Materiały źródłowe

• #1 Ovarian cancer: Pathogenesis and current recommendations for prophylactic surgery

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6501866/

  Ovarian cancer is one of the most common gynecologic cancers, and one of the leading causes of cancer-associated female mortality in the world. Currently, no widely accepted pathogenesis is available, which may explain the entire disease. […] To date, no widely accepted pathogenesis of ovarian cancer has been described. One of the biggest problems in uncovering the pathogenesis of ovarian cancer is the heterogeneous nature of ovarian cancer, comprising various histologic types with different behaviors and characteristics. […] Initially, all ovarian cancers were thought to originate from the epithelium of the ovarian cell surface. During ovulation, these surface epithelial cells experience physical trauma, which is repaired immediately. During a woman’s life cycle, ovulation occurs repeatedly, which causes repetitive trauma to the epithelium, ultimately causing cellular DNA damage. Epithelial cells that have undergone DNA damage are very susceptible to change, which facilitates invagination to the cortical stroma. This invagination eventually becomes trapped and forms a sphere of epithelial cells in the stroma called cortical inclusion cysts. While inside the ovary, the epithelial cells are exposed to ovarian hormones that stimulate cell proliferation, which in turn transforms into cancer cells.

• #2

  https://journals.lww.com/ajsp/fulltext/2010/03000/the_origin_and_pathogenesis_of_epithelial_ovarian.18.aspx

  Ovarian cancer is the most lethal gynecologic malignancy. Efforts at early detection and new therapeutic approaches to reduce mortality have been largely unsuccessful, because the origin and pathogenesis of epithelial ovarian cancer are poorly understood. […] This has led to the proposal that ovarian cancer develops de novo. […] The origin and pathogenesis of epithelial ovarian cancer has perplexed investigators for decades. […] It is clear that de novo reflects our ignorance about the early events of ovarian carcinogenesis rather than our insight into its perplexing origin. […] The time-honored concepts that have forged our views of ovarian carcinogenesis can be summarized as follows: (1) although it is recognized that there are profound differences among the various histologic types, the vast majority of ovarian carcinomas are high-grade serous carcinomas and therefore ovarian cancer is regarded as a single disease; (2) ovarian cancer originates from the ovarian surface epithelium (mesothelium) that invaginates into the underlying stroma resulting in inclusion cysts that eventually undergo malignant transformation; (3) ovarian cancer spreads from the ovary to the pelvis, abdomen, and distant sites.

• #3 Pathogenesis of Ovarian Cancer. Lessons from Morphology and Molecular Biology and their Clinical Implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2794425/

  The received view of ovarian carcinogenesis is that carcinoma begins in the ovary, undergoes progressive dedifferentiation from a well to a poorly differentiated tumor and then spreads to the pelvic and abdominal cavities before metastasizing to distant sites. […] We believe that one of the main reasons for this is that the dogma underlying ovarian carcinogenesis is flawed. […] In this model, ovarian tumors are divided into two groups designated Type I and Type II. Type I tumors are slow growing, generally confined to the ovary at diagnosis and develop from well established precursor lesions that are termed borderline tumors. […] Type II tumors are rapidly growing, highly aggressive neoplasms for which well defined precursor lesions have not been described. […] This group of tumors has a high level of genetic instability and is characterized by mutation of TP53.

• #4

  https://journals.lww.com/ajsp/fulltext/2010/03000/the_origin_and_pathogenesis_of_epithelial_ovarian.18.aspx

  Recent morphologic and molecular genetic studies have illuminated our understanding of ovarian carcinogenesis in ways that have been quite unexpected and have challenged the conventional wisdom regarding their origin and development. […] One of the major problems in elucidating the pathogenesis of ovarian cancer is that it is a heterogeneous disease composed of different types of tumors with widely differing clinicopathologic features and behavior. […] Type I tumors are clinically indolent and usually present at a low stage. […] Type II tumors are highly aggressive and almost always present in advanced stage. […] The cell of origin of ovarian cancer and the mechanisms by which cancer develops have been long debated. […] The traditional view of ovarian carcinogenesis has been that the various tumors are all derived from the ovarian surface epithelium (mesothelium), and that subsequent metaplastic changes lead to the development of the different cell types.

• #5 Pathogenesis of Ovarian Cancer. Lessons from Morphology and Molecular Biology and their Clinical Implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2794425/

  The received view of ovarian carcinogenesis is that carcinoma begins in the ovary, undergoes progressive dedifferentiation from a well to a poorly differentiated tumor and then spreads to the pelvic and abdominal cavities before metastasizing to distant sites. […] We believe that one of the main reasons for this is that the dogma underlying ovarian carcinogenesis is flawed. […] In this model, ovarian tumors are divided into two groups designated Type I and Type II. Type I tumors are slow growing, generally confined to the ovary at diagnosis and develop from well established precursor lesions that are termed borderline tumors. […] Type II tumors are rapidly growing, highly aggressive neoplasms for which well defined precursor lesions have not been described. […] This group of tumors has a high level of genetic instability and is characterized by mutation of TP53.

• #6

  https://journals.lww.com/ajsp/fulltext/2010/03000/the_origin_and_pathogenesis_of_epithelial_ovarian.18.aspx

  Recent morphologic and molecular genetic studies have illuminated our understanding of ovarian carcinogenesis in ways that have been quite unexpected and have challenged the conventional wisdom regarding their origin and development. […] One of the major problems in elucidating the pathogenesis of ovarian cancer is that it is a heterogeneous disease composed of different types of tumors with widely differing clinicopathologic features and behavior. […] Type I tumors are clinically indolent and usually present at a low stage. […] Type II tumors are highly aggressive and almost always present in advanced stage. […] The cell of origin of ovarian cancer and the mechanisms by which cancer develops have been long debated. […] The traditional view of ovarian carcinogenesis has been that the various tumors are all derived from the ovarian surface epithelium (mesothelium), and that subsequent metaplastic changes lead to the development of the different cell types.

• #7 Ovarian carcinoma: pathology review with an emphasis in their molecular characteristics – Lino-Silva – Chinese Clinical Oncology

  https://cco.amegroups.org/article/view/42910/html

  The vast majority of OC are epithelial (75% to 80%). […] OCAs have typically been described as high-grade tumors, with serous histology, which occurs in patients 60 years and diagnosed in an advanced stage (75% in stage IIIIV), are poorly differentiated, and they rarely express estrogen receptors. […] It is evident today that these generalities apply especially to high-grade serous OCAs that in fact constitute only a proportion of OCAs. […] More recently, a dualistic model widely adopted by the scientific community divides OCAs into two groups according to their grade and morphology: type I includes low-grade serous tumors, mucinous tumors, endometrioid tumors, clear cell tumors, and transitional tumors; type II includes high-grade serous OCAs, carcinosarcomas and undifferentiated carcinomas.

• #8 Pathogenesis of Ovarian Cancer. Lessons from Morphology and Molecular Biology and their Clinical Implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2794425/

  The received view of ovarian carcinogenesis is that carcinoma begins in the ovary, undergoes progressive dedifferentiation from a well to a poorly differentiated tumor and then spreads to the pelvic and abdominal cavities before metastasizing to distant sites. […] We believe that one of the main reasons for this is that the dogma underlying ovarian carcinogenesis is flawed. […] In this model, ovarian tumors are divided into two groups designated Type I and Type II. Type I tumors are slow growing, generally confined to the ovary at diagnosis and develop from well established precursor lesions that are termed borderline tumors. […] Type II tumors are rapidly growing, highly aggressive neoplasms for which well defined precursor lesions have not been described. […] This group of tumors has a high level of genetic instability and is characterized by mutation of TP53.

• #9

  https://journals.lww.com/ajsp/fulltext/2010/03000/the_origin_and_pathogenesis_of_epithelial_ovarian.18.aspx

  Recent morphologic and molecular genetic studies have illuminated our understanding of ovarian carcinogenesis in ways that have been quite unexpected and have challenged the conventional wisdom regarding their origin and development. […] One of the major problems in elucidating the pathogenesis of ovarian cancer is that it is a heterogeneous disease composed of different types of tumors with widely differing clinicopathologic features and behavior. […] Type I tumors are clinically indolent and usually present at a low stage. […] Type II tumors are highly aggressive and almost always present in advanced stage. […] The cell of origin of ovarian cancer and the mechanisms by which cancer develops have been long debated. […] The traditional view of ovarian carcinogenesis has been that the various tumors are all derived from the ovarian surface epithelium (mesothelium), and that subsequent metaplastic changes lead to the development of the different cell types.

