RESUMO
Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.
Assuntos
Vesículas Extracelulares , Ácidos Graxos , Fígado Gorduroso , Fígado , Neoplasias Pancreáticas , Animais , Camundongos , Sistema Enzimático do Citocromo P-450/genética , Vesículas Extracelulares/metabolismo , Ácidos Graxos/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Microambiente Tumoral , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Neoplasias Hepáticas/secundário , Humanos , Inflamação/metabolismo , Ácido Palmítico/metabolismo , Células de Kupffer , Fosforilação Oxidativa , Proteínas rab27 de Ligação ao GTP/deficiênciaRESUMO
The majority of breast cancers expresses the estrogen receptor (ER+) and is treated with anti-estrogen therapies, particularly tamoxifen in premenopausal women. However, tamoxifen resistance is responsible for a large proportion of breast cancer deaths. Using small molecule inhibitors, phospho-mimetic proteins, tamoxifen-sensitive and tamoxifen-resistant breast cancer cells, a tamoxifen-resistant patient-derived xenograft model, patient tumor tissues, and genome-wide transcription and translation studies, we show that tamoxifen resistance involves selective mRNA translational reprogramming to an anti-estrogen state by Runx2 and other mRNAs. Tamoxifen-resistant translational reprogramming is shown to be mediated by increased expression of eIF4E and its increased availability by hyperactive mTOR and to require phosphorylation of eIF4E at Ser209 by increased MNK activity. Resensitization to tamoxifen is restored only by reducing eIF4E expression or mTOR activity and also blocking MNK1 phosphorylation of eIF4E. mRNAs specifically translationally up-regulated with tamoxifen resistance include Runx2, which inhibits ER signaling and estrogen responses and promotes breast cancer metastasis. Silencing Runx2 significantly restores tamoxifen sensitivity. Tamoxifen-resistant but not tamoxifen-sensitive patient ER+ breast cancer specimens also demonstrate strongly increased MNK phosphorylation of eIF4E. eIF4E levels, availability, and phosphorylation therefore promote tamoxifen resistance in ER+ breast cancer through selective mRNA translational reprogramming.
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Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/metabolismo , Antagonistas de Estrogênios/farmacologia , Fator de Iniciação 4E em Eucariotos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Biossíntese de Proteínas , Proteínas Serina-Treonina Quinases/metabolismo , Tamoxifeno/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Fosforilação , RNA Mensageiro/metabolismoRESUMO
PURPOSE: Late alopecia, defined as incomplete hair regrowth > 6 months following cytotoxic chemotherapy or > 6 months from initiation of endocrine therapy, negatively impacts quality of life and may affect dose intensity of adjuvant therapy. This study investigates the effect of oral minoxidil in women with chemotherapy and/or endocrine therapy-induced late alopecia. METHODS: The rate of clinical response was assessed by standardized photography and quantitated with trichoscopy. RESULTS: Two hundred and sixteen patients (mean age 57.8 ± 13.7) were included. The most common cancer diagnosis was breast, in 170 patients (79.1%). Alopecia developed after chemotherapy in 31 (14.4%) patients, endocrine monotherapy in 65 (30.1%) patients, and chemotherapy followed by endocrine therapy in 120 (55.6%) patients. In 119 patients, standardized photography assessments were used to determine clinical change in alopecia after a median of 105 (IQR = 70) days on oral minoxidil and revealed improvement in 88 (74%) patients. Forty-two patients received quantitative trichoscopic assessments at baseline and at follow-up after a median of 91 (IQR = 126) days on oral minoxidil. Patients had clinically and statistically significant increases in frontal hair shaft density (from 124.2 hairs/cm2 at initial to 153.2 hairs/cm2 at follow-up assessment, p = 0.008) and occipital shaft density (from 100.3 hairs/cm2 at initial to 123.5 hairs/cm2 at follow-up assessment. p = 0.004). No patients discontinued oral minoxidil due to adverse events. CONCLUSIONS: Overall, oral minoxidil was well tolerated by patients and may benefit both frontal and occipital late alopecia in cancer survivors treated with cytotoxic and/or endocrine therapy by increasing hair shaft and follicle density.
