RESUMO
Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8+ T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BRD4 degrader potentiated immunotherapy in a murine B7-H4+ breast cancer model. Thus, our work unravels a mechanistic and biological connection of a female sex hormone (progesterone) to onco-fetal immune tolerance via B7-H4 and suggests that the PR-P300-BRD4 axis is targetable for treating B7-H4+ cancer.
Assuntos
Tolerância Imunológica , Progesterona , Progestinas , Inibidor 1 da Ativação de Células T com Domínio V-Set , Animais , Feminino , Inibidor 1 da Ativação de Células T com Domínio V-Set/metabolismo , Humanos , Camundongos , Gravidez , Progestinas/farmacologia , Progestinas/metabolismo , Progesterona/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Receptores de Progesterona/metabolismo , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Camundongos Endogâmicos C57BL , Placenta/metabolismo , Placenta/imunologiaRESUMO
Aldehyde dehydrogenase (ALDH) enzymatic activity is a marker of cancer-initiating cells (CIC) in many tumor types. Our group and others have found that ALDH1A family inhibitors (ALDHi) can preferentially induce death of ovarian CIC in established ovarian cancer. We sought to determine if ALDHi, by targeting CIC at the time of tumor initiation, could function as a chemopreventive for ovarian cancer. As BRCA1/2 mutation carriers represent a population who could benefit from an ovarian cancer chemopreventive, we focused on BRCA mutation-associated tumor cell lines and murine tumor models. We found that, compared to BRCA wild-type cells, BRCA mutant ovarian cancer cells are more sensitive to the ALDHi673A. Similarly, while 673A treatment of wild-type fallopian tube epithelial (FTE) cells is non-toxic, 673A induces death in FTE cells with BRCA1 knockdown. Using a murine fallopian tube organoid model of ovarian carcinogenesis, we show that 673A reduced organoid complexity and significantly reduce colony formation of BRCA-mutant cells. Organoids that persisted after 673A treatment were predominantly BRCA1wt, but NF1 mutant, suggesting a resistance mechanism. Finally, using the BPRN (Brca1, Trp53, Rb1, Nf1 inactivated) mouse model of tubo-ovarian cancer, we evaluated the impact of intermittent 673A therapy on carcinogenesis. 673A treatment resulted in a significant reduction in serous tubal intraepithelial carcinoma (STIC) lesions and carcinomas. Collectively, the findings suggest that ALDHi, such as 673A, could serve as chemopreventive agents for BRCA1/2 mutation carriers.
Assuntos
Cistadenocarcinoma Seroso , Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Feminino , Humanos , Camundongos , Animais , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Mutação , Neoplasias das Tubas Uterinas/patologia , Tubas Uterinas/patologia , Cistadenocarcinoma Seroso/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Neoplasias Ovarianas/metabolismo , Inibidores Enzimáticos , Quimioprevenção , CarcinogêneseRESUMO
OBJECTIVES: The "incessant ovulation" hypothesis links increased risk for tubo-ovarian high-grade serous carcinoma (HGSC) due to more ovulations and reduced risk conferred by pre-menopausal exposures like oral contraceptive use, multiparity, and breastfeeding. However, most women diagnosed with HGSC are postmenopausal, implying age is a major risk factor for HGSC. Our mouse model for HGSC, based on tamoxifen (TAM)-induced somatic inactivation of the Brca1, Trp53, Rb1, and Nf1 (BPRN) tumor suppressor genes in oviductal epithelium, recapitulates key genetic, histopathologic, and biological features of human HGSCs. We aimed to credential the model for future efforts to define biological and risk modification factors in HGSC pathogenesis. METHODS: BPRN mice were treated with TAM to induce tumors at defined ages and parity status. RESULTS: BPRN mice aged 9-months prior to tumor induction had markedly shorter survival than 6-8 week old mice induced to form tumors (median 46.5 weeks versus 61.5 weeks, log-rank test P = 0.0006). No significant differences in cancer phenotypes were observed between multiparous versus nulliparous BPRN mice. However, using a modified tumor model with one wild-type Nf1 allele (BPRNfl/+), nulliparous mice had more advanced tumors than multiparous mice (Mantel-Haenszel Chi-square test of association, P = 0.01). CONCLUSIONS: Our findings show aging is associated with significantly shortened survival post tumor induction in the BRPN model and multiparity delays development and/or progression of HGSC in certain genetic contexts. The findings support relevance of our mouse model to gain mechanistic insights into how known factors exert their protective effects and to test novel approaches for HGSC prevention.
