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1.
Clin Cancer Res ; 27(15): 4277-4286, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-34035068

RESUMEN

PURPOSE: Due to the lack of effective screening approaches and early detection biomarkers, ovarian cancer has the highest mortality rates among gynecologic cancers. Herein, we undertook a systematic biomarker discovery and validation approach to identify microRNA (miRNA) biomarkers for the early detection of ovarian cancer. EXPERIMENTAL DESIGN: During the discovery phase, we performed small RNA sequencing in stage I high-grade serous ovarian cancer (n = 31), which was subsequently validated in multiple, independent data sets (TCGA, n = 543; GSE65819, n = 87). Subsequently, we performed multivariate logistic regression-based training in a serum data set (GSE106817, n = 640), followed by its independent validation in three retrospective data sets (GSE31568, n = 85; GSE113486, n = 140; Czech Republic cohort, n = 192) and one prospective serum cohort (n = 95). In addition, we evaluated the specificity of OCaMIR, by comparing its performance in several other cancers (GSE31568 cohort, n = 369). RESULTS: The OCaMIR demonstrated a robust diagnostic accuracy in the stage I high-grade serous ovarian cancer patients in the discovery cohort (AUC = 0.99), which was consistently reproducible in both stage I (AUC = 0.96) and all stage patients (AUC = 0.89) in the TCGA cohort. Logistic regression-based training and validation of OCaMIR achieved AUC values of 0.89 (GSE106817), 0.85 (GSE31568), 0.86 (GSE113486), and 0.82 (Czech Republic cohort) in the retrospective serum validation cohorts, as well as prospective validation cohort (AUC = 0.92). More importantly, OCaMIR demonstrated a significantly superior diagnostic performance compared with CA125 levels, even in stage I patients, and was more cost-effective, highlighting its potential role for screening and early detection of ovarian cancer. CONCLUSIONS: Small RNA sequencing identified a robust noninvasive miRNA signature for early-stage serous ovarian cancer detection.


Asunto(s)
Biomarcadores de Tumor/análisis , Cistadenocarcinoma Seroso/química , Cistadenocarcinoma Seroso/diagnóstico , Detección Precoz del Cáncer/métodos , MicroARNs/análisis , Neoplasias Ováricas/química , Neoplasias Ováricas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Cistadenocarcinoma Seroso/patología , Femenino , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Estudios Prospectivos , Estudios Retrospectivos
2.
Trends Cancer ; 7(6): 541-556, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33341430

RESUMEN

Nuclear receptors are a family of transcription factors localized in cell nuclei, sensing specific ligands and fine-tuning a variety of cell physiological events. They have been intensively investigated in cancer biology. With their excellent properties of druggability and actionability, nuclear receptors have demonstrated much promise as novel therapeutic targets for different cancer types. Accumulating evidence has highlighted the essential roles of certain nuclear receptors in tumor immunology, suggesting the possibility for them to serve as cancer immunotherapeutic targets. Here, we summarize the roles of nuclear receptors in cancer biology and tumor immunology, and underscore the current advances of clinical trials for nuclear receptor-based cancer therapeutics.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Inhibidores de Puntos de Control Inmunológico/farmacología , Proteínas de Punto de Control Inmunitario/metabolismo , Neoplasias/tratamiento farmacológico , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Núcleo Celular/metabolismo , Ensayos Clínicos como Asunto , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Oncología Médica/historia , Oncología Médica/tendencias , Terapia Molecular Dirigida/métodos , Neoplasias/inmunología , Neoplasias/patología , Receptores Citoplasmáticos y Nucleares/metabolismo
3.
iScience ; 23(9): 101458, 2020 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-32861994

RESUMEN

The emerging immune checkpoint blockade (ICB) therapy has ushered the cancer therapeutics field into an era of immunotherapy. Although ICB treatment provides remarkable clinical responses in a subset of patients with cancer, this regimen fails to extend survival in a large proportion of patients. Here, we found that a combined treatment of estrogen receptor beta (ERß) agonist and PD-1 antibody treatment improved therapeutic efficacy in mouse tumor models, compared with monotherapies, by reducing infiltration of myeloid-derived suppressor cells (MDSCs) and increasing CD8+ T cells in tumors. Mechanistically, LY500307 treatment reduced tumor-derived CSF1 and decreased infiltration of CSF1R+ MDSCs in the tumor bed. CSF1 released by tumor cells induced CSF1R+ MDSC chemotaxis in vitro and blockade of CSF1R demonstrated similar therapeutic effects as ERß activation in vivo. Collectively, our study proved combined treatment of ERß agonist and PD-1 antibody reduced MDSC infiltration in the tumor and enhanced tumor response to ICB therapy.

4.
Clin Cancer Res ; 25(12): 3476-3478, 2019 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-30952637

RESUMEN

Cancer-associated fibroblasts (CAF) are essential for cancer hallmarks. While CAFs are molecularly heterogeneous, a CXCL14-expressing subset has been a critical player in the cancer context. In breast cancer, an autocrine fibroblast CXCL14/ACKR2 axis mediates epithelial-to-mesenchymal transition and endows metastatic traits, which offers novel therapeutic potential in the clinical setting.See related article by Sjöberg et al., p. 3702.


