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1.
Gynecol Oncol ; 185: 75-82, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38368816

RESUMEN

OBJECTIVE: EGFL6, a growth factor produced by adipocytes, is upregulated in and implicated in the tumorigenesis of multiple tumor types. Given the strong link between obesity and endometrial cancer, we sought to determine the impact of EGFL6 on endometrial cancer. METHODS: EGFL6 expression in endometrial cancer and correlation with patient outcomes was evaluated in the human protein atlas and TCGA. EGFL6 treatment, expression upregulation, and shRNA knockdown were used to evaluate the impact of EGFL6 on the proliferation and migration of 3 endometrial cancer cell lines in vitro. Similarly, the impact of EGFL6 expression and knockdown on tumor growth was evaluated. Western blotting was used to evaluate the impact of EGFL6 on MAPK phosphorylation. RESULTS: EGFL6 is upregulated in endometrial cancer, primarily in cony-number high tumors. High tumor endometrial cancer expression of EGFL6 predicts poor patient prognosis. We find that EGFL6 acts to activate the MAPK pathway increasing cellular proliferation and migration. In xenograft models, EGFL6 overexpression increases endometrial cancer tumor growth while EGFL6 knockdown decreases endometrial cancer tumor growth. CONCLUSIONS: EGFL6 is a marker of poor prognosis endometrial cancers, driving cancer cell proliferation and growth. As such EGFL6 represents a potential therapeutic target in endometrial cancer.


Asunto(s)
Movimiento Celular , Proliferación Celular , Neoplasias Endometriales , Femenino , Humanos , Neoplasias Endometriales/patología , Neoplasias Endometriales/genética , Neoplasias Endometriales/metabolismo , Animales , Línea Celular Tumoral , Ratones , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Ratones Desnudos , Sistema de Señalización de MAP Quinasas , Factores de Crecimiento Endotelial/genética , Factores de Crecimiento Endotelial/metabolismo , Regulación hacia Arriba , Moléculas de Adhesión Celular
2.
Stem Cells ; 40(8): 705-715, 2022 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-35583414

RESUMEN

The interaction between tumor cells and non-malignant hosts cells within the tumor microenvironment (TME) is critical to the pathophysiology of cancer. These non-malignant host cells, consisting of a variety of stromal, immune, and endothelial cells, engage in a complex bidirectional crosstalk with the malignant tumor cells. Mesenchymal stem/stromal cells (MSCs) are one of these host cells, and they play a critical role in directing the formation and function of the entire TME. These MSCs are epigenetically reprogrammed by cancer cells to assume a strongly pro-tumorigenic phenotype and are referred to as carcinoma-associated mesenchymal stem/stromal cells (CA-MSCs). Studies over the last decade demonstrate that CA-MSCs not only directly interact with cancer cells to promote tumor growth and metastasis but also orchestrate the formation of the TME. Carcinoma-associated mesenchymal stem/stromal cells can differentiate into virtually all stromal sub-lineages present in the TME, including pro-tumorigenic cancer-associated fibroblasts (CAF), myofibroblasts, and adipocytes. carcinoma-associated mesenchymal stem/stromal cells and the CAFs they produce, secrete much of the extracellular matrix in the TME. Furthermore, CA-MSC secreted factors promote angiogenesis, and recruit immunosuppressive myeloid cells effectively driving tumor immune exclusion. Thus CA-MSCs impact nearly every aspect of the TME. Despite their influence on cancer biology, as CA-MSCs represent a heterogenous population without a single definitive marker, significant confusion remains regarding the origin and proper identification CA-MSCs. This review will focus on the impact of CA-MSCs on cancer progression and metastasis and the ongoing work on CA-MSC identification, nomenclature and mechanism of action.


Asunto(s)
Fibroblastos Asociados al Cáncer , Carcinoma , Células Madre Mesenquimatosas , Carcinogénesis , Línea Celular Tumoral , Células Endoteliales , Humanos , Microambiente Tumoral
3.
Gynecol Oncol ; 176: 139-146, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37535994

RESUMEN

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.