Assuntos
Carcinoma , Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Envelhecimento , Animais , Transformação Celular Neoplásica/patologia , Cistadenocarcinoma Seroso/patologia , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/patologia , Paridade , GravidezRESUMO
Recently, ovarian cancer research has evolved considerably because of the emerging recognition that rather than a single disease, ovarian carcinomas comprise several different histotypes that vary by etiologic origin, risk factors, molecular profiles, therapeutic approaches and clinical outcome. Despite significant progress in our understanding of the etiologic heterogeneity of ovarian cancer, as well as important clinical advances, it remains the eighth most frequently diagnosed cancer in women worldwide and the most fatal gynecologic cancer. The International Agency for Research on Cancer and the United States National Cancer Institute jointly convened an expert panel on ovarian carcinoma to develop consensus research priorities based on evolving scientific discoveries. Expertise ranged from etiology, prevention, early detection, pathology, model systems, molecular characterization and treatment/clinical management. This report summarizes the current state of knowledge and highlights expert consensus on future directions to continue advancing etiologic, epidemiologic and prognostic research on ovarian carcinoma.
Assuntos
Prova Pericial , Carga Global da Doença/tendências , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/prevenção & controle , Congressos como Assunto , Feminino , Carga Global da Doença/estatística & dados numéricos , Humanos , Agências Internacionais , National Cancer Institute (U.S.) , Neoplasias Ovarianas/patologia , Estados UnidosRESUMO
PURPOSE: Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival. METHODS: Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery. RESULTS: Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend <0.01 for duration of MHT use). Residual disease mediated some (17%) of the relationship between MHT and survival. CONCLUSIONS: Pre-diagnosis MHT use for 5+ years was a favorable prognostic factor for women with ovarian cancer. This large study is consistent with prior smaller studies, and further work is needed to understand the underlying mechanism.
Assuntos
Terapia de Reposição de Estrogênios/estatística & dados numéricos , Terapia de Reposição Hormonal/estatística & dados numéricos , Neoplasias Ovarianas/mortalidade , Progestinas/administração & dosagem , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasia Residual/patologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Pós-Menopausa , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Taxa de SobrevidaRESUMO
Mesonephric adenocarcinoma is a rare tumor, accounting for <1% of cervical cancers. Well-differentiated mesonephric adenocarcinoma can be difficult to distinguish from diffuse mesonephric hyperplasia. Herein, we report a case of well-differentiated mesonephric adenocarcinoma with an FGFR2 mutation not previously reported in the literature. Nonselective tyrosine kinase inhibitors or FGFR2 inhibitors may represent options for targeted therapy.
Assuntos
Adenocarcinoma/diagnóstico , Mesonefroma/diagnóstico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Neoplasias do Colo do Útero/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Colo do Útero/patologia , Diagnóstico Diferencial , Feminino , Humanos , Mesonefroma/genética , Mesonefroma/patologia , Mutação , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologiaRESUMO
Most high-grade serous carcinomas are thought to arise from Fallopian tube epithelium (FTE), but some likely arise outside of the tube, perhaps from ectopic tubal-type epithelium known as endosalpingiosis. Importantly, the origin of endosalpingiosis is poorly understood. The proximity of the tubal fimbriae to the ovaries has led to the proposal that disruptions in the ovarian surface that occur during ovulation may allow detached FTE to implant in the ovary and form tubal-type glands and cysts. An alternative model suggests that cells present in ectopic locations outside the Müllerian tract retain the capacity for multi-lineage differentiation and can form glands with tubal-type epithelium. We used double transgenic Ovgp1-iCreERT2 ;R26RLSL-eYFP mice, which express an eYFP reporter protein in OVGP1-positive tissues following transient tamoxifen (TAM) treatment, to track the fate of oviductal epithelial cells. Cohorts of adult mice were given TAM to activate eYFP expression in oviductal epithelium, and ovaries were examined at time points ranging from 2 days to 12 months post-TAM. To test whether superovulation might increase acquisition of endosalpingiosis, additional cohorts of TAM-treated mice underwent up to five cycles of superovulation and ovaries were examined at 1, 