Asunto(s)
Fibroblastos Asociados al Cáncer , Línea Celular Tumoral , Movimiento Celular , Quimiocinas CXC , Transición Epitelial-Mesenquimal , Fibroblastos , Humanos
5.
Mol Cancer ; 17(1): 109, 2018 07 31.
Artículo en Inglés | MEDLINE | ID: mdl-30064416

RESUMEN

Malignant ovarian tumors bear the highest mortality rate among all gynecological cancers. Both late tumor diagnosis and tolerance to available chemical therapy increase patient mortality. Therefore, it is both urgent and important to identify biomarkers facilitating early identification and novel agents preventing recurrence. Accumulating evidence demonstrates that epigenetic aberrations (particularly histone modifications) are crucial in tumor initiation and development. Histone acetylation and methylation are respectively regulated by acetyltransferases-deacetylases and methyltransferases-demethylases, both of which are implicated in ovarian cancer pathogenesis. In this review, we summarize the most recent discoveries pertaining to ovarian cancer development arising from the imbalance of histone acetylation and methylation, and provide insight into novel therapeutic interventions for the treatment of ovarian carcinoma.


Asunto(s)
Histonas/metabolismo , Neoplasias Ováricas/metabolismo , Acetilación , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Humanos , Metilación , Neoplasias Ováricas/genética
6.
Genome Biol ; 19(1): 35, 2018 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-29548303

RESUMEN

BACKGROUND: Ovarian cancer constitutes one of the most lethal gynecologic malignancies for females. Currently, early detection strategies and therapeutic options for ovarian cancer are far from satisfactory, leading to high diagnosis rates at late stages and disease relapses. New avenues of therapy are needed that target key processes in ovarian cancer progression. While a variety of non-coding RNAs have been proven to regulate ovarian cancer metastatic progression, the functional roles of RNA-binding proteins (RBPs) in this process are less well defined. RESULTS: In this study, we identify that the RBP sorbin and SH3 domain containing 2 (SORBS2) is a potent suppressor of ovarian cancer metastatic colonization. Mechanistic studies show that SORBS2 binds the 3' untranslated regions (UTRs) of WFDC1 (WAP four-disulfide core domain 1) and IL-17D (Interleukin-17D), two secreted molecules that are shown to act as metastasis suppressors. Enhanced expression of either WFDC1 or IL-17D potently represses SORBS2 depletion-mediated cancer metastasis promotion. By enhancing the stability of these gene transcripts, SORBS2 suppresses ovarian cancer invasiveness and affects monocyte to myeloid-derived suppressor cell and M2-like macrophage polarization, eliciting a tumor-suppressive immune microenvironment. CONCLUSIONS: Our data illustrate a novel post-transcriptional network that links cancer progression and immunomodulation within the tumor microenvironment through SORBS2-mediated transcript stabilization.


Asunto(s)
Proteínas de Homeodominio/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/secundario , Estabilidad del ARN , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Línea Celular Tumoral , Femenino , Proteínas de Homeodominio/química , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Macrófagos/inmunología , Ratones Desnudos , Proteínas de Microfilamentos/genética , Células Supresoras de Origen Mieloide/inmunología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/metabolismo , Dominios Proteicos , Proteínas/genética , Proteínas/metabolismo , Proteínas de Unión al ARN/química , Microambiente Tumoral
7.
Proc Natl Acad Sci U S A ; 115(16): E3673-E3681, 2018 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-29592953

RESUMEN

Metastases constitute the greatest causes of deaths from cancer. However, no effective therapeutic options currently exist for cancer patients with metastasis. Estrogen receptor ß (ERß), as a member of the nuclear receptor superfamily, shows potent tumor-suppressive activities in many cancers. To investigate whether modulation of ERß could serve as a therapeutic strategy for cancer metastasis, we examined whether the selective ERß agonist LY500307 could suppress lung metastasis of triple-negative breast cancer (TNBC) and melanoma. Mechanistically, while we observed that LY500307 potently induced cell death of cancer cells metastasized to lung in vivo, it does not mediate apoptosis of cancer cells in vitro, indicating that the cell death-inducing effects of LY500307 might be mediated by the tumor microenvironment. Pathological examination combined with flow cytometry assays indicated that LY500307 treatment induced significant infiltration of neutrophils in the metastatic niche. Functional experiments demonstrated that LY500307-treated cancer cells show chemotactic effects for neutrophils and that in vivo neutrophil depletion by Ly6G antibody administration could reverse the effects of LY500307-mediated metastasis suppression. RNA sequencing analysis showed that LY500307 could induce up-regulation of IL-1ß in TNBC and melanoma cells, which further triggered antitumor neutrophil chemotaxis. However, the therapeutic effects of LY500307 treatment for suppression of lung metastasis was attenuated in IL1B-/- murine models, due to failure to induce antitumor neutrophil infiltration in the metastatic niche. Collectively, our study demonstrated that pharmacological activation of ERß could augment innate immunity to suppress cancer metastatic colonization to lung, thus providing alternative therapeutic options for cancer patients with metastasis.


Asunto(s)
Antineoplásicos/farmacología , Benzopiranos/farmacología , Moduladores de los Receptores de Estrógeno/farmacología , Receptor beta de Estrógeno/agonistas , Inmunidad Innata/efectos de los fármacos , Neoplasias Pulmonares/secundario , Neoplasias Mamarias Experimentales/patología , Melanoma Experimental/secundario , Infiltración Neutrófila/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/terapia , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Benzopiranos/uso terapéutico , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Moduladores de los Receptores de Estrógeno/uso terapéutico , Estrógenos , Femenino , Interleucina-1beta/deficiencia , Interleucina-1beta/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/terapia , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias Hormono-Dependientes/inmunología , Neoplasias Hormono-Dependientes/secundario , Neoplasias Hormono-Dependientes/terapia , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Organismos Libres de Patógenos Específicos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología
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