RESUMO
BACKGROUND: Breast cancer mortality is principally due to tumor recurrence, which can occur following extended periods of clinical remission that may last decades. While clinical latency has been postulated to reflect the ability of residual tumor cells to persist in a dormant state, this hypothesis remains unproven since little is known about the biology of these cells. Consequently, defining the properties of residual tumor cells is an essential goal with important clinical implications for preventing recurrence and improving cancer outcomes. METHODS: To identify conserved features of residual tumor cells, we modeled minimal residual disease using inducible transgenic mouse models for HER2/neu and Wnt1-driven tumorigenesis that recapitulate cardinal features of human breast cancer progression, as well as human breast cancer cell xenografts subjected to targeted therapy. Fluorescence-activated cell sorting was used to isolate tumor cells from primary tumors, residual lesions following oncogene blockade, and recurrent tumors to analyze gene expression signatures and evaluate tumor-initiating cell properties. RESULTS: We demonstrate that residual tumor cells surviving oncogenic pathway inhibition at both local and distant sites exist in a state of cellular dormancy, despite adequate vascularization and the absence of adaptive immunity, and retain the ability to re-enter the cell cycle and give rise to recurrent tumors after extended latency periods. Compared to primary or recurrent tumor cells, dormant residual tumor cells possess unique features that are conserved across mouse models for human breast cancer driven by different oncogenes, and express a gene signature that is strongly associated with recurrence-free survival in breast cancer patients and similar to that of tumor cells in which dormancy is induced by the microenvironment. Although residual tumor cells in both the HER2/neu and Wnt1 models are enriched for phenotypic features associated with tumor-initiating cells, limiting dilution experiments revealed that residual tumor cells are not enriched for cells capable of giving rise to primary tumors, but are enriched for cells capable of giving rise to recurrent tumors, suggesting that tumor-initiating populations underlying primary tumorigenesis may be distinct from those that give rise to recurrence following therapy. CONCLUSIONS: Residual cancer cells surviving targeted therapy reside in a well-vascularized, desmoplastic microenvironment at both local and distant sites. These cells exist in a state of cellular dormancy that bears little resemblance to primary or recurrent tumor cells, but shares similarities with cells in which dormancy is induced by microenvironmental cues. Our observations suggest that dormancy may be a conserved response to targeted therapy independent of the oncogenic pathway inhibited or properties of the primary tumor, that the mechanisms underlying dormancy at local and distant sites may be related, and that the dormant state represents a potential therapeutic target for preventing cancer recurrence.
Assuntos
Terapia de Alvo Molecular , Neoplasia Residual/patologia , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Terapia de Alvo Molecular/efeitos adversos , Metástase Neoplásica , Recidiva Local de Neoplasia , Neoplasia Residual/irrigação sanguínea , Neoplasia Residual/etiologia , Neoplasia Residual/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Proteína Wnt1/antagonistas & inibidores , Proteína Wnt1/genéticaRESUMO
Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.
Assuntos
Corticosteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Hiperplasia do Linfonodo Gigante/patologia , Hiperplasia do Linfonodo Gigante/terapia , Ensaios Clínicos como Assunto , Estado Terminal/terapia , Gerenciamento Clínico , Medicina Baseada em Evidências , Humanos , Guias de Prática Clínica como AssuntoRESUMO
Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.
