RESUMO
BACKGROUND: Metastatic esophagogastric cancers (EGCs) have a poor prognosis with an approximately 5% 5-year survival. Additional treatment approaches are needed. c-MET gene-amplified tumors are an uncommon but potentially targetable subset of EGC. Clinical characteristics and outcomes were evaluated in patients with MET-amplified EGC and compared with those without MET amplification to facilitate identification of these patients and possible treatment approaches. PATIENTS AND METHODS: Patients with locally advanced or metastatic MET-amplified EGC at Massachusetts General Hospital (MGH) were identified using fluorescent in situ hybridization analysis, with a gene-to-control ratio of ≥2.2 defined as positive. Non-MET-amplified patients identified during the same time period who had undergone tumor genotyping and treatment at MGH were evaluated as a comparison group. RESULTS: We identified 233 patients evaluated for MET amplification from 2002 to 2019. MET amplification was seen in 28 (12%) patients versus 205 (88%) patients without amplification. Most MET-amplified tumors occurred in either the distal esophagus (n = 9; 32%) or gastroesophageal junction (n = 10; 36%). Of MET-amplified patients, 16 (57%) had a TP53 mutation, 5(18%) had HER2 co-amplification, 2 (7.0%) had EGFR co-amplification, and 1 (3.5%) had FGFR2 co-amplification. MET-amplified tumors more frequently had poorly differentiated histology (19/28, 68.0% vs. 66/205, 32%; p = .02). Progression-free survival to initial treatment was substantially shorter for all MET-amplified patients (5.6 vs. 8.8 months, p = .026) and for those with metastatic disease at presentation (4.0 vs. 7.6 months, p = .01). Overall, patients with MET amplification had shorter overall survival (19.3 vs. 24.6 months, p = .049). No difference in survival was seen between low MET-amplified tumors (≥2.2 and <25 MET copy number) compared with highly amplified tumors (≥25 MET copy number). CONCLUSION: MET-amplified EGC represents a distinct clinical entity characterized by rapid progression and short survival. Ideally, the identification of these patients will provide opportunities to participate in clinical trials in an attempt to improve outcomes. IMPLICATIONS FOR PRACTICE: This article describes 233 patients who received MET amplification testing and reports (a) a positivity rate of 12%, similar to the rate of HER2 positivity in this data set; (b) the clinical characteristics of poorly differentiated tumors and nodal metastases; and (c) markedly shorter progression-free survival and overall survival in MET-amplified tumors. Favorable outcomes are reported for patients treated with MET inhibitors. Given the lack of published data in MET-amplified esophagogastric cancers and the urgent clinical importance of identifying patients with MET amplification for MET-directed therapy, this large series is a valuable addition to the literature and will have an impact on future practice.
Assuntos
Neoplasias Esofágicas , Amplificação de Genes , Neoplasias Gástricas , Adulto , Idoso , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Junção Esofagogástrica , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Massachusetts , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-met , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Resultado do TratamentoRESUMO
The Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap-/- mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis. Transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap-/- mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improves Yap deficiency phenotypes, indicating functional importance of glucose-fueled nucleotide biosynthesis. Yap-regulated glut1 expression and glucose uptake are conserved in mammals, suggesting that stimulation of anabolic glucose metabolism is an evolutionarily conserved mechanism by which the Hippo pathway controls organ growth. Together, our results reveal a central role for Hippo signaling in glucose metabolic homeostasis.
Assuntos
Glucose/metabolismo , Fígado/embriologia , Nucleotídeos/biossíntese , Transdução de Sinais/fisiologia , Transativadores/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Animais , Glucose/genética , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Camundongos , Nucleotídeos/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Serina-Treonina Quinase 3 , Transativadores/genética , Proteínas de Sinalização YAP , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaAssuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Receptor de Morte Celular Programada 1/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas Tirosina Quinases/uso terapêutico , Radioterapia Adjuvante , Radioterapia Conformacional , Estudos Retrospectivos , Tórax , Resultado do TratamentoRESUMO
Meningiomas account for approximately one-third of primary central nervous system tumors with a subset that are aggressive and carry significant morbidity and mortality. Treatment of these high-grade meningiomas, classified by the World Health Organization as grade II (atypical) and grade III (anaplastic) meningiomas, typically includes the combination of surgery and radiotherapy. However, current data guiding the timing, dosage, and modality of radiation treatment (RT) has been limited to case series and retrospective studies. Nevertheless, most studies support that radiation therapy reduces recurrence risk and improves overall survival (OS) for patients with high-grade meningiomas. In this review, we examine the evidence for radiation therapy in the management of patients with atypical and anaplastic meningiomas and discuss current ongoing prospective trials that will further elucidate the optimal role of radiotherapy in the treatment of these aggressive tumors.
