Recently, many types of in vitro 3‐D culture systems have been developed to recapitulate the in vivo growth conditions of cancer. The cancer 3‐D culture methods aim to preserve the biological ...characteristics of original tumors better than conventional 2‐D monolayer cultures, and include tumor‐derived organoids, tumor‐derived spheroids, organotypic multicellular spheroids, and multicellular tumor spheroids. The 3‐D culture methods differ in terms of cancer cell sources, protocols for cell handling, and the required time intervals. Tumor‐derived spheroids are unique because they are purposed for the enrichment of cancer stem cells (CSCs) or cells with stem cell‐related characteristics. These spheroids are grown as floating spheres and have been used as surrogate systems to evaluate the CSC‐related characteristics of solid tumors in vitro. Because eradication of CSCs is likely to be of clinical importance due to their association with the malignant nature of cancer cells, such as tumorigenicity or chemoresistance, the investigation of tumor‐derived spheroids may provide invaluable clues to fight against cancer. Spheroid cultures have been established from cancers including glioma, breast, colon, ovary, and prostate cancers, and their biological and biochemical characteristics have been investigated by many research groups. In addition to the investigation of CSCs, tumor‐derived spheroids may prove to be instrumental for a high‐throughput screening platform or for the cultivation of CSC‐related tumor cells found in the circulation or body fluids.
Tumor‐derived spheroid culture is one of the representative 3D culture methods in which cancer cells with stem cell‐like features are expanded in vitro as floating spheres. In this review, we summarize the major discoveries from studies using tumor‐derived spheroids and future clinical applications.
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. Treatment of epithelial ovarian cancer is based on the combination of cytoreductive surgery and combination chemotherapy using taxane and platinum. Although clear cell type is categorized in indolent type, it is known to show relatively strong resistance to carboplatin and paclitaxel regimen and thus poor prognosis compared to serous adenocarcinoma, especially in advanced stages. Irinotecan plus cisplatin therapy may effective for the clear cell adenocarcinoma. The larger expectation for improved prognosis in ovarian carcinoma is related to the use of the new biological agents. One of the most investigated and promising molecular targeted drugs in ovarian cancer is bevacizumab, a monoclonal antibody directed against VEGF. PARP inhibitor is another one. A few recent studies demonstrated positive results of bevacizumab on progression-free survival in ovarian cancer patients, however, investigation of molecular targeting drugs in patients with ovarian cancer are still underway.
Endometriosis is characterized by ectopic endometrial-like epithelium and stroma, of which molecular characteristics remain to be fully elucidated. We sequenced 107 ovarian endometriotic and 82 ...normal uterine endometrial epithelium samples isolated by laser microdissection. In both endometriotic and normal epithelium samples, numerous somatic mutations were identified within genes frequently mutated in endometriosis-associated ovarian cancers. KRAS is frequently mutated in endometriotic epithelium, with a higher mutant allele frequency (MAF) accompanied by arm-level allelic imbalances. Analyses of MAF, combined with multiregional sequencing, illuminated spatiotemporal evolution of the endometriosis and uterine endometrium genomes. We sequenced 109 single endometrial glands and found that each gland carried distinct cancer-associated mutations, demonstrating the heterogeneity of the genomic architecture of endometrial epithelium. Remarkable increases in MAF of mutations in cancer-associated genes in endometriotic epithelium suggest retrograde flow of endometrial cells already harboring cancer-associated mutations, with selective advantages at ectopic sites, leading to the development of endometriosis.
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•Endometriosis and uterine endometrium exhibit cancer-associated somatic mutations•Clonal expansion of epithelial cells with cancer-associated mutations in endometriosis•Genomic architecture of epithelial cells in uterine endometrium is heterogeneous•Single endometrial glands carry distinct mutations in cancer-associated genes
Suda et al. identify numerous cancer-associated mutations in epithelial cells from ovarian endometriosis and normal endometrium. They describe a heterogeneous and mosaic-like uterine endometrial epithelium, shaped by endometrial glands with distinct somatic mutations. They suggest clonal expansion of epithelial cells with cancer-associated mutations leads to the development of endometriosis.
To examine the trends of epithelial ovarian cancer histologic subtypes in Japan.
A nationwide retrospective registry study was performed between 2002 and 2015 (Japan cohort, n = 48,640). Trends were ...also examined in The Surveillance, Epidemiology, and End Results Program (US cohort, n = 49,936). Time-specific proportional changes of four major histological subtypes (serous, clear cell, endometrioid, and mucinous) were examined.