Assuntos
Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/etiologia , Herpesvirus Humano 8 , Consenso , Diagnóstico Diferencial , Humanos , Internacionalidade , Guias de Prática Clínica como AssuntoRESUMO
Human Herpesvirus-8 (HHV-8)-negative/idiopathic multicentric Castleman disease (iMCD) is a poorly understood disease involving polyclonal lymphoproliferation with dysmorphic germinal centers, constitutional symptoms, and multi-organ failure. Patients can experience thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly, and normal immunoglobulin levels, - iMCD-TAFRO. Others experience thrombocytosis, milder effusions, and hypergammaglobulinemia, -iMCD-Not Otherwise Specified (iMCD-NOS). Though the etiology is unknown in both subtypes, iMCD symptoms and disease progression are believed to be driven by a cytokine storm, often including interleukin-6 (IL-6). However, approximately two-thirds of patients do not respond to anti-IL-6 therapy; alternative drivers and signaling pathways are not known for anti-IL-6 nonresponders. To identify potential mediators of iMCD pathogenesis, we quantified 1129 proteins in 13 plasma samples from six iMCD patients during flare and remission. The acute phase reactant NPS-PLA2 was the only significantly increased protein (P = .017); chemokines and complement were significantly enriched pathways. Chemokines represented the greatest proportion of upregulated cytokines, suggesting that iMCD involves a chemokine storm. The chemokine CXCL13, which is essential in homing B cells to germinal centers, was the most upregulated cytokine across all patients (log2 fold-change = 3.22). Expression of CXCL13 was also significantly increased in iMCD lymph node germinal centers compared to controls in a stromal meshwork pattern. We observed distinct proteomic profiles between the two iMCD-TAFRO patients, who both failed anti-IL-6-therapy, and the four iMCD-NOS patients, in whom all three treated with anti-IL-6-therapy responded, suggesting that differing mechanisms may exist. This study reveals proteomic differences between flare and remission and the potential to molecularly define iMCD subgroups.
Assuntos
Hiperplasia do Linfonodo Gigante/etiologia , Quimiocinas/metabolismo , Plasma/química , Proteômica/métodos , Adulto , Anticorpos Monoclonais/uso terapêutico , Hiperplasia do Linfonodo Gigante/sangue , Quimiocina CXCL13/metabolismo , Feminino , Humanos , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Regulação para CimaRESUMO
Castleman disease (CD) is a rare and heterogeneous disorder characterized by lymphadenopathy that may occur in a single lymph node (unicentric) or multiple lymph nodes (multicentric), the latter typically occurring secondary to excessive proinflammatory hypercytokinemia. While a cohort of multicentric Castleman disease (MCD) cases are caused by Human Herpes Virus-8 (HHV-8), the etiology of HHV-8 negative, idiopathic MCD (iMCD), remains unknown. Breakthroughs in "omics" technologies that have facilitated the development of precision medicine hold promise for elucidating disease pathogenesis and identifying novel therapies for iMCD. However, in order to leverage precision medicine approaches in rare diseases like CD, stakeholders need to overcome several challenges. To address these challenges, the Castleman Disease Collaborative Network (CDCN) was founded in 2012. In the past 3 years, the CDCN has worked to transform the understanding of the pathogenesis of CD, funded and initiated genomics and proteomics research, and united international experts in a collaborative effort to accelerate progress for CD patients. The CDCN's collaborative structure leverages the tools of precision medicine and serves as a model for both scientific discovery and advancing patient care.
Assuntos
Pesquisa Biomédica/métodos , Hiperplasia do Linfonodo Gigante/diagnóstico , Medicina de Precisão/métodos , Hiperplasia do Linfonodo Gigante/etiologia , Hiperplasia do Linfonodo Gigante/terapia , Comportamento Cooperativo , Humanos , Doenças Raras/diagnóstico , Doenças Raras/etiologia , Doenças Raras/terapia , PesquisaRESUMO
Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti-IL-6 therapy, siltuximab, is the only US Food and Drug Administration-approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8-associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration.
Assuntos
Hiperplasia do Linfonodo Gigante , Herpesvirus Humano 8 , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Humanos , Interleucina-6 , Proteômica , Transdução de Sinais , Estados UnidosRESUMO
Geographically dispersed patients, inconsistent treatment tracking, and limited infrastructure slow research for many orphan diseases. We assess the feasibility of a patient-powered study design to overcome these challenges for Castleman disease, a rare hematologic disorder. Here, we report initial results from the ACCELERATE natural history registry. ACCELERATE includes a traditional physician-reported arm and a patient-powered arm, which enables patients to directly contribute medical data and biospecimens. This study design enables successful enrollment, with the 5-year minimum enrollment goal being met in 2 years. A median of 683 clinical, laboratory, and imaging data elements are captured per patient in the patient-powered arm compared with 37 in the physician-reported arm. These data reveal subgrouping characteristics, identify off-label treatments, support treatment guidelines, and are used in 17 clinical and translational studies. This feasibility study demonstrates that the direct-to-patient design is effective for collecting natural history data and biospecimens, tracking therapies, and providing critical research infrastructure.