6, and 12 months post-TAM. Ovaries were sectioned in their entirety to identify endosalpingiosis. Immunohistochemical staining for PAX8, tubulin, OVGP1, and eYFP was employed to study endosalpingiosis lesions. Ovarian endosalpingiosis was identified in 14.2% of TAM-treated adult mice. The endosalpingiotic inclusion glands and cysts were lined by secretory and ciliated cells and expressed PAX8, tubulin, OVGP1, and eYFP. Neither age nor superovulation was associated with a significant increase in endosalpingiosis. Endosalpingiosis was also occasionally present in the ovaries of pre-pubertal mice. The findings imply that ovarian endosalpingiosis in the mouse does not likely arise as a consequence of detachment and implantation of tubal epithelium and other mechanisms may be relevant. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Linhagem da Célula , Células Epiteliais/patologia , Neoplasias das Tubas Uterinas/patologia , Tubas Uterinas/patologia , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Ovarianas/patologia , Ovário/patologia , Animais , Proteínas de Bactérias/biossíntese , Proteínas de Bactérias/genética , Rastreamento de Células/métodos , Células Epiteliais/metabolismo , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/metabolismo , Tubas Uterinas/metabolismo , Feminino , Glicoproteínas/genética , Integrases/genética , Proteínas Luminescentes/biossíntese , Proteínas Luminescentes/genética , Camundongos Transgênicos , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Císticas, Mucinosas e Serosas/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Ovário/metabolismo , Fator de Transcrição PAX8/metabolismo , RNA não Traduzido/genética , Superovulação , Tubulina (Proteína)/metabolismoRESUMO
Somatic APC (adenomatous polyposis coli), TP53, KRAS mutations are present in roughly 80%, 60%, and 40%, respectively, of human colorectal cancers (CRCs). Most TP53 mutant alleles in CRCs encode missense mutant proteins with loss-of-function (LOF) of p53's transcriptional activity and dominant negative (DN) effects on wild-type p53 function. Missense mutant p53 proteins have been reported to exert gain-of-function (GOF) effects in cancer. We compared the phenotypic effects of the common human cancer-associated TP53 R273H missense mutation to p53 null status in a genetically engineered mouse CRC model. Inactivation of one allele of Apc together with activation of a Kras mutant allele in mouse colon epithelium instigated development of serrated and hyperplastic epithelium and adenomas (AK mice). Addition of a Trp53R270H or Trp53null mutant allele to the model (AKP mice) led to markedly shortened survival and increased tumor burden relative to that of AK mice, including adenocarcinomas in AKP mice. Comparable life span and tumor burden were seen in AKP mice carrying Trp53R270H or Trp53null alleles, along with similar frequencies of spontaneous metastasis to lymph nodes, lung, and liver. The fraction of adenocarcinomas with submucosa or deeper invasion was higher in AKP270/fl mice than in AKPfl/fl mice, but the incidence of adenocarcinomas per mouse did not differ significantly between AKPfl/fl and AKP270/fl mice. In line with their comparable biological behaviors, mouse primary tumors and tumor-derived organoids with the Trp53R270H or Trp53null alleles had highly similar gene expression profiles. Human CRCs with TP53 R273 missense mutant or null alleles also had essentially homogeneous gene expression patterns. Our findings indicate the R270H/R273H p53 mutant protein does not manifest definite GOF biological effects in mouse and human CRCs, suggesting possible GOF effects of mutant p53 in cancer phenotypes are likely allele-specific and/or context-dependent.
Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Proteína Supressora de Tumor p53/genética , Animais , Carcinogênese , Progressão da Doença , Transição Epitelial-Mesenquimal , Expressão Gênica , Humanos , Camundongos Transgênicos , Mutação de Sentido Incorreto , Invasividade Neoplásica , Metástase NeoplásicaRESUMO
Cervical cancer is a malignant epithelial tumor that forms in the uterine cervix. Most cases of cervical cancer are preventable through human papilloma virus (HPV) vaccination, routine screening, and treatment of precancerous lesions. However, due to inadequate screening protocols in many regions of the world, cervical cancer remains the fourth-most common cancer in women globally. The complete NCCN Guidelines for Cervical Cancer provide recommendations for the diagnosis, evaluation, and treatment of cervical cancer. This manuscript discusses guiding principles for the workup, staging, and treatment of early stage and locally advanced cervical cancer, as well as evidence for these recommendations. For recommendations regarding treatment of recurrent or metastatic disease, please see the full guidelines on NCCN.org.