Asunto(s)
Cistadenocarcinoma Seroso , Neoplasias de las Trompas Uterinas , Neoplasias Ováricas , Femenino , Humanos , Ratones , Animales , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Mutación , Neoplasias de las Trompas Uterinas/patología , Trompas Uterinas/patología , Cistadenocarcinoma Seroso/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/prevención & control , Neoplasias Ováricas/metabolismo , Inhibidores Enzimáticos , Quimioprevención , Carcinogénesis
4.
Gynecol Oncol ; 171: 49-58, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36804621

RESUMEN

OBJECTIVES: Epidermal growth factor EGF-like domain multiple-6 (EGFL6) is highly expressed in high grade serous ovarian cancer and promotes both endothelial cell proliferation/angiogenesis and cancer cell proliferation/metastasis. As such it has been implicated as a therapeutic target. As a secreted factor, EGFL6 is a candidate for antibody therapy. The objectives of this study were to create and validate humanized affinity-matured EGFL6 neutralizing antibodies for clinical development. METHODS: A selected murine EGFL6 antibody was humanized using CDR grafting to create 26 variant humanized antibodies. These were screened and the lead candidate was affinity matured. Seven humanized affinity-matured EGFL6 antibodies were screened for their ability to block EGFL6 activity on cancer cells in vitro, two of which were selected and tested their therapeutic activity in vivo. RESULTS: Humanized affinity matured antibodies demonstrated high affinity for EGFL6 (150 pM to 2.67 nM). We found that several humanized affinity-matured EGFL6 antibodies specifically bound to recombinant, and native human EGFL6. Two lead antibodies were able to inhibit EGFL6-mediated (i) cancer cell migration, (ii) proliferation, and (iii) increase in ERK phosphorylation in cancer cells in vitro. Both lead antibodies restricted growth of an EGFL6 expressing ovarian cancer patient derived xenograft. Analysis of treated human tumor xenografts indicated that anti-EGFL6 therapy suppressed angiogenesis, inhibited tumor cell proliferation, and promoted tumor cell apoptosis. CONCLUSIONS: Our studies confirm the ability of these humanized affinity-matured antibodies to neutralize EGFL6 and acting as a therapeutic to restrict cancer growth. This work supports the development of these antibody for first-in-human clinical trials.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Neoplasias Ováricas , Humanos , Animales , Ratones , Femenino , Línea Celular Tumoral , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Proliferación Celular , Proteínas de Unión al Calcio , Moléculas de Adhesión Celular
5.
Gynecol Oncol ; 165(1): 60-66, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35140015

RESUMEN

OBJECTIVE: Evaluate the association between metformin and survival in women with Type 2 diabetes (T2DM) and breast, endometrial and ovarian cancer- 3 hormonally mediated cancers. METHODS: We evaluated outcomes in a cohort of 6225 women with T2DM with a new diagnosis of ovarian, breast or endometrial cancer from 2010 to 2019. We classified glycemic medications at time of first cancer diagnosis into 3 tiers in accordance with ADA guidelines. Approaches compared: (i) metformin (tier 1) vs. no glycemic medication, (ii) metformin vs tier 2 medications (sulfonylureas, thiazolidinediones, SGLT2-inhibitors, DPP4-inhibitors, alpha glucosidase-inhibitors, GLP-1 agonists), (iii) metformin vs tier 3 medications (insulins, amylinomimetics), and (iv) tier 2 vs tier 3 medications. Analyses included Cox proportional-hazards models, Kaplan-Meier curves, and conditional logistic regression in a risk set-sampled nested case-control matched on T2DM duration- all modeling survival. Models were adjusted for demographics, cancer type, A1C, T2DM duration, and number of office visits and hospitalizations. RESULTS: Metformin was the most used medication (n = 3232) and consistently demonstrated survival benefit compared with tier 2 and 3 medications, across all methods. Tier 3-users demonstrated highest risk of death when compared to metformin rather than tier 2 [adjHR = 1.83 (95% CI: 1.58, 2.13) vs. adjHR = 1.32 (95% CI: 1.11, 1.57)], despite similar baseline profiles between tier 1 and 2 users. CONCLUSIONS: Metformin users experienced increased survival even after accounting for surrogates of diabetes progression. Benefit extended beyond that seen in tier 2-users. Our findings, consistent with prior studies, indicate metformin use improves survival in women with T2DM and hormonally mediated women's cancers.