Assuntos
Coleta de Dados , Doenças Raras/terapia , Sistema de Registros/estatística & dados numéricos , Projetos de Pesquisa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/terapia , Criança , Pré-Escolar , Coleta de Dados/normas , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Doenças Raras/diagnóstico , Projetos de Pesquisa/normas , Adulto JovemRESUMO
Castleman disease (CD) describes a spectrum of heterogeneous disorders defined by characteristic lymph node histopathology. Enlarged lymph nodes demonstrating CD histopathology can occur in isolation (unicentric CD; UCD) sometimes accompanied by mild symptoms, or at multiple sites (multicentric CD, MCD) with systemic inflammation and cytokine-driven multi-organ dysfunction. The discovery that Kaposi sarcoma herpesvirus/human herpesvirus (HHV)-8 drives MCD in a subset of patients has led to the hypotheses that UCD and MCD patients with negative HHV-8 testing by conventional methods may represent false negatives, or that these cases are driven by another virus, known or unknown. To investigate these hypotheses, the virome capture sequencing for vertebrate viruses (VirCapSeq-VERT) platform was employed to detect RNA transcripts from known and novel viruses in fresh frozen lymph node tissue from CD patients (12 UCD, 11 HHV-8-negative MCD [idiopathic MCD; iMCD], and two HHV-8-positive MCD) and related diseases (three T cell lymphoma and three Hodgkin lymphoma). This assay detected HHV-8 in both HHV-8-positive cases; however, HHV-8 was not found in clinically HHV-8-negative iMCD or UCD cases. Additionally, no novel viruses were discovered, and no single known virus was detected with apparent association to HHV-8-negative CD cases. Herpesviridae family members, notably including Epstein-Barr virus (EBV), were detected in 7 out of 12 UCD and 5 of 11 iMCD cases with apparent correlations with markers of disease severity in iMCD. Analysis of a separate cohort of archival formalin-fixed, paraffin-embedded lymph node tissue by In situ hybridization revealed significantly fewer EBV-positive cells in UCD and iMCD compared to tissue from HHV-8-positive MCD and EBV-associated lymphoproliferative disorder. In an additional cohort, quantitative testing for EBV by PCR in peripheral blood during disease flare did not detect systemic EBV viremia, suggesting detection lymph node tissue is due to occult, local reactivation in UCD and iMCD. This study confirms that HHV-8 is not present in UCD and iMCD patients. Further, it fails to establish a clear association between any single virus, novel or known, and CD in HHV-8-negative cases. Given that distinct forms of CD exist with viral and non-viral etiological drivers, CD should be considered a group of distinct and separate diseases with heterogeneous causes worthy of further study.
Assuntos
Hiperplasia do Linfonodo Gigante/virologia , Herpesvirus Humano 8/isolamento & purificação , Adulto , Idoso , Estudos de Casos e Controles , Hiperplasia do Linfonodo Gigante/etiologia , Hiperplasia do Linfonodo Gigante/patologia , DNA Viral/isolamento & purificação , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Reações Falso-Negativas , Feminino , Genoma Viral , Infecções por Herpesviridae/complicações , Infecções por Herpesviridae/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/patogenicidade , Humanos , Linfonodos/patologia , Linfonodos/virologia , Masculino , Pessoa de Meia-Idade , Viroses/complicações , Viroses/virologiaRESUMO
BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6-blockade refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype. METHODS: We analyzed tissues and blood samples from three IL-6-blockade refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in three iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor, sirolimus. RESULTS: Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months. CONCLUSION: This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904). FUNDING: Castleman's Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute.
