RESUMO
In response to DNA double-strand breaks, MAD2L2-containing shieldin complex plays a critical role in the choice between homologous recombination (HR) and non-homologous end-joining (NHEJ)-mediated repair. Here we show that EZH2 inhibition upregulates MAD2L2 and sensitizes HR-proficient epithelial ovarian cancer (EOC) to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor in a CARM1-dependent manner. CARM1 promotes MAD2L2 silencing by driving the switch from the SWI/SNF complex to EZH2 through methylating the BAF155 subunit of the SWI/SNF complex on the MAD2L2 promoter. EZH2 inhibition upregulates MAD2L2 to decrease DNA end resection, which increases NHEJ and chromosomal abnormalities, ultimately causing mitotic catastrophe in PARP inhibitor treated HR-proficient cells. Significantly, EZH2 inhibitor sensitizes CARM1-high, but not CARM-low, EOCs to PARP inhibitors in both orthotopic and patient-derived xenografts.
Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Recombinação Homóloga/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Antineoplásicos/uso terapêutico , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Neoplasias Ovarianas/genética , Proteína-Arginina N-Metiltransferases/efeitos dos fármacos , Reparo de DNA por Recombinação/efeitos dos fármacosRESUMO
Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Platinum-based chemotherapy induces cellular senescence. Notably, therapy-induced senescence contributes to chemoresistance by inducing cancer stem-like cells (CSC). However, therapeutic approaches targeting senescence-associated CSCs remain to be explored. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT) inhibition suppresses senescence-associated CSCs induced by platinum-based chemotherapy in EOC. Clinically applicable NAMPT inhibitors suppressed the outgrowth of cisplatin-treated EOC cells both in vitro and in vivo. Moreover, a combination of the NAMPT inhibitor FK866 and cisplatin improved the survival of EOC-bearing mice. These phenotypes correlated with inhibition of the CSCs signature, which consists of elevated expression of ALDH1A1 and stem-related genes, high aldehyde dehydrogenase activity, and CD133 positivity. Mechanistically, NAMPT regulates EOC CSCs in a paracrine manner through the senescence-associated secretory phenotype. Our results suggest that targeting NAMPT using clinically applicable NAMPT inhibitors, such as FK866, in conjunction with platinum-based chemotherapy represents a promising therapeutic strategy by suppressing therapy-induced senescence-associated CSCs. SIGNIFICANCE: This study highlights the importance of NAMPT-mediated NAD+ biosynthesis in the production of cisplatin-induced senescence-associated cancer stem cells, as well as tumor relapse after cisplatin treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Citocinas/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Neoplasias Ovarianas/tratamento farmacológico , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Família Aldeído Desidrogenase 1/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Citocinas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Células-Tronco Neoplásicas/patologia , Nicotinamida Fosforribosiltransferase/metabolismo , Neoplasias Ovarianas/patologia , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Retinal Desidrogenase/metabolismo , Esferoides Celulares , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
ARID1A inactivation causes mitotic defects. Paradoxically, cancers with high ARID1A mutation rates typically lack copy number alterations (CNAs). Here, we show that ARID1A inactivation causes defects in telomere cohesion, which selectively eliminates gross chromosome aberrations during mitosis. ARID1A promotes the expression of cohesin subunit STAG1 that is specifically required for telomere cohesion. ARID1A inactivation causes telomere damage that can be rescued by STAG1 expression. Colony formation capability of single cells in G2/M, but not G1 phase, is significantly reduced by ARID1A inactivation. This correlates with an increase in apoptosis and a reduction in tumor growth. Compared with ARID1A wild-type tumors, ARID1A-mutated tumors display significantly less CNAs across multiple cancer types. Together, these results show that ARID1A inactivation is selective against gross chromosome aberrations through causing defects in telomere cohesion, which reconciles the long-standing paradox between the role of ARID1A in maintaining mitotic integrity and the lack of genomic instability in ARID1A-mutated cancers.
