Despite standard treatment, about 70% of ovarian cancer will recur. Cancer stem cells (CSCs) have been implicated in the drug-resistance mechanism. Several drug resistance mechanisms have been proposed, and among these, autophagy plays a crucial role for the maintenance and tumorigenicity of CSCs. Compared to their differentiated counterparts, CSCs have been demonstrated to display a significantly higher level of autophagy flux. Moreover, mitophagy, a specific type of autophagy that selectively degrades excessive or damaged mitochondria, is shown to contribute to cancer progression and recurrence in several types of tumors. Nanomedicine has been shown to tackle the CSCs problem by overcoming drug resistance. In this work, we developed a nanomedicine, ¹⁸⁸Re-liposome, which was demonstrated to target autophagy and mitophagy in the tumor microenvironment. Of note, the inhibition of autophagy and mitophagy could lead to significant tumor inhibition in two xenograft animal models. Lastly, we presented two cases of recurrent ovarian cancer, both in drug resistance status that received a level I dose from a phase I clinical trial. Both cases developing drug resistance showed drug sensitivity to ¹⁸⁸Re-liposome. These results suggest that inhibition of autophagy and mitophagy by a nanomedicine may be a novel strategy to overcome drug resistance in ovarian cancer.

Endometriosis-associated ovarian cancers (EAOCs) including endometrioid and clear cell ovarian carcinoma are subgroups of epithelial ovarian carcinomas (EOCs), which is generally acknowledged as the most lethal gynecological malignancy. Endometriosis (ES), a common clinical disease among women, presents with clinical symptoms of pelvic pain, infertility, or adnexal masses with the formation of endometrioma. It has long been considered to be a potential risk factor for developing EOCs, mainly of endometrioid and clear cell subtypes. Here, we compiled data from previous researches on deregulated molecular functions among ES and EOCs using gene set–based integrative analysis to decipher molecular and genetic relationships between ovarian ES and EOCs, especially EAOCs. We conclude that epidermal growth factor receptor (ERBB) and Phosphoinositide 3-kinases (PI3K)-related pathways are important in the carcinogenesis of type I EOCs, including clear cell, endometrioid, and mucinous ovarian carcinoma. Dysfunctional molecular pathways, such as deregulated oxidoreductase activity, metabolism, hormone activity, inflammatory response, innate immune response, and cell–cell signaling, played key roles in the malignant transformation of EAOCs. Nine genes related to inflammasome complex and inflammasome-related pathway were identified, indicating the importance of inflammation/immunity in EAOC transformation. We also collect progressive treatments of EAOC focused on targeted therapies and immunotherapy so far. This summarized information can contribute toward effective detection and treatment of EAOCs in the future.

Ovarian clear cell carcinoma (OCCC) is the second most common epithelial ovarian carcinoma (EOC). It is refractory to chemotherapy with a worse prognosis after the preliminary optimal debulking operation, such that the treatment of OCCC remains a challenge. OCCC is believed to evolve from endometriosis, a chronic immune/inflammation-related disease, so that immunotherapy may be a potential alternative treatment. Here, gene set-based analysis was used to investigate the immunofunctionomes of OCCC in early and advanced stages. Quantified biological functions defined by 5917 Gene Ontology (GO) terms downloaded from the Gene Expression Omnibus (GEO) database were used. DNA microarray gene expression profiles were used to convert 85 OCCCs and 136 normal controls into to the functionome. Relevant offspring were as extracted and the immunofunctionomes were rebuilt at different stages by machine learning. Several dysregulated pathogenic functions were found to coexist in the immunopathogenesis of early and advanced OCCC, wherein the complement-activation-alternative-pathway may be the headmost dysfunctional immunological pathway in duality for carcinogenesis at all OCCC stages. Several immunological genes involved in the complement system had dual influences on patients’ survival, and immunohistochemistrical analysis implied the higher expression of C3a receptor (C3aR) and C5a receptor (C5aR) levels in OCCC than in controls.

The clinical characteristics of clear cell carcinoma (CCC) and endometrioid carcinoma EC) are concomitant with endometriosis (ES), which leads to the postulation of malignant transformation of ES to endometriosis-associated ovarian carcinoma (EAOC). Different deregulated functional areas were proposed accounting for the pathogenesis of EAOC transformation, and there is still a lack of a data-driven analysis with the accumulated experimental data in publicly-available databases to incorporate the deregulated functions involved in the malignant transformation of EOAC. We used the microarray gene expression datasets of ES, CCC and EC downloaded from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) database. Then, we investigated the pathogenesis of EAOC by a data-driven, function-based analytic model with the quantified molecular functions defined by 1454 Gene Ontology (GO) term gene sets. This model converts the gene expression profiles to the functionome consisting of 1454 quantified GO functions, and then, the key functions involving the malignant transformation of EOAC can be extracted by a series of filters. Our results demonstrate that the deregulated oxidoreductase activity, metabolism, hormone activity, inflammatory response, innate immune response and cell-cell signaling play the key roles in the malignant transformation of EAOC. These results provide the evidence supporting the specific molecular pathways involved in the malignant transformation of EAOC.

Clear cell (CCC), endometrioid (EC), mucinous (MC) and high-grade serous carcinoma (SC) are the four most common subtypes of epithelial ovarian carcinoma (EOC). The widely accepted dualistic model of ovarian carcinogenesis divided EOCs into type I and II categories based on the molecular features. However, this hypothesis has not been experimentally demonstrated. We carried out a gene set-based analysis by integrating the microarray gene expression profiles downloaded from the publicly available databases. These quantified biological functions of EOCs were defined by 1454 Gene Ontology (GO) term and 674 Reactome pathway gene sets. The pathogenesis of the four EOC subtypes was investigated by hierarchical clustering and exploratory factor analysis. The patterns of functional regulation among the four subtypes containing 1316 cases could be accurately classified by machine learning. The results revealed that the ERBB and PI3K-related pathways played important roles in the carcinogenesis of CCC, EC and MC; while deregulation of cell cycle was more predominant in SC. The study revealed that two different functional regulation patterns exist among the four EOC subtypes, which were compatible with the type I and II classifications proposed by the dualistic model of ovarian carcinogenesis.

Serous carcinoma (SC) is the most common and lethal subtype of epithelial ovarian carcinoma; immunotherapy is a potential treatment for SC, however, the global immunological functions of SC as well as their change during the progression of SC have not been investigated in detail till now. We conducted a genome-wide integrative analysis to investigate the immunofunctionomes of SC at four tumor stages by quantifying the immunological functions defined by the Gene Ontology gene sets. DNA microarray gene expression profiles of 1100 SCs and 136 normal ovarian tissue controls were downloaded from the Gene Expression Omnibus database and converted to the functionome. Then the immunofunctionomes were reconstructed by extracting the offspring from the functionome for the four SC staging groups. The key immunological functions extracted from immunofunctionomes with a series of filters revealed that the immunopathy of SC consisted of a group of deregulated functions with the core members including B cell activation and differentiation, regulation of leukocyte chemotaxis/cellular extravasation, antigen receptor mediated signaling pathway, T helper mediated immunity and macrophage activation; and the auxiliary elements included leukocyte mediated immunity, regulation of inflammatory response, T cell differentiation, mononuclear cell migration, megakaryocyte differentiation, complement activation and cytokine production. These deregulated immunological functions reveal the candidates to target in the immunotherapy.