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.
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.
Ovarian cancer is the most lethal gynecological cancer among women worldwide. The majority of malignant ovarian tumors are epithelial ovarian cancer and metastasis occurred in most patients at the time of diagnosis with worse outcome. New target therapy such as anti-angiogenesis therapy was proved to be effective to prolong progression free survival in epithelial ovarian cancer (EOC) patients. In our previous study, we have established an ovarian endometrioid carcinoma cell line OVTW59. By cDNA microarray analysis and further functional analysis, we have identified Insulin-like Growth Factor Binding Protein-3 (IGFBP-3), Calreticulin (CRT) and Thrombospondin-1(THBS1) correlated with tumor invasion in OVTW59. IGFBP3 and CRT was further found related with poor patient survival outcome. In this study, we focused on the mechanism of IGFBP3 in cancer invasion and metastasis. First we focused on the THBS1 related angiogenesis mechanism which was induced by hypoxia. Through this study, we identified HIF-2α, but not HIF-1α, playing as a significant role in EOC. By q-RT-PCR, Western blotting and immunohistochemical staining, HIF-2α showed opposite expression with IGFBP3, and high IGFBP3 was correlated with high THBS1 expression and low CRT expression. Using other cell lines, the IGFBP3/THBS1/HIF-2α/CRT expression patterns were similar in 293T, H1299 and A549. Furthermore, by Luciferase promoter assay, we verified that IGFBP3 could induce THBS1, inhibit HIF-2α expression, but does not regulate the expression of CRT. IGFBP3 is known as an invasion suppressor gene, THBS1 is an endogeneous inhibitor of angiogenesis, HIF-2α is a regulator of the hypoxia response and angiogenesis inducer, and CRT as a cell adhesion and invasion related protein. Overall, our study shows that IGFBP3 could induce tumor progression and metastasis through direct regulation of THBS1, and HIF-2α and indirect regulation of CRT in EOC.
Citation Format: Ho-Jun Shih. The interaction of IGFBP3 with HIF2α in the invasion regulation of ovarian epithelial cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2538.
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