• #10 Ovarian carcinoma: pathology review with an emphasis in their molecular characteristics – Lino-Silva – Chinese Clinical Oncology

  https://cco.amegroups.org/article/view/42910/html

  As will be developed in the following paragraphs, today it has become clear that these histological distinctions have important consequences in the management of each subtype because they correspond to significant differences in terms of tumor carcinogenesis, clinical aggressiveness, chemosensitivity and, above all, genomic abnormalities likely to be the target of new molecules. […] Type II OCAs, whose prototype is high-grade serous carcinoma, also includes carcinosarcomas (or mixed Muller tumors) and undifferentiated carcinomas. […] High-grade OCAs are diagnosed at an advanced stage and most require surgical excision and chemotherapy with platinum salts. […] A 10-15% of high-grade serous OCAs have a constitutional mutation of BRCA1 or BRCA2 (breast cancer 1/2). […] These mutations result in the loss of key proteins involved in genome stability and repair of damaged DNA, particularly in the homologous recombination (RH) repair pathway of double chain breaks generated by platinum salts.

• #11

  https://journals.lww.com/ajsp/fulltext/2010/03000/the_origin_and_pathogenesis_of_epithelial_ovarian.18.aspx

  An alternate theory proposes that tumors with a mullerian phenotype (serous, endometrioid, and clear cell) are derived from mullerian-type tissue and not from mesothelium. […] More recently, another theory has been advanced, which argues that the majority of ovarian carcinomas that are high-grade serous carcinomas arise from high-grade intraepithelial serous carcinomas in the fallopian tube, which then spread to the ovary. […] The most compelling evidence suggests that the vast majority of what seems to be primary ovarian cancers, namely serous, endometrioid, and clear cell carcinomas, are derived from the fallopian tube and endometrium and not directly from the ovary. […] This led to fallopian tube carcinoma being included as part of the cancer spectrum associated with inherited BRCA mutations.

• #12

  https://journals.lww.com/ajsp/fulltext/2010/03000/the_origin_and_pathogenesis_of_epithelial_ovarian.18.aspx

  It was subsequently proposed that a proportion of ovarian carcinomas might develop as a result of implantation of malignant cells from the tubal carcinoma to the ovary. […] Thus, the most persuasive data support the view that serous tumors develop from the fimbriated portion of the fallopian tube, endometrioid, and clear cell tumors from endometrial tissue passing through the fallopian tube resulting in endometriosis and mucinous, and Brenner tumors from transitional-type epithelium located at the tubal-mesothelial junction where the fimbria makes contact with the peritoneum. […] A new paradigm for the pathogenesis of ovarian cancer based on a dualistic model and the recognition that the majority of ovarian carcinomas originate outside the ovary assist in organizing this complex group of neoplasms and facilitates the development of new and novel approaches to prevention, screening, and treatment.

• #13 Therapeutic strategies in epithelial ovarian cancer | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/1756-9966-31-14

  Ovarian cancer is the most lethal gynecologic malignancy. It appears that the vast majority of what seem to be primary epithelial ovarian and primary peritoneal carcinomas is, in fact, secondary from the fimbria, the most distal part of the fallopian tube. […] The origin and pathogenesis of epithelial ovarian cancer (EOC) have long been investigated but still poorly understood. Studies have shown that epithelial ovarian cancer is not a single disease but is composed of a diverse group of tumors that can be classified based on distinctive morphologic and molecular genetic features. […] In summary, it appears that the vast majority of what seem to be primary epithelial ovarian and primary peritoneal carcinomas are, in fact, secondary. Previous data support the view that serous tumors develop from the fimbria, the most distal part of the fallopian tube, endometrioid and clear cell tumors from endometrial tissue passing through the fallopian tube resulting in endometriosis and mucinous and Brenner tumors from transitional-type epithelium located at the tubal-mesothelial junction where the fimbria makes contact to the peritoneum.

• #14 Ovarian cancer: Pathogenesis and current recommendations for prophylactic surgery

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6501866/

  This theory is consistent with epidemiologic data where the number of ovulatory cycles is associated with the risk of ovarian cancer. The weakness of this theory is that it cannot explain the pathogenesis of various histologic types of ovarian cancer and prognostic differences. […] It was reported that epithelial dysplasia was found at a high incidence in the Fallopian tubes (50%) of women with BRCA1/2 gene mutations undergoing prophylactic salpingo-oophorectomy. This epithelial dysplasia resembled high-grade serous ovarian carcinoma, which they called tubal intraepithelial carcinoma (TIC). […] Based on these studies, it can be concluded that the fallopian tube would likely be the location of the ovarian cancer precursor lesions, which eventually spread to the adjacent ovary. […] In contrast to type I ovarian cancer, precursor lesions of type II ovarian cancer are thought to originate from outside the ovary, one of which is from the fallopian tube. Type II ovarian cancers tend to grow more aggressively, are genetically unstable, and are usually diagnosed at a more advanced stage.

• #15

  https://link.springer.com/article/10.1007/s00404-013-3041-3

  Among all gynecological malignancies, ovarian cancer is associated with the highest rate of mortality. Recent findings now propose a pivotal role for the fallopian tube during ovarian cancer pathogenesis. […] Until recently, ovarian cancer was thought to derive from the ovarian surface epithelium. Nevertheless, attempts to define a precursor lesion from this tissue failed. Instead, prophylactic surgery performed on BRCA mutation carriers and subsequent histological analyses revealed a characteristic pre-neoplastic alteration at the fimbriated end of the fallopian tubes, the so-called serous tubal intraepithelial carcinoma (STIC). By morphology and molecular genetics, STIC was found to resemble serous ovarian cancer. As STIC can also be detected in 60 % of BRCA-unrelated serous ovarian carcinomas, it is now considered to be the precursor of the most common ovarian cancer subtype.

• #16 The Pathogenesis of Epithelial Ovarian Cancer – Onkologie – Universimed – Knowledge that matters

  https://www.universimed.com/ch/article/onkologie/the-pathogenesis-of-epithelial-ovarian-cancer-2126519

  The first step in tubal transformation from benign to precursor lesion is called p53 signature, characterized by the appearance of benign secretory cells that exhibit evidence of DNA damage, TP53 mutation and p53 protein stabilisation. […] Genetic analysis comparing microdissected paired samples of STIC and HGSOC (high grade serous ovarian carcinoma) revealed a clonal evolution, supporting the hypothesis that these lesions were the precursors of ovarian carcinomas. […] Chronic inflammation and hyperoestrogenism in the pelvis caused by endometriosis seems to be responsible for oxidative stress and specific molecular alterations leading to malignant transformation. […] Recent gene-expression profiling of MOC and single-cell RNA sequencing showed that MOC are more likely to evolve from primordial germ cells than the eutopic tubal or ovarian epithelium, supporting the idea that less than 15 % of ovarian cancer would be of primary ovarian origin.

• #17 The Pathogenesis of Epithelial Ovarian Cancer – Onkologie – Universimed – Knowledge that matters

  https://www.universimed.com/ch/article/onkologie/the-pathogenesis-of-epithelial-ovarian-cancer-2126519

  The first step in tubal transformation from benign to precursor lesion is called p53 signature, characterized by the appearance of benign secretory cells that exhibit evidence of DNA damage, TP53 mutation and p53 protein stabilisation. […] Genetic analysis comparing microdissected paired samples of STIC and HGSOC (high grade serous ovarian carcinoma) revealed a clonal evolution, supporting the hypothesis that these lesions were the precursors of ovarian carcinomas. […] Chronic inflammation and hyperoestrogenism in the pelvis caused by endometriosis seems to be responsible for oxidative stress and specific molecular alterations leading to malignant transformation. […] Recent gene-expression profiling of MOC and single-cell RNA sequencing showed that MOC are more likely to evolve from primordial germ cells than the eutopic tubal or ovarian epithelium, supporting the idea that less than 15 % of ovarian cancer would be of primary ovarian origin.

• #18 Ovarian Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/255771-overview

  These mechanisms of dissemination represent the rationale to conduct surgical staging, debulking surgery, and intraperitoneal administration of chemotherapy. In contrast, hematogenous spread is clinically unusual early on in the disease process, although it is not infrequent in patients with advanced disease. […] Epithelial tumors represent the most common histology (90%) of ovarian tumors. Other histologies include the following: Sex-cord stromal tumors, Germ cell tumors, Primary peritoneal carcinoma, Metastatic tumors of the ovary. […] Epithelial ovarian cancer is thought to arise from epithelium covering the fimbria of the fallopian tubes, or the ovaries, both of which are derived from the coelomic epithelium in fetal development. This coelomic epithelium is also involved in formation of the mullerian ducts, from which the fallopian tubes, uterus, cervix, and upper vagina develop.