Assuntos
Oncologia/normas , Infecções por Papillomavirus/terapia , Neoplasias do Colo do Útero/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Braquiterapia/métodos , Braquiterapia/normas , Colo do Útero/diagnóstico por imagem , Colo do Útero/patologia , Colo do Útero/virologia , Quimiorradioterapia Adjuvante/normas , Feminino , Preservação da Fertilidade/métodos , Preservação da Fertilidade/normas , Humanos , Histerectomia/normas , Programas de Rastreamento/métodos , Programas de Rastreamento/normas , Oncologia/métodos , Estadiamento de Neoplasias , Tratamentos com Preservação do Órgão/métodos , Tratamentos com Preservação do Órgão/normas , Teste de Papanicolaou/normas , Papillomaviridae/isolamento & purificação , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Sociedades Médicas/normas , Estados Unidos , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologiaRESUMO
The aim of this article is to propose guidelines and recommendations in problematic areas in pathologic reporting of endometrial carcinoma (EC) regarding special techniques and ancillary studies. An organizing committee designed a comprehensive survey with different questions related to pathologic features, diagnosis, and prognosis of EC that was sent to all members of the International Society of Gynecological Pathologists. The special techniques/ancillary studies group received 4 different questions to be addressed. Five members of the group reviewed the literature and came up with recommendations and an accompanying text which were discussed and agreed upon by all members of the group. Twelve different recommendations are made. They address the value of immunohistochemistry, ploidy, and molecular analysis for assessing prognosis in EC, the value of steroid hormone receptor analysis to predict response to hormone therapy, and parameters regarding applying immunohistochemistry and molecular tests for assessing mismatch deficiency in EC.
Assuntos
Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Ginecologia , Humanos , Imuno-Histoquímica , Patologistas , Patologia Molecular , Ploidias , Guias de Prática Clínica como Assunto , Prognóstico , Sociedades MédicasRESUMO
Endometrial carcinoma is a malignant epithelial tumor that forms in the inner lining, or endometrium, of the uterus. Endometrial carcinoma is the most common gynecologic malignancy. Approximately two-thirds of endometrial carcinoma cases are diagnosed with disease confined to the uterus. The complete NCCN Guidelines for Uterine Neoplasms provide recommendations for the diagnosis, evaluation, and treatment of endometrial cancer and uterine sarcoma. This manuscript discusses guiding principles for the diagnosis, staging, and treatment of early-stage endometrial carcinoma as well as evidence for these recommendations.
Assuntos
Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/terapia , Feminino , Humanos , Neoplasias Uterinas/etiologiaRESUMO
Recent studies have suggested that the most common and lethal type of 'ovarian' cancer, i.e. high-grade serous carcinoma (HGSC), usually arises from epithelium on the fallopian tube fimbriae, and not from the ovarian surface epithelium. We have developed Ovgp1-iCreERT2 mice in which the Ovgp1 promoter controls expression of tamoxifen-regulated Cre recombinase in oviductal epithelium - the murine equivalent of human fallopian tube epithelium (FTE). We employed Ovgp1-iCreERT2 mice to show that FTE-specific inactivation of several different combinations of tumour suppressor genes that are recurrently mutated in human HGSCs - namely Brca1, Trp53, Rb1, and Nf1 - results in serous tubal intraepithelial carcinomas (STICs) that progress to HGSC or carcinosarcoma, and to widespread metastatic disease in a subset of mice. The cancer phenotype is highly penetrant and more rapid in mice carrying engineered alleles of all four tumour suppressor genes. Brca1, Trp53 and Pten inactivation in the oviduct also results in STICs and HGSCs, and is associated with diffuse epithelial hyperplasia and mucinous metaplasia, which are not observed in mice with intact Pten. Oviductal tumours arise earlier in these mice than in those with Brca1, Trp53, Rb1 and Nf1 inactivation. Tumour initiation and/or progression in mice lacking conditional Pten alleles probably require the acquisition of additional defects, a notion supported by our identification of loss of the wild-type Rb1 allele in the tumours of mice carrying only one floxed Rb1 allele. Collectively, the models closely recapitulate the heterogeneity and histological, genetic and biological features of human HGSC. These models should prove useful for studying the pathobiology and genetics of HGSC in vivo, and for testing new approaches for prevention, early detection, and treatment. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma in Situ/genética , Carcinossarcoma/genética , Neoplasias das Tubas Uterinas/genética , Tubas Uterinas/patologia , Neoplasias Císticas, Mucinosas e Serosas/genética , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Carcinossarcoma/patologia , Neoplasias das Tubas Uterinas/metabolismo , Neoplasias das Tubas Uterinas/patologia , Tubas Uterinas/metabolismo , Feminino , Genes BRCA1 , Genes da Neurofibromatose 1 , Genes do Retinoblastoma/genética , Genes p53 , Predisposição Genética para Doença , Glicoproteínas/genética , Humanos , Hiperplasia , Integrases/genética , Metaplasia , Camundongos Transgênicos , Mutação , Gradação de Tumores , Neoplasias Císticas, Mucinosas e Serosas/metabolismo , Neoplasias Císticas, Mucinosas e Serosas/patologia , PTEN Fosfo-Hidrolase/genética , Fenótipo , Regiões Promotoras GenéticasRESUMO
Ovarian cancer is a generic term that encompasses several different tumor types. The most common and lethal type is known as high-grade serous carcinoma. The cellular origin of high-grade serous carcinoma has been debated for many years, but recent studies suggest that many, if not most, arise from epithelium in the fallopian tube rather than from the ovarian surface epithelium. Genetically engineered mice have been used to study the consequences of transforming epithelium in the oviduct (mouse fallopian tube equivalent) versus the ovarian surface epithelium, and to test whether genetic alterations characteristic of specific types of human ovarian cancers will lead to morphologically and biologically similar tumors in the mouse. Recent studies show that the mouse tumor phenotype is highly dependent on both cell of origin and the specific genetic alterations underlying neoplastic transformation, with mouse tumors based on transformation of oviductal epithelium more closely recapitulating their human tumor counterparts than those based on ovarian surface epithelium transformation. Understanding the cellular origins of ovarian cancer has significant implications for improving ovarian cancer prevention and early detection.
Assuntos
Biomarcadores Tumorais/genética , Linhagem da Célula , Transformação Celular Neoplásica/genética , Células Epiteliais/patologia , Tubas Uterinas/patologia , Neoplasias Ovarianas/genética , Ovário/patologia , Animais , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Células Epiteliais/metabolismo , Tubas Uterinas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Mutação , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ovário/metabolismo , Fenótipo , Terminologia como AssuntoRESUMO
Adenomatous polyposis coli (APC) inactivating mutations are present in most human colorectal cancers and some other cancers. The APC protein regulates the ß-catenin protein pool that functions as a co-activator of T cell factor (TCF)-regulated transcription in Wnt pathway signaling. We studied effects of reduced dosage of the Ctnnb1 gene encoding ß-catenin in Apc-mutation-induced colon and ovarian mouse tumorigenesis and cell culture models. Concurrent somatic inactivation of one Ctnnb1 allele, dramatically inhibited Apc mutation-induced colon polyposis and greatly extended Apc-mutant mouse survival. Ctnnb1 hemizygous dose markedly inhibited increases in ß-catenin levels in the cytoplasm and nucleus following Apc inactivation in colon epithelium, with attenuated expression of key ß-catenin/TCF-regulated target genes, including those encoding the EphB2/B3 receptors, the stem cell marker Lgr5, and Myc, leading to maintenance of crypt compartmentalization and restriction of stem and proliferating cells to the crypt base. A critical threshold for ß-catenin levels in TCF-regulated transcription was uncovered for Apc mutation-induced effects in colon epithelium, along with evidence of a feed-forward role for ß-catenin in Ctnnb1 gene expression and CTNNB1 transcription. The active ß-catenin protein pool was highly sensitive to CTNNB1 transcript levels in colon cancer cells. In mouse ovarian endometrioid adenocarcinomas (OEAs) arising from Apc- and Pten-inactivation, while Ctnnb1 hemizygous dose affected ß-catenin levels and some ß-catenin/TCF target genes, Myc induction was retained and OEAs arose in a fashion akin to that seen with intact Ctnnb1 gene dose. Our findings indicate Ctnnb1 gene dose exerts tissue-specific differences in Apc mutation-instigated tumorigenesis. Differential expression of selected ß-catenin/TCF-regulated genes, such as Myc, likely underlies context-dependent effects of Ctnnb1 gene dosage in tumorigenesis.
