Serous ovarian carcinoma is biologically heterogeneous, and signaling and DNA damage tolerance/repair pathways may jointly influence tumor behavior. This study aimed to perform an integrated immunohistochemical evaluation of JAK/STAT signaling markers and DNA damage tolerance/repair-related markers and to investigate their clinicopathological associations and co-expression patterns. This retrospective cohort included 70 primary serous ovarian carcinomas (66 high-grade serous carcinomas [HGSCs] and four low-grade serous carcinomas [LGSCs]) treated at the Oncology Center, Mansoura University, Egypt, between 2017 and 2024. Tissue microarrays were constructed from formalin-fixed paraffin-embedded surgical tumor tissue and stained for total JAK2, total STAT3, POLH, UBE2T, and REV7. The JAK2 and STAT3 antibodies were not phospho-specific. Marker-clinicopathological and pairwise biomarker associations were evaluated with Benjamini-Hochberg false discovery rate control. Sensitivity analyses were performed in the HGSC cohort (n = 66) and in documented NACT-treated HGSC cases (n = 38). Associations between NACT response category and biomarker expression were explored among 39 documented NACT recipients. Time-to-event analyses were withdrawn following a chronology audit that identified unresolved inconsistencies in the available dates. Positive expression was observed in 58.6% of cases for JAK2, 51.4% for STAT3, 54.3% for POLH, 67.1% for UBE2T, and 62.9% for REV7. UBE2T and REV7 positivity showed nominal associations with earlier primary tumor stage (raw p = 0.019 and p = 0.021, respectively), but neither survived false discovery rate correction across the 85 biomarker-clinicopathological comparisons (q = 0.822 for both). Nine of 10 binary pairwise biomarker associations remained significant after correction, including JAK2-STAT3 (raw p = 0.009; q = 0.011) and JAK2-POLH (raw p = 0.039; q = 0.043). In the HGSC-restricted analysis, the JAK2-STAT3 association remained significant (binary q = 0.003; intensity-correlation q < 0.001). Among the 39 documented NACT recipients, no biomarker was associated with partial versus minimal response after correction (all q = 1.000). In the 38 documented NACT-treated HGSC cases, selected co-expression patterns remained significant, including binary STAT3-UBE2T, POLH-REV7, and UBE2T-REV7 associations (all q < 0.001).t Integrated immunohistochemical profiling identified several FDR-robust co-expression patterns among the evaluated proteins. However, no full-cohort clinicopathological association remained statistically significant after correction for multiple comparisons. Because phosphorylated JAK2 and STAT3 were not assessed, these findings concern total protein abundance rather than pathway activation. The results are exploratory and require replication in larger, independent cohorts using application-specific, independently validated antibodies and prospectively collected clinical data.

Ovarian high-grade serous carcinoma (HGSC) is an aggressive ovarian cancer with a heterogeneous tumor microenvironment (TME). Advances in single-cell RNA sequencing (scRNA-seq) and spatially-resolved transcriptomics have enabled the study of complex TME. This study explores connections between molecular subtypes described from bulk transcriptomes and spatial domains characterized by distinct gene expression in HGSC and their variability between patients. We quantify both intra- and intertumor heterogeneity across 2D space and identify differing spatial patterns of gene expression pertaining to immune pathways and vasculature development. Functional characterization of tumor spaces reveals potentially shared cell states across molecular subtypes, while correlation analysis underscores subtype-specific spatial anti-colocalization between spots exhibiting antigen-presenting functions and B cell-mediated immunity. Lastly, we perform spatially-aware cell-cell communication analysis on the spatial samples and identify a molecular subtype specific difference in total signaling activity and heterogeneity in Midkine signaling between the differentiated subtype. Our results suggest that generating multiple tissue slices per patient might be necessary to enable comprehensive characterization of HGSC spatial transcriptomes.