• #19 Etiology and Pathophysiology of Ovarian Cancer – Focus on Ovarian Cancer

  https://www.medpagetoday.com/resource-centers/focus-ovarian-cancer/etiology-and-pathophysiology-ovarian-cancer/1663

  Recent evidence suggests that HGSC arises from the fallopian tube. The risk for cancer of the fallopian tube increases in women with BRCA1/2 mutations, who are more likely to have serous carcinomas, and studies of prophylactic salpingo-oophorectomy specimens from BRCA1/2 mutation carriers have shown that the most common pathologic abnormality is the finding of a serous tubal intraepithelial carcinoma (STIC) in the fimbriated end of the fallopian tube. Most HGSC exhibit a histology similar to that seen in the fallopian tube, rather than the ovarian surface epithelium, and genetic alterations and expression patterns are similar among HGSC, coexisting STIC, and tubal epithelium. This evidence suggests a model in which injury to the secretory epithelial cells of the distal fallopian tube triggers a chain of events leading to the entity classically referred to as ovarian cancer.

• #20

  https://link.springer.com/article/10.1007/s00404-013-3041-3

  Based on this hypothesis, a salpingectomy, i.e., the removal of the post-reproductive fallopian tubes may remove the actual site of tumorigenesis and thereby prevent spreading over the ovarian surface and throughout the peritoneum. Consequently, prophylactic salpingectomy might protect against serous ovarian cancer. Moreover, the procedure interrupts the connection between the uterine cavity and the lesser pelvis. Hence, it prevents the ascension of exfoliated endometrial cells which will likely reduce the incidence of endometrioid and clear cell ovarian cancers. Increasing evidence suggests that serous ovarian cancer originates from the fimbriated distal end of the fallopian tube, whereas the ovary gets only involved at a later stage. […] Given the lack of suitable screening or early detection strategies for ovarian cancer, post-reproductive salpingectomy deserves serious consideration as a prophylactic intervention that will likely confer significant protection against an often deadly disease.

• #21 Ovarian Cancer: Mechanism, Mutations and Therapeutic Targets | CMAR

  https://www.dovepress.com/cellular-mechanism-of-gene-mutations-and-potential-therapeutic-targets-peer-reviewed-fulltext-article-CMAR

  Ovarian cancer is a common and complex malignancy with poor prognostic outcome. […] Therefore, novel treatment strategies are needed to improve the treatment of ovarian cancer patients. Recent advances of next generation sequencing technologies have both confirmed previous known mutated genes and discovered novel candidate genes in ovarian cancer. […] In this review, we illustrate recent advances in identifying ovarian cancer gene mutations, including those of TP53, BRCA1/2, PIK3CA, and KRAS genes. […] The expression of P53 mutation is the most common mutation in HGSOC. […] The potential mechanisms between the mutations and OC are described as: loss of function of genes regulating tumor suppression, abnormalities of DNA repair genes, apoptosis, gain in function of oncogenes, and epigenetic inactivation.

• #22 Ovarian Cancer: Mechanism, Mutations and Therapeutic Targets | CMAR

  https://www.dovepress.com/cellular-mechanism-of-gene-mutations-and-potential-therapeutic-targets-peer-reviewed-fulltext-article-CMAR

  In OC, a recently whole-genome sequencing of DNA found mainly P53 mutation is missense mutation. […] The missense mutation occurs predominantly in exons 5-10. […] The most common codons of mutation are R273C, R273H, and R273L mutants. […] More remarkably, there was a high prevalence of the P53 mutations in stage 1 or 2 HGSOC. […] The BRCA mutation rate increases to 40% in recurrent HGSOC. […] The PIK3CA mutation clearly identified as mechanisms of inducing oncogenic PI3K signaling. […] The PIK3CA mutation results in somatic mutations in a majority of human cancer, including OC. […] The KRAS mutations are the most common RAS isoforms, including KRas4A and KRas4B, which are encoded by alternative fourth exons and the common activating mutations occur in exons 1 or 2. […] KRAS mutation plays a key role in LGSOC and mucinous OC subtypes.

• #23 Ovarian Cancer: Mechanism, Mutations and Therapeutic Targets | CMAR

  https://www.dovepress.com/cellular-mechanism-of-gene-mutations-and-potential-therapeutic-targets-peer-reviewed-fulltext-article-CMAR

  Ovarian cancer is a common and complex malignancy with poor prognostic outcome. […] Therefore, novel treatment strategies are needed to improve the treatment of ovarian cancer patients. Recent advances of next generation sequencing technologies have both confirmed previous known mutated genes and discovered novel candidate genes in ovarian cancer. […] In this review, we illustrate recent advances in identifying ovarian cancer gene mutations, including those of TP53, BRCA1/2, PIK3CA, and KRAS genes. […] The expression of P53 mutation is the most common mutation in HGSOC. […] The potential mechanisms between the mutations and OC are described as: loss of function of genes regulating tumor suppression, abnormalities of DNA repair genes, apoptosis, gain in function of oncogenes, and epigenetic inactivation.

• #24 Ovarian Cancer: Mechanism, Mutations and Therapeutic Targets | CMAR

  https://www.dovepress.com/cellular-mechanism-of-gene-mutations-and-potential-therapeutic-targets-peer-reviewed-fulltext-article-CMAR

  In OC, a recently whole-genome sequencing of DNA found mainly P53 mutation is missense mutation. […] The missense mutation occurs predominantly in exons 5-10. […] The most common codons of mutation are R273C, R273H, and R273L mutants. […] More remarkably, there was a high prevalence of the P53 mutations in stage 1 or 2 HGSOC. […] The BRCA mutation rate increases to 40% in recurrent HGSOC. […] The PIK3CA mutation clearly identified as mechanisms of inducing oncogenic PI3K signaling. […] The PIK3CA mutation results in somatic mutations in a majority of human cancer, including OC. […] The KRAS mutations are the most common RAS isoforms, including KRas4A and KRas4B, which are encoded by alternative fourth exons and the common activating mutations occur in exons 1 or 2. […] KRAS mutation plays a key role in LGSOC and mucinous OC subtypes.

• #25 Ovarian Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/255771-overview

  Increasing evidence suggests that a high proportion of high-grade serous carcinoma originates from distal fallopian tube epithelium or the tuboperitoneal junction rather than the ovarian surface epithelium. Serous intraepithelial or early invasive carcinoma has been found in up to 10% of fallopian tubes from BRCA mutation carriers who had undergone prophylactic bilateral salpingo-oophorectomies. Clinical, molecular, and genetic studies, as well as in vitro and animal models, have also supported a tubal origin for high-grade serous ovarian carcinoma. […] The precise cause of ovarian cancer is unknown. However, several risk and contributing factors (including both reproductive and genetic factors) have been identified. […] Integrated genomic analyses by the Cancer Genome Atlas Research Network have revealed high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumors. The findings also include the low prevalence but statistically recurrent somatic mutations in 9 further genes, including NF1, BRCA1, BRCA2, RB1, and CDK12, along with 113 significant focal DNA copy number aberrations and promoter methylation events involving 168 genes. Pathway analyses revealed defective homologous recombination in about half of all tumors, and that NOTCH and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.

• #26 Ovarian Cancer: Mechanism, Mutations and Therapeutic Targets | CMAR

  https://www.dovepress.com/cellular-mechanism-of-gene-mutations-and-potential-therapeutic-targets-peer-reviewed-fulltext-article-CMAR

  In OC, a recently whole-genome sequencing of DNA found mainly P53 mutation is missense mutation. […] The missense mutation occurs predominantly in exons 5-10. […] The most common codons of mutation are R273C, R273H, and R273L mutants. […] More remarkably, there was a high prevalence of the P53 mutations in stage 1 or 2 HGSOC. […] The BRCA mutation rate increases to 40% in recurrent HGSOC. […] The PIK3CA mutation clearly identified as mechanisms of inducing oncogenic PI3K signaling. […] The PIK3CA mutation results in somatic mutations in a majority of human cancer, including OC. […] The KRAS mutations are the most common RAS isoforms, including KRas4A and KRas4B, which are encoded by alternative fourth exons and the common activating mutations occur in exons 1 or 2. […] KRAS mutation plays a key role in LGSOC and mucinous OC subtypes.

• #27 Ovarian cancer: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/ovarian-cancer/

  Somatic mutations in the TP53 gene occur in almost half of all ovarian cancers. The protein produced from this gene is described as a tumor suppressor because it helps keep cells from growing and dividing too fast or in an uncontrolled way. […] Germline mutations are involved in more than one-fifth of ovarian cancer cases. Between 65 and 85 percent of these mutations are in the BRCA1 or BRCA2 gene. […] The proteins produced from the BRCA1 and BRCA2 genes are tumor suppressors that are involved in fixing damaged DNA, which helps to maintain the stability of a cell’s genetic information. Mutations in these genes impair DNA repair, allowing potentially damaging mutations to persist in DNA. […] A significantly increased risk of ovarian cancer is also a feature of certain rare genetic syndromes, including a disorder called Lynch syndrome. […] In addition to genetic changes, researchers have identified many personal and environmental factors that contribute to a woman’s risk of developing ovarian cancer.