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AIMS: The most appropriate timing of exercise therapy to improve cardiorespiratory fitness (CRF) among patients initiating chemotherapy is not known. The effects of exercise therapy administered during, following, or during and following chemotherapy were examined in patients with breast cancer. METHODS AND RESULTS: Using a parallel-group randomized trial design, 158 inactive women with breast cancer initiating (neo)adjuvant chemotherapy were allocated to receive (1:1 ratio): usual care or one of three exercise regimens-concurrent (during chemotherapy only), sequential (after chemotherapy only), or concurrent and sequential (continuous) (n = 39/40 per group). Exercise consisted of treadmill walking three sessions/week, 20-50 min at 55%-100% of peak oxygen consumption (VO2peak) for ≈16 (concurrent, sequential) or ≈32 (continuous) consecutive weeks. VO2peak was evaluated at baseline (pre-treatment), immediately post-chemotherapy, and ≈16 weeks after chemotherapy. In intention-to-treat analysis, there was no difference in the primary endpoint of VO2peak change between concurrent exercise and usual care during chemotherapy vs. VO2peak change between sequential exercise and usual care after chemotherapy [overall difference, -0.88 mL O2·kg-1·min-1; 95% confidence interval (CI): -3.36, 1.59, P = 0.48]. In secondary analysis, continuous exercise, approximately equal to twice the length of the other regimens, was well-tolerated and the only strategy associated with significant improvements in VO2peak from baseline to post-intervention (1.74 mL O2·kg-1·min-1, P < 0.001). CONCLUSION: There was no statistical difference in CRF improvement between concurrent vs. sequential exercise therapy relative to usual care in women with primary breast cancer. The promising tolerability and CRF benefit of ≈32 weeks of continuous exercise therapy warrant further evaluation in larger trials.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Qualidade de Vida , Consumo de Oxigênio , Terapia por Exercício/métodos , Quimioterapia AdjuvanteRESUMO
PURPOSE: Chemotherapy with or without immunotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC). A subset of TNBCs express the androgen receptor (AR), representing a potential new therapeutic target. This study assessed the feasibility of adjuvant enzalutamide, an AR antagonist, in early-stage, AR-positive (AR +) TNBC. METHODS: This study was a single-arm, open-label, multicenter trial in which patients with stage I-III, AR ≥ 1% TNBC who had completed standard-of-care therapy were treated with enzalutamide 160 mg/day orally for 1 year. The primary objective of this study was to evaluate the feasibility of 1 year of adjuvant enzalutamide, defined as the treatment discontinuation rate of enzalutamide due to toxicity, withdrawal of consent, or other events related to tolerability. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and genomic features of recurrent tumors. RESULTS: Fifty patients were enrolled in this study. Thirty-five patients completed 1 year of therapy, thereby meeting the prespecified trial endpoint for feasibility. Thirty-two patients elected to continue with an optional second year of treatment. Grade ≥ 3 treatment-related adverse events were uncommon. The 1-year, 2-year, and 3-year DFS were 94%, 92% , and 80%, respectively. Median OS has not been reached. CONCLUSION: This clinical trial demonstrates that adjuvant enzalutamide is a feasible and well-tolerated regimen in patients with an early-stage AR + TNBC. Randomized trials in the metastatic setting may inform patient selection through biomarker development; longer follow-up is needed to determine the effect of anti-androgens on DFS and OS in this patient population.
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Neoplasias de Mama Triplo Negativas , Benzamidas , Estudos de Viabilidade , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Nitrilas/uso terapêutico , Feniltioidantoína/efeitos adversos , Receptores Androgênicos/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
PURPOSE: Rash develops in approximately 50% of patients receiving alpelisib for breast cancer, often requiring dose modifications. Here, we describe the clinicopathologic, laboratory, and management characteristics of alpelisib-related dermatologic adverse events (dAEs). METHODS: A single center-retrospective analysis was conducted. Data were abstracted from electronic medical records. RESULTS: A total of 102 patients (mean age 56 years, range 27-83) receiving alpelisib most frequently in combination with endocrine therapy (79, 77.5%) were included. We identified 41 (40.2%) patients with all-grade rash distributed primarily along the trunk (78%) and extremities (70%) that developed approximately within two weeks of treatment initiation (mean 12.8 ± 1.5 days) and lasted one-week (mean duration 7.1 ± 0.8 days). Of 29 patients with documented morphology of alpelisib-related dAEs, 26 (89.7%) had maculopapular rash. Histology showed perivascular and interface lymphocytic dermatitis. All-grade rash correlated with an increase in serum eosinophils from 2.7 to 4.4%, p < 0.05, and prophylaxis with non-sedating antihistamines (n = 43) was correlated with a reduction of grade 1/2 rash (OR 0.39, p = 0.09). Sixteen (84.2%) of 19 patients with grade 3 dAEs resulted in interruption of alpelisib, which were managed with antihistamines, topical and systemic corticosteroids. We did not observe rash recurrence in 12 (75%) patients who were re-challenged. CONCLUSIONS: A maculopapular rash associated with increased blood eosinophils occurs frequently with alpelisib. While grade 3 rash leads to alpelisib therapy interruption, dermatologic improvement is evident with systemic corticosteroids; and most patients can continue oncologic treatment at a maintained or reduced dose upon re-challenge with alpelisib.
