Insuline-Like Growth Factor-2 (IGF2) and Hepatocyte Growth Factor (HGF) Promote Lymphomagenesis in p53-null Mice in Tissue-specific and Estrogen-signaling Dependent Manners

Abstract

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.

Insulin‐like growth factor (IGF) and hepatocyte growth factor (HGF) in follicular fluid cooperatively promote the oncogenesis of high‐grade serous carcinoma from fallopian tube epithelial cells: Dissection of the molecular effects

“…The result is consistent with our early studies in a spontaneous lymphomagenesis model of Trp53‐null mice—injection of the same growth factors to the mammary fat pad induced early onset lymphomas. The combination of IGF2 and HGF also showed a synergistic effect 18 . Thus, IGF and HGF cooperatively promote oncogenesis in different cell lineages with preinitiated p53 deficiency.…”

“…When injected into the mammary fat pad of Trp53 −/− mice at a concentration equivalent to that in FF, IGF2, and HGF each induced lymphomas in 36% (4/11) and 38% (3/8) of the mice, respectively. When injected together, the tumorigenic frequency increased to 67% (6/9), a level even higher than that (50%, 8/16) of FF in the same mouse injection model 18 . IGF2 and HGF seem to exert a synergistic oncogenic effect in the Trp53‐knock‐out mice.…”

“…Exposure of fimbrial epithelium to the high level of reactive oxygen species (ROS) in FF would induce DNA double‐strand breaks 16,17 . When injected into the mammary fat pad of Trp53‐null mice, FF readily caused lymphomagenesis 16,18 . The oncogenic effect of ovulation in the genesis of EOC is supported by multiple epidemiology studies 19 .…”

“…After ovulation, IGF2 was released from insulin‐like growth factor‐binding protein (IGFBP) binding and acted on fimbrial epithelial cells to promote stemness and clonal expansion. In the p53‐ and Rb/CCNE1‐immortalized FTE cells, the signal would induce malignant transformation and tumorigenesis through the IGF‐1R/AKT/mammalian target of rapamycin (mTOR) and IGF‐1R/AKT/NANOG signaling pathways, respectively 18,27 …”

Heterocyclic compounds as a magic bullet for diabetes mellitus: a review

“… 120 Appropriate care and early diabetes diagnosis should be prioritized in order to lessen the impact of diabetes on a person and society. 121 Insulin is a vital hormone 122 that plays a key role in the development of human tissues 123 and leads to glucose homeostasis. 124 The active molecule of insulin is a small protein that contains two chains α and β which have two disulfide bonds.…”