• #28 Ovarian Cancer: Mechanism, Mutations and Therapeutic Targets | CMAR

  https://www.dovepress.com/cellular-mechanism-of-gene-mutations-and-potential-therapeutic-targets-peer-reviewed-fulltext-article-CMAR

  In OC, a recently whole-genome sequencing of DNA found mainly P53 mutation is missense mutation. […] The missense mutation occurs predominantly in exons 5-10. […] The most common codons of mutation are R273C, R273H, and R273L mutants. […] More remarkably, there was a high prevalence of the P53 mutations in stage 1 or 2 HGSOC. […] The BRCA mutation rate increases to 40% in recurrent HGSOC. […] The PIK3CA mutation clearly identified as mechanisms of inducing oncogenic PI3K signaling. […] The PIK3CA mutation results in somatic mutations in a majority of human cancer, including OC. […] The KRAS mutations are the most common RAS isoforms, including KRas4A and KRas4B, which are encoded by alternative fourth exons and the common activating mutations occur in exons 1 or 2. […] KRAS mutation plays a key role in LGSOC and mucinous OC subtypes.

• #29 Ovarian Cancer: Mechanism, Mutations and Therapeutic Targets | CMAR

  https://www.dovepress.com/cellular-mechanism-of-gene-mutations-and-potential-therapeutic-targets-peer-reviewed-fulltext-article-CMAR

  In OC, a recently whole-genome sequencing of DNA found mainly P53 mutation is missense mutation. […] The missense mutation occurs predominantly in exons 5-10. […] The most common codons of mutation are R273C, R273H, and R273L mutants. […] More remarkably, there was a high prevalence of the P53 mutations in stage 1 or 2 HGSOC. […] The BRCA mutation rate increases to 40% in recurrent HGSOC. […] The PIK3CA mutation clearly identified as mechanisms of inducing oncogenic PI3K signaling. […] The PIK3CA mutation results in somatic mutations in a majority of human cancer, including OC. […] The KRAS mutations are the most common RAS isoforms, including KRas4A and KRas4B, which are encoded by alternative fourth exons and the common activating mutations occur in exons 1 or 2. […] KRAS mutation plays a key role in LGSOC and mucinous OC subtypes.

• #30 Ovarian Cancer: Mechanism, Mutations and Therapeutic Targets | CMAR

  https://www.dovepress.com/cellular-mechanism-of-gene-mutations-and-potential-therapeutic-targets-peer-reviewed-fulltext-article-CMAR

  The sequencing analysis showed KRAS gene mutation was the most frequent in borderline serous tumor, LGSOC, and mucinous carcinomas. […] The frequent occurrence of KRAS mutations in this subtype of tumors led to the presumption that the development of LGSOC begins in a stepwise mode from serous cystadenoma or adenofibroma, borderline serous tumor, and serous carcinoma, and its carcinogenic processes are closely related to RAS signaling. […] The defective HR pathway in BRCA-mutated cells is associated with OC tumorigenesis, due to DNA DSBs failure to repair. […] The absence of PARP activity does not completely repair SSBs, leading to an increase in deleterious DSB, thereby preventing BRCA1/2 mutations or HR cells from being effectively repaired. […] A number of studies on ctDNA, representing a small percentage of cfDNA that is shed in circulation by tumor cells and carries tumor specific mutations, attempted to evaluate its clinical value in OC.

• #31 Drug resistance in ovarian cancer: from mechanism to clinical trial | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01967-3

  We summarized four major mechanisms (Fig. 1) from the published literature: 1) abnormalities in transmembrane transport, 2) alterations in DNA damage repair (DDR), 3) dysregulation of cancer-associated signaling pathways, and 4) epigenetic modifications. […] The ABC transporter family is mainly responsible for drug efflux. Abnormal expression of miRNAs (e.g., the miR-200 family, let-7 family and miR-130a/b) plays a role in ABC transporter regulation, thereby inducing resistance in ovarian cancer. […] Whole-genome microarray analysis revealed that ABCB1 was the only drug transporter with increased expression in resistant ovarian cancer cells, while the expression of several other ABC transporters was significantly decreased. […] Notably, dysregulated miRNAs can mediate the overexpression of ABCB1, resulting in MDR.

• #32 Drug resistance in ovarian cancer: from mechanism to clinical trial | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01967-3

  The classical mechanisms of action of common drugs can be disrupted or altered, possibly resulting in impaired therapeutic effects. […] If DNA damage is not repaired promptly, cellular senescence or apoptotic signals are activated, while abnormal activation of DDR maintains the viability of cancer cells, significantly inducing resistance to chemotherapeutic drugs and PARPis and affecting therapeutic efficacy. […] HR deficiency is characteristic of many HGSOC cases (approximately 50%) and is considered a predictive biomarker of sensitivity to platinum agents and PARPis. […] The TGF- pathway has biphasic effects and acts as a tumor suppressor at early stages but later stimulates cancer progression by impacting tumor cells and their microenvironment. […] The Hippo pathway confers resistance to therapeutic agents that are commonly used to treat ovarian cancer.

• #33 Drug resistance in ovarian cancer: from mechanism to clinical trial | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01967-3

  The classical mechanisms of action of common drugs can be disrupted or altered, possibly resulting in impaired therapeutic effects. […] If DNA damage is not repaired promptly, cellular senescence or apoptotic signals are activated, while abnormal activation of DDR maintains the viability of cancer cells, significantly inducing resistance to chemotherapeutic drugs and PARPis and affecting therapeutic efficacy. […] HR deficiency is characteristic of many HGSOC cases (approximately 50%) and is considered a predictive biomarker of sensitivity to platinum agents and PARPis. […] The TGF- pathway has biphasic effects and acts as a tumor suppressor at early stages but later stimulates cancer progression by impacting tumor cells and their microenvironment. […] The Hippo pathway confers resistance to therapeutic agents that are commonly used to treat ovarian cancer.

• #34 Researchers uncover novel dual-target mechanism in treatment-resistant ovarian cancer | U-M Rogel Cancer Center

  https://www.rogelcancercenter.org/news/archive/researchers-uncover-novel-dual-target-mechanism-treatment-resistant-ovarian-cancer

  Researchers from the University of Michigan Rogel Cancer Center and BenevolentAI have identified a promising new therapeutic approach for platinum-resistant ovarian cancer. […] The analysis prioritized 74 promising targets for experimental testing, leading to the identification of two key molecular drivers of the disease: TRAF2 and NCK interacting kinase, or TNIK, and cyclin-dependent kinase 9, or CDK9. […] Further molecular analysis also revealed a novel interaction between these proteins, with CDK9 playing a previously unknown role in activating the Wnt signaling pathway, a crucial molecular mechanism that enables cancer cells to resist chemotherapy. […] „This research represents a significant advancement in our understanding of treatment resistance in ovarian cancer,” said study author Analisa DiFeo, Ph.D., professor of pathology and obstetrics and gynecology at Michigan Medicine. „By uncovering the interaction between TNIK and CDK9, and validating their combined role in treatment resistance across multiple patient-derived models, we have identified a promising new therapeutic approach. The discovery that CDK9 regulates the Wnt signalling pathway could have far-reaching implications for treating other cancers where these mechanisms are active.”

• #35 Drug resistance in ovarian cancer: from mechanism to clinical trial | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01967-3

  The classical mechanisms of action of common drugs can be disrupted or altered, possibly resulting in impaired therapeutic effects. […] If DNA damage is not repaired promptly, cellular senescence or apoptotic signals are activated, while abnormal activation of DDR maintains the viability of cancer cells, significantly inducing resistance to chemotherapeutic drugs and PARPis and affecting therapeutic efficacy. […] HR deficiency is characteristic of many HGSOC cases (approximately 50%) and is considered a predictive biomarker of sensitivity to platinum agents and PARPis. […] The TGF- pathway has biphasic effects and acts as a tumor suppressor at early stages but later stimulates cancer progression by impacting tumor cells and their microenvironment. […] The Hippo pathway confers resistance to therapeutic agents that are commonly used to treat ovarian cancer.

• #36

  https://link.springer.com/article/10.1007/s12672-010-0054-2

  Considerable progress has been made in comprehending the genetic makeup and physiological processes involved in ovarian cancer, but its underlying etiology is not well understood. […] The fact that there is a positive correlation between the number of ovulatory cycles with risk of ovarian cancer paved the way to the incessant ovulation hypothesis by Fathalla in 1971. […] Pitfalls in the incessant ovulation theory and evidence of increased risk among women using fertility drugs in order to conceive led to the gonadotropin hypothesis. […] Therefore, current studies suggest a role for gonadotropins in ovarian cancer progression, but not necessarily in causality. […] Various inflammatory processes are involved with each ovulation and are believed to be the causative process responsible for priming OECs to genetic damage and carcinogenesis.