Assuntos
Neoplasias Meníngeas/radioterapia , Meningioma/radioterapia , Humanos , Neoplasias Meníngeas/patologia , Meningioma/patologia , Gradação de Tumores , Estudos Prospectivos , Radiocirurgia , Estudos RetrospectivosRESUMO
The rapidly growing array of therapeutic options in cancer requires informative biomarkers to guide the rational selection and precision application of appropriate therapies. Circulating biomarkers such as circulating tumor cells have immense potential as noninvasive, serial 'liquid biopsies' that may be more representative of the complete spectrum of a patient's individual malignancy than spatially and temporally restricted tumor biopsies. In this review, we discuss the current state-of-the-art in the isolation and molecular characterization of circulating tumor cells as well as their utility in a wide range of clinical applications such as prognostics, treatment monitoring and identification of novel therapeutic targets and resistance mechanisms to enable real-time adjustments in the clinical management of cancer.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias/diagnóstico , Células Neoplásicas Circulantes/metabolismo , Transição Epitelial-Mesenquimal , Humanos , Metástase Neoplásica , Neoplasias/terapia , Prognóstico , Antígeno Prostático Específico/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêuticoRESUMO
Selenium, an essential micronutrient known for its cancer prevention properties, is incorporated into a class of selenocysteine-containing proteins (selenoproteins). Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LC-MS/MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels.
Assuntos
Carcinogênese/genética , Proteínas de Ligação a DNA/genética , Neoplasias Gastrointestinais/genética , Selenoproteínas/genética , Proteína Supressora de Tumor p53/genética , Animais , Dano ao DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Neoplasias Gastrointestinais/patologia , Regulação Neoplásica da Expressão Gênica , Homeostase , Humanos , Masculino , Oxirredução , Estresse Oxidativo/genética , Selênio/metabolismo , Selenoproteínas/metabolismo , Transcriptoma/genética , Peixe-Zebra/genéticaRESUMO
The Hippo pathway is an important regulator of organ size and tumorigenesis. It is unclear, however, how Hippo signalling provides the cellular building blocks required for rapid growth. Here, we demonstrate that transgenic zebrafish expressing an activated form of the Hippo pathway effector Yap1 (also known as YAP) develop enlarged livers and are prone to liver tumour formation. Transcriptomic and metabolomic profiling identify that Yap1 reprograms glutamine metabolism. Yap1 directly enhances glutamine synthetase (glul) expression and activity, elevating steady-state levels of glutamine and enhancing the relative isotopic enrichment of nitrogen during de novo purine and pyrimidine biosynthesis. Genetic or pharmacological inhibition of GLUL diminishes the isotopic enrichment of nitrogen into nucleotides, suppressing hepatomegaly and the growth of liver cancer cells. Consequently, Yap-driven liver growth is susceptible to nucleotide inhibition. Together, our findings demonstrate that Yap1 integrates the anabolic demands of tissue growth during development and tumorigenesis by reprogramming nitrogen metabolism to stimulate nucleotide biosynthesis.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Transformação Celular Neoplásica/genética , Fígado/crescimento & desenvolvimento , Fosfoproteínas/genética , Transativadores/genética , Proteínas de Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Transformação Celular Neoplásica/patologia , Glutamina/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Fosfoproteínas/metabolismo , Fatores de Transcrição , Proteínas de Sinalização YAP , Peixe-ZebraRESUMO
Liver and pancreatic cancers are amongst the leading causes of cancer death. In recent years, genetic and chemical approaches in zebrafish have elucidated cellular and molecular mechanisms of liver and pancreatic cancer formation and progression. In this chapter, we review the recent approaches and advances in the field to study both hepatocellular carcinomas and pancreatic cancer.