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

Abstract

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 Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

“…Inter-tumour heterogeneity occurs if the genotypic and phenotypic variation exists between multiple tumour cells from one patient, for example the primary lesion of OC patients may be different in genotype and phenotype from the tumours of distant omental metastasis [34]. On the other hand, intra-tumour heterogeneity occurs if genotypic and phenotypic variation occurs within the same tumour of primary lesion or distant metastases [7,35]. Both inter-and intra-tumour heterogeneity occurs in OC as well as in most cancers and is the primary cause of disease progression and importantly therapeutic resistance and relapse [7].…”

miR‐211 sponges lncRNA MALAT1 to suppress tumor growth and progression through inhibiting PHF19 in ovarian carcinoma

“…In addition, tumor recurrence frequently occurs in the majority of patients with OC who undergo surgery followed by chemotherapy at a median of 15 mo from diagnosis (1). Most deaths from this disease are attributed to remote metastasis, and the 5-yr survival rate for patients with OC remains ,30% (2)(3)(4). Conversely, the mechanisms underlying OC cell proliferation, migration, and metastasis have not been fully defined.…”

Prostaglandin F2α-induced TGFβ-PMEPA1 pathway is a critical mediator of epithelial plasticity and ovarian carcinoma progression

“…The TGF superfamily plays an important role in ovarian function and pathogenesis (41) while, remarkably, mutations in genes of this pathway are infrequent in ovarian cancer (27). Importantly, we observed TGFB1 is up-regulated in ovarian cancer.…”

“…PMEPA1 has been also described as a Wnt/β-catenin cascade target gene (24,25), which aberrant activation could contribute to neoplasia. In the case of endometrioid ovarian carcinomas, this stabilization is due to mutations identified in the CTNNB1 gene (26), while for the rest, this pathway remains unaltered (27). β-catenin also binds with the intracellular domain of epithelial-cadherin (E-Cadherin) to form a complex which subsequently connects to the actin cytoskeleton, mediates intercellular adhesion, and regulates tumor cell invasion and metastasis (28).…”