• #37 The Pathogenesis of Epithelial Ovarian Cancer – Onkologie – Universimed – Knowledge that matters

  https://www.universimed.com/ch/article/onkologie/the-pathogenesis-of-epithelial-ovarian-cancer-2126519

  The main epidemiologic argument to support the “incessant ovulation” theory is the decrease in the incidence of EOC when ovulation is suppressed by parity or contraceptive pills. […] Excessive exposure to gonadotrophins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), regulatory hormones secreted by the anterior pituitary gland during menopause, ovulation and infertility therapy, raised the question of their role in ovarian cancer pathogenesis. […] A third hypothesis called “incessant menstruation” has recently emerged. […] Epidemiological arguments supporting this hypothesis are the observation that hysterectomy without oophorectomy and tubal ligation plays a protective role against EOC, particularly clear-cell and endometroid carcinomas.

• #38

  https://link.springer.com/article/10.1007/s12672-010-0054-2

  Considerable progress has been made in comprehending the genetic makeup and physiological processes involved in ovarian cancer, but its underlying etiology is not well understood. […] The fact that there is a positive correlation between the number of ovulatory cycles with risk of ovarian cancer paved the way to the incessant ovulation hypothesis by Fathalla in 1971. […] Pitfalls in the incessant ovulation theory and evidence of increased risk among women using fertility drugs in order to conceive led to the gonadotropin hypothesis. […] Therefore, current studies suggest a role for gonadotropins in ovarian cancer progression, but not necessarily in causality. […] Various inflammatory processes are involved with each ovulation and are believed to be the causative process responsible for priming OECs to genetic damage and carcinogenesis.

• #39 The Pathogenesis of Epithelial Ovarian Cancer – Onkologie – Universimed – Knowledge that matters

  https://www.universimed.com/ch/article/onkologie/the-pathogenesis-of-epithelial-ovarian-cancer-2126519

  The main epidemiologic argument to support the “incessant ovulation” theory is the decrease in the incidence of EOC when ovulation is suppressed by parity or contraceptive pills. […] Excessive exposure to gonadotrophins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), regulatory hormones secreted by the anterior pituitary gland during menopause, ovulation and infertility therapy, raised the question of their role in ovarian cancer pathogenesis. […] A third hypothesis called “incessant menstruation” has recently emerged. […] Epidemiological arguments supporting this hypothesis are the observation that hysterectomy without oophorectomy and tubal ligation plays a protective role against EOC, particularly clear-cell and endometroid carcinomas.

• #40 Ovarian cancer: Pathogenesis and current recommendations for prophylactic surgery

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6501866/

  Ovarian cancer is one of the most common gynecologic cancers, and one of the leading causes of cancer-associated female mortality in the world. Currently, no widely accepted pathogenesis is available, which may explain the entire disease. […] To date, no widely accepted pathogenesis of ovarian cancer has been described. One of the biggest problems in uncovering the pathogenesis of ovarian cancer is the heterogeneous nature of ovarian cancer, comprising various histologic types with different behaviors and characteristics. […] Initially, all ovarian cancers were thought to originate from the epithelium of the ovarian cell surface. During ovulation, these surface epithelial cells experience physical trauma, which is repaired immediately. During a woman’s life cycle, ovulation occurs repeatedly, which causes repetitive trauma to the epithelium, ultimately causing cellular DNA damage. Epithelial cells that have undergone DNA damage are very susceptible to change, which facilitates invagination to the cortical stroma. This invagination eventually becomes trapped and forms a sphere of epithelial cells in the stroma called cortical inclusion cysts. While inside the ovary, the epithelial cells are exposed to ovarian hormones that stimulate cell proliferation, which in turn transforms into cancer cells.

• #41

  https://link.springer.com/article/10.1007/s12672-010-0054-2

  Considerable progress has been made in comprehending the genetic makeup and physiological processes involved in ovarian cancer, but its underlying etiology is not well understood. […] The fact that there is a positive correlation between the number of ovulatory cycles with risk of ovarian cancer paved the way to the incessant ovulation hypothesis by Fathalla in 1971. […] Pitfalls in the incessant ovulation theory and evidence of increased risk among women using fertility drugs in order to conceive led to the gonadotropin hypothesis. […] Therefore, current studies suggest a role for gonadotropins in ovarian cancer progression, but not necessarily in causality. […] Various inflammatory processes are involved with each ovulation and are believed to be the causative process responsible for priming OECs to genetic damage and carcinogenesis.

• #42 The Pathogenesis of Epithelial Ovarian Cancer – Onkologie – Universimed – Knowledge that matters

  https://www.universimed.com/ch/article/onkologie/the-pathogenesis-of-epithelial-ovarian-cancer-2126519

  The main epidemiologic argument to support the “incessant ovulation” theory is the decrease in the incidence of EOC when ovulation is suppressed by parity or contraceptive pills. […] Excessive exposure to gonadotrophins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), regulatory hormones secreted by the anterior pituitary gland during menopause, ovulation and infertility therapy, raised the question of their role in ovarian cancer pathogenesis. […] A third hypothesis called “incessant menstruation” has recently emerged. […] Epidemiological arguments supporting this hypothesis are the observation that hysterectomy without oophorectomy and tubal ligation plays a protective role against EOC, particularly clear-cell and endometroid carcinomas.

• #43 The Pathogenesis of Epithelial Ovarian Cancer – Onkologie – Universimed – Knowledge that matters

  https://www.universimed.com/ch/article/onkologie/the-pathogenesis-of-epithelial-ovarian-cancer-2126519

  The main epidemiologic argument to support the “incessant ovulation” theory is the decrease in the incidence of EOC when ovulation is suppressed by parity or contraceptive pills. […] Excessive exposure to gonadotrophins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), regulatory hormones secreted by the anterior pituitary gland during menopause, ovulation and infertility therapy, raised the question of their role in ovarian cancer pathogenesis. […] A third hypothesis called “incessant menstruation” has recently emerged. […] Epidemiological arguments supporting this hypothesis are the observation that hysterectomy without oophorectomy and tubal ligation plays a protective role against EOC, particularly clear-cell and endometroid carcinomas.

• #44

  https://link.springer.com/article/10.1007/s12672-010-0054-2

  Considerable progress has been made in comprehending the genetic makeup and physiological processes involved in ovarian cancer, but its underlying etiology is not well understood. […] The fact that there is a positive correlation between the number of ovulatory cycles with risk of ovarian cancer paved the way to the incessant ovulation hypothesis by Fathalla in 1971. […] Pitfalls in the incessant ovulation theory and evidence of increased risk among women using fertility drugs in order to conceive led to the gonadotropin hypothesis. […] Therefore, current studies suggest a role for gonadotropins in ovarian cancer progression, but not necessarily in causality. […] Various inflammatory processes are involved with each ovulation and are believed to be the causative process responsible for priming OECs to genetic damage and carcinogenesis.

• #45 The Pathogenesis of Epithelial Ovarian Cancer – Onkologie – Universimed – Knowledge that matters

  https://www.universimed.com/ch/article/onkologie/the-pathogenesis-of-epithelial-ovarian-cancer-2126519

  The first step in tubal transformation from benign to precursor lesion is called p53 signature, characterized by the appearance of benign secretory cells that exhibit evidence of DNA damage, TP53 mutation and p53 protein stabilisation. […] Genetic analysis comparing microdissected paired samples of STIC and HGSOC (high grade serous ovarian carcinoma) revealed a clonal evolution, supporting the hypothesis that these lesions were the precursors of ovarian carcinomas. […] Chronic inflammation and hyperoestrogenism in the pelvis caused by endometriosis seems to be responsible for oxidative stress and specific molecular alterations leading to malignant transformation. […] Recent gene-expression profiling of MOC and single-cell RNA sequencing showed that MOC are more likely to evolve from primordial germ cells than the eutopic tubal or ovarian epithelium, supporting the idea that less than 15 % of ovarian cancer would be of primary ovarian origin.

• #46 Ovarian Cancer Metastasis: A Unique Mechanism of Dissemination | IntechOpen

  https://www.intechopen.com/chapters/51874

  Ovarian cancer is the most lethal of all gynecologic malignancies and has witnessed minimal improvements in patient outcomes in the past three decades. About 70% of ovarian cancer patients present with disseminated disease at the time of diagnosis. Even though metastasis is the leading cause of ovarian cancer related fatalities, our understanding of the process remains limited. Ovarian cancer has a unique pattern of metastasis where the hematogenous spread is less common. Ovarian cancer cells mainly metastasize within the peritoneal cavity, which involves exfoliation from the primary tumor, survival, and transport in the peritoneal fluid followed by metastatic colonization of the organs within the peritoneal cavity. A key step for successful metastasis is their attachment and productive interactions with the mesothelial cells covering the metastatic organs for the establishment of metastatic tumors.