Asunto(s)
Diabetes Mellitus Tipo 2 , Metformina , Neoplasias Ováricas , Glucemia , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Incidencia , Masculino , Metformina/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Estudios Retrospectivos
6.
Stem Cells ; 37(2): 257-269, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30353617

RESUMEN

Carcinoma-associated mesenchymal stem cells (CA-MSCs) are critical stromal progenitor cells within the tumor microenvironment (TME). We previously demonstrated that CA-MSCs differentially express bone morphogenetic protein family members, promote tumor cell growth, increase cancer "stemness," and chemotherapy resistance. Here, we use RNA sequencing of normal omental MSCs and ovarian CA-MSCs to demonstrate global changes in CA-MSC gene expression. Using these expression profiles, we create a unique predictive algorithm to classify CA-MSCs. Our classifier accurately distinguishes normal omental, ovary, and bone marrow MSCs from ovarian cancer CA-MSCs. Suggesting broad applicability, the model correctly classifies pancreatic and endometrial cancer CA-MSCs and distinguishes cancer associated fibroblasts from CA-MSCs. Using this classifier, we definitively demonstrate ovarian CA-MSCs arise from tumor mediated reprograming of local tissue MSCs. Although cancer cells alone cannot induce a CA-MSC phenotype, the in vivo ovarian TME can reprogram omental or ovary MSCs to protumorigenic CA-MSCs (classifier score of >0.96). In vitro studies suggest that both tumor secreted factors and hypoxia are critical to induce the CA-MSC phenotype. Interestingly, although the breast cancer TME can reprogram bone marrow MSCs into CA-MSCs, the ovarian TME cannot, demonstrating for the first time that tumor mediated CA-MSC conversion is tissue and cancer type dependent. Together these findings (a) provide a critical tool to define CA-MSCs and (b) highlight cancer cell influence on distinct normal tissues providing powerful insights into the mechanisms underlying cancer specific metastatic niche formation. Stem Cells 2019;37:257-269.


Asunto(s)
Células Madre Mesenquimatosas/metabolismo , Neoplasias Ováricas/genética , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Neoplasias Ováricas/patología , Microambiente Tumoral
7.
Proc Natl Acad Sci U S A ; 112(50): E6882-8, 2015 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-26621735

RESUMEN

Whether human cancer follows a hierarchical or stochastic model of differentiation is controversial. Furthermore, the factors that regulate cancer stem-like cell (CSC) differentiation potential are largely unknown. We used a novel microfluidic single-cell culture method to directly observe the differentiation capacity of four heterogeneous ovarian cancer cell populations defined by the expression of the CSC markers aldehyde dehydrogenase (ALDH) and CD133. We evaluated 3,692 progeny from 2,833 cells. We found that only ALDH(+)CD133(+) cells could generate all four ALDH(+/-)CD133(+/-) cell populations and identified a clear branched differentiation hierarchy. We also observed a single putative stochastic event. Within the hierarchy of cells, bone morphologenetic protein 2 (BMP2) is preferentially expressed in ALDH(-)CD133(-) cells. BMP2 promotes ALDH(+)CD133(+) cell expansion while suppressing the proliferation of ALDH(-)CD133(-) cells. As such, BMP2 suppressed bulk cancer cell growth in vitro but increased tumor initiation rates, tumor growth, and chemotherapy resistance in vivo whereas BMP2 knockdown reduced CSC numbers, in vivo growth, and chemoresistance. These data suggest a hierarchical differentiation pattern in which BMP2 acts as a feedback mechanism promoting ovarian CSC expansion and suppressing progenitor proliferation. These results explain why BMP2 suppresses growth in vitro and promotes growth in vivo. Together, our results support BMP2 as a therapeutic target in ovarian cancer.


