Epithelial ovarian cancer (EOC) represents the deadliest of all gynecological malignancies. This is primarily due to the fact that up to 80% of patients are diagnosed with EOC at a late stage. The most readily identifiable risk factor is a family history of ovarian and breast cancer; this may indicate the presence of an inherited germline mutation in BRCA-1 or BRCA-2 and promote prevention in women who belong in the same family. At the somatic level, EOC is an extremely heterogeneous disease. To date, a broad spectrum of multiple (epi)genetic alterations have been observed that may alter the pathways that promote cell growth and drive tumorigenesis of EOC. Indeed, numerous deregulations have been observed in cellular biological signal transduction pathways. The most studied pathways are those that control DNA repair, cell proliferation, apoptosis, cell adhesion and motility.
High-grade serous ovarian carcinoma (HGS) appears to be the most prevalent type of EOC. It is an aggressive disease with a high rate of recurrence and development of metastases in the abdominal cavity, often characterized by TP53 mutations and pronounced genomic instability. Inherited and somatic mutations in the BRCA1 and BRCA2 genes are usually found in this ovarian cancer type. Emerging evidence suggests that EOC cells acquire invasive properties through a loss of epithelial characteristics and a gain of mesenchymal ones. Thus, progression occurs through an "invasion-metastasis cascade" involving epithelial-to-mesenchymal cell transition (EMT), cancer stem cell (CSC) generation, and invasion spread into adjacent tissues of the abdominal cavity. In these processes, cells are powered by the inflammatory response, which is considered a hallmark of cancer. Chronic inflammation appears to be generated by inflammatory cytokines secreted by the tumor and tumor-associated cells in the tumor microenvironment, but also by different tissues in the abdominal “macro” environment.
An uncontrolled increase in pro-inflammatory cytokines and reactive oxygen species are capable of causing epigenetic alterations, chromosomal aberrations, and DNA mutations, that drive proto-oncogene activation, persistent cell proliferation and EMT. Signaling pathways involved in the repair of oxidative DNA damage are critical for the suppression of inflammation-associated carcinogenesis. BRCA1 may also induce antioxidant response gene expression and stimulate the activity of key enzymes in the base excision repair (BER) pathway. Low activity and/or reduced expression of MUTYH and OGG1 enzymes may result in impaired DNA repair and the inability to induce apoptosis in response to oxidative damage, resulting in survival of cells with oncogenic mutations.
New answers to this concern must be sought by assessing both individual characteristics (e.g., genetics and hormone levels) and environmental factors (e.g., infections and pollutants) in causing a reduced immune response, increased tumor aggressiveness, and ineffective therapeutic response. Studies that can help elucidate the role played by the network of DNA damage repair systems in the ovarian and Fallopian tube epithelium in relation to signaling pathways of epithelial renewal and immune system surveillance are welcome.
Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.
Epithelial ovarian cancer (EOC) represents the deadliest of all gynecological malignancies. This is primarily due to the fact that up to 80% of patients are diagnosed with EOC at a late stage. The most readily identifiable risk factor is a family history of ovarian and breast cancer; this may indicate the presence of an inherited germline mutation in BRCA-1 or BRCA-2 and promote prevention in women who belong in the same family. At the somatic level, EOC is an extremely heterogeneous disease. To date, a broad spectrum of multiple (epi)genetic alterations have been observed that may alter the pathways that promote cell growth and drive tumorigenesis of EOC. Indeed, numerous deregulations have been observed in cellular biological signal transduction pathways. The most studied pathways are those that control DNA repair, cell proliferation, apoptosis, cell adhesion and motility.
High-grade serous ovarian carcinoma (HGS) appears to be the most prevalent type of EOC. It is an aggressive disease with a high rate of recurrence and development of metastases in the abdominal cavity, often characterized by TP53 mutations and pronounced genomic instability. Inherited and somatic mutations in the BRCA1 and BRCA2 genes are usually found in this ovarian cancer type. Emerging evidence suggests that EOC cells acquire invasive properties through a loss of epithelial characteristics and a gain of mesenchymal ones. Thus, progression occurs through an "invasion-metastasis cascade" involving epithelial-to-mesenchymal cell transition (EMT), cancer stem cell (CSC) generation, and invasion spread into adjacent tissues of the abdominal cavity. In these processes, cells are powered by the inflammatory response, which is considered a hallmark of cancer. Chronic inflammation appears to be generated by inflammatory cytokines secreted by the tumor and tumor-associated cells in the tumor microenvironment, but also by different tissues in the abdominal “macro” environment.
An uncontrolled increase in pro-inflammatory cytokines and reactive oxygen species are capable of causing epigenetic alterations, chromosomal aberrations, and DNA mutations, that drive proto-oncogene activation, persistent cell proliferation and EMT. Signaling pathways involved in the repair of oxidative DNA damage are critical for the suppression of inflammation-associated carcinogenesis. BRCA1 may also induce antioxidant response gene expression and stimulate the activity of key enzymes in the base excision repair (BER) pathway. Low activity and/or reduced expression of MUTYH and OGG1 enzymes may result in impaired DNA repair and the inability to induce apoptosis in response to oxidative damage, resulting in survival of cells with oncogenic mutations.
New answers to this concern must be sought by assessing both individual characteristics (e.g., genetics and hormone levels) and environmental factors (e.g., infections and pollutants) in causing a reduced immune response, increased tumor aggressiveness, and ineffective therapeutic response. Studies that can help elucidate the role played by the network of DNA damage repair systems in the ovarian and Fallopian tube epithelium in relation to signaling pathways of epithelial renewal and immune system surveillance are welcome.
Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.
