Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
1.
Blood ; 138(10): 871-884, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-33876201

RESUMO

Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a substantial therapeutic challenge. DLBCL can be classified into at least 2 major subtypes (germinal center B cell [GCB]-like and activated B cell [ABC]-like DLBCL), each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad antitumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. As a result of the high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis, particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases. Interestingly, the BCL-2-specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCLs.


Assuntos
Fumarato de Dimetilo/farmacologia , Ferroptose/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/metabolismo , NF-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Camundongos , NF-kappa B/genética , Proteínas de Neoplasias/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
2.
Proc Natl Acad Sci U S A ; 117(42): 26328-26339, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33020261

RESUMO

Dendritic cell (DC) maturation is a prerequisite for the induction of adaptive immune responses against pathogens and cancer. Transcription factor (TF) networks control differential aspects of early DC progenitor versus late-stage DC cell fate decisions. Here, we identified the TF C/EBPß as a key regulator for DC maturation and immunogenic functionality under homeostatic and lymphoma-transformed conditions. Upon cell-specific deletion of C/EBPß in CD11c+MHCIIhi DCs, gene expression profiles of splenic C/EBPß-/- DCs showed a down-regulation of E2F cell cycle target genes and associated proliferation signaling pathways, whereas maturation signatures were enriched. Total splenic DC cell numbers were modestly increased but differentiation into cDC1 and cDC2 subsets were unaltered. The splenic CD11c+MHCIIhiCD64+ DC compartment was also increased, suggesting that C/EBPß deficiency favors the expansion of monocytic-derived DCs. Expression of C/EBPß could be mimicked in LAP/LAP* isoform knockin DCs, whereas the short isoform LIP supported a differentiation program similar to deletion of the full-length TF. In accordance with E2F1 being a negative regulator of DC maturation, C/EBPß-/- bone marrow-derived DCs matured much faster enabling them to activate and polarize T cells stronger. In contrast to a homeostatic condition, lymphoma-exposed DCs exhibited an up-regulation of the E2F transcriptional pathways and an impaired maturation. Pharmacological blockade of C/EBPß/mTOR signaling in human DCs abrogated their protumorigenic function in primary B cell lymphoma cocultures. Thus, C/EBPß plays a unique role in DC maturation and immunostimulatory functionality and emerges as a key factor of the tumor microenvironment that promotes lymphomagenesis.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Células Dendríticas/metabolismo , Animais , Proteína beta Intensificadora de Ligação a CCAAT/fisiologia , Diferenciação Celular , Linhagem Celular , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/metabolismo , Isoformas de Proteínas/genética , Transdução de Sinais , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Microambiente Tumoral/fisiologia
3.
Blood ; 135(2): 121-132, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31794606

RESUMO

Diffuse large B-cell lymphoma (DLBCL) represents the most common adult lymphoma and can be divided into 2 major molecular subtypes: the germinal center B-cell-like and the aggressive activated B-cell-like (ABC) DLBCL. Previous studies suggested that chronic B-cell receptor signaling and increased NF-κB activation contribute to ABC DLBCL survival. Here we show that the activity of the transcription factor NFAT is chronically elevated in both DLBCL subtypes. Surprisingly, NFAT activation is independent of B-cell receptor signaling, but mediated by an increased calcium flux and calcineurin-mediated dephosphorylation of NFAT. Intriguingly, although NFAT is activated in both DLBCL subtypes, long-term calcineurin inhibition with cyclosporin A or FK506, both clinically approved drugs, triggers potent cytotoxicity specifically in ABC DLBCL cells. The antitumor effects of calcineurin inhibitors are associated with the reduced expression of c-Jun, interleukin-6, and interleukin-10, which were identified as NFAT target genes that are particularly important for the survival of ABC DLBCL. Furthermore, calcineurin blockade synergized with BCL-2 and MCL-1 inhibitors in killing ABC DLBCL cells. Collectively, these findings identify constitutive NFAT signaling as a crucial functional driver of ABC DLBCL and highlight calcineurin inhibition as a novel strategy for the treatment of this aggressive lymphoma subtype.


