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1.
Gut ; 63(3): 480-93, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23585469

RESUMO

OBJECTIVE: Colorectal cancer (CRC) is a major contributor to cancer mortality and morbidity. LIM kinase 2 (LIMK2) promotes tumour cell invasion and metastasis. The objectives of this study were to determine how LIMK2 expression is associated with CRC progression and patient outcome, and to use genetically modified Drosophila and mice to determine how LIMK2 deletion affects gastrointestinal stem cell regulation and tumour development. DESIGN: LIMK2 expression and activity were measured by immunostaining tumours from CRC-prone mice, human CRC cell lines and 650 human tumours. LIMK knockdown in Drosophila or Limk2 deletion in mice allowed for assessment of their contributions to gastrointestinal stem cell homeostasis and tumour development. RESULTS: LIMK2 expression was reduced in intestinal tumours of cancer-prone mice, as well as in human CRC cell lines and tumours. Reduced LIMK2 expression and substrate phosphorylation were associated with shorter patient survival. Genetic analysis in Drosophila midgut and intestinal epithelial cells isolated from genetically modified mice revealed a conserved role for LIMK2 in constraining gastrointestinal stem cell proliferation. Limk2 deletion increased colon tumour size in a colitis-associated colorectal mouse cancer model. CONCLUSIONS: This study revealed that LIMK2 expression and activity progressively decrease with advancing stage, and supports the hypothesis that there is selective pressure for reduced LIMK2 expression in CRC to relieve negative constraints imposed upon gastrointestinal stem cells.


Assuntos
Biomarcadores Tumorais/metabolismo , Colo/enzimologia , Neoplasias Colorretais/enzimologia , Mucosa Intestinal/enzimologia , Quinases Lim/metabolismo , Células-Tronco Neoplásicas/enzimologia , Animais , Biomarcadores Tumorais/deficiência , Linhagem Celular Tumoral , Proliferação de Células , Colo/patologia , Colo/fisiopatologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/fisiopatologia , Metilação de DNA , Progressão da Doença , Regulação para Baixo , Drosophila melanogaster , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Mucosa Intestinal/patologia , Mucosa Intestinal/fisiopatologia , Quinases Lim/deficiência , Camundongos , Camundongos Knockout , Células-Tronco Neoplásicas/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise Serial de Tecidos
2.
Neuro Oncol ; 26(4): 625-639, 2024 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-37936324

RESUMO

BACKGROUND: Glioblastomas have highly infiltrative growth patterns that contribute to recurrence and poor survival. Despite infiltration being a critical therapeutic target, no clinically useful therapies exist that counter glioblastoma invasion. Here, we report that inhibition of ataxia telangiectasia and Rad 3 related kinase (ATR) reduces invasion of glioblastoma cells through dysregulation of cytoskeletal networks and subsequent integrin trafficking. METHODS: Glioblastoma motility and invasion were assessed in vitro and in vivo in response to ATR inhibition (ATRi) and ATR overexpression using time-lapse microscopy, two orthotopic glioblastoma models, and intravital imaging. Disruption to cytoskeleton networks and endocytic processing were investigated via high-throughput, super-resolution and intravital imaging. RESULTS: High ATR expression was associated with significantly poorer survival in clinical datasets while histological, protein expression, and spatial transcriptomics using glioblastoma tumor specimens revealed higher ATR expression at infiltrative margins. Pharmacological inhibition with two different compounds and RNAi targeting of ATR opposed the invasion of glioblastoma, whereas overexpression of ATR drove migration. Subsequent investigation revealed that cytoskeletal dysregulation reduced macropinocytotic internalization of integrins at growth-cone-like structures, resulting in a tumor microtube retraction defect. The biological relevance and translational potential of these findings were confirmed using two orthotopic in vivo models of glioblastoma and intravital imaging. CONCLUSIONS: We demonstrate a novel role for ATR in determining invasion in glioblastoma cells and propose that pharmacological targeting of ATR could have far-reaching clinical benefits beyond radiosensitization.


