The signaling events involved in the onset of ovarian cancer from the fallopian tube epithelium (FTE) are crucial for early detection and treatment of the disease, but they remain poorly defined. Conditional homozygous knockout of PTEN mediated by PAX8-cre recombinase was sufficient to drive endometrioid and serous borderline ovarian carcinoma, providing the first model of FTE-derived borderline tumors. In addition, heterozygous PTEN deletion in the FTE resulted in hyperplasia, providing a model to study early events of human ovarian pathogenesis. To uncover the mechanism underlying the invasion of cancerous oviductal cells to the ovary, PTEN-deficient murine oviductal cells were developed and tagged with green fluorescent protein. Loss of PTEN increased cell migration, invasion, and upregulated WNT4, a key regulator of Müllerian duct development during embryogenesis. Further investigation revealed that WNT4 was required for increased migration and colonization of the ovary by PTEN-deficient oviductal cells in a β-catenin independent manner. Human tumor microarrays and ovarian cancer cells lines confirmed WNT4 expression in cancer and its role in migration. Together, these findings provide a novel model to study the mechanism of fallopian tube tumor initiation and invasion to the ovary mediated by loss of PTEN, which may help to define early events of human ovarian carcinogenesis.
Factors that stimulate the migration of fallopian tube epithelial (FTE)-derived high-grade serous ovarian cancer (HGSOC) to the ovary are poorly elucidated. This study characterized the effect of the ovarian hormone, activin A, on normal FTE and HGSOC. Activin A and TGFβ1 induced an epithelial-to-mesenchymal transition in murine oviductal epithelial (MOE) cells, but only activin A increased migration. The migratory effect of activin A was independent of Smad2/3 and required phospho-AKT, phospho-ERK, and Rac1. Exogenous activin A stimulated migration of the HGSOC cell line OVCAR3 through a similar mechanism. Activin A signaling inhibitors, SB431542 and follistatin, reduced migration in OVCAR4 cells, which expressed activin A subunits (encoded by INHBA). Murine superovulation increased phospho-Smad2/3 immunostaining in the FTE. In Oncomine, transcripts for the activin A receptors (ACVR1B and ACVR2A) were higher in serous tumors relative to the normal ovary, while inhibitors of activin A signaling (INHA and TGFB3) were lower. High expression of both INHBA and ACVR2A, but not TGFβ receptors or co-receptors, was associated with shorter disease-free survival in serous cancer patients. These results suggest activin A stimulates migration of FTE-derived tumors to the ovary.
Pregnancy loss is common during the peri-implantation period in mammals when glucose is required for both embryonic development and decidualization of the endometrium. As the uterus cannot synthesize glucose, all glucose must come directly from maternal circulation as needed or transiently stored as the macromolecule glycogen. Glycogen acts as a glucose reservoir, storing up to 55 000 glucose moieties per molecule. Endometrial glycogen concentrations are correlated with fertility in humans, indicating that glycogen is an essential source of glucose during early pregnancy. In humans and primates, endometrial glycogen concentrations peak during the luteal phase due to progesterone. In contrast, in rats and mink, estradiol triggers an accumulation of uterine glycogen during proestrus and estrus. In mated rats, the glycogen content of the endometrium increases again after implantation due to high levels of glycogen stored in the decidua. In mink, endometrial glycogen reserves are localized in the uterine epithelia at estrus. These reserves are mobilized before implantation, suggesting they are used to support embryonic growth. Uterine glycogen concentrations continue to decrease after implantation in mink, probably due to a lack of decidualization. How ovarian steroids stimulate glycogenesis in the endometrium is unclear, but current evidence suggests that estradiol/progesterone interacts with insulin or insulin-like growth factor signaling. In summary, endometrial glycogen is an essential source of glucose during the peri-implantation period. More work is needed to characterize differences among species, elucidate the fate of the glucose liberated from glycogen, and understand how ovarian steroids regulate glycogen metabolism in the uterus.
Foods and botanical supplements can interfere with the endocrine system through the presence of phytosteroids – chemicals that interact with steroids receptors. Phytoestrogens are well studied, but compounds such as kaempferol, apigenin, genistein, ginsenoside Rf, and glycyrrhetinic acid have been shown to interact with non-estrogen nuclear receptors. These compounds can have agonist, antagonist, or mixed agonist/antagonist activity depending on compound, receptor, cell line or tissue, and concentration. Some phytosteroids have also been shown to inhibit steroid metabolizing enzymes, resulting in biological effects through altered endogenous steroid concentrations. An interesting example, compound A (4-[1-chloro-2-(methylamino)ethyl]phenyl acetate hydrochloride (1:1)) is a promising selective glucocorticoid receptor modulator (SGRM) based on a phytosteroid isolated from Salsola tuberculatiformis Botschantzev. Given that $6.9 billion of herbal supplements are sold each year, is clear that further identification and characterization of phytosteroids is needed to ensure the safe and effective use of botanical supplements.
High grade serous ovarian cancer (HGSOC) is the fifth leading cause of cancer deaths among women. New evidence suggests that HGSOC arises in the fallopian tube and then colonizes the ovary before spreading into the peritoneal space. Therefore, due to the proximity of this metastasis, an experimental design was optimized using imaging mass spectrometry to capture the spatial composition of small molecules uniquely expressed when fallopian-tube-derived tumor cells were grown in the microenvironment of the ovary as a model of primary metastasis. The observed mass-to-charge ratios (m/z’s) that were induced specifically in coculture represent small molecules that may contribute to the metastasis of HGSOC selectively to the ovary. Human fallopian tube epithelial HGSOC and tumorigenic murine oviductal epithelial cells, but not normal cell types, repeatedly induced a signal from the ovary at m/z 170. This signal was identified as norepinephrine, which was confirmed to stimulate invasion of ovarian cancer cells lacking wild-type p53. These molecules may reveal pathways that contribute to metastasis and biological targets for therapeutic intervention to block ovarian metastasis of fallopian-tube-derived HGSOC. The developed mass spectrometry method can be adapted to other mammalian-based model systems for investigation of untargeted metabolomics that facilitate metastasis.
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