Differential expression of hypoxia-inducible factors related to the invasiveness of epithelial ovarian cancer.

Ovarian cancer is the most lethal gynecological cancer, and it is frequently diagnosed at advanced stages, with recurrences after treatments. Treatment failure and resistance are due to hypoxia-inducible factors (HIFs) activated by cancer cells adapt to hypoxia. IGFBP3, which was previously identified as a growth/invasion/metastasis suppressor of ovarian cancer, plays a key role in inhibiting tumor angiogenesis. Although IGFBP3 can effectively downregulate tumor proliferation and vasculogenesis, its effects are only transient. Tumors enter a hypoxic state when they grow large and without blood vessels; then, the tumor cells activate HIFs to regulate cell metabolism, proliferation, and induce vasculogenesis to adapt to hypoxic stress. After IGFBP3 was transiently expressed in highly invasive ovarian cancer cell line and heterotransplant on mice, the xenograft tumors demonstrated a transient growth arrest with de-vascularization, causing tumor cell hypoxia. Tumor re-proliferation was associated with early HIF-1α and later HIF-2α activations. Both HIF-1α and HIF-2α were related to IGFBP3 expressions. In the down-expression of IGFBP3 in xenograft tumors and transfectants, HIF-2α was the major activated protein. This study suggests that HIF-2α presentation is crucial in the switching of epithelial ovarian cancer from dormancy to proliferation states. In highly invasive cells, the cancer hallmarks associated with aggressiveness could be activated to escape from the growth restriction state.

IGFBP3 inhibits angiogenesis through intracellular regulation of THBS1 expression.

Insulin-like growth factor binding protein-3 (IGFBP3) has been postulated to be a mediator of growth suppression signaling. It was shown to function as a suppressor of invasion in epithelial ovarian cancer (EOC). In this study, we identified an angiogenesis inhibitor, thrombospondin-1 (THBS1), which correlated with IGFBP3 expression in EOC cells. After restoring IGFBP3 expression in an EOC cell line using an inducible plasmid, the transfectants showed an increase in IGFBP3 associated with a parallel increase in THBS1. IGFBP3 decreased cell capillary tube formation in HUVECs, which was reversed after anti-THBS1 treatment. IGFBP3 also decreased blood vessel development in chick embryo chorioallantoic membrane (CAM) assay, which was reversed after THBS1 silencing using THBS1 siRNA. Heterotransplantation of IGFBP3 transfectants significantly decreased tumor growth and vascular formation. Luciferase promoter assay illustrated that THBS1 promoter was activated in the presence of both intracellular and extracellular IGFBP3. The signal was stronger in intracellular IGFBP3 expression than that in extracellular IGFBP3 neutralization. In conclusion, we have identified a novel association between IGFBP3 expression and THBS1 elevation, which consequently results in a decrease in angiogenesis. IGFBP3 could activate THBS1 through promoter regulation mainly via an intracellular signaling pathway. Such angiogenesis-regulating ability could be associated with tumor progression and may represent a major function of IGFBP3 as an onco-suppressor in the pathogenesis of ovarian cancer.

Learning curve in concurrent application of laparoscopic and robotic-assisted hysterectomy with lymphadenectomy in endometrial cancer.

OBJECTIVE: To evaluate the concurrent interaction of laparoscopic and robotic-assisted surgery in the initial learning period of endometrial cancer staging. MATERIALS AND METHODS: A retrospective cohort study was performed for the first 44 consecutive patients with endometrial cancer underwent laparoscopic (LSS) or robotic-assisted staging surgery (RSS) from February 2012 to October 2015 by a single surgeon in a tertiary care referral hospital. Demographics, diagnosis, perioperative variables, and complications were recorded. Quality of surgery was determined by the number of lymph nodes dissected and learning curve was estimated by operative time with respect to chronologic order of operation. RESULTS: Twenty-four patients received LSS and 20 patients received RSS. RSS required longer operative time, but obtained more total number of lymph nodes compared with LSS (286.9 vs. 201.9 min (p < 0.001); 26.2 vs. 20.7 (p < 0.05), respectively. There were no difference in blood loss, number of para-aortic nodes removed, complications and hospital stay between the two types of surgery. An additive model based on tumor grade, body mass index, estimated blood loss and chronological order of operation was constructed to fit operative time of these two types of surgery. Proficiency of achievement was not observed for LSS and was 6 for RSS. CONCLUSIONS: Operative time was longer but Lymph node dissection was easier in RSS. Learning curve for LSS to maintain similar surgical quality as RSS was not observed. The concurrent use of robotic platform in the initial practice of minimally invasive staging surgery could optimize surgical technique for LSS.

Clinical outcome affected by tumor morcellation in unexpected early uterine leiomyosarcoma.

OBJECTIVE: To evaluate the influence of morcellation during surgery on clinical outcome in unexpected early uterine leiomyosarcomas (LMSs) using a tumor-size-matched comparison study. MATERIALS AND METHODS: We retrospectively reviewed the clinicopathological characteristics, prognostic factors, and treatment outcomes of patients with Stage 1 uterine LMS from April 1993 to April 2014 in a university-based tertiary hospital. Patients who received morcellation via abdomen, vagina, or laparoscopy were compared with tumor-size-matched patients who underwent total hysterectomy without morcellation. RESULTS: In total, 34 consecutive patients were identified, including 14 patients with morcellation and 20 patients without morcellation. There were no significant difference between the two groups of patients in age, parity, mitotic count, lymph node dissection, and adjuvant therapy. Six (42.9%) patients with morcellation were reoperated at 18.5 days after the initial surgery. Tumor recurrence rates at local and distant sites showed no difference between the two groups of patients. Patients with morcellation had a marginally lower disease-free survival (DFS) and overall survival (OS) rates compared with patients without morcellation. In univariate analysis, morcellation was marginally significantly associated with lower DFS [hazard ratio (HR), 2.62; 95% confidence interval, 0.89-7.71; p = 0.08] and OS (HR, 2.70; 95% confidence interval, 0.89-8.20; p = 0.08). In multivariate analysis, morcellation was associated with lower OS in marginal significance (HR, 2.94; 95% confidence interval, 0.83-10.39; p = 0.09). CONCLUSION: Tumor morcellation did not increase the abdominal-pelvic recurrence rate, but may be associated with lower DFS and OS in Stage 1 LMS.