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1.
J Cancer ; 12(20): 6021-6030, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34539876

RESUMO

Background: Trp53-/- mice are prone to develop lymphomas at old ages. Factors promoting this tumorigenesis are unknown. Here, we showed human ovulatory follicular fluid (FF) largely promotes lymphomagenesis in Trp53-/- mice at earlier ages. Meanwhile, we clarified that IGF2 and HGF are important cell transforming factors within FF. Methods: To induce tumor formation, 5% FFs, 100 ng/ml IGF2, 20 ng/ml HGF, or both IGF2 and HGF in a volume of 200 µl PBS, was injected into 8-wk-old female Trp53 -/- mice at the mammary fat pad. The injection was repeated weekly for up to 7 weeks or extending to 13 weeks to observe the accumulative incidence of lymphomagenesis. Immunohistochemistry staining and gene rearrangement analysis were used to identify the tumor type. Results: By injecting FF into the mammary fat pad weekly, lymphomas developed in 8/16 (50%) of mice by seven weeks. We identified IGF2 and HGF in FF is largely responsible for this activity. The same weekly injection of IGF2, HGF, and their combination induced lymphomas in 4/11 (36%), 3/8 (38%), and 6/9 (67%) mice, respectively. Interestingly, tumorigenesis was induced only when those were injected into the adipose tissues in the mammary gland, but not when injected into non-adipose sites. We also found this tumor-promoting activity is estradiol (E2)-dependent and relies on estrogen receptor (ER) α expression in the adipose stroma. No tumor or only tiny tumor was yielded when the ovaries were resected or when ER is antagonized. Finally, an extension of the weekly FF-injection to 13 weeks did not further increase the lymphomagenesis rate, suggesting an effect on pre-initiated cancer cells. Conclusions: Taken together, the study disclosed a robust tumor-promoting effect of IGF2 and HGF in the p53 loss-initiated lymphomagenesis depending on an adipose microenvironment in the presence of E2. In light of the clarity of this spontaneous tumor promotion model, we provide a new tool for studying p53-mediated lymphomagenesis and suggest that, as a chemoprevention test, this is a practical model to perform.

2.
Cell Rep ; 18(11): 2557-2565, 2017 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-28297660

RESUMO

High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs) and hemoglobin-rich follicular fluid (FF) after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4) could eliminate p53-defective FT cells. Here we show that P4, via P4 receptors (PRs), induces necroptosis in Trp53-/- mouse oviduct epithelium and in immortalized human p53-defective fimbrial epithelium through the TNF-α/RIPK1/RIPK3/MLKL pathway. Necroptosis occurs specifically at diestrus, recovers at the proestrus phase of the estrus cycle, and can be augmented with P4 supplementation. These results reveal the mechanism of the well-known ability of progesterone to prevent ovarian cancer.


Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/patologia , Tubas Uterinas/patologia , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/prevenção & controle , Progesterona/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/patologia , Ciclo Estral/efeitos dos fármacos , Feminino , Humanos , Camundongos , Necrose , Gradação de Tumores , Neoplasias Císticas, Mucinosas e Serosas/metabolismo , Oviductos/efeitos dos fármacos , Oviductos/patologia , Oviductos/ultraestrutura , Receptores de Progesterona/metabolismo , Transdução de Sinais/efeitos dos fármacos
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