in ovarian cancer incidence in women taking it for the treatment of type II diabetes [ 31 ]. In addition, the presence of age-associated fibrosis, which had been previously demonstrated in mice [ 32 ], was recently confirmed by McCloskey and colleagues in a cohort of human samples [ 31 ]. This age-associated fibrosis may explain the pro-tumor niche of the ovary that supports the growth and spread of tumor cells originating from the fallopian tubes [ 31 ].…”

Ovulation and ovarian wound healing are impaired with advanced reproductive age

“…We and others have demonstrated that the ovarian stroma becomes fibrotic with age [15,16]. However, the functional consequences of this fibrotic transition in the ovary have not been investigated.…”

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“…Increasing age in women has long been understood to be associated with the gradual loss of fertility due to the shrinking ovarian reserve. In a recent article published in "Clinical Cancer Research", McCloskey et al [1] provided the first evidence that human ovaries undergo additional structural changes with age, including a significant change in the collagen architecture similar to fibrosis. Notably, we also reported preliminary data on the possible role of metformin in abrogating age-related ovarian fibrosis.…”