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Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Toxidermias/etiologia , Exantema/induzido quimicamente , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/efeitos adversos , Tiazóis/efeitos adversos , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias da Mama/complicações , Relação Dose-Resposta a Droga , Toxidermias/tratamento farmacológico , Eosinofilia/induzido quimicamente , Eosinofilia/tratamento farmacológico , Exantema/tratamento farmacológico , Feminino , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Estudos Retrospectivos , Tiazóis/administração & dosagem , Tiazóis/uso terapêuticoRESUMO
PURPOSE: To describe ablation of bone, liver, lung, and soft tissue tumors from oligometastatic breast cancer and to define predictors of local progression and progression-free survival (PFS). MATERIALS AND METHODS: A total of 33 women (mean age 52 ± 12 years old; range, 28-69 years), underwent 46 thermal ablations of liver (n = 35), lung (n = 7), and bone/soft tissue (n = 4) metastases. Mean tumor diameter was 18 ± 15 mm (range, 6-50 mm). Ablations were performed to eradicate all evident sites of disease (n = 24) or to control growing sites in the setting of other stable or responding sites of disease (n = 22). Patient characteristics, ablation margins, imaging responses, and cases of PFS were assessed. Follow-up imaging was performed using contrast-enhanced computed tomography (CT), magnetic resonance (MR) imaging, or positron-emission tomography/ CT. RESULTS: Median PFS was 10 months (95% confidence interval [CI], 6.2 -14.5 months), and time to local progression was 11 months (95% CI, 5-16 months). Eight patients (24%) maintained no evidence of disease during a median follow-up period of 39 months. Ablation margin ≥5 mm was associated with no local tumor progression. Longer PFS was noted in estrogen receptor-positive patients (12 vs 4 months; P = .037) and younger patients (12 vs 4 months; P = .039) treated to eradicate all sites of disease (13 vs 5 months; P = .05). Eighteen patients (55%) developed new metastases during study follow-up. CONCLUSIONS: Thermal ablation of oligometastatic pulmonary, hepatic, bone, and soft tissue tumors can eliminate local tumor progression if margins are ≥5 mm. Longer PFS was observed in patients who were estrogen receptor-positive and patients who were younger and in whom all sites of disease were eradicated.
