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Tissue Specific Pathways for Estrogen Regulation of Ovarian Cancer Growth and Metastasis

ABSTRACT: Menopausal estrogen (E2) replacement therapy increases the risk of estrogen receptor (ER)-positive epithelial ovarian cancers (EOC). Whether E2 is tumorigenic or promotes expansion of undiagnosed pre-existing disease is unknown. To determine E2 effects on tumor promotion, we developed an intraperitoneal mouse xenograft model using ZsGreen fluorescent ER- 2008 and ER+ PEO4 human EOC cells. Tumor growth was quantified by in vivo fluorescent imaging. In ER+ tumors, E2 significantly increased size, induced progesterone receptors, and promoted lymph node metastasis, confirming that ER are functional and foster aggressiveness. Laser captured human EOC cells from ER- and ER+ xenografted tumors were profiled for expression of E2-regulated genes. Three classes of E-regulated EOC genes were defined, but less than 10% were shared with E-regulated breast cancer genes. Since breast cancer selective ER modulators (SERM) are therapeutically ineffective in EOC, we suggest that our EOC-specific E-regulated genes can assist pharmacologic discovery of ovarian targeted SERM. 15 samples were included in this experiment with a 2x2 factorial design with 2 different cell lines (2008 and PEO4) and 2 different hormone treatments (E for Estrogen and C for Placebo Control) and 4 replicates per treatment. 1 sample was excluded (a replicate of PEO4 with C treatment) because of poor quality.

ORGANISM(S): Homo sapiens

SUBMITTER: Spillman MA

PROVIDER: S-ECPF-GEOD-22600 | biostudies-other | 2010 Nov

REPOSITORIES: biostudies-other

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Tissue-specific pathways for estrogen regulation of ovarian cancer growth and metastasis.

Project description:Menopausal estrogen (E2) replacement therapy increases the risk of estrogen receptor (ER)-positive epithelial ovarian cancers (EOC). Whether E2 is tumorigenic or promotes expansion of undiagnosed preexisting disease is unknown. To determine E2 effects on tumor promotion, we developed an intraperitoneal mouse xenograft model using ZsGreen fluorescent ER(-) 2008 and ER(+) PEO4 human EOC cells. Tumor growth was quantified by in vivo fluorescent imaging. In ER(+) tumors, E2 significantly increased size, induced progesterone receptors, and promoted lymph node metastasis, confirming that ERs are functional and foster aggressiveness. Laser-captured human EOC cells from ER(-) and ER(+) xenografted tumors were profiled for expression of E2-regulated genes. Three classes of E2-regulated EOC genes were defined, but <10% were shared with E2-regulated breast cancer genes. Because breast cancer selective ER modulators (SERM) are therapeutically ineffective in EOC, we suggest that our EOC-specific E2-regulated genes can assist pharmacologic discovery of ovarian-targeted SERM.

| S-EPMC3804411 | biostudies-literature

Tissue Specific Pathways for Estrogen Regulation of Ovarian Cancer Growth and Metastasis

Project description:Menopausal estrogen (E2) replacement therapy increases the risk of estrogen receptor (ER)-positive epithelial ovarian cancers (EOC). Whether E2 is tumorigenic or promotes expansion of undiagnosed pre-existing disease is unknown. To determine E2 effects on tumor promotion, we developed an intraperitoneal mouse xenograft model using ZsGreen fluorescent ER- 2008 and ER+ PEO4 human EOC cells. Tumor growth was quantified by in vivo fluorescent imaging. In ER+ tumors, E2 significantly increased size, induced progesterone receptors, and promoted lymph node metastasis, confirming that ER are functional and foster aggressiveness. Laser captured human EOC cells from ER- and ER+ xenografted tumors were profiled for expression of E2-regulated genes. Three classes of E-regulated EOC genes were defined, but less than 10% were shared with E-regulated breast cancer genes. Since breast cancer selective ER modulators (SERM) are therapeutically ineffective in EOC, we suggest that our EOC-specific E-regulated genes can assist pharmacologic discovery of ovarian targeted SERM. 15 samples were included in this experiment with a 2x2 factorial design with 2 different cell lines (2008 and PEO4) and 2 different hormone treatments (E for Estrogen and C for Placebo Control) and 4 replicates per treatment. 1 sample was excluded (a replicate of PEO4 with C treatment) because of poor quality.

2011-05-13 | E-GEOD-22600 | biostudies-arrayexpress

Tissue Specific Pathways for Estrogen Regulation of Ovarian Cancer Growth and Metastasis

Project description:Menopausal estrogen (E2) replacement therapy increases the risk of estrogen receptor (ER)-positive epithelial ovarian cancers (EOC). Whether E2 is tumorigenic or promotes expansion of undiagnosed pre-existing disease is unknown. To determine E2 effects on tumor promotion, we developed an intraperitoneal mouse xenograft model using ZsGreen fluorescent ER- 2008 and ER+ PEO4 human EOC cells. Tumor growth was quantified by in vivo fluorescent imaging. In ER+ tumors, E2 significantly increased size, induced progesterone receptors, and promoted lymph node metastasis, confirming that ER are functional and foster aggressiveness. Laser captured human EOC cells from ER- and ER+ xenografted tumors were profiled for expression of E2-regulated genes. Three classes of E-regulated EOC genes were defined, but less than 10% were shared with E-regulated breast cancer genes. Since breast cancer selective ER modulators (SERM) are therapeutically ineffective in EOC, we suggest that our EOC-specific E-regulated genes can assist pharmacologic discovery of ovarian targeted SERM.

