Ovulation sources coagulation protease cascade and hepatocyte growth factor to support physiological growth and malignant transformation

Huang, Hsuan-Shun; Chen, Pao-Chu; Chu, Sung‐Chao; Lee, Ming-Hsun; Huang, Chi-Ya; Chu, Tang–Yuan

doi:10.1016/j.neo.2021.09.006

Cited by 11 publications

(34 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to the endometriotic lesions, the fimbriae, which pick up oocytes, are exposed to the ovulatory follicular fluid (FF) during and after ovulation. The FF carries growth factors, such as IGF2 and hepatocyte growth factor (HGF), to ensure the regeneration of damaged fimbrial and ovarian epithelia after ovulation, as well as the malignant transformation [ 21 , 34 , 35 , 36 ]. Ovulation sources the follicular ingredients into the peritoneal fluid and constitutes the main contents of the peritoneal fluid, which is regarded as an ovarian exudate [ 37 , 38 ].…”

Section: Missing Link 1: Ovulation Is An Overlooked Etiological Facto...mentioning

confidence: 99%

“…The FF has a high reserve of these coagulation cascade proteins and HGFA/HGF. The cascade is slowly and continuously activated by a tissue factor released in the FF and peritoneal fluid [ 36 ]. Thus, c-MET-expressing tissues, including the FTE and the endometriosis lesions, all receive the signal and may exhibit growth and invasion phenotypes [ 44 ].…”

Section: Missing Link 1: Ovulation Is An Overlooked Etiological Facto...mentioning

confidence: 99%

“…This prolonged HGF activity, which lasts for the whole menstrual cycle, promotes the proliferative repair of the ovarian surface and fallopian tube fimbrial epithelia, as well as the growth of the corpus luteum. The same activity also inadvertently promotes the malignant transformation of the fimbrial epithelium [ 36 ] and, likely, the development of endometriosis.…”

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

The Double Engines and Single Checkpoint Theory of Endometriosis

et al. 2022

Self Cite

View full text Add to dashboard Cite

Endometriosis is a chronic disease characterized by the ectopic localization of the endometrial tissue in the peritoneal cavity. Consequently, it causes local pathological changes and systemic symptoms, affecting at least one in every ten women. This disease is difficult to diagnose early, it is prone to dissemination, is difficult to eradicate, tends to recur, and is regarded as “a cancer of no kill”. Indeed, the development of endometriosis closely resembles that of cancer in the way of mutagenesis, pelvic spreading, and immunological adaptation. While retrograde menstruation has been regarded as the primary cause of endometriosis, the role of ovulation and menstrual stimuli in the development of endometriosis has long been overlooked. The development of ovarian and peritoneal endometrioses, similar to the development of high-grade serous carcinoma in the fallopian tube fimbriae with intraperitoneal metastasis, depends highly on the carcinogens released during ovulation. Moreover, endometriosis carries an extremely hypermutated genome, which is non-inferior to the ultra-mutated endometrial cancer. The hypermutation would lead to an overproduction of new proteins or neoantigens. Because of this, the developing endometriosis may have to turn on the PD-1/PDL-1 “self-tolerance” checkpoint to evade immune surveillance, leaving an Achilles tendon for an immune checkpoint blockade. In this review, we present the double engines and single checkpoint theory of the genesis of endometriosis, provide the current pieces of evidence supporting the hypothesis, and discuss the new directions of prevention and treatment.

show abstract

Section: Missing Link 1: Ovulation Is An Overlooked Etiological Facto...mentioning

confidence: 99%

Section: Missing Link 1: Ovulation Is An Overlooked Etiological Facto...mentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

The Double Engines and Single Checkpoint Theory of Endometriosis

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…The mechanisms of the ovulation-induced FTE transformation are becoming increasingly clear. Ovulatory follicular fluid (FF) contains high levels of various carcinogens, such as reactive oxygen species (ROS), insulin-like growth factor (IGF) axis proteins, and coagulation factor-hepatocyte growth factor (HGF) activation cascade proteinases, which confer a range of cell transformation phenotypes, including DNA double-strand breaks [ 8 , 9 ], stemness activation, clonal expansion [ 10 ], anchorage-independent growth, and xenograft tumorigenesis [ 10 , 11 ]. The transformation effect of ovulatory FF is not limited to the FTE transformation.…”

