New Trends in the Detection of Gynecological Precancerous Lesions and Early-Stage Cancers

The prevention and early diagnostics of precancerous stages are key aspects of contemporary oncology. In cervical cancer, well-organized screening and vaccination programs, especially in developed countries, are responsible for the dramatic decline of invasive cancer incidence and mortality. Cytological screening has a long and successful history, and the ongoing implementation of HPV triage with increased sensitivity can further decrease mortality. On the other hand, endometrial and ovarian cancers are characterized by a poor accessibility to specimen collection, which represents a major complication for early diagnostics. Therefore, despite relatively promising data from evaluating the combined effects of genetic variants, population screening does not exist, and the implementation of new biomarkers is, thus, necessary. The introduction of various circulating biomarkers is of potential interest due to the considerable heterogeneity of cancer, as highlighted in this review, which focuses exclusively on the most common tumors of the genital tract, namely, cervical, endometrial, and ovarian cancers. However, it is clearly shown that these malignancies represent different entities that evolve in different ways, and it is therefore necessary to use different methods for their diagnosis and treatment.

FBXO22 Promotes Growth and Metastasis and Inhibits Autophagy in Epithelial Ovarian Cancers via the MAPK/ERK Pathway

E3 ubiquitin ligase F-box only protein 22 (FBXO22), which targets the key regulators of cellular activities for ubiquitylation and degradation, plays an important role in tumorigenesis and metastasis. However, the function of FBXO22 in epithelial ovarian cancers has not been reported. This study aims to explore the biological function of FBXO22 in epithelial ovarian cancers progression and metastasis and its specific regulation mechanism. Immunohistochemistry analysis of tissue microarray was performed to evaluate the expression of FBXO22 in epithelial ovarian cancers patients. The proliferative ability of epithelial ovarian cancers cells was examined by the CCK8. The metastasis ability was detected by the wound healing assay, migration and invasion assays. Western blot was used to verify the relationship between FBXO22 expression and mitogen-activated protein kinase related proteins. Autophagic flux was detected by electron microscopy, mRFP-GFP-LC3 adenovirus, lysosomal tracker and western blot. For in vivo experiments, the effect of FBXO22 on epithelial ovarian cancers resistance was observed in a xenograft tumor model and a metastatic mice model. We found that FBXO22 expression was significantly increased in epithelial ovarian cancers tissues and was closely correlated with clinical pathological factors. As a result, we found that FBXO22 promoted the growth and metastasis, as well as inhibited the autophagy flux. In addition, we identified that FBXO22 performed these functions via the MAPK/ERK pathway. Our results first reported the function of FBXO22 in epithelial ovarian cancer and the correlation between FBXO22 and autophagy, suggesting FBXO22 as a novel target of epithelial ovarian cancers assessment and treatment.

The developing landscape of combinatorial therapies of immune checkpoint blockade with DNA damage repair inhibitors for the treatment of breast and ovarian cancers

The use of immune checkpoint blockade (ICB) using antibodies against programmed death receptor (PD)-1, PD ligand (PD-L)-1, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) has redefined the therapeutic landscape in solid tumors, including skin, lung, bladder, liver, renal, and breast tumors. However, overall response rates to ICB therapy remain limited in PD-L1-negative patients. Thus, rational and effective combination therapies will be needed to address ICB treatment resistance in these patients, as well as in PD-L1-positive patients who have progressed under ICB treatment. DNA damage repair inhibitors (DDRis) may activate T-cell responses and trigger inflammatory cytokines release and eventually immunogenic cancer cell death by amplifying DNA damage and generating immunogenic neoantigens, especially in DDR-defective tumors. DDRi may also lead to adaptive PD-L1 upregulation, providing a rationale for PD-L1/PD-1 blockade. Thus, based on preclinical evidence of efficacy and no significant overlapping toxicity, some ICB/DDRi combinations have rapidly progressed to clinical testing in breast and ovarian cancers. Here, we summarize the available clinical data on the combination of ICB with DDRi agents for treating breast and ovarian cancers and discuss the mechanisms of action and other lessons learned from translational studies conducted to date. We also review potential biomarkers to select patients most likely to respond to ICB/DDRi combination therapy.

miRNA-148b and its role in various cancers

miRNA-148b belongs to the family miR-148/-152, with significant differences in nonseed sequences, which can target diverse mRNA molecules. Reportedly, it may undergo deregulation in lung and ovarian cancers and downregulation in gastric, pancreatic and colon cancers. However, there is a need for further studies to better characterize its mechanism of action and in different types of cancer. In this review, we focus on the aberrant expression of miR-148b in different cancer types and highlight its main target genes and signaling pathways, as well as its pathophysiologic role and relevance to tumorigenesis in several types of cancer.