Assuntos
Neoplasias do Colo/genética , Genes APC , Mutação , Neoplasias Ovarianas/genética , beta Catenina/metabolismo , Animais , Feminino , CamundongosRESUMO
Vulvar cancer is a rare gynecologic malignancy. Ninety percent of vulvar cancers are predominantly squamous cell carcinomas (SCCs), which can arise through human papilloma virus (HPV)-dependent and HPV-independent pathways. The NCCN Vulvar Cancer panel is an interdisciplinary group of representatives from NCCN Member Institutions consisting of specialists in gynecological oncology, medical oncology, radiation oncology, and pathology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Vulvar Cancer provide an evidence- and consensus-based approach for the management of patients with vulvar SCC. This manuscript discusses the recommendations outlined in the NCCN Guidelines for diagnosis, staging, treatment, and follow-up.
Assuntos
Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Recidiva Local de Neoplasia/diagnóstico , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/terapia , Neoplasias Vulvares/diagnóstico , Neoplasias Vulvares/terapia , Antineoplásicos/uso terapêutico , Biópsia , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia , Feminino , Humanos , Oncologia/normas , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/patologia , Radioterapia Adjuvante , Fatores de Risco , Taxa de Sobrevida , Neoplasias Vulvares/epidemiologia , Neoplasias Vulvares/patologiaRESUMO
Inactivation of the ARID1A tumour suppressor gene is frequent in ovarian endometrioid (OEC) and clear cell (OCCC) carcinomas, often in conjunction with mutations activating the PI3K-AKT and/or canonical Wnt signalling pathways. Prior work has shown that conditional bi-allelic inactivation of the Apc and Pten tumour suppressor genes in the mouse ovarian surface epithelium (OSE) promotes outgrowth of tumours that reflect the biological behaviour and gene expression profiles of human OECs harbouring comparable Wnt and PI3K-AKT pathway defects, although the mouse tumours are more poorly differentiated than their human tumour counterparts. We found that conditional inactivation of one or both Arid1a alleles in OSE concurrently with Apc and Pten inactivation unexpectedly prolonged the survival of tumour-bearing mice and promoted striking epithelial differentiation of the cancer cells, resulting in morphological features akin to those in human OECs. Enhanced epithelial differentiation was linked to reduced expression of the mesenchymal markers N-cadherin and vimentin, and increased expression of the epithelial markers Crb3 and E-cadherin. Global gene expression profiling showed enrichment for genes associated with mesenchymal-epithelial transition in the Arid1a-deficient tumours. We also found that an activating (E545K) Pik3ca mutation, unlike Pten inactivation or Pik3ca H1047R mutation, cannot cooperate with Arid1a loss to promote ovarian cancer development in the mouse. Our results indicate that the Arid1a tumour suppressor gene has a key role in regulating OEC differentiation, and paradoxically the mouse cancers with more initiating tumour suppressor gene defects had a less aggressive phenotype than cancers arising from fewer gene alterations. Microarray data have been deposited in NCBI's Gene Expression Omnibus (GSE67695).
Assuntos
Proteínas de Ligação a DNA/genética , Genes APC , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , PTEN Fosfo-Hidrolase/genética , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Animais , Western Blotting , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Diferenciação Celular/genética , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Epitélio/patologia , Feminino , Humanos , Imuno-Histoquímica , Camundongos , Análise Serial de Tecidos , Fatores de Transcrição , TranscriptomaRESUMO
Endometrioid carcinoma (EC) is a relatively indolent ovarian carcinoma subtype that is nonetheless deadly if detected late. Existing genetically engineered mouse models (GEMMs) of the disease, based on transformation of the ovarian surface epithelium (OSE), take advantage of known ovarian EC driver gene lesions, but do not fully recapitulate the disease features seen in patients. An EC model in which the Apc and Pten tumour suppressor genes are conditionally deleted in murine OSE yields tumours that are biologically more aggressive and significantly less differentiated than human ECs. Importantly, OSE is not currently thought to be the tissue of origin of most ovarian cancers, including ECs, suggesting that tumour initiation in Müllerian epithelium may produce tumours that more closely resemble their human tumour counterparts. We have developed Ovgp1-iCreERT2 mice in which the Ovgp1 promoter controls expression of tamoxifen (TAM)-regulated Cre recombinase in oviductal epithelium - the murine equivalent of human Fallopian tube epithelium. Ovgp1-iCreERT2 ;Apcfl/fl ;Ptenfl/fl mice treated with TAM or injected with adenovirus