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

Abstract

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.

Autocrine IGF-II-Associated Cancers: From a Rare Paraneoplastic Event to a Hallmark in Malignancy

“…Such a working hypothesis envisions systemic (bloodstream) circulating IGFs in cancer as an epiphenomenon rather than a causal and/or primary risk factor. Indeed, our interpretation of the reviewed literature supports a view by which circulating IGFs levels are secondary to underlying processes such as cancer-associated inflammation [89] and/or tumor-microenvironment-mediated hormonal/growth factor loops [90][91][92][93], where prolonged, locally enhanced IGFs signals in parenchymal and/or stromal cancer components may underlie the epidemiologically (IGF-I) and/or clinically (hypoglycemia by big-IGF-II) reported ligand-specific systemic spillover effects. Our analysis of the published literature on the role of IGFs with specific regards to solid cancers is compliant with our evidence-based premises, pointing at a differential production source (IGF-I from cancer stroma acting as paracrine factor, and IGF-II from overt cancer cells acting as an autocrine factor, respectively) and pattern (with pro-hormone IGF-II variant being preferred in the cancer-secreted form).…”