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Neoplasias Ósseas/cirurgia , Neoplasias da Mama/patologia , Criocirurgia , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/cirurgia , Metastasectomia/métodos , Ablação por Radiofrequência , Neoplasias de Tecidos Moles/cirurgia , Adulto , Idoso , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Neoplasias da Mama/mortalidade , Criocirurgia/efeitos adversos , Criocirurgia/mortalidade , Bases de Dados Factuais , Progressão da Doença , Estudos de Viabilidade , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Margens de Excisão , Metastasectomia/efeitos adversos , Metastasectomia/mortalidade , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Ablação por Radiofrequência/efeitos adversos , Ablação por Radiofrequência/mortalidade , Estudos Retrospectivos , Fatores de Risco , Neoplasias de Tecidos Moles/diagnóstico por imagem , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/secundário , Fatores de Tempo , Carga TumoralRESUMO
The horizontal transfer of mtDNA and its role in mediating resistance to therapy and an exit from dormancy have never been investigated. Here we identified the full mitochondrial genome in circulating extracellular vesicles (EVs) from patients with hormonal therapy-resistant (HTR) metastatic breast cancer. We generated xenograft models of HTR metastatic disease characterized by EVs in the peripheral circulation containing mtDNA. Moreover, these human HTR cells had acquired host-derived (murine) mtDNA promoting estrogen receptor-independent oxidative phosphorylation (OXPHOS). Functional studies identified cancer-associated fibroblast (CAF)-derived EVs (from patients and xenograft models) laden with whole genomic mtDNA as a mediator of this phenotype. Specifically, the treatment of hormone therapy (HT)-naive cells or HT-treated metabolically dormant populations with CAF-derived mtDNAhi EVs promoted an escape from metabolic quiescence and HTR disease both in vitro and in vivo. Moreover, this phenotype was associated with the acquisition of EV mtDNA, especially in cancer stem-like cells, expression of EV mtRNA, and restoration of OXPHOS. In summary, we have demonstrated that the horizontal transfer of mtDNA from EVs acts as an oncogenic signal promoting an exit from dormancy of therapy-induced cancer stem-like cells and leading to endocrine therapy resistance in OXPHOS-dependent breast cancer.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , DNA Mitocondrial/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Exossomos/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , DNA Mitocondrial/genética , Feminino , Fibroblastos/patologia , Transferência Genética Horizontal , Genoma Mitocondrial/genética , Humanos , Células MCF-7 , NADH Desidrogenase/genética , Fosforilação Oxidativa , Receptores de Estrogênio/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Purpose To assess the clinical safety, pharmacokinetics, and tumor imaging characteristics of fluorine 18-(2S,4R)-4-fluoroglutamine (FGln), a glutamine analog radiologic imaging agent. Materials and Methods This study was approved by the institutional review board and conducted under a U.S. Food and Drug Administration-approved Investigational New Drug application in accordance with the Helsinki Declaration and the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Between January 2013 and October 2016, 25 adult patients with cancer received an intravenous bolus of FGln tracer (mean, 244 MBq ± 118, <100 µg) followed by positron emission tomography (PET) and blood radioassays. Patient data were summarized with descriptive statistics. FGln biodistribution and plasma amino acid levels in nonfasting patients (n = 13) were compared with those from patients who fasted at least 8 hours before injection (n = 12) by using nonparametric one-way analysis of variance with Bonferroni correction. Tumor FGln avidity versus fluorodeoxyglucose (FDG) avidity in patients with paired PET scans (n = 15) was evaluated with the Fisher exact test. P < .05 was considered indicative of a statistically significant difference. Results FGln PET depicted tumors of different cancer types (breast, pancreas, renal, neuroendocrine, lung, colon, lymphoma, bile duct, or glioma) in 17 of the 25 patients, predominantly clinically aggressive tumors with genetic mutations implicated in abnormal glutamine metabolism. Acute fasting had no significant effect on FGln biodistribution and plasma amino acid levels. FGln-avid tumors were uniformly FDG-avid but not vice versa (P = .07). Patients experienced no adverse effects. Conclusion Preliminary human FGln PET trial results provide clinical validation of abnormal glutamine metabolism as a potential tumor biomarker for targeted radiotracer imaging in several different cancer types. © RSNA, 2018 Online supplemental material is available for this article. Clinical trial registration no. NCT01697930.
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Radioisótopos de Flúor/farmacocinética , Glutamina/análogos & derivados , Glutamina/metabolismo , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Tomografia por Emissão de Pósitrons , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica , Feminino , Radioisótopos de Flúor/metabolismo , Glutamina/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Distribuição Tecidual/efeitos dos fármacos , Estados Unidos , United States Food and Drug AdministrationRESUMO
PURPOSE: To describe imaging response and survival after radioembolization for metastatic breast cancer and to delineate genetic predictors of imaging responses and outcomes. MATERIALS AND METHODS: This retrospective study included 31 women (average age, 52 y) with liver metastasis from invasive ductal carcinoma who underwent resin and glass radioembolization (average cumulative dose, 2.0 GBq ± 1.8) between January 2011 and September 2017 after receiving ≥ 3 lines of chemotherapy. Twenty-four underwent genetic profiling with MSK-IMPACT or Sequenom; 26 had positron-emission tomography (PET)/CT imaging before and after treatment. Survival after the first radioembolization and 2-4-month PET/CT imaging response were assessed. Laboratory and imaging features were assessed to determine variables predictive of outcomes. Unpaired Student t tests and Fisher exact tests were used to compare responders and nonresponders categorized by changes in fluorodeoxyglucose avidity. Kaplan-Meier survival analysis was used to determine the impact of predictors on survival after radioembolization. RESULTS: Median survival after radioembolization was 11 months (range, 1-49 mo). Most patients (18 of 26; 69%) had complete or partial response based on changes in fluorodeoxyglucose avidity. Imaging response was associated with longer survival (P = .005). Whereas 100% of patients with PI3K pathway mutations showed an imaging response, only 45% of wild-type patients showed a response (P = .01). Median survival did not differ between PI3K pathway wild-type (10.9 mo) and mutant (undefined) patients (P = .50). CONCLUSIONS: These preliminary data suggest that genomic profiling may predict which patients with metastatic breast cancer benefit most from radioembolization. PI3K pathway mutations are associated with improved imaging response, which is associated with longer survival.