expressing Cre into the ovarian bursa uniformly develop oviductal or ovarian ECs, respectively. On the basis of their morphology and global gene expression profiles, the oviduct-derived tumours more closely resemble human ovarian ECs than do OSE-derived tumours. Furthermore, mice with oviductal tumours survive much longer than their counterparts with ovarian tumours. The slow progression and late metastasis of oviductal tumours resembles the relatively indolent behaviour characteristic of so-called Type I ovarian carcinomas in humans, for which EC is a prototype. Our studies demonstrate the utility of Ovgp1-iCreERT2 mice for manipulating genes of interest specifically in the oviductal epithelium, and establish that the cell of origin is an important consideration in mouse ovarian cancer GEMMs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Carcinoma Endometrioide , Neoplasias Epiteliais e Glandulares , Neoplasias Ovarianas , PTEN Fosfo-Hidrolase/genética , Animais , Animais Geneticamente Modificados , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Carcinoma Epitelial do Ovário , Diferenciação Celular , Modelos Animais de Doenças , Células Epiteliais/patologia , Epitélio/patologia , Tubas Uterinas/patologia , Feminino , Glicoproteínas/genética , Humanos , Integrases/genética , Integrases/metabolismo , Masculino , Camundongos , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ovário/patologia , Fenótipo , Regiões Promotoras Genéticas/genética , Tamoxifeno/metabolismoRESUMO
Preclinical models are relatively underutilized and underfunded resources for modeling the pathogenesis and prevention of ovarian cancers. Several reviews have detailed the numerous published models of ovarian cancer. In this review, we will provide an overview of experimental model systems, their strengths and limitations, and use selected models to illustrate how they can be used to address specific issues about ovarian cancer pathogenesis. We will then highlight some of the preclinical prevention studies performed to date and discuss experiments needed to address important unanswered questions about ovarian cancer prevention strategies.
Assuntos
Carcinoma/prevenção & controle , Quimioprevenção/métodos , Neoplasias Ovarianas/prevenção & controle , Procedimentos Cirúrgicos Profiláticos/métodos , Animais , Carcinoma/patologia , Galinhas , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/patologia , Ovariectomia/métodos , Salpingectomia/métodosRESUMO
AIMS: To report a previously undescribed phenomenon of incidentally detected microscopic proliferations of sex cord cells, often mimicking adult granulosa cell tumour or sex cord tumour with annular tubules, in extraovarian locations. METHODS AND RESULTS: The six cases were in patients aged 23-58 years. The proliferations were located in the fallopian tube in three cases, and in paraovarian connective tissues, the pelvic side wall, and appendiceal serosa (one case each). Microscopically, they were typically composed of well-demarcated nests of regular cells with round/ovoid vesicular nuclei, some containing grooves. Microfollicular and/or cribriform arrangements were present in three cases. In five cases, the sex cord lineage was confirmed by positive staining with inhibin and/or calretinin and other sex cord markers. FOXL2 mutation analysis was performed in one case, but was inconclusive. Bilateral oophorectomies and bilateral cystectomies were performed in three cases and one case respectively; there was no sex cord-stromal neoplasm in the removed ovaries. In the two cases in which the ovaries were not removed, imaging showed no suspicious features. Follow-up in four cases (11 months-6 years) has been uneventful. CONCLUSIONS: The pathogenesis of these microscopic extraovarian sex cord proliferations is unknown, but they may represent non-neoplastic proliferations of embryonic remnants.
Assuntos
Proliferação de Células , Neoplasias das Tubas Uterinas/patologia , Tumor de Células da Granulosa/patologia , Neoplasias Ovarianas/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
The NCCN Guidelines for Cervical Cancer provide interdisciplinary recommendations for treating cervical cancer. These NCCN Guidelines Insights summarize the NCCN Cervical Cancer Panel's discussion and major guideline updates from 2014 and 2015. The recommended systemic therapy options for recurrent and metastatic cervical cancer were amended upon panel review of new survival data and the FDA's approval of bevacizumab for treating late-stage cervical cancer. This article outlines relevant data and provides insight into panel decisions regarding various combination regimens. Additionally, a new section was added to provide additional guidance on key principles of evaluation and surgical staging in cervical cancer. This article highlights 2 areas of active investigation and debate from this new section: sentinel lymph node mapping and fertility-sparing treatment approaches.