• #47 Ovarian Cancer Metastasis: A Unique Mechanism of Dissemination | IntechOpen

  https://www.intechopen.com/chapters/51874

  Ovarian cancer predominantly metastasizes within the peritoneal cavity and through the pelvic lymph nodes. However, recent evidence suggests the possibility of hematogenous metastasis of ovarian cancer. […] The first step in the peritoneal metastasis is exfoliation of the ovarian cancer cells from the primary tumor into the peritoneal cavity. The prerequisite for this step is the loss of cell-cell contact between the cancer cells. As mentioned earlier, ovarian cancer can potentially arise from the fallopian tube epithelial cells or ovarian surface epithelium. Both express the classic epithelial marker epithelial cadherin (E-cadherin). […] The loss of E-cadherin expression and the resulting decrease in the cell-cell attachment promotes the dissemination of the cells into the peritoneal cavity.

• #48 Ovarian Cancer Metastasis: A Unique Mechanism of Dissemination | IntechOpen

  https://www.intechopen.com/chapters/51874

  Once the cancer cells have been shed into the peritoneal fluid, it significantly affects the prognosis of the patient as evidenced by the 29% relapse rate of stage 1A ovarian cancer compared to 59% relapse rate of stage 1C. […] The disseminated ovarian cancer cells floating in the ascites either as spheroids or as single cells develop resistance to anoikis and acquire cancer stem cell-like properties. […] The process of attaching to and developing metastatic tumors in the new organ is known as metastatic colonization. It is considered the least efficient step in the whole process of metastasis. […] The increased expression of the fibronectin receptor in the ovarian cancer cells is also beneficial in coupling attachment to growth factor signaling to promote metastasis. […] The metastasizing ovarian cancer cells were found to recruit the resident normal fibroblasts in the basement membrane of the omentum and reprogram them into cancer-associated fibroblasts (CAFs).

• #49 Ovarian Cancer Metastasis: A Unique Mechanism of Dissemination | IntechOpen

  https://www.intechopen.com/chapters/51874

  Once the cancer cells have been shed into the peritoneal fluid, it significantly affects the prognosis of the patient as evidenced by the 29% relapse rate of stage 1A ovarian cancer compared to 59% relapse rate of stage 1C. […] The disseminated ovarian cancer cells floating in the ascites either as spheroids or as single cells develop resistance to anoikis and acquire cancer stem cell-like properties. […] The process of attaching to and developing metastatic tumors in the new organ is known as metastatic colonization. It is considered the least efficient step in the whole process of metastasis. […] The increased expression of the fibronectin receptor in the ovarian cancer cells is also beneficial in coupling attachment to growth factor signaling to promote metastasis. […] The metastasizing ovarian cancer cells were found to recruit the resident normal fibroblasts in the basement membrane of the omentum and reprogram them into cancer-associated fibroblasts (CAFs).

• #50 Ovarian Cancer Metastasis: A Unique Mechanism of Dissemination | IntechOpen

  https://www.intechopen.com/chapters/51874

  Once the cancer cells have been shed into the peritoneal fluid, it significantly affects the prognosis of the patient as evidenced by the 29% relapse rate of stage 1A ovarian cancer compared to 59% relapse rate of stage 1C. […] The disseminated ovarian cancer cells floating in the ascites either as spheroids or as single cells develop resistance to anoikis and acquire cancer stem cell-like properties. […] The process of attaching to and developing metastatic tumors in the new organ is known as metastatic colonization. It is considered the least efficient step in the whole process of metastasis. […] The increased expression of the fibronectin receptor in the ovarian cancer cells is also beneficial in coupling attachment to growth factor signaling to promote metastasis. […] The metastasizing ovarian cancer cells were found to recruit the resident normal fibroblasts in the basement membrane of the omentum and reprogram them into cancer-associated fibroblasts (CAFs).

• #51 Ovarian Cancer Metastasis: A Unique Mechanism of Dissemination | IntechOpen

  https://www.intechopen.com/chapters/51874

  An important and abundant cellular component of the omentum is adipocytes. Until recently, not much was known about the direct role of the omental adipocytes in promoting ovarian cancer metastasis to the omentum even though it is well established that omentum is one of the main sites of ovarian cancer metastasis and that it is a predominantly fatty tissue.

• #52 Discovery reveals how ovarian cancer disables immune cells | Cornell Chronicle

  https://news.cornell.edu/stories/2024/10/discovery-reveals-how-ovarian-cancer-disables-immune-cells

  Weill Cornell Medicine researchers have discovered a mechanism that ovarian tumors use to cripple immune cells and impede their attack blocking the energy supply T cells depend on. […] A significant obstacle in treating ovarian cancer is the tumor microenvironment the complex ecosystem of cells, molecules and blood vessels that shields cancer cells from the immune system. […] Within this hostile environment, T cells lose their ability to take up lipid (fat) molecules, which are necessary for energy to mount an effective attack. […] However, the molecular mechanisms that govern this critical energy supply are still not well understood. […] Lipids are abundant in ovarian tumors, but T cells seem unable to utilize them in this environment. […] Hwang discovered that in patient-derived tumor specimens and mouse models of ovarian cancer, FABP5 becomes trapped inside the cytoplasm of T cells instead of moving to the cell surface, where it would normally help take up lipids from the surroundings.

• #53 Discovery reveals how ovarian cancer disables immune cells | Cornell Chronicle

  https://news.cornell.edu/stories/2024/10/discovery-reveals-how-ovarian-cancer-disables-immune-cells

  Since FABP5 is not getting to the surface, it couldn’t bring in the lipids necessary for energy production. […] Further experiments revealed that ovarian tumors somehow suppress the production of Transgelin 2 in infiltrating T cells. […] Without Transgelin 2, FABP5 cannot move to the surface of the T cells and pick up lipids, rendering the T cells unable to attack the tumor. […] Just like normal T cells in the tumor microenvironment, the engineered CAR T cells had FABP5 tangled in the cytoplasm. […] As a result, the CAR T cells were unable access lipids for energy to effectively attack the tumor, highlighting a critical barrier in using this immunotherapy for solid tumors like ovarian cancer. […] Our findings reveal a key mechanism of immune suppression in ovarian cancer and suggest new avenues to improve the efficacy of adoptive T cell immunotherapies in aggressive solid malignancies.

• #54 Drug resistance in ovarian cancer: from mechanism to clinical trial | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01967-3

  Ovarian cancer is the leading cause of gynecological cancer-related death. Drug resistance is the bottleneck in ovarian cancer treatment. The increasing use of novel drugs in clinical practice poses challenges for the treatment of drug-resistant ovarian cancer. […] We reviewed the literature regarding various drug resistance mechanisms in ovarian cancer and found that the main resistance mechanisms are as follows: abnormalities in transmembrane transport, alterations in DNA damage repair, dysregulation of cancer-associated signaling pathways, and epigenetic modifications. DNA methylation, histone modifications and noncoding RNA activity, three key classes of epigenetic modifications, constitute pivotal mechanisms of drug resistance. […] Even if resistance can develop to different drugs, the underlying mechanisms may be similar. Thus, instead of simply distinguishing resistance by agent, we attempted to classify drug resistance by mechanism.

• #55 Drug resistance in ovarian cancer: from mechanism to clinical trial | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01967-3

  We summarized four major mechanisms (Fig. 1) from the published literature: 1) abnormalities in transmembrane transport, 2) alterations in DNA damage repair (DDR), 3) dysregulation of cancer-associated signaling pathways, and 4) epigenetic modifications. […] The ABC transporter family is mainly responsible for drug efflux. Abnormal expression of miRNAs (e.g., the miR-200 family, let-7 family and miR-130a/b) plays a role in ABC transporter regulation, thereby inducing resistance in ovarian cancer. […] Whole-genome microarray analysis revealed that ABCB1 was the only drug transporter with increased expression in resistant ovarian cancer cells, while the expression of several other ABC transporters was significantly decreased. […] Notably, dysregulated miRNAs can mediate the overexpression of ABCB1, resulting in MDR.

• #56 ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells | British Journal of Cancer

  https://www.nature.com/articles/bjc2016203

  Paclitaxel-resistant cells were cross-resistant to olaparib, doxorubicin and rucaparib but not to veliparib or AZD2461. […] We describe a common ABCB1-mediated mechanism of paclitaxel and olaparib resistance in ovarian cancer cells. […] Increased understanding of causal molecular mechanisms may facilitate biomarker development to predict and monitor the onset of drug-resistant disease in individual patients and inform the most rational prescription of alternative second-line chemotherapy, where a variety of drugs are currently being evaluated in clinical trials, including the PARP inhibitors (PARPis) olaparib, veliparib (ABT-888) and rucaparib. […] Increased ABCB1 copy number resulting from a chromosomal amplification event at 7q11.2-21 has been correlated with increased P-glycoprotein expression in paclitaxel-resistant cells from various cancers, including ovarian cancer.