Assuntos
Glioblastoma , Humanos , Glioblastoma/patologia , Integrinas/metabolismo , Linhagem Celular Tumoral , Citoesqueleto/metabolismo , Citoesqueleto/patologia , Invasividade Neoplásica , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo
3.
Int J Radiat Oncol Biol Phys ; 112(1): 197-211, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34478832

RESUMO

PURPOSE: Low-dose whole lung radiation therapy (LDLR) has been proposed as a treatment for patients with acute respiratory distress syndrome associated with SARS-CoV-2 infection, and clinical trials are underway. There is an urgent need for preclinical evidence to justify this approach and inform dose, scheduling, and mechanisms of action. METHODS AND MATERIALS: Female C57BL/6 mice were treated with intranasal bleomycin sulfate (7.5 or 11.25 units/kg, day 0) and then exposed to whole lung radiation therapy (0.5, 1.0, or 1.5 Gy, or sham; day 3). Bodyweight was measured daily, and lung tissue was harvested for histology and flow cytometry on day 10. Computed tomography lung imaging was performed before radiation (day 3) and pre-endpoint (day 10). RESULTS: Bleomycin caused pneumonitis of variable severity, which correlated with weight loss. LDLR at 1.0 Gy was associated with a significant increase in the proportion of mice recovering to 98% of initial bodyweight, and a proportion of these mice exhibited less severe histopathologic lung changes. Mice experiencing moderate initial weight loss were more likely to respond to LDLR than those experiencing severe initial weight loss. In addition, LDLR (1.0 Gy) significantly reduced bleomycin-induced increases in interstitial macrophages, CD103+ dendritic cells (DCs), and neutrophil-DC hybrids. Overall, bleomycin-treated mice exhibited significantly higher percentages of nonaerated lung in left than right lungs, and LDLR (1.0 Gy) limited further reductions in aerated lung volume in right but not left lungs. LDLR at 0.5 and 1.5 Gy did not improve bodyweight, flow cytometric, or radiologic readouts of bleomycin-induced pneumonitis. CONCLUSIONS: Our data support the concept that LDLR can ameliorate acute inflammatory lung injury, identify 1.0 Gy as the most effective dose, and provide evidence that it is more effective in the context of moderate than severe pneumonitis. Mechanistically, LDLR at 1.0 Gy significantly suppressed bleomycin-induced accumulation of pulmonary interstitial macrophages, CD103+ DCs, and neutrophil-DC hybrids.


Assuntos
Pneumonia , Radioterapia , Animais , Bleomicina , COVID-19/radioterapia , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/induzido quimicamente , Redução de Peso
4.
Cell Death Differ ; 29(10): 2089-2104, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35473984

RESUMO

Glioblastoma (GBM) is the most prevalent malignant primary brain tumour in adults. GBM typically has a poor prognosis, mainly due to a lack of effective treatment options leading to tumour persistence or recurrence. We investigated the therapeutic potential of targeting anti-apoptotic BCL-2 proteins in GBM. Levels of anti-apoptotic BCL-xL and MCL-1 were consistently increased in GBM compared with non-malignant cells and tissue. Moreover, we found that relative to their differentiated counterparts, patient-derived GBM stem-like cells also displayed higher expression of anti-apoptotic BCL-2 family members. High anti-apoptotic BCL-xL and MCL-1 expression correlated with heightened susceptibility of GBM to BCL-2 family protein-targeting BH3-mimetics. This is indicative of increased apoptotic priming. Indeed, GBM displayed an obligate requirement for MCL-1 expression in both tumour development and maintenance. Investigating this apoptotic sensitivity, we found that sequential inhibition of BCL-xL and MCL-1 led to robust anti-tumour responses in vivo, in the absence of overt toxicity. These data demonstrate that BCL-xL and MCL-1 pro-survival function is a fundamental prerequisite for GBM survival that can be therapeutically exploited by BH3-mimetics.