Asunto(s)
Proteína Morfogenética Ósea 2/fisiología , Neoplasias Ováricas/patología , Antígeno AC133 , Aldehído Deshidrogenasa/metabolismo , Antígenos CD/metabolismo , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Proteína Morfogenética Ósea 2/genética , Línea Celular Tumoral , Proliferación Celular , Femenino , Técnicas de Silenciamiento del Gen , Glicoproteínas/metabolismo , Humanos , Microfluídica , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Péptidos/metabolismo
8.
Gynecol Oncol ; 138(1): 181-9, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25913133

RESUMEN

BACKGROUND: Ovarian cancer grows and metastasizes from multicellular spheroidal aggregates within the ascites fluid. Multicellular tumor spheroids are therefore physiologically significant 3D in vitro models for ovarian cancer research. Conventional hanging drop cultures require high starting cell numbers, and are tedious for long-term maintenance. In this study, we generate stable, uniform multicellular spheroids using very small number of ovarian cancer cells in a novel 384 well hanging drop array platform. METHODS: We used novel tumor spheroid platform and two ovarian cancer cell lines (A2780 and OVCAR3) to demonstrate the stable incorporation of as few as 10 cells into a single spheroid. RESULTS: Spheroids had uniform geometry, with projected areas (42.60×10(3)µm-475.22×10(3)µm(2) for A2780 spheroids and 37.24×10(3)µm(2)-281.01×10(3)µm(2) for OVCAR3 spheroids) that varied as a function of the initial cell seeding density. Phalloidin and nuclear stains indicated cells formed tightly packed spheroids with demarcated boundaries and cell-cell interaction within spheroids. Cells within spheroids demonstrated over 85% viability. 3D tumor spheroids demonstrated greater resistance (70-80% viability) to cisplatin chemotherapy compared to 2D cultures (30-50% viability). CONCLUSIONS: Ovarian cancer spheroids can be generated from limited cell numbers in high throughput 384 well plates with high viability. Spheroids demonstrate therapeutic resistance relative to cells in traditional 2D culture. Stable incorporation of low cell numbers is advantageous when translating this research to rare patient-derived cells. This system can be used to understand ovarian cancer spheroid biology, as well as carry out preclinical drug sensitivity assays.


Asunto(s)
Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales/métodos , Femenino , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Esferoides Celulares
9.
Lancet Oncol ; 15(11): 1207-14, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25218906

RESUMEN

BACKGROUND: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. METHODS: In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. FINDINGS: Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7-not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7-16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23-0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none). INTERPRETATION: Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy. FUNDING: American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario , Cisplatino/administración & dosificación , Intervalos de Confianza , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Quinazolinas/administración & dosificación , Medición de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento
10.
J Proteome Res ; 13(4): 2197-204, 2014 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-24575722

RESUMEN

Altered glycosylation in glycoproteins is associated with carcinogenesis, and certain glycan structures and glycoproteins are well-known markers for tumor progression. To identify potential diagnostic candidate markers, we have developed a novel method for analysis of glycosylation changes of glycoproteins from crude serum samples using lectin-based glycoprotein capture followed by detection with biotin/HRP-conjugated antibodies. The amount of lectin coated on the microplate well was optimized to achieve low background and improved S/N compared with current lectin ELISA methods. In the presence of competing sugars of lectin AAL or with sialic acid removed from the glycoproteins, we confirmed that this method specifically detects glycosylation changes of proteins rather than protein abundance variation. Using our reverse lectin-based ELISA assay, increased fucosylated haptoglobin was observed in sera of patients with ovarian cancer, while the protein level of haptoglobin remained the same between cancers and noncases. The combination of fucosylated haptoglobin and CA125 (AUC = 0.88) showed improved performance for distinguishing stage-III ovarian cancer from noncases compared with CA125 alone (AUC = 0.86). In differentiating early-stage ovarian cancer from noncases, fucosylated haptoglobin showed comparable performance to CA125. The combination of CA125 and fucosylated haptoglobin resulted in an AUC of 0.855, which outperforms CA125 to distinguish early-stage cancer from noncases. Our study provides an alternative method to quantify glycosylation changes of proteins from serum samples, which will be essential for biomarker discovery and validation studies.


Asunto(s)
Ensayo de Inmunoadsorción Enzimática/métodos , Glicoproteínas/química , Glicoproteínas/aislamiento & purificación , Lectinas/química , Polisacáridos/química , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/química , Biomarcadores de Tumor/aislamiento & purificación , Biomarcadores de Tumor/metabolismo , Femenino , Glicoproteínas/sangre , Glicoproteínas/metabolismo , Glicosilación , Humanos , Lectinas/metabolismo , Persona de Mediana Edad , Neoplasias Ováricas , Polisacáridos/sangre , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Adulto Joven
11.
Commun Biol ; 7(1): 20, 2024 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-38182756