Section: Introductionmentioning

confidence: 99%

“…In all the previous studies, the pro-metastasis activities of ovulation were demonstrated by human FF exposure in vitro or ex vivo [ 8 , 10 , 11 ] or by co-injection of FF, transforming human FTE cells into the peritoneal cavity of immune-compromised mice [ 9 , 12 ]. An in vivo demonstration of the effect of ovulation on HGSC development is lacking.…”

Section: Introductionmentioning

confidence: 99%

Ovulation Enhances Intraperitoneal and Ovarian Seedings of High-Grade Serous Carcinoma Cells Originating from the Fallopian Tube: Confirmation in a Bursa-Free Mouse Xenograft Model

Hsu

Seenan

Wang

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

Background: Recently, new paradigms for the etiology and origin of ovarian high-grade serous carcinoma (HGSC) have emerged. The carcinogens released during ovulation transform fallopian tube epithelial cells, exfoliating and metastasizing to the peritoneal organs, including the ovaries. Solid in vivo evidence of the paradigms in a mouse model is urgently needed but is hampered by the differing tubo-ovarian structures. In mice, there is a bursa structure surrounding the distal oviduct and ovary. This, on one hand, prevents the direct influence of ovulatory follicular fluid (FF) on the exfoliated tumor cells. On the other hand, it hinders the seeding of exfoliated tumor cells into the ovary. Methods: In this study, we created a bursa-free mouse xenograft model to examine the effect of superovulation on peritoneal and ovarian metastases of transformed human tubal epithelial cells after intraperitoneal injection in NSG mice. Results: The bursa-free mouse model showed a better effect of ovulation on peritoneal metastasis. In this model, superovulation increased the number of transformed human tubal epithelial cell seedlings after intraperitoneal injection. Compared to the bursa-intact state, bursa-free ovaries were more vulnerable to external tumor seeding in either normal ovulation or superovulation state. Conclusions: This study provides the first in vivo evidence that intraperitoneal spreading of tubal HGSC cells is enhanced by ovulation. This study also demonstrated a mouse model for studying ovary-peritoneum interaction in cancer development.

show abstract

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

Chu

Khine

et al. 2023

Molecular Carcinogenesis

View full text Add to dashboard Cite

Incessant ovulation is believed to be a potential cause of epithelial ovarian cancer (EOC). Our previous investigations have shown that insulin‐like growth factor (IGF2) and hepatocyte growth factor (HGF) in the ovulatory follicular fluid (FF) contributed to the malignant transformation initiated by p53 mutations. Here we examined the individual and synergistic impacts of IGF2 and HGF on enhancing the malignant properties of high‐grade serous carcinoma (HGSC), the most aggressive type of EOC, and its precursor lesion, serous tubal intraepithelial carcinoma (STIC). In a mouse xenograft co‐injection model, we observed that FF co‐injection induced tumorigenesis of STIC‐mimicking cells, FE25. Co‐injection with IGF2 or HGF partially recapitulated the tumorigenic effects of FF, but co‐injection with both resulted in a higher tumorigenic rate than FF. We analyzed the different transformation phenotypes influenced by these FF growth signals through receptor inhibition. The IGF signal was necessary for clonogenicity, while the HGF signal played a crucial role in the migration and invasion of STIC and HGSC cells. Both signals were necessary for the malignant phenotype of anchoring‐independent growth but had little impact on cell proliferation. The downstream signals responsible for these HGF activities were identified as the tyrosine‐protein kinase Met (cMET)/mitogen‐activated protein kinase and cMET/AKT pathways. Together with the previous finding that the FF‐IGF2 could mediate clonogenicity and stemness activities via the IGF‐1R/AKT/mammalian target of rapamycin and IGF‐1R/AKT/NANOG pathways, respectively, this study demonstrated the cooperation of the FF‐sourced IGF and HGF growth signals in the malignant transformation and progression of HGSC through both common and distinct signaling pathways. These findings help develop targeted prevention of HGSC.

show abstract

Ovulation sources coagulation protease cascade and hepatocyte growth factor to support physiological growth and malignant transformation

Cited by 11 publications

References 51 publications

The Double Engines and Single Checkpoint Theory of Endometriosis

The Double Engines and Single Checkpoint Theory of Endometriosis

Ovulation Enhances Intraperitoneal and Ovarian Seedings of High-Grade Serous Carcinoma Cells Originating from the Fallopian Tube: Confirmation in a Bursa-Free Mouse Xenograft Model

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

Contact Info

Product

Resources

About