The Japan cohort had more stage I disease (44.1% versus 24.9%) and less stage IV disease (10.0% versus 23.1%) than the US cohort (P < 0.001). The Japan cohort had more non-serous histology, particularly clear cell carcinoma (26.9% versus 8.4%), than the US cohort (P < 0.001). In the Japan cohort, proportion of clear cell carcinoma increased significantly from 23.4% to 29.1% between 2002 and 2010 (P < 0.001). Among stage I disease, clear cell carcinoma increased significantly in the Japan cohort from 32.9% to 40.3% between 2002 and 2015 (P < 0.001), whereas mucinous carcinoma increased significantly in the US cohort from 15.0% to 24.8% (P = 0.01). In 2015, clear cell carcinoma was most common among women aged <50 years from the Japan cohort (30.2%) versus serous carcinoma in the US cohort (50.8%). In the Japan cohort, the peak age was 75 years for serous, 57 for clear cell, and 45 for endometrioid carcinoma (P < 0.001). Mucinous carcinoma decreased until 43 years and increased again after age 73 years (P < 0.001).
Characteristics of epithelial ovarian cancer in Japan are largely different compared to the US. In Japan, clear cell carcinoma has increased significantly in recent years to account for nearly 30% of epithelial ovarian cancer.
•The trends in four major histological subtypes of epithelial ovarian cancer (EOC) in Japan and the US were examined.•The characteristics of the histological subtypes of EOC in Japan are distinct from those in the US.•The frequency of clear cell carcinoma has increased in Japan, accounting for almost 30% of EOC in recent years.•The frequency of mucinous carcinoma has increased significantly among elderly in both countries.
Clear cell carcinoma of the ovary is thought to arise from endometriosis. In addition, retrograde menstruation of shed endometrium is considered the origin of endometriosis. However, little evidence ...supports cellular continuity from uterine endometrium to clear cell carcinoma through endometriosis at the genomic level. Here, we performed multiregional whole‐exome sequencing to clarify clonal relationships among uterine endometrium, ovarian endometriosis and ovarian clear cell carcinoma in a 56‐year‐old patient. Many somatic mutations including cancer‐associated gene mutations in ARID1A, ATM, CDH4, NRAS and PIK3CA were shared among epithelium samples from uterine endometrium, endometriotic lesions distant from and adjacent to the carcinoma, and the carcinoma. The mutant allele frequencies of shared mutations increased from uterine endometrium to distant endometriosis, adjacent endometriosis, and carcinoma. Although a splice site mutation of ARID1A was shared among the four epithelium samples, a frameshift insertion in ARID1A was shared by adjacent endometriosis and carcinoma samples, suggesting that the biallelic mutations triggered malignant transformation. Somatic copy number alterations, including loss of heterozygosity events at PIK3CA and ATM, were identified only in adjacent endometriosis and carcinoma, suggesting that mutant allele‐specific imbalance is another key factor driving malignant transformation. By reconstructing a clonal evolution tree based on the somatic mutations, we showed that the epithelium samples were derived from a single ancestral clone. Although the study was limited to a single patient, the results from this illustrative case could suggest the possibility that epithelial cells of ovarian endometriosis and clear cell carcinoma were descendants of uterine endometrial epithelium.
Suda et al performed whole‐exome sequencing for normal endometrial endometrium, two ovarian endometriotic epitheliums that were distant from or contiguous to the carcinoma, and carcinoma. A substantial number of somatic mutations were shared among four epithelium samples, and the mutant allele frequencies of shared mutations increased sequentially from uterine endometrium to carcinoma. Clonal evolution analysis revealed that epithelial cells of ovarian endometriosis and clear cell carcinoma were descendants of uterine endometrial epithelium.
gene mutations are associated with hereditary ovarian cancer.
plays a key role in genome integrity, and mutations result in an increased risk for ovarian cancer. Although various guidelines recommend
...testing in patients with ovarian cancer, data on germline
(g
) mutation frequency in ovarian cancer in Japan are scarce.
This study aimed to determine g
mutations in Japanese patients with ovarian cancer, stratified by clinicopathological characteristics, and to assess patients' satisfaction with pre-test genetic counseling.
The CHARLOTTE study (CHARacterizing the cross-sectionaL approach to Ovarian cancer: geneTic TEsting of
; UMIN000025597) is the first large multicenter epidemiological survey of Japanese women, aged ≥20, with newly diagnosed ovarian cancer (epithelial, primary peritoneal, or fallopian tube cancer), with histologically confirmed specimens. Patients were enrolled sequentially and underwent pre-test genetic counseling for
testing. Blood samples were centrally tested for the presence or absence of known g
mutations. A questionnaire was used to assess patient satisfaction with pre-test genetic counseling.