RESUMEN

High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease, and a highstromal/desmoplastic tumor microenvironment (TME) is associated with a poor outcome. Stromal cell subtypes, including fibroblasts, myofibroblasts, and cancer-associated mesenchymal stem cells, establish a complex network of paracrine signaling pathways with tumor-infiltrating immune cells that drive effector cell tumor immune exclusion and inhibit the antitumor immune response. In this work, we integrate single-cell transcriptomics of the HGSOC TME from public and in-house datasets (n = 20) and stratify tumors based upon high vs. low stromal cell content. Although our cohort size is small, our analyses suggest a distinct transcriptomic landscape for immune and non-immune cells in high-stromal vs. low-stromal tumors. High-stromal tumors have a lower fraction of certain T cells, natural killer (NK) cells, and macrophages, and increased expression of CXCL12 in epithelial cancer cells and cancer-associated mesenchymal stem cells (CA-MSCs). Analysis of cell-cell communication indicate that epithelial cancer cells and CA-MSCs secrete CXCL12 that interacte with the CXCR4 receptor, which is overexpressed on NK and CD8+ T cells. Dual IHC staining show that tumor infiltrating CD8 T cells localize in proximity of CXCL12+ tumor area. Moreover, CXCL12 and/or CXCR4 antibodies confirm the immunosuppressive role of CXCL12-CXCR4 in high-stromal tumors.


Asunto(s)
Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/genética , Análisis de la Célula Individual , Transducción de Señal , Anticuerpos , Microambiente Tumoral
12.
bioRxiv ; 2024 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-39026889

RESUMEN

Quiescence is a reversible cell cycle exit traditionally thought to be associated with a metabolically inactive state. Recent work in muscle cells indicates that metabolic reprogramming is associated with quiescence. Whether metabolic changes occur in cancer to drive quiescence is unclear. Using a multi-omics approach, we found that the metabolic enzyme ACSS2, which converts acetate into acetyl-CoA, is both highly upregulated in quiescent ovarian cancer cells and required for their survival. Indeed, quiescent ovarian cancer cells have increased levels of acetate-derived acetyl-CoA, confirming increased ACSS2 activity in these cells. Furthermore, either inducing ACSS2 expression or supplementing cells with acetate was sufficient to induce a reversible quiescent cell cycle exit. RNA-Seq of acetate treated cells confirmed negative enrichment in multiple cell cycle pathways as well as enrichment of genes in a published G0 gene signature. Finally, analysis of patient data showed that ACSS2 expression is upregulated in tumor cells from ascites, which are thought to be more quiescent, compared to matched primary tumors. Additionally, high ACSS2 expression is associated with platinum resistance and worse outcomes. Together, this study points to a previously unrecognized ACSS2-mediated metabolic reprogramming that drives quiescence in ovarian cancer. As chemotherapies to treat ovarian cancer, such as platinum, have increased efficacy in highly proliferative cells, our data give rise to the intriguing question that metabolically-driven quiescence may affect therapeutic response.

13.
J Clin Invest ; 2024 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-39312740

RESUMEN

Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) play a critical role in resistance to immunotherapy. In this study, we identified epidermal growth factor-like 6 (Egfl6) as a new regulator of myeloid cell functions. Our analyses indicated that Egfl6, via binding with ß3 integrins and activation of p38 and SYK signaling, acts as a chemotactic factor for myeloid cells migration and promotes their differentiation towards an immunosuppressive state. In syngeneic mouse models of ovarian cancer (OvCa), tumor expression of Egfl6 increased the intra-tumoral accumulation of polymorphonuclear (PMN) MDSCs and TAMs and their expression of immunosuppressive factors, including CXCL2, IL-10 and PD-L1. Consistent with this, in an immune 'hot' tumor model, Egfl6 expression eliminated response to a-PD-L1 therapy, while Egfl6 neutralizing antibody decreased the accumulation of tumor-infiltrating CD206+ TAMs and PMN-MDSCs and restored the efficacy of a-PD-L1 therapy. Supporting a role in human tumors, in human OvCa tissue samples, areas of high EGFL6 expression co-localized with myeloid cell infiltration. scRNAseq analyses revealed a correlation between EGFL6 and immune cell expression of immunosuppressive factors. Our data provide mechanistic insights into the onco-immunologic functions of EGFL6 in mediating tumor immune suppression and identified EGFL6 as a potential novel therapeutic target to enhance immunotherapy in OvCa patients.

