Ovarian clear cell carcinoma meets metabolism; HNF-1β confers survival benefits through the Warburg effect and ROS reduction.

Ovarian clear cell carcinoma (OCCC) constitutes one of the subtypes of ovarian cancers, but it has unique clinical, histological and biological characteristics, one of which is chemo-resistance. It is also known to develop from endometriotic cyst, a benign ovarian tumor, at relatively high frequency. Recently, it is becoming well known that most of OCCCs express HNF1β, a transcription factor, which is closely associated with the development of liver, pancreas and kidney, as well as occurrence of familial forms of type 2 diabetes. Expression of HNF1β is now regarded as a hallmark of this tumor. Nevertheless, exact biological function of this gene in OCCC has not been clarified. We have shown in previous studies that microenvironment in endometriotic cysts contains severe oxidative stress and OCCC develops under such stressful environment as stress-resistant tumor, which may lead to chemo-resistance. We also showed that increased expression of HNF1β facilitates glucose uptake and glycolysis, which is known as Warburg effect. In the previous issue of this journal, by using comprehensive metabolome analysis, we report that HNF1β actually reduces and protects themselves from internal oxidative stress by dramatically changing cellular metabolism. In this article, we review the relevance and significance of cancer-specific metabolism and how they are associated with biological characteristics of OCCC via expression of HNF1β, along with future clinical implications of targeting cancer-specific metabolism

PDK2 leads to cisplatin resistance through suppression of mitochondrial function in ovarian clear cell carcinoma

Ovarian clear cell carcinoma (CCC) exhibits an association with endometriosis, resistance to oxidative stress, and poor prognosis owing to its resistance to conventional platinum-based chemotherapy. A greater understanding of the molecular characteristics and pathogenesis of ovarian cancer subtypes may facilitate the development of targeted therapeutic strategies, though the mechanism of drug resistance in ovarian CCC has yet to be determined. In this study, we assessed exome sequencing data to identify new therapeutic targets of mitochondrial function in ovarian CCC because of the central role of mitochondria in redox homeostasis. Copy number analyses revealed that chromosome 17q21-24 (chr.17q21-24) amplification was associated with recurrence in ovarian CCC. Cell viability assays identified an association between cisplatin resistance and chr.17q21-24 amplification, and mitochondrion-related genes were enriched in patients with chr.17q21-24 amplification. Patients with high expression of pyruvate dehydrogenase kinase 2 (PDK2) had a worse prognosis than those with low PDK2 expression. Furthermore, inhibition of PDK2 synergistically enhanced cisplatin sensitivity by activating the electron transport chain and by increasing the production of mitochondrial reactive oxygen species. Mouse xenograft models showed that inhibition of PDK2 with cisplatin inhibited tumor growth. This evidence suggests that targeting mitochondrial metabolism and redox homeostasis is an attractive therapeutic strategy for improving drug sensitivity in ovarian CCC

Peritoneal dissemination of high-grade serous ovarian cancer: pivotal roles of chromosomal instability and epigenetic dynamics

Epithelial ovarian cancer remains the lethal gynecological malignancy in women. The representative histotype is high-grade serous carcinoma (HGSC), and most patients with HGSC present at advanced stages with peritoneal dissemination. Since the peritoneal dissemination is the most important factor for poor prognosis of the patients, complete exploration for its molecular mechanisms is mandatory. In this narrative review, being based on the clinical, pathologic, and genomic findings of HGSC, chromosomal instability and epigenetic dynamics have been discussed as the potential drivers for cancer development in the fallopian tube, acquisition of cancer stem cell (CSC)-like properties, and peritoneal metastasis of HGSC. The natural history of carcinogenesis with clonal evolution, and adaptation to microenvironment of peritoneal dissemination of HGSC should be targeted in the novel development of strategies for prevention, early detection, and precision treatment for patients with HGSC