An Assessment of Ovarian Cancer Histotypes Across the African Diaspora

ObjectiveOvarian cancer in Black women is common in many West African countries but is relatively rare in North America. Black women have worse survival outcomes when compared to White women. Ovarian cancer histotype, diagnosis, and age at presentation are known prognostic factors for outcome. We sought to conduct a preliminary comparative assessment of these factors across the African diaspora.MethodsPatients diagnosed with ovarian cancer (all histologies) between June 2016-December 2019 in Departments of Pathology at 25 participating sites in Nigeria were identified. Comparative population-based data, inclusive of Caribbean-born Blacks (CBB) and US-born Blacks (USB), were additionally captured from the International Agency for Research on Cancer and Florida Cancer Data Systems. Histology, country of birth, and age at diagnosis data were collected and evaluated across the three subgroups: USB, CBB and Nigerians. Statistical analyses were done using chi-square and student’s t-test with significance set at p<0.05.ResultsNigerians had the highest proportion of germ cell tumor (GCT, 11.5%) and sex-cord stromal (SCST, 16.2%) ovarian cancers relative to CBB and USB (p=0.001). CBB (79.4%) and USB (77.3%) women were diagnosed with a larger proportion of serous ovarian cancer than Nigerians (60.4%) (p<0.0001). Nigerians were diagnosed with epithelial ovarian cancers at the youngest age (51.7± 12.8 years) relative to USB (58.9 ± 15.0) and CBB (59.0± 13.0,p<0.001). Black women [CBB (25.2 ± 15.0), Nigerians (29.5 ± 15.1), and USB (33.9 ± 17.9)] were diagnosed with GCT younger than White women (35.4 ± 20.5, p=0.011). Black women [Nigerians (47.5 ± 15.9), USB (50.9 ± 18.3) and CBB (50.9 ± 18.3)] were also diagnosed with SCST younger than White women (55.6 ± 16.5, p<0.01).ConclusionThere is significant variation in age of diagnosis and distribution of ovarian cancer histotype/diagnosis across the African diaspora. The etiology of these findings requires further investigation.

Current ideas about molecular genetic subtypes of ovarian cancer: a personalized approach and a new platform for further research

Highly malignant ovarian cancers are a histopathological diagnosis, but can be multiple diseases at the molecular level. Research aimed at identifying molecular genetic subtypes of ovarian cancer is being conducted to find an answer to the question: can different molecular subgroups influence the choice of treatment? One of the achievements of this direction is the recognition of the dualistic theory of the origin of ovarian carcinomas with their division into High-grade and Low-grade subtypes. However, the data of sequencing of the tumor genome suggest the existence of 6 subtypes of carcinoma, including two LG and four HG subtypes. Patients of subtype C1 are characterized by a high stromal response and have the lowest survival, tumors of C2 and C4 subtypes have a higher rate of intratumoral CD3 + cells, lower stroma gene expression and better survival than C1. The mesenchymal subtype C5 is widely represented by mesenchymal cells, characterized by overexpression of N-cadherins and P-cadherins, low expression of differentiation markers and lower survival than C2 and C4. The use of a consensus algorithm to determine the subtype allows the identification of only a minority of ovarian cancers (approximately 25%). In this regard, the practical significance of this classification still requires additional research, and today it is permissible to talk about the existence of only 2-3 reproducible subtypes. It is thought that it makes sense to randomize tumors into groups with altered expression of angiogenic genes and with overexpression of immune response genes, as in the angiogenic group there is a comparison of the advantage in survival (prescribing bevacizumab improves it, and in the immune group even increases bevacizumab). Molecular subtypes with poorer survival rates (proliferative and mesenchymal) also benefit most from bevacizumab treatment. The review focuses on some advances in understanding molecular, cellular, and genetic changes related to ovarian cancers with the results achieved so far in describing molecular subtypes of ovarian cancer. The available information is the basis for planning further research.