14.
Mol Metab ; 89: 102031, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39304063

RESUMEN

Quiescence is a reversible cell cycle exit traditionally thought to be associated with a metabolically inactive state. Recent work in muscle cells indicates that metabolic reprogramming is associated with quiescence. Whether metabolic changes occur in cancer to drive quiescence is unclear. Using a multi-omics approach, we found that the metabolic enzyme ACSS2, which converts acetate into acetyl-CoA, is both highly upregulated in quiescent ovarian cancer cells and required for their survival. Indeed, quiescent ovarian cancer cells have increased levels of acetate-derived acetyl-CoA, confirming increased ACSS2 activity in these cells. Furthermore, either inducing ACSS2 expression or supplementing cells with acetate was sufficient to induce a reversible quiescent cell cycle exit. RNA-Seq of acetate treated cells confirmed negative enrichment in multiple cell cycle pathways as well as enrichment of genes in a published G0 gene signature. Finally, analysis of patient data showed that ACSS2 expression is upregulated in tumor cells from ascites, which are thought to be more quiescent, compared to matched primary tumors. Additionally, high ACSS2 expression is associated with platinum resistance and worse outcomes. Together, this study points to a previously unrecognized ACSS2-mediated metabolic reprogramming that drives quiescence in ovarian cancer. As chemotherapies to treat ovarian cancer, such as platinum, have increased efficacy in highly proliferative cells, our data give rise to the intriguing question that metabolically-driven quiescence may affect therapeutic response.


Asunto(s)
Acetato CoA Ligasa , Acetatos , Acetilcoenzima A , Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , Acetilcoenzima A/metabolismo , Acetato CoA Ligasa/metabolismo , Acetato CoA Ligasa/genética , Acetatos/metabolismo , Acetatos/farmacología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Ciclo Celular/efectos de los fármacos
15.
Chem Biol Interact ; 391: 110910, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38364885

RESUMEN

Aldehyde dehydrogenase 1A (ALDH1A) isoforms may be a useful target for overcoming chemotherapy resistance in high-grade serous ovarian cancer (HGSOC) and other solid tumor cancers. However, as different cancers express different ALDH1A isoforms, isoform selective inhibitors may have a limited therapeutic scope. Furthermore, resistance to an ALDH1A isoform selective inhibitor could arise via induction of expression of other ALDH1A isoforms. As such, we have focused on the development of pan-ALDH1A inhibitors, rather than on ALDH1A isoform selective compounds. Herein, we report the development of a new group of pan-ALDH1A inhibitors to assess whether broad spectrum ALDH1A inhibition is an effective adjunct to chemotherapy in HGSOC. Optimization of the CM10 scaffold, aided by ALDH1A1 crystal structures, led to improved biochemical potencies, improved cellular efficacy as demonstrated by reduction in ALDEFLUOR signal in HGSOC cells, and substantial improvements in liver microsomal stability. Based on this work we identified two compounds 17 and 25 suitable for future in vivo proof of concept experiments.


Asunto(s)
Isoenzimas , Neoplasias , Humanos , Aldehído Deshidrogenasa/metabolismo , Retinal-Deshidrogenasa/metabolismo , Aldehído Oxidorreductasas/metabolismo
16.
J Clin Oncol ; 42(21): 2537-2545, 2024 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-38776484