• #57 ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells | British Journal of Cancer

  https://www.nature.com/articles/bjc2016203

  We now describe the creation of a novel olaparib-resistant A2780-derived ovarian cancer cell line (A2780olapR) and highlight an ABCB1-mediated resistance mechanism common to paclitaxel, doxorubicin and rucaparib. […] Our data confirm many previous reports of an ABCB1-mediated adaptive resistance mechanism in paclitaxel-resistant ovarian cancer cell lines and xenograft models and describes a common mechanism of resistance to PARPis, including olaparib and rucaparib. […] ABCB1-mediated resistance to PARPis is a novel finding in ovarian cancer and is of particular clinical relevance as olaparib and related drugs are currently being evaluated in multiple clinical trials as second-line or maintenance chemotherapy options, often in paclitaxel pretreated patients. […] Our data suggest that both paclitaxel- and olaparib-induced resistance is reversible following combination treatment with a P-glycoprotein inhibitor.

• #58 Drug resistance in ovarian cancer: from mechanism to clinical trial | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01967-3

  The classical mechanisms of action of common drugs can be disrupted or altered, possibly resulting in impaired therapeutic effects. […] If DNA damage is not repaired promptly, cellular senescence or apoptotic signals are activated, while abnormal activation of DDR maintains the viability of cancer cells, significantly inducing resistance to chemotherapeutic drugs and PARPis and affecting therapeutic efficacy. […] HR deficiency is characteristic of many HGSOC cases (approximately 50%) and is considered a predictive biomarker of sensitivity to platinum agents and PARPis. […] The TGF- pathway has biphasic effects and acts as a tumor suppressor at early stages but later stimulates cancer progression by impacting tumor cells and their microenvironment. […] The Hippo pathway confers resistance to therapeutic agents that are commonly used to treat ovarian cancer.

• #59 Drug resistance in ovarian cancer: from mechanism to clinical trial | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01967-3

  The classical mechanisms of action of common drugs can be disrupted or altered, possibly resulting in impaired therapeutic effects. […] If DNA damage is not repaired promptly, cellular senescence or apoptotic signals are activated, while abnormal activation of DDR maintains the viability of cancer cells, significantly inducing resistance to chemotherapeutic drugs and PARPis and affecting therapeutic efficacy. […] HR deficiency is characteristic of many HGSOC cases (approximately 50%) and is considered a predictive biomarker of sensitivity to platinum agents and PARPis. […] The TGF- pathway has biphasic effects and acts as a tumor suppressor at early stages but later stimulates cancer progression by impacting tumor cells and their microenvironment. […] The Hippo pathway confers resistance to therapeutic agents that are commonly used to treat ovarian cancer.

• #60 Researchers uncover novel dual-target mechanism in treatment-resistant ovarian cancer | U-M Rogel Cancer Center

  https://www.rogelcancercenter.org/news/archive/researchers-uncover-novel-dual-target-mechanism-treatment-resistant-ovarian-cancer

  Researchers from the University of Michigan Rogel Cancer Center and BenevolentAI have identified a promising new therapeutic approach for platinum-resistant ovarian cancer. […] The analysis prioritized 74 promising targets for experimental testing, leading to the identification of two key molecular drivers of the disease: TRAF2 and NCK interacting kinase, or TNIK, and cyclin-dependent kinase 9, or CDK9. […] Further molecular analysis also revealed a novel interaction between these proteins, with CDK9 playing a previously unknown role in activating the Wnt signaling pathway, a crucial molecular mechanism that enables cancer cells to resist chemotherapy. […] „This research represents a significant advancement in our understanding of treatment resistance in ovarian cancer,” said study author Analisa DiFeo, Ph.D., professor of pathology and obstetrics and gynecology at Michigan Medicine. „By uncovering the interaction between TNIK and CDK9, and validating their combined role in treatment resistance across multiple patient-derived models, we have identified a promising new therapeutic approach. The discovery that CDK9 regulates the Wnt signalling pathway could have far-reaching implications for treating other cancers where these mechanisms are active.”

• #61 Drug resistance in ovarian cancer: from mechanism to clinical trial | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01967-3

  Increasing evidence shows that abnormal epigenetic regulation leads to tumor drug resistance. […] Epigenetic alterations in the docking protein 2 (DOK2) gene can induce carboplatin resistance in ovarian cancer via suppression of apoptosis. […] The resistance mechanisms cross-talk with each other and may interfere by generating an immunosuppressive environment, thus resulting in drug resistance, including immunotherapy resistance. […] In summary, the therapeutic efficacy and underlying mechanisms of CHK1/2 inhibitors are unknown, and further studies are attractive and needed.

• #62 Mechanism of resistance to novel targeted therapy for ovarian cancer identified

  https://medicalxpress.com/news/2018-10-mechanism-resistance-therapy-ovarian-cancer.html

  Scientists at The Wistar Institute have unraveled a mechanism of resistance to EZH2 inhibitors in ovarian cancers with mutations in the ARID1A gene. The study, published in Nature Communications, suggests that inhibition of the cell death regulator BCL2 may be used to circumvent or prevent ovarian cancer treatment resistance. […] Mutations in the ARID1A gene are frequent in clear cell ovarian cancer and represent a known genetic driver in this type of malignancy. […] Zhang and colleagues discovered a molecular switch that happens in the SWI/SNF protein complex, of which ARID1A is a component, in ovarian cancer cells resistant to EZH2 pharmacologic inhibition. Because the SWI/SNF complex remodels chromatin and modulates gene transcription, this switch causes a shift in expression of a subset of genes and activation of factors that favor tumor cell survival.

• #63 Mechanism of resistance to novel targeted therapy for ovarian cancer identified

  https://medicalxpress.com/news/2018-10-mechanism-resistance-therapy-ovarian-cancer.html

  The two proteins involved in the switch, namely SMARCA2 and SMARCA4, perform similar functions in the complex but do not work simultaneously, each being specific of certain conditions, like workers in different shifts. […] Consequently, several genes that are normally repressed by SMARCA4 are expressed at higher level and drive cell survival by inhibiting programmed cell death. The most relevant of these genes is BCL2, the Zhang Lab found. […] Consistent with this finding, a small molecule inhibitor of BCL2 killed ovarian cancer cells resistant to EZH2 inhibition in vitro and caused shrinking of tumors established by injection of resistant cells in mice. […] „We discovered a potential therapeutic strategy to revert resistance to EZH2 inhibition in ovarian clear cell carcinoma,” said Shuai Wu, Ph.D., first author of the study and a postdoctoral researcher in the Zhang Lab. Our study also suggests that BCL2 inhibition may be used in combination with EZH2 inhibitors to prevent the onset of resistance. […] The study identified a new therapeutic use for BCL2 inhibitors, which are approved for treatment of lymphoma.

• #64 Pathogenesis of Ovarian Cancer. Lessons from Morphology and Molecular Biology and their Clinical Implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2794425/

  The model helps to explain why current screening techniques, aimed at detecting stage I disease, have not been effective. […] Although the reasons for this are not entirely clear, it appears that some tumors evolve rapidly and spread to extra-ovarian sites early in their development. […] Therefore, a more realistic endpoint for the early detection of ovarian carcinoma may be volume and not stage of disease. […] The model, by drawing attention to molecular genetic pathways that play a role in tumor progression, can shed light on new approaches to early detection and novel methods of treatment. […] The proposed model for ovarian carcinogenesis also has important implications for targeted treatment. […] With the characterization of specific genetic changes that occur early in the development of Type II tumors, treatment could be administered using drugs that target the pathways affected by the mutations, for example mutant TP53. […] In summary, this model is an initial attempt to organize our thinking about what is undoubtedly a highly complex process.

• #65

  https://link.springer.com/article/10.1007/s00404-013-3041-3

  Based on this hypothesis, a salpingectomy, i.e., the removal of the post-reproductive fallopian tubes may remove the actual site of tumorigenesis and thereby prevent spreading over the ovarian surface and throughout the peritoneum. Consequently, prophylactic salpingectomy might protect against serous ovarian cancer. Moreover, the procedure interrupts the connection between the uterine cavity and the lesser pelvis. Hence, it prevents the ascension of exfoliated endometrial cells which will likely reduce the incidence of endometrioid and clear cell ovarian cancers. Increasing evidence suggests that serous ovarian cancer originates from the fimbriated distal end of the fallopian tube, whereas the ovary gets only involved at a later stage. […] Given the lack of suitable screening or early detection strategies for ovarian cancer, post-reproductive salpingectomy deserves serious consideration as a prophylactic intervention that will likely confer significant protection against an often deadly disease.