Assuntos
Inibidores de Calcineurina/farmacologia , Calcineurina/química , Cálcio/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Fatores de Transcrição NFATC/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proliferação de Células , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Fatores de Transcrição NFATC/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Células Tumorais Cultivadas
4.
Blood ; 130(3): 310-322, 2017 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-28202458

RESUMO

Activated B-cell-like (ABC) and germinal center B-cell-like diffuse large B-cell lymphoma (DLBCL) represent the 2 major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these 2 subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) α/δ (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor κB signaling, prompting us to combine AZD8835 with the Bruton's tyrosine kinase inhibitor ibrutinib. This combination was synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively, our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Oxidiazóis/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Animais , Apoptose/efeitos dos fármacos , Combinação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Camundongos , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Especificidade de Órgãos , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cancers (Basel) ; 15(8)2023 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-37190302

RESUMO

Multiple myeloma (MM) is an incurable, malignant B cell disorder characterized by frequent relapses and a poor prognosis. Thus, new therapeutic approaches are warranted. The phosphatidylinositol-3-kinase (PI3K) pathway plays a key role in many critical cellular processes, including cell proliferation and survival. Activated PI3K/AKT (protein kinases B)/mTOR (mammalian target of rapamycin) signaling has been identified in MM primary patient samples and cell lines. In this study, the efficacy of PI3K and mTOR inhibitors in various MM cell lines representing three different prognostic subtypes was tested. Whereas MM cell lines were rather resistant to PI3K inhibition, treatment with the mTOR inhibitor temsirolimus decreases the phosphorylation of key molecules in the PI3K pathway in MM cell lines, leading to G0/G1 cell cycle arrest and thus reduced proliferation. Strikingly, the efficacy of temsirolimus was amplified by combining the treatment with the Mitogen-activated protein kinase kinase (MEK) inhibitor trametinib. Our findings provide a scientific rationale for the simultaneous inhibition of mTOR and MEK as a novel strategy for the treatment of MM.

6.
Leukemia ; 37(1): 178-189, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36352190

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease that exhibits constitutive activation of phosphoinositide 3-kinase (PI3K) driven by chronic B-cell receptor signaling or PTEN deficiency. Since pan-PI3K inhibitors cause severe side effects, we investigated the anti-lymphoma efficacy of the specific PI3Kß/δ inhibitor AZD8186. We identified a subset of DLBCL models within activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL that were sensitive to AZD8186 treatment. On the molecular level, PI3Kß/δ inhibition decreased the pro-survival NF-κB and AP-1 activity or led to downregulation of the oncogenic transcription factor MYC. In AZD8186-resistant models, we detected a feedback activation of the PI3K/AKT/mTOR pathway following PI3Kß/δ inhibition, which limited AZD8186 efficacy. The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3Kß/δ inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kß/δ signaling and thus identifies a previously unappreciated role of the PI3Kß isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kß/δ and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.


Assuntos
Linfoma Difuso de Grandes Células B , Fosfatidilinositol 3-Quinases , Humanos , Animais , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Linfoma Difuso de Grandes Células B/patologia , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular Tumoral
7.
Leukemia ; 37(3): 670-679, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36604606

RESUMO

Epstein-Barr virus (EBV) associated diffuse large B-cell lymphoma (DLBCL) represents a rare aggressive B-cell lymphoma subtype characterized by an adverse clinical outcome. EBV infection of lymphoma cells has been associated with different lymphoma subtypes while the precise role of EBV in lymphomagenesis and specific molecular characteristics of these lymphomas remain elusive. To further unravel the biology of EBV associated DLBCL, we present a comprehensive molecular analysis of overall 60 primary EBV positive (EBV+) DLBCLs using targeted sequencing of cancer candidate genes (CCGs) and genome-wide determination of recurrent somatic copy number alterations (SCNAs) in 46 cases, respectively. Applying the LymphGen classifier 2.0, we found that less than 20% of primary EBV + DLBCLs correspond to one of the established molecular DLBCL subtypes underscoring the unique biology of this entity. We have identified recurrent mutations activating the oncogenic JAK-STAT and NOTCH pathways as well as frequent amplifications of 9p24.1 contributing to immune escape by PD-L1 overexpression. Our findings enable further functional preclinical and clinical studies exploring the therapeutic potential of targeting these aberrations in patients with EBV + DLBCL to improve outcome.