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Neoplasias da Mama/diagnóstico por imagem , Embolização Terapêutica/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Mutação , Fosfatidilinositol 3-Quinases/genética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/administração & dosagem , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Tomada de Decisão Clínica , Análise Mutacional de DNA , Embolização Terapêutica/efeitos adversos , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Pessoa de Meia-Idade , Cidade de Nova Iorque , Seleção de Pacientes , Projetos Piloto , Medicina de Precisão , Valor Preditivo dos Testes , Dados Preliminares , Compostos Radiofarmacêuticos/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Transdução de Sinais/genética , Fatores de Tempo , Resultado do TratamentoRESUMO
IL-6 signaling plays a prominent role in tumorigenesis and metastasis. In this review we discuss the recent evidence describing the tumor intrinsic and extrinsic functions of this signaling pathway. Although blockade of this pathway in pre-clinical models leads to a reduction in tumor growth and metastasis, its clinical success is less evident. Thus, identifying the features of tumors/patients that predict response to anti-IL6 therapy are needed.
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Transformação Celular Neoplásica/metabolismo , Interleucina-6/metabolismo , Neoplasias/metabolismo , Transdução de Sinais , Animais , Transformação Celular Neoplásica/genética , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Cancer cells acquire genetic and epigenetic alterations that often lead to dysregulation of oncogenic signal transduction pathways, which in turn alters downstream transcriptional programs. Numerous methods attempt to deduce aberrant signaling pathways in tumors from mRNA data alone, but these pathway analysis approaches remain qualitative and imprecise. In this study, we present a statistical method to link upstream signaling to downstream transcriptional response by exploiting reverse phase protein array (RPPA) and mRNA expression data in The Cancer Genome Atlas (TCGA) breast cancer project. Formally, we use an algorithm called affinity regression to learn an interaction matrix between upstream signal transduction proteins and downstream transcription factors (TFs) that explains target gene expression. The trained model can then predict the TF activity, given a tumor sample's protein expression profile, or infer the signaling protein activity, given a tumor sample's gene expression profile. Breast cancers are comprised of molecularly distinct subtypes that respond differently to pathway-targeted therapies. We trained our model on the TCGA breast cancer data set and identified subtype-specific and common TF regulators of gene expression. We then used the trained tumor model to predict signaling protein activity in a panel of breast cancer cell lines for which gene expression and drug response data was available. Correlations between inferred protein activities and drug responses in breast cancer cell lines grouped several drugs that are clinically used in combination. Finally, inferred protein activity predicted the clinical outcome within the METABRIC Luminal A cohort, identifying high- and low-risk patient groups within this heterogeneous subtype.
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Neoplasias da Mama/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais/genética , Fatores de Transcrição/genética , Algoritmos , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Análise por Conglomerados , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Genéticos , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Análise Serial de Proteínas/métodos , Análise de Regressão , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismoRESUMO
Hepatocellular adenoma (HCA) is a rare benign epithelial neoplasm with potential for hemorrhage, rupture, or malignant transformation. Reported annual incidence of HCA is approximately 1/1,000,000. We identified 12 cases of HCA among adults with a history of childhood or young adult cancer. The most common cancer diagnosis was leukemia (N = 4). Five had undergone allogeneic hematopoietic stem cell transplant with total body irradiation. All 11 females had prior estrogen therapy; the male case was hypogonadal. This report suggests childhood and young adult cancer survivors may be at increased risk for HCA, but further investigation is needed.