Assuntos
Hiperplasia do Linfonodo Gigante , Interleucina-6/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Adolescente , Adulto , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Hiperplasia do Linfonodo Gigante/metabolismo , Hiperplasia do Linfonodo Gigante/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , ProteômicaRESUMO
BACKGROUND: Multicentric Castleman's disease describes a group of poorly understood lymphoproliferative disorders driven by proinflammatory hypercytokinaemia. Patients have heterogeneous clinical features, characteristic lymph node histopathology, and often deadly multiple organ dysfunction. Human herpesvirus 8 (HHV8) causes multicentric Castleman's disease in immunosuppressed patients. The cause of HHV8-negative multicentric Castleman's disease is idiopathic; such cases are called idiopathic multicentric Castleman's disease. An absence of centralised information about idiopathic multicentric Castleman's disease represents a major challenge for clinicians and researchers. We aimed to characterise clinical features of, treatments for, and outcomes of idiopathic multicentric Castleman's disease. METHODS: We did a systematic literature review and searched PubMed, the Cochrane database, and ClinicalTrials.gov from January, 1995, with keywords including "Castleman's disease" and "giant lymph node hyperplasia". Inclusion criteria were pathology-confirmed Castleman's disease in multiple nodes and minimum clinical and treatment information on individual patients. Patients with HHV8 or HIV infection or diseases known to cause Castleman-like histopathology were excluded. FINDINGS: Our search identified 626 (33%) patients with HHV8-negative multicentric Castleman's disease from 1923 cases of multicentric Castleman's disease. 128 patients with idiopathic multicentric Castleman's disease met all inclusion criteria for the systematic review. Furthermore, aggregated data for 127 patients with idiopathic multicentric Castleman's disease were presented from clinical trials, which were excluded from primary analyses because patient-level data were not available. Clinical features of idiopathic multicentric Castleman's disease included multicentric lymphadenopathy (128/128), anaemia (79/91), elevated C-reactive protein (65/79), hypergammaglobulinaemia (63/82), hypoalbuminaemia (57/63), elevated interleukin 6 (57/63), hepatomegaly or splenomegaly (52/67), fever (33/64), oedema, ascites, anasarca, or a combination (29/37), elevated soluble interleukin 2 receptor (20/21), and elevated VEGF (16/20). First-line treatments for idiopathic multicentric Castleman's disease included corticosteroids (47/128 [37%]), cytotoxic chemotherapy (47/128 [37%]), and anti-interleukin 6 therapy (11/128 [9%]). 49 (42%) of 116 patients failed first-line therapy, 2-year survival was 88% (95% CI 81-95; 114 total patients, 12 events, 36 censored), and 27 (22%) of 121 patients died by the end of their observed follow-up (median 29 months [IQR 12-50]). 24 (19%) of 128 patients with idiopathic multicentric Castleman's disease had a diagnosis of a separate malignant disease, significantly higher than the frequency expected in age-matched controls (6%). INTERPRETATION: Our systematic review provides comprehensive information about clinical features, treatment, and outcomes of idiopathic multicentric Castleman's disease, which accounts for at least 33% of all cases of multicentric Castleman's disease. Our findings will assist with prompt recognition, diagnostic criteria development, and effective management of the disease. FUNDING: None.
Assuntos
Hiperplasia do Linfonodo Gigante/fisiopatologia , Hiperplasia do Linfonodo Gigante/terapia , Infecções por HIV , Infecções por Herpesviridae , Herpesvirus Humano 8 , Humanos , Linfonodos/patologiaRESUMO
The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. We observed increased intracellular concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP) in cells harboring MTAP deletions. Furthermore, MTA specifically inhibited PRMT5 enzymatic activity. Administration of either MTA or a small-molecule PRMT5 inhibitor showed a modest preferential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-expressing counterparts. Together, our findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common "passenger" genomic alteration.