Assuntos
Infecções por Vírus Epstein-Barr , Linfoma Difuso de Grandes Células B , Humanos , Herpesvirus Humano 4/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Linfoma Difuso de Grandes Células B/patologia , Mutação
8.
Front Immunol ; 14: 1220558, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37600821

RESUMO

Background: Despite recent advances in the treatment of aggressive lymphomas, a significant fraction of patients still succumbs to their disease. Thus, novel therapies are urgently needed. As the anti-CD20 antibody rituximab and the CD19-targeting antibody tafasitamab share distinct modes of actions, we investigated if dual-targeting of aggressive lymphoma B-cells by combining rituximab and tafasitamab might increase cytotoxic effects. Methods: Antibody single and combination efficacy was determined investigating different modes of action including direct cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in in vitro and in vivo models of aggressive B-cell lymphoma comprising diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Results: Three different sensitivity profiles to antibody monotherapy or combination treatment were observed in in vitro models: while 1/11 cell lines was primarily sensitive to tafasitamab and 2/11 to rituximab, the combination resulted in enhanced cell death in 8/11 cell lines in at least one mode of action. Treatment with either antibody or the combination resulted in decreased expression of the oncogenic transcription factor MYC and inhibition of AKT signaling, which mirrored the cell line-specific sensitivities to direct cytotoxicity. At last, the combination resulted in a synergistic survival benefit in a PBMC-humanized Ramos NOD/SCID mouse model. Conclusion: This study demonstrates that the combination of tafasitamab and rituximab improves efficacy compared to single-agent treatments in models of aggressive B-cell lymphoma in vitro and in vivo.


Assuntos
Linfoma de Burkitt , Linfoma Difuso de Grandes Células B , Camundongos , Animais , Camundongos Endogâmicos NOD , Camundongos SCID , Rituximab/farmacologia , Rituximab/uso terapêutico , Leucócitos Mononucleares , Anticorpos Monoclonais Humanizados , Linfoma de Burkitt/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico
9.
Leukemia ; 37(10): 2058-2065, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37563306

RESUMO

Knowledge on the pathogenesis of FL is mainly based on data derived from advanced/systemic stages of FL (sFL) and only small cohorts of localized FL (lFL) have been characterized intensively so far. Comprehensive analysis with profiling of somatic copy number alterations (SCNA) and whole exome sequencing (WES) was performed in 147 lFL and 122 sFL. Putative targets were analyzed for gene and protein expression. Overall, lFL and sFL, as well as BCL2 translocation-positive (BCL2+) and -negative (BCL2-) FL showed overlapping features in SCNA and mutational profiles. Significant differences between lFL and sFL, however, were detected for SCNA frequencies, e.g., in 18q-gains (14% lFL vs. 36% sFL; p = 0.0003). Although rare in lFL, gains in 18q21 were associated with inferior progression-free survival (PFS). The mutational landscape of lFL and sFL included typical genetic lesions. However, ARID1A mutations were significantly more often detected in sFL (29%) compared to lFL (6%, p = 0.0001). In BCL2 + FL mutations in KMT2D, BCL2, ABL2, IGLL5 and ARID1A were enriched, while STAT6 mutations more frequently occurred in BCL2- FL. Although the landscape of lFL and sFL showed overlapping features, molecular profiling revealed novel insights and identified gains in 18q21 as prognostic marker in lFL.


Assuntos
Linfoma Folicular , Humanos , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Translocação Genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Mutação , Hibridização in Situ Fluorescente
10.
Leukemia ; 36(10): 2479-2487, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35963941

RESUMO

Mantle cell lymphoma (MCL) is a rare, incurable lymphoma subtype characterized by heterogeneous outcomes. To better understand the clinical behavior and response to treatment, predictive biomarkers are needed. Using residual archived material from patients enrolled in the MCL3001 (RAY) study, we performed detailed analyses of gene expression and targeted genetic sequencing. This phase III clinical trial randomized patients with relapsed or refractory MCL to treatment with either ibrutinib or temsirolimus. We confirmed the prognostic capability of the gene expression proliferation assay MCL35 in this cohort treated with novel agents; it outperformed the simplified MCL International Prognostic Index in discriminating patients with different outcomes. Regardless of treatment arm, our data demonstrated that this assay captures the risk conferred by known biological factors, including increased MYC expression, blastoid morphology, aberrations of TP53, and truncated CCND1 3' untranslated region. We showed the negative impact of BIRC3 mutations/deletions on outcomes in this cohort and identified that deletion of chromosome 8p23.3 also negatively impacts survival. Restricted to patients with deletions/alterations in TP53, ibrutinib appeared to abrogate the deleterious impact on outcome. These data illustrate the potential to perform a molecular analysis of predictive biomarkers on routine patient samples that can meaningfully inform clinical practice.