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Adenoma de Células Hepáticas/etiologia , Carcinoma Hepatocelular/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Neoplasias Hepáticas/etiologia , Neoplasias/complicações , Sobreviventes , Irradiação Corporal Total/efeitos adversos , Adenoma de Células Hepáticas/patologia , Adolescente , Adulto , Carcinoma Hepatocelular/patologia , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Lactente , Neoplasias Hepáticas/patologia , Masculino , Estadiamento de Neoplasias , Neoplasias/patologia , Neoplasias/terapia , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
PTPRD, which encodes the protein tyrosine phosphatase receptor-δ, is one of the most frequently inactivated genes across human cancers, including glioblastoma multiforme (GBM). PTPRD undergoes both deletion and mutation in cancers, with copy number loss comprising the primary mode of inactivation in GBM. However, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo, and the mechanistic basis of PTPRD function in tumors is unclear. Here, using genomic analysis and a glioma mouse model, we demonstrate that loss of Ptprd accelerates tumor formation and define the oncogenic context in which Ptprd loss acts. Specifically, we show that in human GBMs, heterozygous loss of PTPRD is the predominant type of lesion and that loss of PTPRD and the CDKN2A/p16(INK4A) tumor suppressor frequently co-occur. Accordingly, heterozygous loss of Ptprd cooperates with p16 deletion to drive gliomagenesis in mice. Moreover, loss of the Ptprd phosphatase resulted in phospho-Stat3 accumulation and constitutive activation of Stat3-driven genetic programs. Surprisingly, the consequences of Ptprd loss are maximal in the heterozygous state, demonstrating a tight dependence on gene dosage. Ptprd loss did not increase cell proliferation but rather altered pathways governing the macrophage response. In total, we reveal that PTPRD is a bona fide tumor suppressor, pinpoint PTPRD loss as a cause of aberrant STAT3 activation in gliomas, and establish PTPRD loss, in the setting of CDKN2A/p16(INK4A) deletion, as a driver of glioma progression.
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Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/metabolismo , Proliferação de Células , Galinhas , Inibidor p16 de Quinase Dependente de Ciclina/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/fisiologia , Genes Supressores de Tumor/fisiologia , Glioblastoma/imunologia , Glioblastoma/patologia , Heterozigoto , Humanos , Camundongos , Camundongos Knockout , Transplante de Neoplasias , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Microambiente Tumoral/imunologiaRESUMO
Although tyrosine-phosphorylated or activated STAT3 (pY-STAT3) is a well-described mediator of tumorigenesis, its role in thyroid cancer has not been investigated. We observed that 63 of 110 (57%) human primary papillary thyroid carcinoma (PTC) cases expressed nuclear pY-STAT3 in tumor cells, preferentially in association with the tumor stroma. An inverse relationship between pY-STAT3 expression with tumor size and the presence of distant metastases was observed. Using human thyroid cancer-derived cell lines [harboring rearranged during transfection (RET)/PTC, v-RAF murine sarcoma viral oncogene homolog B (BRAF), or rat sarcoma virus oncogene (RAS) alterations], we determined that IL-6/gp130/JAK signaling is responsible for STAT3 activation. STAT3 knockdown by shRNA in representative thyroid cancer cell lines that express high levels of pY-STAT3 had no effect on in vitro growth. However, xenografted short hairpin STAT3 cells generated larger tumors than control cells. Similarly, STAT3 deficiency in a murine model of BRAFV600E-induced PTC led to thyroid tumors that were more proliferative and larger than those tumors expressing STAT3wt. Genome expression analysis revealed that STAT3 knockdown resulted in the down-regulation of multiple transcripts, including the tumor suppressor insulin-like growth factor binding protein 7. Furthermore, STAT3 knockdown led to an increase in glucose consumption, lactate production, and expression of Hypoxia-inducible factor 1 (HIF1α) target genes, suggesting that STAT3 is a negative regulator of aerobic glycolysis. Our studies show that, in the context of thyroid cancer, STAT3 is paradoxically a negative regulator of tumor growth. These findings suggest that targeting STAT3 in these cancers could enhance tumor size and highlight the complexities of the role of STAT3 in tumorigenesis.