The DNA/RNA helicase Schlafen11 (SLFN11) is considered a sensitivity marker of various tumor cells for cytotoxic treatment with DNA damaging agents (DDA), such as cisplatin and PARP inhibitors (PARPi). Cells can epigenetically silence SLFN11 expression to gain chemoresistance, which can be targeted by HDAC inhibitors (HDACi). Here, we investigate the predictive value of SLFN11 expression for the response to three different PARPi in ovarian cancer cells. Furthermore, we target its epigenetic downregulation via HDACi for sensitization to cisplatin and PARPi. We show that HDAC3 plays a key role in SLFN11 silencing in W1 and W1CR ovarian cancer cells, confirmed by an HDAC3 knockdown approach. Therefore, addressing HDAC3 by novel class I HDACi DS-103 and FL-007 at non-toxic concentrations restored SLFN11 expression with various consequences for DDA treatment in W1, W1CR, and SKOV-3 cells. While DS-103 and FL-007 significantly sensitized cisplatin-resistant W1CR cells to cisplatin to the level of W1 cells, the response to various PARPi remains divergent. Whereas both HDACi induced significant sensitization in W1 and W1CR cells, and DS-103 in SKOV-3 cells for niraparib cytotoxicity, cells remain unaffected in response to olaparib and rucaparib. Both compounds were also shown to be less dependent on, or independent of, SLFN11 in different ovarian cancer cells. In sum, the first time reported functional link of HDAC3 and SLFN11 appears an attractive co-treatment opportunity of DDA with HDACi. This is particularly promising for niraparib as it has a broader approval independent of BRCA status compared to other PARPi.

Huge ovarian tumors in paediatric patients pose a surgical challenge, particularly in distinguishing tumor margins from ovarian parenchyma. While ovarian preservation is recommended for benign masses, concerns about tumor size may limit its application. This study evaluates the feasibility and outcomes of ovarian-sparing surgery (OSS) in children with giant ovarian tumors.

Enzyme-induced cytotoxicity can be considered the main challenge in modern cancer therapy that provides unique opportunities for targeted apoptosis. To address this challenge, we implemented enzyme-triggered activation of alkoxyamine-galactose conjugates with the formation of active carbon-centered radical species for the apoptosis of cancer cells. The comparative analysis of two alkoxyamine derivatives, bearing stable and self-immolative linkers between the radical precursor and galactose moiety, revealed the crucial role of molecular structure in anticancer activity. The study of cytotoxicity and induced oxidative stress of free amine and two galactosides revealed the enzyme-dependent nature of the activity of alkoxyamines having a self-immolative linker against distinct cancer cell lines such as PC-3 (prostate adenocarcinoma), SKOV-3 (ovarian adenocarcinoma), MCF-7 (breast adenocarcinoma), A-431 (epidermoid carcinoma), and Jurkat cells (human T-lymphoblastic leukemia). The collected data prove the applicability of enzyme-triggered glycosylated alkoxyamines as a new family of targeted prodrugs against cancer.

In recent years, gold(I) complexes have attracted increasing interest as an alternative to conventional metallo-chemotherapeutic agents. Their mode of action differs significantly from that of traditional platinum-based drugs. However, the identification of their intracellular targets and the elucidation of their mechanisms of action remain major challenges, largely due to the lack of suitable molecular tools for tracking these compounds in biological systems. To address these issues, three novel gold(I) complexes bearing two different fluorescent labels were synthesized and characterized. These complexes include an N-heterocyclic monocarbene gold(I) complex 3 and the corresponding biscarbene 4, both of which are functionalized with an anthracenyl moiety, as well as an NHC gold(I) monocarbene complex bearing a BODIPY label 5. The specific aim of this study was to generate trackable metallodrug models for mechanistic and metallomics-oriented research. These compounds were characterized using 1H and 13C NMR spectroscopy and elemental analysis. The crystallographic structure of the anthracenyl gold monocarbene was also determined. Interaction studies with human serum albumin (HSA) using UV-vis absorption spectroscopy and ESI-MS provided clear evidence of metallodrug-protein interactions. The uptake of the complexes in A2780 ovarian cancer cells was measured using fluorescence-activated cell sorting (FACS) cytofluorimetry, which indicated strong cellular uptake for the anthracenyl-labeled compounds 3 and 4. A cell fractionation approach was used for the quantitative analysis of subcellular drug disposition. These approaches collectively enabled a direct visualization of the intracellular fate of the gold complexes, providing a framework for correlating cellular distribution with biological activity. Finally, the gold complexes bearing the anthracenyl probe were evaluated for their cytotoxic activity in cisplatin-sensitive and -resistant A2780 cancer cells; the BODIPY complex could not be evaluated due to its insolubility. Overall, this study provides solid evidence that gold complexes bearing the anthracenyl probe retain significant cytotoxic properties and enable monitoring the uptake and fate of these gold species inside cancer cells, thus providing a proof-of-concept that fluorescently labeled gold complexes can serve as powerful tools for mechanistic investigations, including metallomics and proteomics-oriented studies aimed at identifying molecular targets and affected pathways.