Assuntos
Glioblastoma , Adulto , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína bcl-X
5.
Biochem Soc Trans ; 38(2): 445-51, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20298200

RESUMO

Understanding how cognitive processes including learning, memory, decision making and ideation are encoded by the genome is a key question in biology. Identification of sets of genes underlying human mental disorders is a path towards this objective. Schizophrenia is a common disease with cognitive symptoms, high heritability and complex genetics. We have identified genes involved with schizophrenia by measuring differences in DNA copy number across the entire genome in 91 schizophrenia cases and 92 controls in the Scottish population. Our data reproduce rare and common variants observed in public domain data from >3000 schizophrenia cases, confirming known disease loci as well as identifying novel loci. We found copy number variants in PDE10A (phosphodiesterase 10A), CYFIP1 [cytoplasmic FMR1 (Fragile X mental retardation 1)-interacting protein 1], K(+) channel genes KCNE1 and KCNE2, the Down's syndrome critical region 1 gene RCAN1 (regulator of calcineurin 1), cell-recognition protein CHL1 (cell adhesion molecule with homology with L1CAM), the transcription factor SP4 (specificity protein 4) and histone deacetylase HDAC9, among others (see http://www.genes2cognition.org/SCZ-CNV). Integrating the function of these many genes into a coherent model of schizophrenia and cognition is a major unanswered challenge.


Assuntos
Variações do Número de Cópias de DNA , Genes , Esquizofrenia/genética , Estudos de Casos e Controles , Cognição/fisiologia , Variações do Número de Cópias de DNA/fisiologia , Análise Mutacional de DNA , Genes/fisiologia , Estudo de Associação Genômica Ampla , Humanos , Estudos de Validação como Assunto
6.
Neuro Oncol ; 22(12): 1840-1850, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-32347934

RESUMO

BACKGROUND: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ. METHODS: Preclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines. RESULTS: Olaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. CONCLUSION: Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.


Assuntos
Glioblastoma , Adulto , Animais , Antineoplásicos Alquilantes/uso terapêutico , Glioblastoma/tratamento farmacológico , Humanos , Camundongos , Ftalazinas/uso terapêutico , Piperazinas , Ratos , Temozolomida/uso terapêutico
7.
Cancer Res ; 78(17): 5060-5071, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29976574

RESUMO

Glioblastoma (GBM) is a lethal primary brain tumor characterized by treatment resistance and inevitable tumor recurrence, both of which are driven by a subpopulation of GBM cancer stem-like cells (GSC) with tumorigenic and self-renewal properties. Despite having broad implications for understanding GSC phenotype, the determinants of upregulated DNA-damage response (DDR) and subsequent radiation resistance in GSC are unknown and represent a significant barrier to developing effective GBM treatments. In this study, we show that constitutive DDR activation and radiation resistance are driven by high levels of DNA replication stress (RS). CD133+ GSC exhibited reduced DNA replication velocity and a higher frequency of stalled replication forks than CD133- non-GSC in vitro; immunofluorescence studies confirmed these observations in a panel of orthotopic xenografts and human GBM specimens. Exposure of non-GSC to low-level exogenous RS generated radiation resistance in vitro, confirming RS as a novel determinant of radiation resistance in tumor cells. GSC exhibited DNA double-strand breaks, which colocalized with "replication factories" and RNA: DNA hybrids. GSC also demonstrated increased expression of long neural genes (>1 Mbp) containing common fragile sites, supporting the hypothesis that replication/transcription collisions are the likely cause of RS in GSC. Targeting RS by combined inhibition of ATR and PARP (CAiPi) provided GSC-specific cytotoxicity and complete abrogation of GSC radiation resistance in vitro These data identify RS as a cancer stem cell-specific target with significant clinical potential.Significance: These findings shed new light on cancer stem cell biology and reveal novel therapeutics with the potential to improve clinical outcomes by overcoming inherent radioresistance in GBM. Cancer Res; 78(17); 5060-71. ©2018 AACR.