Assuntos
Carcinoma Papilar/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Neoplasias da Glândula Tireoide/metabolismo , Animais , Carcinoma Papilar/secundário , Divisão Celular/fisiologia , Linhagem Celular Tumoral , Receptor gp130 de Citocina/metabolismo , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Camundongos , Camundongos Transgênicos , Transplante de Neoplasias , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Fator de Transcrição STAT3/genética , Neoplasias da Glândula Tireoide/patologia , Transplante Heterólogo , Microambiente Tumoral/fisiologiaRESUMO
Lymphedema (LE) is a morbid disease characterized by chronic limb swelling and adipose deposition. Although it is clear that lymphatic injury is necessary for this pathology, the mechanisms that underlie lymphedema remain unknown. IL-6 is a known regulator of adipose homeostasis in obesity and has been shown to be increased in primary and secondary models of lymphedema. Therefore, the purpose of this study was to determine the role of IL-6 in adipose deposition in lymphedema. The expression of IL-6 was analyzed in clinical tissue specimens and serum from patients with or without LE, as well as in two mouse models of lymphatic injury. In addition, we analyzed IL-6 expression/adipose deposition in mice deficient in CD4(+) cells (CD4KO) or IL-6 expression (IL-6KO) or mice treated with a small molecule inhibitor of IL-6 or CD4 depleting antibodies to determine how IL-6 expression is regulated and the effect of changes in IL-6 expression on adipose deposition after lymphatic injury. Patients with LE and mice treated with lymphatic excision of the tail had significantly elevated tissue and serum expression of IL-6 and its downstream mediator. The expression of IL-6 was associated with adipose deposition and CD4(+) inflammation and was markedly decreased in CD4KO mice. Loss of IL-6 function resulted in significantly increased adipose deposition after tail lymphatic injury. Our findings suggest that IL-6 is increased as a result of adipose deposition and CD4(+) cell inflammation in lymphedema. In addition, our study suggests that IL-6 expression in lymphedema acts to limit adipose accumulation.
Assuntos
Adiposidade/fisiologia , Homeostase/fisiologia , Interleucina-6/fisiologia , Linfedema/fisiopatologia , Tecido Adiposo/patologia , Tecido Adiposo/fisiopatologia , Animais , Biópsia , Linfócitos T CD4-Positivos/patologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-6/deficiência , Interleucina-6/genética , Linfedema/patologia , Tecido Linfoide/lesões , Tecido Linfoide/patologia , Tecido Linfoide/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Lymphedema is a dreaded complication of cancer treatment. However, despite the fact that >5 million Americans are affected by this disorder, the development of effective treatments is limited by the fact that the pathology of lymphedema remains unknown. The purpose of these studies was to determine the role of inflammatory responses in lymphedema pathology. Using mouse models of lymphedema, as well as clinical lymphedema specimens, we show that lymphatic stasis results in a CD4 T-cell inflammation and T-helper 2 (Th2) differentiation. Using mice deficient in T cells or CD4 cells, we show that this inflammatory response is necessary for the pathological changes of lymphedema, including fibrosis, adipose deposition, and lymphatic dysfunction. Further, we show that inhibition of Th2 differentiation using interleukin-4 (IL-4) or IL-13 blockade prevents initiation and progression of lymphedema by decreasing tissue fibrosis and significantly improving lymphatic function, independent of lymphangiogenic growth factors. We show that CD4 inflammation is a critical regulator of tissue fibrosis and lymphatic dysfunction in lymphedema and that inhibition of Th2 differentiation markedly improves lymphatic function independent of lymphangiogenic cytokine expression. Notably, preventing and/or reversing the development of pathological tissue changes that occur in lymphedema may be a viable treatment strategy for this disorder.