Assuntos
Instabilidade Genômica , Mutação , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Telômero/genética , Fatores de Transcrição/genética , Animais , Apoptose/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Variações do Número de Cópias de DNA , Proteínas de Ligação a DNA , Feminino , Humanos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Telômero/metabolismo , Fatores de Transcrição/metabolismo , Transplante Heterólogo/métodos , Carga Tumoral/genética , CoesinasRESUMO
New plasma and tissue biomarkers of epithelial ovarian cancer (EOC) could improve early diagnosis and post-diagnosis clinical management. Here we investigated tissue staining and tissue secretion of CLIC1 and CLIC4 across EOC subtypes. CLIC1 and CLIC4 are two promising biomarkers we previously showed were elevated in EOC patient sera. Individually, CLIC1 or CLIC4 stained larger percentages of malignant tumors across all EOC subtypes compared with CA125, particularly early stage and mucinous tumors. CLIC4 also stained benign tumors but staining was limited to nuclei; whereas malignant tumors showed diffuse cellular staining of stromal and tumor cells. Both proteins were shed by all EOC subtypes tumors in short term organ culture at more consistent levels than CA125, supporting their potential as pan-subtype serum and tissue biomarkers. Elevated CLIC4 expression, but not CLIC1 expression, was a negative indicator of patient survival, and CLIC4 knockdown in cultured cells decreased cell proliferation and migration indicating a potential role in tumor progression. These results suggest CLIC1 and CLIC4 are promising serum and tissue biomarkers as well as potential therapeutic targets for all EOC subtypes. This justifies development of high throughput serum/plasma biomarker assays to evaluate utility of a biomarker panel consisting of CLIC1, CLIC4 and CA125.
Assuntos
Antígeno Ca-125/genética , Carcinoma Epitelial do Ovário/genética , Canais de Cloreto/genética , Proteínas de Membrana/genética , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Antígeno Ca-125/sangue , Carcinoma Epitelial do Ovário/sangue , Carcinoma Epitelial do Ovário/diagnóstico , Canais de Cloreto/sangue , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/sangue , Pessoa de Meia-IdadeRESUMO
We present the case of a 28-year-old nulliparous female with malignant transformation of an ectopic focus of endometriosis in the right ischioanal fossa. A 28-year-old nulliparous patient with a past medical history of polycystic ovarian syndrome (PCOS) was diagnosed with endometrioid adenocarcinoma in her right ischioanal fossa. Initially, patient presented to an emergency department and underwent a CT scan of the appendix to rule out appendicitis. A multiloculated cystic lesion adjacent to the right obturator internus muscle was found. She underwent surgical resection of the mass, which confirmed FIGO grade 2 endometrioid adenocarcinoma, followed by localized radiation therapy. Malignancy arising in endometriosis is rare, and the influence of PCOS on the rate of malignant transformation is not well established.
RESUMO
PURPOSE: To define the safety and effectiveness of T cells redirected against follicle-stimulating hormone receptor (FSHR)-expressing ovarian cancer cells. EXPERIMENTAL DESIGN: FSHR expression was determined by Western blotting, immunohistochemistry, and qPCR in 77 human ovarian cancer specimens from 6 different histologic subtypes and 20 human healthy tissues. The effectiveness of human T cells targeted with full-length FSH in vivo was determined against a panel of patient-derived xenografts. Safety and effectiveness were confirmed in immunocompetent tumor-bearing mice, using constructs targeting murine FSHR and syngeneic T cells. RESULTS: FSHR is expressed in gynecologic malignancies of different histologic types but not in nonovarian healthy tissues. Accordingly, T cells expressing full-length FSHR-redirected chimeric receptors mediate significant therapeutic effects (including tumor rejection) against a panel of patient-derived tumors in vivo In immunocompetent mice growing syngeneic, orthotopic, and aggressive ovarian tumors, fully murine FSHR-targeted T cells also increased survival without any measurable toxicity. Notably, chimeric receptors enhanced the ability of endogenous tumor-reactive T cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, FSHR-targeted T cells persisted as memory lymphocytes without noticeable PD-1-dependent exhaustion during end-stage disease, in the absence of tumor cell immunoediting. However, exosomes in advanced tumor ascites diverted the effector activity of this and other chimeric receptor-transduced T cells away from targeted tumor cells. CONCLUSIONS: T cells redirected against FSHR+ tumor cells with full-length FSH represent a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries. Clin Cancer Res; 23(2); 441-53. ©2016 AACR.
