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.

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.

Natural history of ovarian high-grade serous carcinoma from time effects of ovulation inhibition and progesterone clearance of p53-defective lesions.

High-grade serous carcinoma is the most common and devastating type of ovarian cancer; its etiology, mechanism of malignant transformation, and origin remain controversial. Recent studies have identified secretory cells at the fimbria of the fallopian tube as the cell-of-origin of high-grade serous carcinoma, acquiring TP53 mutation, evolving to tubal precursor lesions, including "p53 signature" and serous tubal intraepithelial carcinoma, and metastasizing to the ovary as clinically evident ovarian cancer. The etiological mechanisms associated with known epidemiological risk factors, i.e., ovulation and retrograde menstruation, have also been suggested. Mutagens and transforming growth factors, such as reactive oxygen species and insulin-like growth factor axis proteins, as well as the apoptosis-rescuing protein hemoglobin are abundantly present in the ovulatory follicular fluid and peritoneum fluid, which bathes the fimbrial epithelium, and induces malignant transformation after repeated exposure. In accordance with the proposed cleansing effect of progesterone from studies on oral contraceptive use or term pregnancy, a recent study indicated that the p53-null tubal epithelial cells are selectively cleared by progesterone depending on its progesterone receptor. In this report, by analyzing different time effects of oral contraceptive use or pregnancy in the prevention of ovarian cancer and by aligning them with the carcinogenic and cleansing clearance concepts of ovulation and progesterone, as well as the fact of progressive loss of progesterone receptor during tubal transformation, we deduced the natural history of ovarian high-grade serous carcinoma. The natural history begins at the first ovulation and spans for more than 30 years, taking 10 years from the normal tubal epithelium to the "p53 signature" status, another 15 years to progesterone receptor negative serous tubal intraepithelial carcinoma, and a final 5+ years to high-grade serous carcinoma. The estimated natural history may help understand the pathogenesis of high-grade serous carcinoma and defines the window for early detection and chemoprevention.

Comparison of survival outcomes of neoadjuvant therapy and direct surgery in IB2/IIA2 cervical adenocarcinoma: a retrospective study.

PURPOSE: This retrospective study compared the efficacy and survival of patients with cervical adenocarcinoma (IB2/IIA2; FIGO2009) treated with neoadjuvant chemotherapy before radical surgery (NACT + RS), neoadjuvant chemoradiation therapy before radical surgery (NACRT + RS), or primary radical surgery (RS). METHODS: Between January 2008 and November 2015, 91 patients diagnosed with stage IB2/IIA2 cervical adenocarcinoma were enrolled, including 29 patients who received RS, 24 patients who received NACT + RS, and 38 patients who received NACRT + RS. RESULTS: The characteristics of patients were balanced among the three groups, and the median follow-up time was 72 months. The 5 year disease-free survival (DFS) rate was 75.8% and the 5 year overall survival (OS) rate was 85.0%. Univariate analysis revealed that effectiveness of neoadjuvant treatment, tumor size, lymph node metastases, and depth of stromal invasion were the factors predicting recurrence and mortality. Multivariate Cox proportional analysis revealed that the occurrence of a lymph node metastasis was an independent prognostic factor of DFS (hazard ratio [HR] = 0.223; 95% confidence interval [CI]: 0.060-0.827) and OS (HR = 0.088; 95% CI: 0.017-0.470). On survival analysis of preoperative adjuvant chemotherapy and primary surgery, the 5 year OS (P = 0.010) and DFS (P = 0.016) rates for the NACRT + RS group were significantly lower than those for the RS group. CONCLUSION: Stage IB2/IIA2 cervical adenocarcinoma patients who received primary RS had a better DFS and OS than those who received preoperative NACRT. There was no significant difference when compared to the preoperative NACT group.

SOX1 and PAX1 Are Hypermethylated in Cervical Adenocarcinoma and Associated with Better Prognosis.

BACKGROUND: The increased risk and poor survival outcome of cervical adenocarcinoma (CAC) demand for effective early diagnostic biomarkers that can predict the disease progression and outcome. The purpose of this study was to investigate the value of methylation status of SOX1 and PAX1 in the detection and prognosis of CAC. METHODS: We performed a quantitative methylation-specific polymerase chain reaction in 205 cervical paraffin-embedded specimens (175 CACs, 30 noncancer cervical tissues). Overall and progression-free survival (OS and PFS, respectively) rates were calculated and compared using the Kaplan-Meier method. The prognostic value of SOX1m and PAX1m on CAC patients was assessed by the Cox regression model. A mathematical formula combining SOX1m , PAX1m , and age was constructed for survival prediction. RESULTS: The methylation status of SOX1 and PAX1 was higher in CAC tissues than in noncancer cervical tissues. In addition, SOX1m -positive CAC patients showed a higher 5-year OS rate than SOX1m -negative patients. In CAC patients with smaller tumor size (<4 cm), the PAX1m -positive group showed a higher 5-year PFS rate than the PAX1m -negative group. In the algorithm combining SOX1m , PAX1m , and age, the low-risk group showed a better 5-year OS and PFS rate than the high-risk group. CONCLUSION: SOX1 and PAX1 methylation levels are higher in CAC than in normal cervical tissues and are potential biomarkers for monitoring CAC prognosis.

High methylation of ZNF582 in cervical adenocarcinoma affects radiosensitivity and prognosis.

BACKGROUND: Our previous study demonstrated hypermethylation of the ZNF582 gene in cervical cancer, but its prognostic value in cervical cancer, especially in cervical adenocarcinoma (CAC), remains unclear. The present study aimed to investigate the value of ZNF582 gene methylation for diagnosis and prediction of radiochemotherapy sensitivity and prognosis in CAC. METHODS: We first determined ZNF582 methylation levels using quantitative methylation-specific PCR in a training set. Disease-free survival and overall survival (DFS and OS) rates were estimated using the Kaplan-Meier method. A Cox regression model was used to assess the prognostic significance of ZNF582 gene methylation in CAC patients. Immunohistochemistry was used to test ZNF582 protein expression in CAC tissues, and an MTT assay evaluated the sensitivity of Hela cells (with or without ZNF582 transfection) to radiation and chemotherapy. RESULTS: The ZNF582 gene showed a higher level of methylation in the CAC group than in the noncancer group, and patients negative for ZNF582 methylation had worse prognoses. We also found that ZNF582 methylation levels were reduced in concomitant chemo-radio-therapy (NCRT) patients compared with that in non-NCRT patients. Methylation-negative status was correlated with high ZNF582 protein expression, and ZNF582 protein overexpression could increase resistance to radiation and chemotherapy in Hela cells. CONCLUSIONS: Aberrant high methylation of ZNF582 may be a potential biomarker for CAC detection and prognosis monitoring. Overexpression of ZNF582 protein could increase CAC chemoradiotherapy resistance.