Assuntos
Diferenciação Celular/imunologia , Linfedema/imunologia , Células Th2/imunologia , Animais , Modelos Animais de Doenças , Fibrose/genética , Fibrose/imunologia , Fibrose/patologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Linfedema/etiologia , Linfedema/genética , Linfedema/patologia , Camundongos , Camundongos Knockout , Camundongos Nus , Células Th2/patologiaRESUMO
Signal transducer and activator of transcription 3 (STAT3) plays a central role in the activation of multiple oncogenic pathways. Splicing variant STAT3ß uses an alternative acceptor site within exon 23 that leads to a truncated isoform lacking the C-terminal transactivation domain. Depending on the context, STAT3ß can act as a dominant-negative regulator of transcription and promote apoptosis. We show that modified antisense oligonucleotides targeted to a splicing enhancer that regulates STAT3 exon 23 alternative splicing specifically promote a shift of expression from STAT3α to STAT3ß. Induction of endogenous STAT3ß leads to apoptosis and cell-cycle arrest in cell lines with persistent STAT3 tyrosine phosphorylation compared with total STAT3 knockdown obtained by forced splicing-dependent nonsense-mediated decay (FSD-NMD). Comparison of the molecular effects of splicing redirection to STAT3 knockdown reveals a unique STAT3ß signature, with a down-regulation of specific targets (including lens epithelium-derived growth factor, p300/CBP-associated factor, CyclinC, peroxisomal biogenesis factor 1, and STAT1ß) distinct from canonical STAT3 targets typically associated with total STAT3 knockdown. Furthermore, similar in vivo redirection of STAT3 alternative splicing leads to tumor regression in a xenograft cancer model, demonstrating how pharmacological manipulation of a single key splicing event can manifest powerful antitumorigenic properties and validating endogenous splicing reprogramming as an effective cancer therapeutic approach.
Assuntos
Processamento Alternativo/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Animais , Western Blotting , Linhagem Celular , Primers do DNA/genética , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Nus , Análise em Microsséries , Oligonucleotídeos Antissenso/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Extracellular vesicles and particles (EVPs) are pivotal mediators of pre-metastatic niche formation and cancer progression, including induction of vascular permeability, which facilitates tumor cell extravasation and metastasis. However, the mechanisms through which EVPs exert this effect remain poorly understood. Here, we elucidate a novel mechanism by which tumor EVPs enhance endothelial cell permeability, tumor extravasation, and lung metastasis to different degrees, depending on tumor type. Strikingly, vascular leakiness is observed within 48h following tumor implantation and as early as one hour following intravenous injection of tumour-derived EVPs in naïve mice. Surprisingly, rather than acting directly on endothelial cells, EVPs first activate interstitial macrophages (IMs) leading to activation of JAK/STAT signaling and IL-6 secretion in IMs which subsequently promote endothelial permeability. Depletion of IMs significantly reduces tumour-derived EVP-dependent vascular leakiness and metastatic potential. Tumour EVPs that strongly induce vascular leakiness express high levels of ITGα5, and ITGα5 ablation impairs IM activation, cytokine secretion, and subsequently vascular permeability and metastasis. Importantly, IL-6 expression is elevated in IMs from non-involved tumor-adjacent lung tissue compared to distal lung tissue in lung cancer patients, highlight the clinical relevance of our discovery. Our findings identify a key role for IM activation as an initiating step in tumor type-specific EVP-driven vascular permeability and metastasis, offering promising targets for therapeutic intervention.
RESUMO
After disease progression on endocrine therapy (ET) plus a CDK4/6 inhibitor, there is no standardized sequence for subsequent treatment lines for estrogen receptor positive (ER+) metastatic breast cancer (MBC). CDK4/6i retrial as a treatment strategy is commonplace in modern clinical practice; however, the available prospective data investigating this strategy have had inconclusive results. To frame this data in a real-world context, we performed a retrospective analysis assessing the efficacy of CDK4/6is in 195 patients who had previous exposure to CDK4/6i in a prior treatment line at our institution. Among patients who had stopped a CDK4/6i due to toxicity, CDK4/6i retrial either immediately after with a different CDK4/6i or in a further treatment line with the same initial CDK4/6i was both safe and effective, with a median time to treatment failure (TTF) of 10.1 months (95%CI, 4.8-16.9). For patients whose disease progressed on a prior CDK4/6i, we demonstrated comparable median TTFs for patients rechallenged with the same CDK4/6i (4.3 months, 95%CI 3.2-5.5) and with a different CDK4/6i (4.7 months, 95%CI 3.7-6.0) when compared to the recent PACE, PALMIRA, and MAINTAIN trials. Exploratory genomic analysis suggested that the presence of mutations known to confer CDK4/6i resistance, such as TP53 mutations, CDK4 amplifications, and RB1 or FAT1 loss of function mutations may be molecular biomarkers predictive of CDK4/6i retrial failure.