2011-05-13 | GSE22600 | GEO

Tissue Factor and Cancer: Regulation, Tumor Growth, and Metastasis.

Project description:There is a strong relationship between tissue factor (TF) and cancer. Many cancer cells express high levels of both full-length TF and alternatively spliced (as) TF. TF expression in cancer is associated with poor prognosis. In this review, the authors summarize the regulation of TF expression in cancer cells and the roles of TF and asTF in tumor growth and metastasis. A variety of different signaling pathways, transcription factors and micro ribonucleic acids regulate TF gene expression in cancer cells. The TF/factor VIIa complex enhances tumor growth by activating protease-activated receptor 2 signaling and by increasing the expression of angiogenic factors, such as vascular endothelial growth factor. AsTF increases tumor growth by enhancing integrin β1 signaling. TF and asTF also contribute to metastasis via multiple thrombin-dependent and independent mechanisms that include protecting tumor cells from natural killer cells. Finally, a novel anticancer therapy is using tumor TF as a target to deliver cytotoxic drugs to the tumor. TF may be useful in diagnosis, prognosis, and treatment of cancer.

| S-EPMC6546519 | biostudies-literature

TIPE1 Suppresses Growth and Metastasis of Ovarian Cancer.

Project description:TIPE1, a newly identified member in TIPE (TNFAIP8) family, plays an important role in tumorigenesis and immune regulation, but its role in ovarian cancer, especially in tumor metastasis, remains unknown. In the current study, we aimed to reveal the protein expression spectrum of TIPE1 in normal human tissues and explored its relationship with metastasis in ovarian cancer. The results of IHC staining showed that TIPE1 protein was not only detected in cytoplasm in most human tissues but also expressed in both cytoplasm and nucleus in squamous epithelium and some epithelial-derived cells with secretory functions, such as esophagus, cervix uteri and ovary, and thyroid gland. Moreover, TIPE1 protein was downregulated in ovarian cancer tissues compared with that in the paracancerous. More importantly, TIPE1 suppressed tumorigenesis and metastasis of ovarian cancer in vitro and in vivo, as evidence shows its ability to suppress growth, colony formation, migration, and epithelial-mesenchymal transition (EMT) of ovarian cancer. Taken together, our results demonstrate the suppressor role of TIPE1 in ovarian cancer metastasis, indicating TIPE1 might be a metastasis predictor and a novel therapeutic target for ovarian cancer.

| S-EPMC8195659 | biostudies-literature

CPT2 down-regulation promotes tumor growth and metastasis through inducing ROS/NFκB pathway in ovarian cancer.

Project description:BackgroundCarnitine palmitoyltransferase 2 (CPT2) is a rate-limiting enzyme involved in fatty acid β-oxidation (FAO) regulation. Recently, it has been increasingly recognized that lipid metabolism dysregulation is closely implicated in tumorigenesis. However, the involvement of CPT2 in the progression of cancer is still largely unclear, especially in ovarian cancer (OC).MethodsIn the present study, CPT2 expression and its clinical significance were determined in OC tissues and cells. The biological functions and molecular mechanisms of CPT2 in OC growth and metastasis were determined by in vitro and in vivo assays.FindingsWe found that CPT2 was frequently down-regulated in primary ovarian serous carcinomas, which is significantly correlated with poor survival of ovarian cancer patients. Functional experiments revealed that CPT2 inhibited OC cell growth and metastasis via suppression of G1/S cell cycle transition and epithelial to mesenchymal transition (EMT), as well as induction of cell apoptosis. Mechanistically, suppression of ROS/NFκB signaling pathway by increasing fatty acid oxidation-derived NADPH production was involved in the anti-tumorigenic functions of CPT2 in OC cells.InterpretationAltogether, our findings demonstrate that CPT2 functions as a potential tumor suppressor in OC progression. CPT2 may serve as a novel prognostic marker and therapeutic target in OC.

| S-EPMC7821038 | biostudies-literature

Host Wnt5a Potentiates Microenvironmental Regulation of Ovarian Cancer Metastasis.

Project description:The noncanonical Wnt ligand Wnt5a is found in high concentrations in ascites of women with ovarian cancer. In this study, we elucidated the role of Wnt5a in ovarian cancer metastasis. Wnt5a promoted ovarian tumor cell adhesion to peritoneal mesothelial cells as well as migration and invasion, leading to colonization of peritoneal explants. Host components of the ovarian tumor microenvironment, notably peritoneal mesothelial cells and visceral adipose, secreted Wnt5a. Conditional knockout of host WNT5A significantly reduced peritoneal metastatic tumor burden. Tumors formed in WNT5A knockout mice had elevated cytotoxic T cells, increased M1 macrophages, and decreased M2 macrophages, indicating that host Wnt5a promotes an immunosuppressive microenvironment. The Src family kinase Fgr was identified as a downstream effector of Wnt5a. These results highlight a previously unreported role for host-expressed Wnt5a in ovarian cancer metastasis and suggest Fgr as a novel target for inhibition of ovarian cancer metastatic progression.Significance: This study establishes host-derived Wnt5a, expressed by peritoneal mesothelial cells and adipocytes, as a primary regulator of ovarian cancer intraperitoneal metastatic dissemination and identifies Fgr kinase as novel target for inhibition of metastasis.

| S-EPMC8245162 | biostudies-literature

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

Project description: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.

| S-EPMC6317723 | biostudies-literature

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| S-EPMC3731129 | biostudies-literature

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| S-EPMC7578908 | biostudies-literature

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