Uterine tumor resembling ovarian sex-cord tumor (UTROSCT) is an extremely rare uterine stromal neoplasm of uncertain origin that accounts for less than 0.5% of uterine malignancies. Here, we report, using MRI, 18F-FDG, and 68Ga-FAPI-04 PET/CT, the imaging findings for peritoneal metastatic lesions from postoperative UTROSCT in a 58-year-old woman. The peritoneal lesions showed only mild uptake on 18F-FDG PET/CT. Subsequent 68Ga-FAPI-04 PET/CT revealed intense tracer uptake in the lesions, indicating the potential value of this modality for detecting recurrence and metastasis in UTROSCT.

Ovarian cancer (OC) is a leading cause of gynecologic cancer-related mortality and is frequently diagnosed at advanced stages due to the absence of effective early detection tools. Epigenetic alterations, particularly DNA methylation, play a critical role in tumorigenesis and represent promising non-invasive biomarkers. This study investigated the methylation status of the ANKRD23 gene in OC and evaluated its diagnostic potential using peripheral blood samples. A total of 385 serous OC patients, 50 individuals with benign ovarian conditions, and 99 healthy controls were included. DNA methylation was assessed using methylation-sensitive restriction enzymes followed by real-time PCR. ANKRD23 methylation was significantly associated with clinical stage (p = 0.029), histological grade (p = 0.009), and ethnicity (p = 0.024). Moreover, methylation levels differed significantly among OC patients, benign cases, and healthy controls (p = 0.026). These findings support blood-based ANKRD23 methylation as a promising biomarker for non-invasive ovarian cancer diagnosis and risk stratification.

Krukenberg tumors are an uncommon metastatic malignancy most commonly originating primarily from the gastrointestinal tract, particularly the stomach, colon, and/or rectum. Due to the rarity of these malignancies, most patients are believed to have primary metastatic ovarian malignancy instead. Here, we present the case of a patient who was presumed to have ovarian metastatic cancer; however, pathology results showed that the malignancy was gastrointestinal primary in nature. In this instance, intraoperative findings and immunohistochemical profiling played a crucial role in differentiating a Krukenberg tumor with a gastrointestinal primary versus ovarian metastatic cancer. In this case, proper diagnosis resulted in a change of management, highlighting that even the most unlikely differentials should still be considered.

Ovarian cancer is often diagnosed at an advanced stage because its early symptoms are nonspecific, and the prognosis remains poor due to frequent recurrence and the development of drug resistance even after standard treatment. This review includes 19 in vitro studies and seeks to mechanistically summarize how reactive oxygen species (ROS) reinforce the tumorigenic program from the early stages of ovarian carcinogenesis to tumor progression, metastasis, and treatment resistance. Collectively, the selected studies suggest that exposure to environmental toxicants can increase ROS levels in ovarian epithelial cells, accompanied by inflammatory responses and elevated DNA damage markers, thereby creating a carcinogenesis-priming environment. During the progression stage, hypoxia, hormones, growth factors, and lipid signaling repeatedly activate survival and growth pathways, such as those involving HIF-1α/VEGF, JAK/STAT3, and AKT/mTOR, through ROS-mediated mechanisms to promote tumor cell proliferation, anti-apoptotic activity, and angiogenesis. In addition, ROS are associated with alterations in epithelial-to-mesenchymal transition-related markers, remodeling of the extracellular matrix, and regulation of matrix metalloproteinases, which enhance the metastatic and invasive potential of tumor cells. In the therapeutic context, ROS have been suggested to contribute to platinum-based chemotherapy resistance through mechanisms including changes in mitochondrial dynamics, activation of the DNA damage response, and reprogramming of ROS-dependent phosphorylation networks. Understanding the diverse molecular mechanisms and clinical manifestations associated with ROS expression in high-grade serous ovarian cancer (HGSOC) will contribute to a more precise understanding of its pathophysiology. Furthermore, studies on redox-targeted therapeutic strategies, particularly the application of mitochondria-targeted antioxidants, may provide valuable translational insights for the treatment of ovarian cancer and other ROS-related diseases.