• #66 Clues to the origins of ovarian cancer

  https://www.contemporaryobgyn.net/view/clues-to-the-origins-of-ovarian-cancer

  A Swedish study found that compared with controls, patients with endometriosis were 1.3 to 2.0 times more likely to develop ovarian cancer and to receive a diagnosis at a younger age. […] The overall lifetime risk of developing ovarian cancer in the general population is 1.3% to 1.5%, with a majority of cases occurring in the later years of life. […] Approximately 18% to 24% of patients with ovarian cancer have a genetic predisposition due to inheritance of germline mutations. […] The most common germline mutations associated with the development of ovarian or fallopian tube cancer are in BRCA1 or BRCA2, genes involved in the homologous recombination DNA repair pathway. […] The risk of ovarian cancer for BRCA carriers increases with age. […] RRSO has been found to decrease the risk of OC by 75% to 95% but also contributes to the reduction in hormone production that is protective against development of breast cancer. […] Bilateral RRSO in women with a genetic predisposition or family history of ovarian cancer has been shown to decrease the risk of ovarian cancer by up to 95%.

• #67 Pathogenesis of Ovarian Cancer. Lessons from Morphology and Molecular Biology and their Clinical Implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2794425/

  The model helps to explain why current screening techniques, aimed at detecting stage I disease, have not been effective. […] Although the reasons for this are not entirely clear, it appears that some tumors evolve rapidly and spread to extra-ovarian sites early in their development. […] Therefore, a more realistic endpoint for the early detection of ovarian carcinoma may be volume and not stage of disease. […] The model, by drawing attention to molecular genetic pathways that play a role in tumor progression, can shed light on new approaches to early detection and novel methods of treatment. […] The proposed model for ovarian carcinogenesis also has important implications for targeted treatment. […] With the characterization of specific genetic changes that occur early in the development of Type II tumors, treatment could be administered using drugs that target the pathways affected by the mutations, for example mutant TP53. […] In summary, this model is an initial attempt to organize our thinking about what is undoubtedly a highly complex process.

• #68 Pathogenesis of Ovarian Cancer. Lessons from Morphology and Molecular Biology and their Clinical Implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2794425/

  The model helps to explain why current screening techniques, aimed at detecting stage I disease, have not been effective. […] Although the reasons for this are not entirely clear, it appears that some tumors evolve rapidly and spread to extra-ovarian sites early in their development. […] Therefore, a more realistic endpoint for the early detection of ovarian carcinoma may be volume and not stage of disease. […] The model, by drawing attention to molecular genetic pathways that play a role in tumor progression, can shed light on new approaches to early detection and novel methods of treatment. […] The proposed model for ovarian carcinogenesis also has important implications for targeted treatment. […] With the characterization of specific genetic changes that occur early in the development of Type II tumors, treatment could be administered using drugs that target the pathways affected by the mutations, for example mutant TP53. […] In summary, this model is an initial attempt to organize our thinking about what is undoubtedly a highly complex process.

• #69 Drug resistance in ovarian cancer: from mechanism to clinical trial | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01967-3

  The classical mechanisms of action of common drugs can be disrupted or altered, possibly resulting in impaired therapeutic effects. […] If DNA damage is not repaired promptly, cellular senescence or apoptotic signals are activated, while abnormal activation of DDR maintains the viability of cancer cells, significantly inducing resistance to chemotherapeutic drugs and PARPis and affecting therapeutic efficacy. […] HR deficiency is characteristic of many HGSOC cases (approximately 50%) and is considered a predictive biomarker of sensitivity to platinum agents and PARPis. […] The TGF- pathway has biphasic effects and acts as a tumor suppressor at early stages but later stimulates cancer progression by impacting tumor cells and their microenvironment. […] The Hippo pathway confers resistance to therapeutic agents that are commonly used to treat ovarian cancer.

• #70 Researchers uncover novel dual-target mechanism in treatment-resistant ovarian cancer | U-M Rogel Cancer Center

  https://www.rogelcancercenter.org/news/archive/researchers-uncover-novel-dual-target-mechanism-treatment-resistant-ovarian-cancer

  Researchers from the University of Michigan Rogel Cancer Center and BenevolentAI have identified a promising new therapeutic approach for platinum-resistant ovarian cancer. […] The analysis prioritized 74 promising targets for experimental testing, leading to the identification of two key molecular drivers of the disease: TRAF2 and NCK interacting kinase, or TNIK, and cyclin-dependent kinase 9, or CDK9. […] Further molecular analysis also revealed a novel interaction between these proteins, with CDK9 playing a previously unknown role in activating the Wnt signaling pathway, a crucial molecular mechanism that enables cancer cells to resist chemotherapy. […] „This research represents a significant advancement in our understanding of treatment resistance in ovarian cancer,” said study author Analisa DiFeo, Ph.D., professor of pathology and obstetrics and gynecology at Michigan Medicine. „By uncovering the interaction between TNIK and CDK9, and validating their combined role in treatment resistance across multiple patient-derived models, we have identified a promising new therapeutic approach. The discovery that CDK9 regulates the Wnt signalling pathway could have far-reaching implications for treating other cancers where these mechanisms are active.”

• #71 Researchers uncover novel dual-target mechanism in treatment-resistant ovarian cancer | U-M Rogel Cancer Center

  https://www.rogelcancercenter.org/news/archive/researchers-uncover-novel-dual-target-mechanism-treatment-resistant-ovarian-cancer

  Testing in patient-derived 3D models showed NCB-0846 effectively targeted both TNIK and CDK9, demonstrating superior efficacy compared to targeting either protein individually. […] „This dual-targeting approach highlights our AI platforms ability to uncover new disease biology. This discovery exemplifies the power of combining AI-driven predictions with experimental validation in patient-derived models,” said Ivan Griffin, D.Phil., co-founder and chief business officer of BenevolentAI.

• #72 Ovarian carcinoma: pathology review with an emphasis in their molecular characteristics – Lino-Silva – Chinese Clinical Oncology

  https://cco.amegroups.org/article/view/42910/html

  The DNA repair deficits identified in some high-grade OCAs represent a potentially exploitable Achilles heel for therapeutic purposes. […] Recent extensive studies suggest that 50% of high-grade serous OCAs may be deficient in the hormonal receptors pathway. […] These abnormalities are mutually exclusive, which means that 30% of high-grade OCAs may have a loss of BRCA function. […] The identification and molecular characterization after treatment of these high-grade tumors, enriched with resistant clones, could allow us to better understand how these tumors adapt to chemotherapy and identify possible therapeutic objectives for serous type II carcinomas. […] Given the detectable genomic alterations in the OCAs and the number of new molecules, approved or in development, directed at these same anomalies, it is reasonable to expect that taking the charge adapted to tumor biology is an attainable goal in the near future.

• #73 Mechanism of resistance to novel targeted therapy for ovarian cancer identified

  https://medicalxpress.com/news/2018-10-mechanism-resistance-therapy-ovarian-cancer.html

  The two proteins involved in the switch, namely SMARCA2 and SMARCA4, perform similar functions in the complex but do not work simultaneously, each being specific of certain conditions, like workers in different shifts. […] Consequently, several genes that are normally repressed by SMARCA4 are expressed at higher level and drive cell survival by inhibiting programmed cell death. The most relevant of these genes is BCL2, the Zhang Lab found. […] Consistent with this finding, a small molecule inhibitor of BCL2 killed ovarian cancer cells resistant to EZH2 inhibition in vitro and caused shrinking of tumors established by injection of resistant cells in mice. […] „We discovered a potential therapeutic strategy to revert resistance to EZH2 inhibition in ovarian clear cell carcinoma,” said Shuai Wu, Ph.D., first author of the study and a postdoctoral researcher in the Zhang Lab. Our study also suggests that BCL2 inhibition may be used in combination with EZH2 inhibitors to prevent the onset of resistance. […] The study identified a new therapeutic use for BCL2 inhibitors, which are approved for treatment of lymphoma.

• #74 Cancers | Special Issue : Ovarian Cancer: Pathogenesis, Molecular Mechanism and Opportunities for Interventions

  https://www.mdpi.com/journal/cancers/special_issues/70O82KKS46

  Ovarian cancer is one of the deadliest cancers among women worldwide. Despite advances in treatment, the high rates of late-stage diagnosis and resistance to therapy result in low survival rates. This cancer is characterised by the uncontrolled growth of cells in the ovaries and is classified into several histological types, with high-grade serous carcinoma (HGSC) being the most common and aggressive form. Genetic mutations, epigenetic modifications, defective signalling pathways, cancer-promoting tumour microenvironment, immune evasion, and inflammation are known to contribute to ovarian cancer pathogenesis. […] Understanding the mechanisms underlying ovarian cancer pathogenesis is critical for developing effective therapeutic strategies. Continued research into these mechanisms is essential for the identification of targeted therapies that can improve outcomes for ovarian cancer patients. Companion biomarkers/tests that predict response towards specific treatments could further help develop personalised treatment strategies. […] This special issue will focus on the latest findings regarding the mechanisms involved in ovarian cancer development, progression, and recurrence, the intervention/treatment approaches for ovarian cancer, and the companion biomarkers that could predict treatment outcomes.

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