RESUMEN

PURPOSE: The interleukin-6/Janus kinase (JAK)/signal transducers and activators of transcription 3 axis is a reported driver of chemotherapy resistance. We hypothesized that adding the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and improve progression-free survival (PFS) in patients with ovarian cancer in the upfront setting. MATERIALS AND METHODS: Patients with ovarian/fallopian tube/primary peritoneal carcinoma recommended for neoadjuvant chemotherapy were eligible. In phase I, treatment was initiated with dose-dense paclitaxel (P) 70 mg/m2 once daily on days 1, 8, and 15; carboplatin AUC 5 intravenously day 1; and ruxolitinib 15 mg orally (PO) twice a day, every 21 days (dose level 1). Interval debulking surgery (IDS) was required after cycle 3. Patients then received three additional cycles of chemotherapy/ruxolitinib, followed by maintenance ruxolitinib. In the randomized phase II, patients were randomly assigned to paclitaxel/carboplatin with or without ruxolitinib at 15 mg PO twice a day for three cycles, IDS, followed by another three cycles of chemotherapy/ruxolitinib, without further maintenance ruxolitinib. The primary phase II end point was PFS. RESULTS: Seventeen patients were enrolled in phase I. The maximum tolerated dose and recommended phase II dose were established to be dose level 1. One hundred thirty patients were enrolled in phase II with a median follow-up of 24 months. The regimen was well tolerated, with a trend toward higher grade 3 to 4 anemia (64% v 27%), grade 3 to 4 neutropenia (53% v 37%), and thromboembolic events (12.6% v 2.4%) in the experimental arm. In the randomized phase II, the median PFS in the reference arm was 11.6 versus 14.6 in the experimental, hazard ratio (HR) for PFS was 0.702 (log-rank P = .059). The overall survival HR was 0.785 (P = .24). CONCLUSION: Ruxolitinib 15 mg PO twice a day was well tolerated with acceptable toxicity in combination with paclitaxel/carboplatin chemotherapy. The primary end point of prolongation of PFS was achieved in the experimental arm, warranting further investigation.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Neoadyuvante , Nitrilos , Neoplasias Ováricas , Paclitaxel , Pirazoles , Pirimidinas , Humanos , Femenino , Persona de Mediana Edad , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Pirazoles/administración & dosificación , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/mortalidad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Paclitaxel/administración & dosificación , Carboplatino/administración & dosificación , Supervivencia sin Progresión , Anciano de 80 o más Años
17.
J Proteome Res ; 12(7): 3342-52, 2013 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-23731285

RESUMEN

Herein, we identify and confirm differentially expressed sialoglycoproteins in the serum of patients with ovarian cancer. On the basis of Sambucus nigra (SNA) lectin enrichment and on an isobaric chemical labeling quantitative strategy, clusterin (CLUS), leucine-rich alpha-2-glycoprotein (LRG1), hemopexin (HEMO), vitamin D-binding protein (VDB), and complement factor H (CFH) were found to be differentially expressed in the serum of patients with ovarian cancer compared to benign diseases. The abnormal sialylation levels of CLUS, CFH, and HEMO in serum of ovarian cancer patients were verified by a lectin-based ELISA assay. ELISA assays were further applied to measure total protein level changes of these glycoproteins. Protein levels of CLUS were found to be down-regulated in the serum of ovarian cancer patients, while protein levels of LRG1 were increased. The combination of CLUS and LRG1 (AUC = 0.837) showed improved performance for distinguishing stage III ovarian cancer from benign diseases compared to CA125 alone (AUC = 0.811). In differentiating early stage ovarian cancer from benign diseases or healthy controls, LRG1 showed comparable performance to CA125. An independent sample set was further used to confirm the ability of these candidate markers to detect patients with ovarian cancer. Our study provides a comprehensive strategy for the identification of candidate biomarkers that show the potential for diagnosis of ovarian cancer. Further studies using a large number of samples are necessary to validate the utility of this panel of proteins.


Asunto(s)
Biomarcadores de Tumor/sangre , Glicoproteínas/biosíntesis , Neoplasias Ováricas/sangre , Proteómica/métodos , Ensayo de Inmunoadsorción Enzimática , Femenino , Regulación Neoplásica de la Expresión Génica , Glicoproteínas/aislamiento & purificación , Humanos , Lectinas/química , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Curva ROC
18.
bioRxiv ; 2023 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-37333262

RESUMEN

High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease, and a high stromal/desmoplastic tumor microenvironment (TME) is associated with a poor outcome. Stromal cell subtypes, including fibroblasts, myofibroblasts, and cancer-associated mesenchymal stem cells, establish a complex network of paracrine signaling pathways with tumor-infiltrating immune cells that drive effector cell tumor immune exclusion and inhibit the antitumor immune response. Single-cell transcriptomics of the HGSOC TME from public and in-house datasets revealed a distinct transcriptomic landscape for immune and non-immune cells in high-stromal vs. low-stromal tumors. High-stromal tumors had a lower fraction of certain T cells, natural killer (NK) cells, and macrophages and increased expression of CXCL12 in epithelial cancer cells and cancer-associated mesenchymal stem cells (CA-MSCs). Analysis of cell-cell communication indicated that epithelial cancer cells and CA-MSCs secreted CXCL12 that interacted with the CXCR4 receptor, which was overexpressed on NK and CD8 + T cells. CXCL12 and/or CXCR4 antibodies confirmed the immunosuppressive role of CXCL12-CXCR4 in high-stromal tumors.

