Four main histological subtypes of ovarian cancer exist: serous (the most frequent), endometrioid, mucinous and clear cell; in each subtype, low and high grade. The large majority of ovarian cancers are diagnosed as high-grade serous ovarian cancers (HGS-OvCas). TP53 is the most frequently mutated gene in HGS-OvCas; about 50% of these tumors displayed defective homologous recombination due to germline and somatic BRCA mutations, epigenetic inactivation of BRCA and abnormalities of DNA repair genes; somatic copy number alterations are frequent in these tumors and some of them are associated with prognosis; defective NOTCH, RAS/MEK, PI3K and FOXM1 pathway signaling is frequent. Other histological subtypes were characterized by a different mutational spectrum: LGS-OvCas have increased frequency of BRAF and RAS mutations; mucinous cancers have mutation in ARID1A, PIK3CA, PTEN, CTNNB1 and RAS. Intensive research was focused to characterize ovarian cancer stem cells, based on positivity for some markers, including CD133, CD44, CD117, CD24, EpCAM, LY6A, ALDH1. Ovarian cancer cells have an intrinsic plasticity, thus explaining that in a single tumor more than one cell subpopulation, may exhibit tumor-initiating capacity. The improvements in our understanding of the molecular and cellular basis of ovarian cancers should lead to more efficacious treatments.

Ovarian Cancers: Genetic Abnormalities, Tumor Heterogeneity and Progression, Clonal Evolution and Cancer Stem Cells

High-grade serous ovarian cancer (HGSOC) likely originates from the fallopian tube (FT) epithelium. Here, we established 15 organoid lines from HGSOC primary tumor deposits that closely match the mutational profile and phenotype of the parental tumor. We found that Wnt pathway activation leads to growth arrest of these cancer organoids. Moreover, active BMP signaling is almost always required for the generation of HGSOC organoids, while healthy fallopian tube organoids depend on BMP suppression by Noggin. Fallopian tube organoids modified by stable shRNA knockdown of p53, PTEN, and retinoblastoma protein (RB) also require a low-Wnt environment for long-term growth, while fallopian tube organoid medium triggers growth arrest. Thus, early changes in the stem cell niche environment are needed to support outgrowth of these genetically altered cells. Indeed, comparative analysis of gene expression pattern and phenotypes of normal vs. loss-of-function organoids confirmed that depletion of tumor suppressors triggers changes in the regulation of stemness and differentiation.

https://www.embopress.org/doi/epdf/10.15252/embj.2019104013

Stable expansion of high-grade serous ovarian cancer organoids requires a low-Wnt environment

Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Cancer stem cells (CSCs) that exist within the bulk tumor survive first-line chemotherapy and contribute to resistant disease with metastasis. Understanding the key features of CSC biology provides valuable opportunities to develop OCSC-directed therapeutics, which will eventually improve the clinical outcomes of patients. Although significant developments have occurred since OCSCs were first described, the involvement of CSCs in ovarian tumor metastasis is not fully understood. Here, we discuss putative CSC markers and the fundamental role of CSCs in facilitating tumor dissemination in OC. Additionally, we focus on promising CSC-targeting strategies in preclinical and clinical studies of OC and discuss potential challenges in CSC research.

Ovarian Cancer Stem Cells: Role in Metastasis and Opportunity for Therapeutic Targeting.

Cancer stem-like cells (CSLCs) are defined as cancer cells with stem cell characteristics. Although CSLCs constitute no more than a few percent of the tumor mass, they play important roles in cancer chemo-resistance, metastasis and disease recurrence. Ovarian cancer (OC) is considered the most aggressive gynecological malignancy in which the role of CSLCs is of major significance, although it remains to be specified. The studies describing ovarian CSLC phenotype vary in the definition of the molecular pattern of expression of the main markers such as CD133, CD44, CD117, and CD24. Stem-like features of OC have been shown to correlate with the clinical course of the disease and permit diagnosis, prognosis and treatment outcome to be improved. Identification of CSLC markers could provide hallmarks which, related to the chemo-resistance of the disease, will facilitate treatment selection. This review describes recent advances in research on stem-like cell status in OC, mainly focusing on surface markers of CSLCs and their clinical relevance.

https://www.termedia.pl/Journal/-77/pdf-32001-10?filename=Surface markers of cancer.pdf

Surface markers of cancer stem-like cells of ovarian cancer and their clinical relevance.