Assuntos
Neoplasias/tratamento farmacológico , Proteína-Arginina N-Metiltransferases/metabolismo , Purina-Núcleosídeo Fosforilase/metabolismo , Linhagem Celular Tumoral , Desoxiadenosinas/metabolismo , Desoxiadenosinas/farmacologia , Inibidores Enzimáticos/farmacologia , Deleção de Genes , Humanos , Isoquinolinas/farmacologia , Neoplasias/enzimologia , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/genética , Purina-Núcleosídeo Fosforilase/genética , Pirimidinas/farmacologia , Tionucleosídeos/metabolismo , Tionucleosídeos/farmacologia , Fatores de TranscriçãoRESUMO
UNLABELLED: Breast cancer mortality is principally due to tumor recurrence; however, the molecular mechanisms underlying this process are poorly understood. We now demonstrate that the suppressor of cytokine signaling protein SPSB1 is spontaneously upregulated during mammary tumor recurrence and is both necessary and sufficient to promote tumor recurrence in genetically engineered mouse models. The recurrence-promoting effects of SPSB1 result from its ability to protect cells from apoptosis induced by HER2/neu pathway inhibition or chemotherapy. This, in turn, is attributable to SPSB1 potentiation of c-MET signaling, such that preexisting SPSB1-overexpressing tumor cells are selected for following HER2/neu downregulation. Consistent with this, SPSB1 expression is positively correlated with c-MET activity in human breast cancers and with an increased risk of relapse in patients with breast cancer in a manner that is dependent upon c-MET activity. Our findings define a novel pathway that contributes to breast cancer recurrence and provide the first evidence implicating SPSB proteins in cancer. SIGNIFICANCE: The principal cause of death from breast cancer is recurrence. This study identifies SPSB1 as a critical mediator of breast cancer recurrence, suggests activation of the SPSB1-c-MET pathway as an important mechanism of therapeutic resistance in breast cancers, and emphasizes that pharmacologic targets for recurrence may be unique to this stage of tumor progression.
Assuntos
Neoplasias da Mama/genética , Recidiva Local de Neoplasia/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Supressoras da Sinalização de Citocina/genética , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Mamárias Experimentais , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/metabolismoRESUMO
Most deaths from breast cancer result from tumor recurrence, but mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is downregulated during tumor recurrence and that Par-4 downregulation is necessary and sufficient to promote recurrence. Tumor cells with low Par-4 expression survive therapy by evading a program of Par-4-dependent multinucleation and apoptosis that is otherwise engaged following treatment. Low Par-4 expression is associated with poor response to neoadjuvant chemotherapy and an increased risk of relapse in patients with breast cancer, and Par-4 is downregulated in residual tumor cells that survive neoadjuvant chemotherapy. Our findings identify Par-4-induced multinucleation as a mechanism of cell death in oncogene-addicted cells and establish Par-4 as a negative regulator of breast cancer recurrence.
Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Neoplasias da Mama/etiologia , Recidiva Local de Neoplasia/etiologia , Animais , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Proteínas Quinases Dependentes de Cálcio-Calmodulina/fisiologia , Miosinas Cardíacas/metabolismo , Proteínas Quinases Associadas com Morte Celular , Regulação para Baixo , Feminino , Humanos , Camundongos , Cadeias Leves de Miosina/metabolismo , Fosforilação , Receptor ErbB-2/análise , Proteína Supressora de Tumor p53/fisiologiaAssuntos
Hiperplasia do Linfonodo Gigante/diagnóstico , Doenças Raras , Comportamento Cooperativo , Diagnóstico Diferencial , Progressão da Doença , Humanos , Imuno-Histoquímica , Linfonodos , Imageamento por Ressonância Magnética , Pesquisa , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
In adult tissues, multi-potent progenitor cells are some of the most primitive members of the developmental hierarchies that maintain homeostasis. That progenitors and their more mature progeny share identical genomes, suggests that fate decisions are directed by interactions with extrinsic soluble factors, ECM, and other cells, as well as physical properties of the ECM. To understand regulation of fate decisions, therefore, would require a means of understanding carefully choreographed combinatorial interactions. Here we used microenvironment protein microarrays to functionally identify combinations of cell-extrinsic mammary gland proteins and ECM molecules that imposed specific cell fates on bipotent human mammary progenitor cells. Micropatterned cell culture surfaces were fabricated to distinguish between the instructive effects of cell-cell versus cell-ECM interactions, as well as constellations of signaling molecules; and these were used in conjunction with physiologically relevant 3 dimensional human breast cultures. Both immortalized and primary human breast progenitors were analyzed. We report on the functional ability of those proteins of the mammary gland that maintain quiescence, maintain the progenitor state, and guide progenitor differentiation towards myoepithelial and luminal lineages.