The doctoral dissertation in the field of Clinical Medicine will be examined at the Faculty of Health Sciences at Kuopio Campus.
An increase in angiogenesis is a feature of epithelial ovarian carcinoma, according to the doctoral dissertation of Minna Sopo, Lic Med. In addition, angiogenic factors accumulated in abdominal metastases, which might reflect more active angiogenesis and capacity to disseminate. Antiangiogenic gene therapy with VEGF receptors prolonged the overall survival of mice compared to single chemotherapy, bevacizumab and control groups.
So far, the prognosis of epithelial ovarian cancer (EOC) has not significantly improved despite fast-developing treatment strategies. The antiangiogenic approach has been part of standard treatment in advanced and recurrent ovarian cancer with variable success. The mechanisms behind the resistance to treatment and variable efficacy of the treatment have remained unclear. Biomarkers for optimal patient selection and monitoring the treatment response in addition to new modalities to boost the therapeutic effect are urgently needed. The aim of this study was to explore nine principal angiogenic factors in ovarian carcinoma tissue and to assess their relevance as prognostic biomarkers. Furthermore, the therapeutic efficacy of a new antiangiogenic treatment strategy was investigated in a xenograft model of ovarian cancer.
The clinical study population consisted of 86 patients with epithelial ovarian carcinoma, primarily operated in Kuopio University Hospital between 1999–2007. In addition, 17 patients with borderline and 36 patients with benign epithelial ovarian tumours were included in study IV. Omental metastatic samples were also explored from 16 patients with serous carcinomas. Immunohistochemical stainings of vascular endothelial growth factor (VEGF) -A, -C, -D, VEGF receptors (-R1, -R2, -R3), angiopoietin-2 (Ang-2), tyrosine kinase receptors Tie-1 and Tie-2 were analysed in all malignant primary and metastatic tumour samples, assessing separately the expression in neoplastic, stromal and endothelial cells. Furthermore, micro- and lymph vessel parameters, assessed by cluster of differentiation (CD) 34, 105 and D2-40, were calculated from all 139 patients with different histologies. Additionally, adenovirus-mediated antiangiogenic gene therapy with soluble (s)VEGFR1, -R2 and -R3 was combined with paclitaxel and compared with single chemotherapy and bevacizumab in an ovarian cancer animal model with athymic nude mice.
The researchers found that tumour epithelial expression of VEGF-A, -D, -R1, Ang-2 and Tie-2 was significantly higher in omental metastatic lesions than in primary high-grade serous carcinoma. In addition, high expression of Tie-2 predicted poor overall survival (OS) in high-grade serous carcinoma. In contrast, low expression of VEGF-A and Ang-2 in primary tumours was associated with poor overall survival. Microvessel parameters, assessed by CD34 and CD105, were higher in malignant tumours than in borderline and benign ones. Further, small lymph vessels in ovarian carcinoma predicted shorter survival, and a high density of lymph vessels was related to lymph node metastases and cancer recurrence. In the first study, intravenous antiangiogenic gene therapy with sVEGFR1, -R2 and -R3 in combination with paclitaxel prolonged the overall survival of mice compared to single chemotherapy, bevacizumab and control groups. Tumours of the gene therapy group were also smaller and less vascularized than tumours of other groups.
An increase in angiogenesis is a feature of epithelial ovarian carcinoma. Accumulation of angiogenic factors in abdominal metastases might reflect more active angiogenesis and capacity to disseminate. According to this study, Tie-2 had the most potential as an angiogenic tissue biomarker, warranting further studies on its prognostic value. The endothelial antibodies, CD34 and CD105, define different properties of microvessels. Neither showed superiority over the other to predict angiogenic activity in ovarian cancer. Instead, the prognostic significance of lymphangiogenesis in ovarian cancer became clarified. Antiangiogenic gene therapy with VEGF receptors seems to have treatment efficacy in a xenograft model and could have potential in clinical studies.
The doctoral dissertation of Minna Sopo, Licentiate of Medicine, enttled Epithelial Ovarian Cancer and Angiogenesis - Biomarker and Gene Therapy, will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Docent Johanna Hynninen of the University of Turku, and the Custos will be Professor Leea Keski-Nisula of the University of Eastern Finland. The public examination will be held in Finnish at Kuopio University Hospital on 1 October 2021, starting at 12 noon.
For further information, please contact: Minna Sopo, +358 44 251 2242, minna.sopo (at) kuh.fi