The unmet need for novel therapeutic options for ovarian cancer (OC) deserves further investigation. Among the different novel drugs, small interfering RNAs (siRNAs) are particularly attractive because of their specificity of action and efficacy, as documented in many experimental setups. However, the fragility of these molecules in the biological environment necessitates the use of delivery materials able to protect them and possibly target them to the cancer cells. Among the different delivery materials, those based on polymers and lipids are considered very interesting because of their biocompatibility and ability to carry/deliver siRNAs. Despite these features, polymers and lipids need to be engineered to optimize their delivery properties for OC. In this review, we concentrated on the description of the therapeutic potential of siRNAs and polymer-/lipid-based delivery systems for OC. After a brief description of OC and siRNA features, we summarized the strategies employed to minimize siRNA delivery problems, the targeting strategies to OC, and the preclinical models available. Finally, we discussed the most interesting works published in the last three years about polymer-/lipid-based materials for siRNA delivery.

https://www.mdpi.com/1999-4923/11/10/547/pdf

Strategies for Delivery of siRNAs to Ovarian Cancer Cells

Purpose Cancer stem cells have recently been identified as a key driving factor for tumor metastasis and chemoresistance. CD117 is a well-established cancer stem cell marker, but its clinical significance in epithelial ovarian cancer (EOC) remains controversial. Therefore, we aimed to identify correlations between CD117 expression and clinical features and outcomes in EOC patients in this meta-analysis. Materials and methods A literature search was performed in the PubMed, Cochrane Library, Web of Science, EMBASE, and OVID databases to identify eligible studies. Correlations between CD117 expression and clinicopathological parameters and overall survival or disease-free survival were analyzed. A subgroup analysis was then performed, which was classified by patient ethnicity and age at diagnosis, study sample size, and tumor histological type. Results A total of seven studies enrolling 1,247 EOC patients were included in this meta-analysis. Our results demonstrated that CD117 expression was significantly correlated with age (pooled odds ratio [OR] =1.67, 95% confidence interval [CI] =1.05-2.66), International Federation of Gynecology and Obstetrics stage (pooled OR =1.99, 95% CI =1.31-3.02), tumor differentiation grade (pooled OR =2.46, 95% CI =1.48-4.10), and histological type (pooled OR =1.85, 95% CI =1.05-3.26). EOC patients with high CD117 expression had significantly worse OS (hazard ratio [HR] =1.39, 95% CI =1.03-1.90) than patients with low CD117 expression. However, no significant correlation was found between CD117 expression and disease-free survival (HR =1.31, 95% CI =0.79-2.17). In subgroup analysis, CD117 was identified as a significant prognostic factor for overall survival in European patients (HR =1.59, 95% CI =1.13-2.23), younger patients ( 200 (HR =1.84, 95% CI =1.32-2.56), and the mixed histological types (HR =1.47; 95% CI =1.08-2.00). Conclusion Our meta-analysis suggests that CD117 is associated with EOC progression and can serve as a promising prognostic predictor for EOC patients. However, larger scale multicenter clinical trials are still needed to further validate our results.

/pdf/overexpression-of-the-cancer-stem-cell-marker-cd117-predicts-3sazedzrjz.pdf

Chunyu Jiang

Papers

Overexpression of the cancer stem cell marker CD117 predicts poor prognosis in epithelial ovarian cancer patients: evidence from meta-analysis.