Assuntos
Carcinogênese , Glioblastoma/genética , Recidiva Local de Neoplasia/genética , Células-Tronco Neoplásicas , Tolerância a Radiação/genética , Antígeno AC133/genética , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Replicação do DNA/efeitos dos fármacos , Replicação do DNA/efeitos da radiação , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/radioterapia , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
8.
Cancer Res ; 78(22): 6509-6522, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30279244

RESUMO

Glioblastoma (GBM) is an aggressive and incurable primary brain tumor that causes severe neurologic, cognitive, and psychologic symptoms. Symptoms are caused and exacerbated by the infiltrative properties of GBM cells, which enable them to pervade the healthy brain and disrupt normal function. Recent research has indicated that although radiotherapy (RT) remains the most effective component of multimodality therapy for patients with GBM, it can provoke a more infiltrative phenotype in GBM cells that survive treatment. Here, we demonstrate an essential role of the actin-myosin regulatory kinase myotonic dystrophy kinase-related CDC42-binding kinase (MRCK) in mediating the proinvasive effects of radiation. MRCK-mediated invasion occurred via downstream signaling to effector molecules MYPT1 and MLC2. MRCK was activated by clinically relevant doses per fraction of radiation, and this activation was concomitant with an increase in GBM cell motility and invasion. Furthermore, ablation of MRCK activity either by RNAi or by inhibition with the novel small-molecule inhibitor BDP-9066 prevented radiation-driven increases in motility both in vitro and in a clinically relevant orthotopic xenograft model of GBM. Crucially, treatment with BDP-9066 in combination with RT significantly increased survival in this model and markedly reduced infiltration of the contralateral cerebral hemisphere.Significance: An effective new strategy for the treatment of glioblastoma uses a novel, anti-invasive chemotherapeutic to prevent infiltration of the normal brain by glioblastoma cells.Cancer Res; 78(22); 6509-22. ©2018 AACR.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Miotonina Proteína Quinase/antagonistas & inibidores , Actinas/química , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/radioterapia , Miosinas Cardíacas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Feminino , Glioblastoma/radioterapia , Humanos , Camundongos , Camundongos Nus , Microscopia de Fluorescência , Cadeias Leves de Miosina/metabolismo , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Miosinas/química , Invasividade Neoplásica , Fenótipo , Interferência de RNA , RNA Interferente Pequeno/metabolismo
9.
Mol Oncol ; 9(1): 192-203, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25205037

RESUMO

Resistance to radiotherapy in glioblastoma (GBM) is an important clinical problem and several authors have attributed this to a subpopulation of GBM cancer stem cells (CSCs) which may be responsible for tumour recurrence following treatment. It is hypothesised that GBM CSCs exhibit upregulated DNA damage responses and are resistant to radiation but the current literature is conflicting. We investigated radioresistance of primary GBM cells grown in stem cell conditions (CSC) compared to paired differentiated tumour cell populations and explored the radiosensitising effects of the ATM inhibitor KU-55933. We report that GBM CSCs are radioresistant compared to paired differentiated tumour cells as measured by clonogenic assay. GBM CSC's display upregulated phosphorylated DNA damage response proteins and enhanced activation of the G2/M checkpoint following irradiation and repair DNA double strand breaks (DSBs) more efficiently than their differentiated tumour cell counterparts following radiation. Inhibition of ATM kinase by KU-55933 produced potent radiosensitisation of GBM CSCs (sensitiser enhancement ratios 2.6-3.5) and effectively abrogated the enhanced DSB repair proficiency observed in GBM CSCs at 24 h post irradiation. G2/M checkpoint activation was reduced but not abolished by KU-55933 in GBM CSCs. ATM kinase inhibition overcomes radioresistance of GBM CSCs and, in combination with conventional therapy, has potential to improve outcomes for patients with GBM.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Glioblastoma/radioterapia , Morfolinas/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Células-Tronco Neoplásicas/enzimologia , Pironas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Raios gama , Glioblastoma/enzimologia , Glioblastoma/patologia , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos da radiação , Masculino , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/patologia , Tolerância a Radiação/efeitos da radiação , Células Tumorais Cultivadas
10.
Cell Rep ; 6(5): 855-67, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24582964

RESUMO

High tumor burden is associated with increased levels of circulating inflammatory cytokines that influence the pathophysiology of the tumor and its environment. The cellular and molecular events mediating the organismal response to a growing tumor are poorly understood. Here, we report a bidirectional crosstalk between epithelial tumors and the fat body-a peripheral immune tissue-in Drosophila. Tumors trigger a systemic immune response through activation of Eiger/TNF signaling, which leads to Toll pathway upregulation in adipocytes. Reciprocally, Toll elicits a non-tissue-autonomous program in adipocytes, which drives tumor cell death. Hemocytes play a critical role in this system by producing the ligands Spätzle and Eiger, which are required for Toll activation in the fat body and tumor cell death. Altogether, our results provide a paradigm for a long-range tumor suppression function of adipocytes in Drosophila, which may represent an evolutionarily conserved mechanism in the organismal response to solid tumors.


