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

Published on Dec 28, 2017in Cancer Letters7.36
· DOI :10.1016/J.CANLET.2017.09.028
Elizabeth Loughran7
Estimated H-index: 7
(ND: University of Notre Dame),
Ryan C. Phan1
Estimated H-index: 1
(ND: University of Notre Dame)
+ 12 AuthorsM. Sharon Stack17
Estimated H-index: 17
(ND: University of Notre Dame)
Sources
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.
📖 Papers frequently viewed together
20185.70Neoplasia
9 Citations
12 Citations
References44
Newest
#1Elizabeth Loughran (ND: University of Notre Dame)H-Index: 7
#2Annemarie K. Leonard (ND: University of Notre Dame)H-Index: 2
Last. M. Sharon Stack (ND: University of Notre Dame)H-Index: 17
view all 17 authors...
Abstract Ovarian cancer, the most deadly gynecological malignancy in U.S. women, metastasizes uniquely, spreading through the peritoneal cavity and often generating widespread metastatic sites before diagnosis. The vast majority of ovarian cancer cases occur in women over 40 and the median age at diagnosis is 63. Additionally, elderly women receive poorer prognoses when diagnosed with ovarian cancer. Despite age being a significant risk factor for the development of this cancer, there are little...
9 CitationsSource
#1Nicolas Wentzensen (NIH: National Institutes of Health)H-Index: 80
#2Elizabeth M. Poole (Harvard University)H-Index: 34
Last. Shelley S. Tworoger (Harvard University)H-Index: 82
view all 54 authors...
PurposeAn understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3).Patients and MethodsAmong 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competin...
177 CitationsSource
#1Lan G. Coffman (UM: University of Michigan)H-Index: 15
#2Daniela Burgos-Ojeda (UM: University of Michigan)H-Index: 5
Last. Ronald J. Buckanovich (UM: University of Michigan)H-Index: 42
view all 6 authors...
Emerging evidence suggest that many high-grade serous "ovarian" cancers (HGSOC) start in the fallopian tube. Cancer cells are then recruited to the ovary and then spread diffusely through the abdomen. The mechanism of ovarian cancer spread was thought to be largely due to direct shedding of tumor cells into the peritoneal cavity with vascular spread being of limited importance. Recent work challenges this dogma, suggesting hematogenous spread of ovarian cancer may play a larger role in ovarian c...
41 CitationsSource
#1Kyle A. Lewellen (ND: University of Notre Dame)H-Index: 2
#2Matthew N. Metzinger (ND: University of Notre Dame)H-Index: 3
Last. M. Sharon Stack (ND: University of Notre Dame)H-Index: 17
view all 4 authors...
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States. Mortality is due to diagnosis of 75% of women with late stage disease, when metastasis is already present. EOC is characterized by diffuse and widely disseminated intra-peritoneal metastasis. Cells shed from the primary tumor anchor in the mesothelium that lines the peritoneal cavity as well as in the omentum, resulting in multi-focal metastasis, often in the presence of peritoneal asc...
9 CitationsSource
#1Valerie McGuire (Stanford University)H-Index: 43
#2Patricia HartgeH-Index: 112
Last. Alice S. Whittemore (Stanford University)H-Index: 108
view all 9 authors...
Background: Several studies have suggested that the ovarian cancer risk reductions associated with parity and oral contraceptive use are weaker in postmenopausal than premenopausal women; yet little is known about the persistence of these reductions as women age. This question gains importance with the increasing numbers of older women in the population. Methods: We addressed the question using data from three large US cohort studies involving 310,290 white women aged 50+ years at recruitment, o...
12 CitationsSource
#1Yueying Liu (ND: University of Notre Dame)H-Index: 16
#2Matthew N. Metzinger (ND: University of Notre Dame)H-Index: 3
Last. M. Sharon Stack (ND: University of Notre Dame)H-Index: 17
view all 22 authors...
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy, with high mortality attributable to widespread intraperitoneal metastases. Recent meta-analyses report an association between obesity, ovarian cancer incidence, and ovarian cancer survival, but the effect of obesity on metastasis has not been evaluated. The objective of this study was to use an integrative approach combining in vitro , ex vivo , and in vivo studies to test the hypothesis that obesity contr...
48 CitationsSource
#1Tiffany A. Katz (University of Pittsburgh)H-Index: 10
#2Serena Liao (University of Pittsburgh)H-Index: 8
Last. Adrian V. Lee (University of Pittsburgh)H-Index: 68
view all 13 authors...
The most effective natural prevention against breast cancer is an early first full term pregnancy. Understanding how the protective effect is elicited will inform the development of new prevention strategies. To better understand the role of epigenetics in long-term protection, we investigated parity-induced DNA methylation in the mammary gland. FVB mice were bred or remained nulliparous and mammary glands harvested immediately after involution (early), or 6 months following involution (late), a...
15 CitationsSource
#1Katherine B. Chiappinelli (Johns Hopkins University)H-Index: 16
#2Pamela L. StrisselH-Index: 36
Last. Reiner StrickH-Index: 45
view all 21 authors...
We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a type I interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response 2-fold and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV ove...
765 CitationsSource
#1Simon AndersH-Index: 31
#2Paul Theodor PylH-Index: 6
Last. Wolfgang HuberH-Index: 94
view all 3 authors...
Motivation: A large choice of tools exists for many standard tasks in the analysis of high-throughput sequencing (HTS) data. However, once a project deviates from standard workflows, custom scripts are needed. Results: We present HTSeq, a Python library to facilitate the rapid development of such scripts. HTSeq offers parsers for many common data formats in HTS projects, as well as classes to represent data, such as genomic coordinates, sequences, sequencing reads, alignments, gene model informa...
9,316 CitationsSource
#1Sagar Ghosh (University of Texas Health Science Center at San Antonio)H-Index: 16
#2Fei Gu (University of Texas Health Science Center at San Antonio)H-Index: 18
Last. Rong Li (University of Texas Health Science Center at San Antonio)H-Index: 33
view all 10 authors...
Early pregnancy in women by the age of 20 is known to have a profound effect on reduction of lifelong breast cancer risk as compared to their nulliparous counterparts. Additional pregnancies further enhance the protection against breast cancer development. Nationwide trend of delayed pregnancy may contribute to the recently reported increase in the incidence of advanced breast cancer among young women in this country. The underlying mechanism for the parity-associated reduction of breast cancer ...
17 CitationsSource
Cited By1
Newest
#1Elizabeth Loughran (ND: University of Notre Dame)H-Index: 7
#2Annemarie K. Leonard (ND: University of Notre Dame)H-Index: 2
Last. M. Sharon Stack (ND: University of Notre Dame)H-Index: 17
view all 17 authors...
Abstract Ovarian cancer, the most deadly gynecological malignancy in U.S. women, metastasizes uniquely, spreading through the peritoneal cavity and often generating widespread metastatic sites before diagnosis. The vast majority of ovarian cancer cases occur in women over 40 and the median age at diagnosis is 63. Additionally, elderly women receive poorer prognoses when diagnosed with ovarian cancer. Despite age being a significant risk factor for the development of this cancer, there are little...
9 CitationsSource