Assuntos
Imunoterapia , Neoplasias Ovarianas/terapia , Receptores do FSH/imunologia , Linfócitos T/imunologia , Animais , Ascite/imunologia , Ascite/patologia , Exossomos/imunologia , Exossomos/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imuno-Histoquímica , Camundongos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores do FSH/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The role of estrogens in antitumor immunity remains poorly understood. Here, we show that estrogen signaling accelerates the progression of different estrogen-insensitive tumor models by contributing to deregulated myelopoiesis by both driving the mobilization of myeloid-derived suppressor cells (MDSC) and enhancing their intrinsic immunosuppressive activity in vivo Differences in tumor growth are dependent on blunted antitumor immunity and, correspondingly, disappear in immunodeficient hosts and upon MDSC depletion. Mechanistically, estrogen receptor alpha activates the STAT3 pathway in human and mouse bone marrow myeloid precursors by enhancing JAK2 and SRC activity. Therefore, estrogen signaling is a crucial mechanism underlying pathologic myelopoiesis in cancer. Our work suggests that new antiestrogen drugs that have no agonistic effects may have benefits in a wide range of cancers, independently of the expression of estrogen receptors in tumor cells, and may synergize with immunotherapies to significantly extend survival. SIGNIFICANCE: Ablating estrogenic activity delays malignant progression independently of the tumor cell responsiveness, owing to a decrease in the mobilization and immunosuppressive activity of MDSCs, which boosts T-cell-dependent antitumor immunity. Our results provide a mechanistic rationale to block estrogen signaling with newer antagonists to boost the effectiveness of anticancer immunotherapies. Cancer Discov; 7(1); 72-85. ©2016 AACR.See related commentary by Welte et al., p. 17This article is highlighted in the In This Issue feature, p. 1.
Assuntos
Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Células Supressoras Mieloides/imunologia , Neoplasias/imunologia , Animais , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Janus Quinase 2/metabolismo , Células MCF-7 , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/metabolismo , Transplante de Neoplasias , Neoplasias/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Quinases da Família src/metabolismoRESUMO
The dominant TLR5(R392X) polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extramucosal locations by increasing systemic IL-6, which drives mobilization of myeloid-derived suppressor cells (MDSCs). Mechanistically, expanded granulocytic MDSCs cause γδ lymphocytes in TLR5-responsive tumors to secrete galectin-1, dampening antitumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently upregulated in TLR5-unresponsive tumor-bearing mice but only accelerates malignant progression in IL-6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates TLR5-dependent differences in tumor growth. Contrasting differences in inflammatory cytokines and malignant evolution are recapitulated in TLR5-responsive/unresponsive ovarian and breast cancer patients. Therefore, inflammation, antitumor immunity, and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism.
Assuntos
Interleucina-17/metabolismo , Interleucina-6/metabolismo , Microbiota , Neoplasias/imunologia , Neoplasias/patologia , Receptor 5 Toll-Like/genética , Receptor 5 Toll-Like/metabolismo , Animais , Linhagem Celular Tumoral , Células Cultivadas , Galectina 1/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Transplante de Neoplasias , Polimorfismo de Nucleotídeo Único , Transdução de SinaisRESUMO
BACKGROUND: The aim of the study was to determine whether tumor-infiltrating lymphocytes and/or tumor mitotic activity could identify subgroups of patients with advanced serous epithelial ovarian cancer who would maximally benefit from aggressive surgical cytoreduction. METHODS: Snap-frozen specimens from 134 consecutive patients with stage III or IV serous or poorly differentiated ovarian adenocarcinoma undergoing primary debulking surgery from a single US institution were characterized based on CD3(+), CD8(+), FoxP3(+) tumor-infiltrating lymphocytes, and Ki67 expression. Kaplan-Meier survival curves were estimated and compared using a log-rank statistic. A multivariate Cox model was used to estimate adjusted hazard ratios. Interactions were modeled using recursive partitioning based on maximal prognostic differentiation. RESULTS: Brisk intraepithelial CD8(+) cells (P = .035) and low Ki67 expression (P = .042) portended prolonged survival. The T-cell infiltration was more likely to occur in tumors with high proliferation index. Patients whose tumors exhibited low Ki67 expression and high intraepithelial CD8(+) frequency had a 5-year survival rate of 73.3%. Patients with aggressive tumor behavior, that is, whose tumors exhibited low frequency of intraepithelial CD8(+) T cells or high Ki67 expression were more likely to draw benefit from aggressive surgical cytoreduction. Survival was similar for patients with brisk CD8(+) T cells who had optimal or suboptimal debulking. Likewise, survival was similar for patients with low Ki67 expression who had optimal or suboptimal debulking. CONCLUSIONS: For the first time, these novel interactions of T cells, tumor proliferation index, and surgical treatment reveal that biological prognosticators may be useful for surgical decision making in ovarian cancer.