Assuntos
Adipócitos/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Membrana/metabolismo , Receptores Toll-Like/metabolismo , Animais , Apoptose/fisiologia , Carcinogênese/metabolismo , Processos de Crescimento Celular/fisiologia , Drosophila melanogaster , Feminino , Hemócitos/citologia , Hemócitos/metabolismo , Masculino , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
11.
Curr Biol ; 24(11): 1199-211, 2014 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-24814146

RESUMO

BACKGROUND: Enteroendocrine cells populate gastrointestinal tissues and are known to translate local cues into systemic responses through the release of hormones into the bloodstream. RESULTS: Here we report a novel function of enteroendocrine cells acting as local regulators of intestinal stem cell (ISC) proliferation through modulation of the mesenchymal stem cell niche in the Drosophila midgut. This paracrine signaling acts to constrain ISC proliferation within the epithelial compartment. Mechanistically, midgut enteroendocrine cells secrete the neuroendocrine hormone Bursicon, which acts-beyond its known roles in development-as a paracrine factor on the visceral muscle (VM). Bursicon binding to its receptor, DLGR2, the ortholog of mammalian leucine-rich repeat-containing G protein-coupled receptors (LGR4-6), represses the production of the VM-derived EGF-like growth factor Vein through activation of cAMP. CONCLUSIONS: We therefore identify a novel paradigm in the regulation of ISC quiescence involving the conserved ligand/receptor Bursicon/DLGR2 and a previously unrecognized tissue-intrinsic role of enteroendocrine cells.


Assuntos
Drosophila melanogaster/fisiologia , Células Enteroendócrinas/fisiologia , Células-Tronco Mesenquimais/metabolismo , Comunicação Parácrina , Animais , Diferenciação Celular , Proliferação de Células , AMP Cíclico/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Feminino , Regulação da Expressão Gênica , Homeostase , Intestinos/citologia , Intestinos/fisiologia , Hormônios de Invertebrado/genética , Hormônios de Invertebrado/metabolismo , Músculos/metabolismo , Neurregulinas/genética , Neurregulinas/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo
12.
Dev Cell ; 18(6): 999-1011, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20627081

RESUMO

The roles of inflammatory cytokines and the immune response in cancer remain paradoxical. In the case of tumor necrosis factor (TNF), there is undisputed evidence indicating both protumor and antitumor activities. Recent work in Drosophila indicated that a TNF-dependent mechanism eliminates cells deficient for the polarity tumor suppressors dlg or scrib. In this study, however, we show that in tumors deficient for scrib that also expressed the Ras oncoprotein, the TNF signal was diverted into a protumor signal that enhanced tumor growth through larval arrest and stimulated invasive migration. In this case, TNF promoted malignancy and was detrimental to host survival. TNF was expressed at high levels by tumor-associated hemocytes recruited from the circulation. The expression of TNF by hemocytes was both necessary and sufficient to trigger TNF signaling in tumor cells. Our evidence suggests that tumors can evolve into malignancy through oncogenic Ras activation and the hijacking of TNF signaling.


Assuntos
Carcinógenos/metabolismo , Neoplasias/metabolismo , Oncogenes/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas ras/metabolismo , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Regulação Neoplásica da Expressão Gênica/imunologia , Hemócitos/citologia , Hemócitos/imunologia , Hemócitos/metabolismo , Proteínas de Membrana , Invasividade Neoplásica/genética , Invasividade Neoplásica/imunologia , Neoplasias/genética , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/genética , Proteínas Supressoras de Tumor/genética , Proteínas ras/genética
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