19.
Environ Pollut ; 336: 122419, 2023 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-37598933

RESUMEN

Accumulation of polychlorinated biphenyls (PCBs) within fish tissues has prompted many states to issue consumption advisories. In Pennsylvania such advisories suggest one meal per month for most game species harvested from Lake Erie; however, these advisories do not account for the emergent properties of regional PCB mixtures, and the downstream accumulation of PCB congeners into human tissues is poorly documented. This study aimed to demonstrate the utility of pairing environmental monitoring with pharmacokinetic modeling for the purpose of estimating dietary PCB exposure in humans. We qualified and quantified the PCB congeners present in the filets of five Lake Erie fish species and used these data to estimate exposure under consumption scenarios that matched or exceeded the advisories. Physiologically-based pharmacokinetic (PBPK) modeling was then employed to predict PCB accumulation within seven tissue compartments of a hypothetical man and woman over 10 years. Twenty-one congeners were detected between the five fish species at concentrations ranging from 56.0 to 411.7 ng/g. Predicted accumulation in human tissues varied based on tissue type, the species consumed, biological sex, and fish-consumption rate. Notably, steady-state concentrations were higher in fatty tissue compartments ("Fat" and "Liver") and across all tissues in women compared to men. This study serves as a preliminary blueprint for generating predictions of site-specific and tissue-specific exposure through the integration of environmental monitoring and pharmacokinetic modeling. Although the details may vary across applications, this simple approach could complement traditional exposure assessments for vulnerable communities in the Great Lakes region that continue to suffer from legacy contamination.


Asunto(s)
Bifenilos Policlorados , Masculino , Animales , Humanos , Femenino , Bifenilos Policlorados/análisis , Monitoreo del Ambiente , Peces , Great Lakes Region , Lagos
20.
Clin Cancer Res ; 29(10): 1969-1983, 2023 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-36795892

RESUMEN

PURPOSE: We recently reported that the transcription factor NFATC4, in response to chemotherapy, drives cellular quiescence to increase ovarian cancer chemoresistance. The goal of this work was to better understand the mechanisms of NFATC4-driven ovarian cancer chemoresistance. EXPERIMENTAL DESIGN: We used RNA sequencing to identify NFATC4-mediated differential gene expression. CRISPR-Cas9 and FST (follistatin)-neutralizing antibodies were used to assess impact of loss of FST function on cell proliferation and chemoresistance. ELISA was used to quantify FST induction in patient samples and in vitro in response to chemotherapy. RESULTS: We found that NFATC4 upregulates FST mRNA and protein expression predominantly in quiescent cells and FST is further upregulated following chemotherapy treatment. FST acts in at least a paracrine manner to induce a p-ATF2-dependent quiescent phenotype and chemoresistance in non-quiescent cells. Consistent with this, CRISPR knockout (KO) of FST in ovarian cancer cells or antibody-mediated neutralization of FST sensitizes ovarian cancer cells to chemotherapy treatment. Similarly, CRISPR KO of FST in tumors increased chemotherapy-mediated tumor eradication in an otherwise chemotherapy-resistant tumor model. Suggesting a role for FST in chemoresistance in patients, FST protein in the abdominal fluid of patients with ovarian cancer significantly increases within 24 hours of chemotherapy exposure. FST levels decline to baseline levels in patients no longer receiving chemotherapy with no evidence of disease. Furthermore, elevated FST expression in patient tumors is correlated with poor progression-free, post-progression-free, and overall survival. CONCLUSIONS: FST is a novel therapeutic target to improve ovarian cancer response to chemotherapy and potentially reduce recurrence rates.


Asunto(s)
Folistatina , Neoplasias Ováricas , Humanos , Femenino , Folistatina/genética , Folistatina/metabolismo , Folistatina/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Proliferación Celular , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética
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