Assuntos
Cistadenoma Seroso/cirurgia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Ovarianas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexo CD3/análise , Linfócitos T CD8-Positivos , Proliferação de Células , Cistadenoma Seroso/imunologia , Cistadenoma Seroso/patologia , Feminino , Fatores de Transcrição Forkhead/análise , Humanos , Antígeno Ki-67/análise , Pessoa de Meia-Idade , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Prognóstico , Linfócitos T , Resultado do TratamentoRESUMO
Intraepithelial tumor-infiltrating T cells have been correlated with improved outcomes in ovarian carcinoma, however, it is not known whether there is an association with disease stage, histological subtype, or BRCA mutation/expression. Two case series of ovarian carcinomas were included in the study; a retrospective series of 500 patients, and 40 prospectively collected cases fully characterized for BRCA1 mutation status and expression. Intraepithelial immune cells were assessed as present or absent by immunohistochemical staining of tissue microarrays. In the retrospective case series, the presence of intraepithelial CD8(+) T-cells correlated with improved disease-specific survival (P=0.027), whereas intraepithelial CD3(+) T cells did not (P=0.49). For serous ovarian carcinomas, the presence of intraepithelial CD3(+) and CD8(+) T-cells correlated with improved disease-specific survival (P=0.0016 and PAssuntos
Linfócitos T CD8-Positivos/imunologia
, Genes BRCA1
, Linfócitos do Interstício Tumoral/imunologia
, Neoplasias Ovarianas/imunologia
, Adulto
, Idoso
, Idoso de 80 Anos ou mais
, Complexo CD3/imunologia
, Complexo CD3/metabolismo
, Feminino
, Expressão Gênica
, Humanos
, Imuno-Histoquímica
, Estimativa de Kaplan-Meier
, Linfócitos do Interstício Tumoral/metabolismo
, Pessoa de Meia-Idade
, Mutação
, Estadiamento de Neoplasias
, Neoplasias Ovarianas/genética
, Neoplasias Ovarianas/patologia
, Prognóstico
, Subpopulações de Linfócitos T/imunologia
, Subpopulações de Linfócitos T/metabolismo
, Análise Serial de Tecidos
RESUMO
The protein kinase C (PKC) family plays a key regulatory role in a wide range of cellular functions as well as in various cancer-associated signal transduction pathways. Here, we investigated the genomic alteration and gene expression of most known PKC family members in human ovarian cancer. The DNA copy number of PKC family genes was screened by a high-resolution array-based comparative genomic hybridization in 89 human ovarian cancer specimens. Five PKC genes exhibited significant DNA copy number gains, including PKCiota (43.8%), PKCbeta1 (37.1%), PKCgamma (27.6%), PKCzeta (22.5%), and PKCtheta (21.3%). None of the PKC genes exhibited copy number loss. The mRNA expression level of PKC genes was analyzed by microarray retrieval approach. Two of the amplified PKC genes, PKCiota and PKCtheta, were significantly up-regulated in ovarian cancer compared with normal ovary. Increased PKCiota expression correlated with tumor stage or grade, and PKCiota overexpression was seen mostly in ovarian carcinoma but not in other solid tumors. The above results were further validated by real-time reverse transcription-PCR with 54 ovarian cancer specimens and 24 cell lines; overexpression of PKCiota protein was also confirmed by tissue array and Western blot. Interestingly, overexpressed PKCiota did not affect ovarian cancer cell proliferation or apoptosis in vitro. However, decreased PKCiota expression significantly reduced anchorage-independent growth of ovarian cancer cells, whereas overexpression of PKCiota contributed to murine ovarian surface epithelium transformation in cooperation with mutant Ras. We propose that PKCiota may serve as an oncogene and a biomarker of aggressive disease in human ovarian cancer.
Assuntos
Biomarcadores Tumorais/genética , Isoenzimas/genética , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Proteína Quinase C/genética , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Dosagem de Genes , Humanos , Isoenzimas/biossíntese , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Proteína Quinase C/biossíntese , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Transcrição Gênica , Transfecção , Regulação para Cima , Proteínas ras/genéticaRESUMO
OBJECTIVE: Chances of survival after the diagnosis of recurrent endometrial cancer are poor. Although total pelvic exenteration has been described as a treatment for a select subset of patients with recurrent endometrial cancer, the use of other surgical procedures in this setting has not been well described. The objective of this study was to review our experience with non-exenterative surgery for recurrent endometrial cancer. METHODS: We reviewed the medical records of all patients who underwent non-exenterative surgery for recurrent endometrial cancer between 1/91 and 1/03. Survival was determined from the time of surgery for recurrence to last follow-up. Survival was estimated using Kaplan-Meier methods. Differences in survival were analyzed using the log-rank test. The Fisher's exact test was used to compare optimal versus suboptimal cytoreduction against possible predictive factors. RESULTS: Twenty-seven patients were identified. Fifteen patients (56%) had disease limited to the retroperitoneum, 10 patients (37%) had intraperitoneal disease, and 2 patients (7%) had both intra- and retroperitoneal disease. Cytoreduction to