A total of 634 patients with a mean age of 56.9 years were included. Most patients (84.2%) had epithelial ovarian cancer, and 51.1% had FIGO stage III-IV cancer. Nearly all patients (99.5%) received genetic counseling before the
testing, either by an obstetrician-gynecologist (42.0%) or a clinical geneticist (42.0%). The overall prevalence of g
mutations was 14.7% (93/634), with g
mutations (9.9%) more common than g
mutations (4.7%). High-grade serous carcinoma showed a prevalence of g
mutations of 28.5%. Most patients were satisfied with pre-test counseling, irrespective of the service provider's professional position.
Patients with high-grade serous carcinoma and family history of ovarian cancer had a slightly higher prevalence of g
mutations, but none of the subgroups had considerably high g
mutation prevalence. These data suggest that g
testing should be carried out in all patients with ovarian cancer.
It has become evident that somatic mutations in cancer-associated genes accumulate in the normal endometrium, but spatiotemporal understanding of the evolution and expansion of mutant clones is ...limited. To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we sequence 1311 endometrial glands from 37 women. By collecting endometrial glands from different parts of the endometrium, we show that multiple glands with the same somatic mutations occupy substantial areas of the endometrium. We demonstrate that "rhizome structures", in which the basal glands run horizontally along the muscular layer and multiple vertical glands rise from the basal gland, originate from the same ancestral clone. Moreover, mutant clones detected in the vertical glands diversify by acquiring additional mutations. These results suggest that clonal expansions through the rhizome structures are involved in the mechanism by which mutant clones extend their territories. Furthermore, we show clonal expansions and copy neutral loss-of-heterozygosity events occur early in life, suggesting such events can be tolerated many years in the normal endometrium. Our results of the evolutionary dynamics of mutant clones in the human endometrium will lead to a better understanding of the mechanisms of endometrial regeneration during the menstrual cycle and the development of therapies for the prevention and treatment of endometrium-related diseases.
The Japan Society of Gynecologic Oncology (JSGO) Guidelines 2017 for the Treatment of Uterine Cervical Cancer are for the purpose of providing standard treatment strategies for cervical cancer, ...indicating treatment methods currently considered appropriate for cervical cancer, minimizing variances in treatment methods among institutions, improving the safety of treatment and prognosis of diseases, reducing the economic and psychosomatic burden of patients by promoting performance of appropriate treatment, and enhancing mutual understanding between patients and healthcare professionals. The guidelines were prepared through consensus of the JSGO Guideline Committee, based on careful review of evidence gathered through the literature searches and in view of the medical health insurance system and actual clinical practice situations in Japan. The guidelines comprise eight chapters and five algorithms. The main features of the 2017 revision are as follows: (1) evidence was collected using a search formula and with cooperation of the Japan Library Association. The bibliographical search formula was placed at the end of the book; (2) regarding clinical questions (CQs) where evidence or clinical inspection in Japan was lacking, opinions of the Guidelines Committee were described as “proposals for future directions”; (3) cervical intraepithelial neoplasia (CIN) 3 and adenocarcinoma in situ (AIS) were treated as a cervical precancerous lesion; (4) the CQs of endoscopic surgery, radical trachelectomy, and sentinel node biopsy were newly added in Chapter 3, “primary treatment for stage IB–II cervical cancer”; and (5) the CQ about hormone replacement therapy after cancer treatment was newly established. Each recommendation is accompanied by a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here, we present the English version of the JSGO Guidelines 2017 for the Treatment of Uterine Cervical Cancer.
To provide information including the trend of gynecological malignancies in Japan, we hereby present the Annual Patient Report for 2015 and the Annual Treatment Report for 2010 on the outcomes of ...patients who started treatment in 2010.
The Japan Society of Obstetrics and Gynecology maintains an annual tumor registry where information on gynecological malignancies from various participating institutions is gathered. The data of patients whose treatment was initiated in 2015 were analyzed retrospectively. Survival of the patients who started treatment in 2010 was analyzed by using the Kaplan-Meier, log-rank and Wilcoxson tests.
Treatment was initiated in 2015 for 7527 patients with cervical cancer, 10 119 with endometrial cancer, 6424 with ovarian cancer and 2181 with ovarian borderline tumors. This clinicopathological information was summarized as the Patient Annual Report. Prognoses were analyzed across 4309 patients with cervical cancer, 5054 with endometrial cancer and 3423 with ovarian cancer, whose treatment was initiated in 2010. The 5-year survival rates of the patients with cervical cancer were 92.1%, 74.2%, 52.0%, and 29.8% for stages I, II, III, and IV, respectively. The 5-year survival rates for the patients with endometrial cancer were 94.3%, 88.8%, 74.0% and 26.6% for stages I, II, III and IV, respectively. The 5-year survival rates for the patients with ovarian cancer (surface epithelial-stromal tumors) were 88.5%, 80.1%, 46.3% and 36.2% for stages I, II, III and IV, respectively.
The annual tumor report is an important survey that provides knowledge on gynecological malignancy trends in Japan.
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