Assuntos
Linfoma de Célula do Manto , Regiões 3' não Traduzidas/genética , Adenina/análogos & derivados , Adulto , Fatores Biológicos/uso terapêutico , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Piperidinas , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Sirolimo/análogos & derivados
11.
Nat Commun ; 13(1): 3881, 2022 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794096

RESUMO

While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While TP53 and CCND3 mutation frequencies are not age related, samples from pediatric patients showed a higher frequency of mutations in ID3, DDX3X, ARID1A and SMARCA4, while several genes such as BCL2 and YY1AP1 are almost exclusively mutated in adult patients. An unbiased analysis reveals a transition of the mutational profile between 25 and 40 years of age. Survival analysis in the pediatric cohort confirms that TP53 mutations are significantly associated with higher incidence of relapse (25 ± 4% versus 6 ± 2%, p-value 0.0002). This identifies a promising molecular marker for relapse incidence in pediatric BL which will be used in future clinical trials.


Assuntos
Linfoma de Burkitt , Adulto , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Proteínas de Ciclo Celular/genética , Criança , DNA Helicases/genética , Genes cdc , Humanos , Mutação , Taxa de Mutação , Recidiva Local de Neoplasia/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética
12.
Nat Commun ; 12(1): 5183, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465776

RESUMO

Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.


Assuntos
Linfoma Plasmablástico/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Amplificação de Genes , Dosagem de Genes , Perfilação da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Janus Quinases/genética , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Linfoma Plasmablástico/metabolismo , Linfoma Plasmablástico/mortalidade , Linfoma Plasmablástico/terapia , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Translocação Genética , Sequenciamento do Exoma , Adulto Jovem
13.
Cancer Res ; 80(6): 1316-1329, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31932457

RESUMO

Tumor-induced remodeling of the microenvironment relies on the formation of blood vessels, which go beyond the regulation of metabolism, shaping a maladapted survival niche for tumor cells. In high-grade B-cell lymphoma, angiogenesis correlates with poor prognosis, but attempts to target established proangiogenic pathways within the vascular niche have been inefficient. Here, we analyzed Myc-driven B-cell lymphoma-induced angiogenesis in mice. A few lymphoma cells were sufficient to activate the angiogenic switch in lymph nodes. A unique morphology of dense microvessels emerged without obvious tip cell guidance and reliance on blood endothelial cell (BEC) proliferation. The transcriptional response of BECs was inflammation independent. Conventional HIF1α or Notch signaling routes prevalent in solid tumors were not activated. Instead, a nonconventional hypersprouting morphology was orchestrated by lymphoma-provided VEGFC and lymphotoxin (LT). Interference with VEGF receptor-3 and LTß receptor signaling pathways abrogated lymphoma angiogenesis, thus revealing targets to block lymphomagenesis. SIGNIFICANCE: In lymphoma, transcriptomes and morphogenic patterns of the vasculature are distinct from processes in inflammation and solid tumors. Instead, LTßR and VEGFR3 signaling gain leading roles and are targets for lymphomagenesis blockade.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/80/6/1316/F1.large.jpg.


Assuntos
Linfoma/patologia , Receptor beta de Linfotoxina/metabolismo , Neovascularização Patológica/patologia , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Biópsia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Indóis/administração & dosagem , Linfonodos/irrigação sanguínea , Linfonodos/patologia , Linfoma/tratamento farmacológico , Linfoma/genética , Linfotoxina-alfa/metabolismo , Camundongos , Camundongos Transgênicos , Naftalenos/administração & dosagem , Naftiridinas/administração & dosagem , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA