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1.
Cell ; 170(5): 875-888.e20, 2017 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-28757253

RESUMO

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis.


Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Elementos Facilitadores Genéticos , Regulação Neoplásica da Expressão Gênica , Fator 3-alfa Nuclear de Hepatócito/genética , Neoplasias Pancreáticas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Epigenômica , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Organoides/metabolismo , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia
2.
J Natl Compr Canc Netw ; 22(7): 438-446, 2024 09.
Artigo em Inglês | MEDLINE | ID: mdl-39236750

RESUMO

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel's recommendations regarding the age at which to initiate screening in average-risk individuals and those with increased risk based on personal history of childhood, adolescent, and young adult cancer.


Assuntos
Neoplasias Colorretais , Detecção Precoce de Câncer , Humanos , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/normas , Detecção Precoce de Câncer/métodos , Programas de Rastreamento/métodos , Programas de Rastreamento/normas
3.
Gastroenterology ; 161(5): 1584-1600, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34245764

RESUMO

BACKGROUND & AIMS: SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was used for therapeutic studies in organoids and patient-derived xenografts. RESULTS: SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in patients with PDAC. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited antitumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine. CONCLUSIONS: Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased noncanonic use of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.


Assuntos
Carcinoma Ductal Pancreático/enzimologia , Metabolismo Energético , Neoplasias Pancreáticas/enzimologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Sirtuínas/deficiência , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Aspartato Aminotransferase Citoplasmática/genética , Aspartato Aminotransferase Citoplasmática/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Progressão da Doença , Metabolismo Energético/efeitos dos fármacos , Ativação Enzimática , Ativadores de Enzimas/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais , Sirtuínas/genética , Carga Tumoral , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
4.
Am J Pathol ; 191(4): 759-771, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33453178

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) manifests aggressive tumor growth and early metastasis. Crucial steps in tumor growth and metastasis are survival, angiogenesis, invasion, and immunosuppression. Our prior research showed that chemokine CXC- receptor-2 (CXCR2) is expressed on endothelial cells, innate immune cells, and fibroblasts, and regulates angiogenesis and immune responses. Here, we examined whether tumor angiogenesis, growth, and metastasis of CXCR2 ligands expressing PDAC cells are regulated in vivo by a host CXCR2-dependent mechanism. C57BL6 Cxcr2-/- mice were generated following crosses between Cxcr2-/+ female and Cxcr2-/- male. Cxcr2 ligands expressing Kirsten rat sarcoma (KRAS-PDAC) cells were orthotopically implanted in the pancreas of wild-type or Cxcr2-/- C57BL6 mice. No significant difference in PDAC tumor growth was observed. Host Cxcr2 loss led to an inhibition in microvessel density in PDAC tumors. Interestingly, an enhanced spontaneous and experimental liver metastasis was observed in Cxcr2-/- mice compared with wild-type mice. Increased metastasis in Cxcr2-/- mice was associated with an increase in extramedullary hematopoiesis and expansion of neutrophils and immature myeloid precursor cells in the spleen of tumor-bearing mice. These data suggest a dynamic role of host CXCR2 axis in regulating tumor immune suppression, tumor growth, and metastasis.


Assuntos
Metástase Neoplásica/patologia , Neoplasias Pancreáticas/patologia , Receptores de Interleucina-8B/imunologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Camundongos , Metástase Neoplásica/imunologia , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Neutrófilos/imunologia , Neoplasias Pancreáticas/imunologia , Microambiente Tumoral/imunologia , Neoplasias Pancreáticas
5.
J Surg Oncol ; 123(8): 1764-1772, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33765336

RESUMO

OBJECTIVES: To evaluate the relationship between stathmin expression and clinical outcome in colorectal cancer (CRC). BACKGROUND: Stathmin is a phosphoprotein involved in the regulation of microtubule dynamics and integration of intracellular signaling pathways. Stathmin has been implicated in the tumorigenesis of several cancers and is a potential therapeutic target. METHODS: Stathmin expression was evaluated in 25 metastatic CRC (mCRC) patients by immunohistochemistry (IHC). Ki67 IHC and TUNEL assay were also evaluated in mCRC for cell proliferation and apoptosis. RESULTS: High expression of stathmin was correlated with CRC metastasis (p = .0084), and significantly worse overall survival (OS) in CRC patients (p = .036). There was a significant increase in cell proliferation and a decrease in apoptosis in liver metastasis compared with CRC primary tumors as determined by Ki67 IHC and TUNEL assay (p < .0001). We also observed a significant positive correlation between stathmin level and cell proliferation in both CRC primary tumor and liver metastasis (p = .0429 to 0.0451; r = .4236 to .4288). CONCLUSION: Stathmin expression correlated with worse patient prognosis in mCRC patients and positively correlated with increased cell proliferation. Together, our findings indicate stathmin as a novel potential marker for increased risk of CRC-specific mortality and identify stathmin as an attractive therapeutic target for the treatment of mCRC.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Estatmina/metabolismo , Adenocarcinoma/mortalidade , Idoso , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Taxa de Sobrevida
6.
J Surg Oncol ; 123(1): 42-51, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33179291

RESUMO

OBJECTIVES: To evaluate the relationship between phosphatase of regenerating liver 3 (PRL3) expression and clinical outcome in colorectal cancer (CRC). BACKGROUND: PRL3, a protein tyrosine phosphatase functions as one of the key regulatory enzymes of various signal transduction pathways. PRL3 is highly expressed in a majority of cancers and is a novel potential therapeutic target. METHODS: PRL3 expression was evaluated by immunohistochemistry in 167 patients with CRC, 37 patients with no disease, and 26 patients with metastatic CRC (mCRC). Phosphorylated Akt at serine 473 (p-Akt S473) expression was also evaluated by immunohistochemistry in mCRC patients. RESULTS: High expression of PRL3 was correlated with CRC progression, and every one unit increase in PRL3 level contributed to an increase in the rate of death by 1%-1.7%. PRL3 expression was significantly higher in liver metastases compared with primary tumors and showed a significant positive correlation with the expression level of p-Akt S473. CONCLUSION: PRL3 expression levels associated with CRC progression and metastasis, and positively correlated with activated Akt level in mCRC. Together, these findings indicated that PRL3 might be a potential marker for increased risk of CRC-specific tumor burden and identify PRL3 as an attractive therapeutic target for mCRC treatment.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células em Anel de Sinete/patologia , Neoplasias Colorretais/patologia , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/patologia , Proteínas Tirosina Fosfatases/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Idoso , Carcinoma de Células em Anel de Sinete/metabolismo , Carcinoma de Células em Anel de Sinete/terapia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/terapia , Terapia Combinada , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/terapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
7.
J Natl Compr Canc Netw ; 18(10): 1312-1320, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33022639

RESUMO

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel's recommendations regarding the age to initiate screening in average risk individuals and follow-up for low-risk adenomas.


Assuntos
Neoplasias Colorretais , Detecção Precoce de Câncer , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Humanos , Programas de Rastreamento
8.
J Surg Oncol ; 121(3): 547-560, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31867736

RESUMO

BACKGROUND: Na+ /H+ exchanger regulatory factor 1 (NHERF1) has been implicated in the tumorigenesis of several cancer types and is a potential therapeutic target. The current study evaluated the relationship between NHERF1 expression and clinical outcome in colorectal cancer (CRC). METHODS: NHERF1 expression was evaluated by immunohistochemistry in 167 patients with CRC primary tumors, 37 patients with no disease, and 27 patients with metastatic CRC (mCRC); and in the orthotopically implanted tumors in mice. NHERF1 expression was manipulated in CRC cells using inducible short hairpin RNAs to determine its biological functions. RESULTS: High expression of NHERF1 correlated with CRC progression and metastasis, as well as significantly worse overall survival, recurrence-free survival, and disease-specific survival. Orthotopic implantation studies demonstrated increased NHERF1 expression in liver metastases. Treatment of CRC xenografts with insulin-like growth factor 1 receptor (IGF1R) inhibitors downregulated NHERF1 expression, indicating NHERF1 is downstream of IGF1R signaling. Knockdown of NHERF1 increased apoptosis and reduced X-linked inhibitor of apoptosis protein (XIAP) and survivin expression, indicating NHERF1 is critical for CRC cell survival. CONCLUSION: NHERF1 expression levels correlated with worse prognosis in patients with CRC and plays a critical role in CRC cell survival. Together, our findings establish NHERF1 as a novel potential marker for increased risk of CRC-specific mortality and identify NHERF1 as an attractive therapeutic target for mCRC treatment.


Assuntos
Neoplasias Colorretais/metabolismo , Fosfoproteínas/biossíntese , Trocadores de Sódio-Hidrogênio/biossíntese , Idoso , Animais , Biomarcadores Tumorais/biossíntese , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Células HCT116 , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Taxa de Sobrevida
9.
J Natl Compr Canc Netw ; 17(9): 1032-1041, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31487681

RESUMO

Identifying individuals with hereditary syndromes allows for improved cancer surveillance, risk reduction, and optimized management. Establishing criteria for assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the assessment and management of patients with high-risk colorectal cancer syndromes. These NCCN Guidelines Insights focus on criteria for the evaluation of Lynch syndrome and considerations for use of multigene testing in the assessment of hereditary colorectal cancer syndromes.


Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/terapia , Neoplasias Colorretais/terapia , Diagnóstico Diferencial , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Medição de Risco
10.
J Natl Compr Canc Netw ; 16(8): 939-949, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30099370

RESUMO

The NCCN Guidelines for Colorectal Cancer (CRC) Screening outline various screening modalities as well as recommended screening strategies for individuals at average or increased-risk of developing sporadic CRC. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize 2018 updates to the NCCN Guidelines, with a primary focus on modalities used to screen individuals at average-risk for CRC.


Assuntos
Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/estatística & dados numéricos , Programas de Rastreamento/normas , Oncologia/normas , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/isolamento & purificação , Colonoscopia/métodos , Colonoscopia/normas , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Detecção Precoce de Câncer/métodos , Fezes/química , Humanos , Imunoquímica/métodos , Imunoquímica/normas , Programas de Rastreamento/métodos , Oncologia/métodos , Pessoa de Meia-Idade , Sangue Oculto , Ensaios Clínicos Controlados Aleatórios como Assunto , Septinas/genética , Sociedades Médicas/normas , Fatores de Tempo , Tomografia Computadorizada por Raios X/métodos , Tomografia Computadorizada por Raios X/normas , Estados Unidos
11.
J Biol Chem ; 291(44): 23208-23223, 2016 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-27605668

RESUMO

Pancreatic ductal adenocarcinomas are highly malignant cancers characterized by extensive invasion into surrounding tissues, metastasis to distant organs, and a limited response to therapy. A main feature of pancreatic ductal adenocarcinomas is desmoplasia, which leads to extensive deposition of collagen I. We have demonstrated that collagen I can induce epithelial-mesenchymal transition (EMT) in pancreatic cancer cells. A hallmark of EMT is an increase in the expression of the mesenchymal cadherin N-cadherin. Previously we showed up-regulation of N-cadherin promotes tumor cell invasion and that collagen I-induced EMT is mediated by two collagen receptors, α2ß1-integrin and discoidin domain receptor 1 (DDR1). DDR1 is a receptor-tyrosine kinase widely expressed during embryonic development and in many adult tissues and is also highly expressed in many different cancers. In the signaling pathway initiated by collagen, we have shown proline-rich tyrosine kinase 2 (Pyk2) is downstream of DDR1. In this study we found isoform b of DDR1 is responsible for collagen I-induced up-regulation of N-cadherin and tyrosine 513 of DDR1b is necessary. Knocking down Shc1, which binds to tyrosine 513 of DDR1b via its PTB (phosphotyrosine binding) domain, eliminates the up-regulation of N-cadherin. The signaling does not require a functional SH2 domain or the tyrosine residues commonly phosphorylated in Shc1 but is mediated by the interaction between a short segment of the central domain of Shc1 and the proline-rich region of Pyk2. Taken together, these data illustrate DDR1b, but not DDR1a, mediates collagen I-induced N-cadherin up-regulation, and Shc1 is involved in this process by coupling to both DDR1 and Pyk2.


Assuntos
Caderinas/genética , Carcinoma Ductal Pancreático/metabolismo , Colágeno Tipo I/metabolismo , Receptor com Domínio Discoidina 1/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , Caderinas/metabolismo , Carcinoma Ductal Pancreático/enzimologia , Carcinoma Ductal Pancreático/genética , Colágeno Tipo I/genética , Receptor com Domínio Discoidina 1/química , Receptor com Domínio Discoidina 1/genética , Humanos , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/química , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética , Ativação Transcricional , Regulação para Cima
12.
J Natl Compr Canc Netw ; 15(12): 1465-1475, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29223984

RESUMO

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the management of patients with high-risk syndromes associated with an increased risk of colorectal cancer (CRC). The NCCN Panel for Genetic/Familial High-Risk Assessment: Colorectal meets at least annually to assess comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. These NCCN Guidelines Insights focus on genes newly associated with CRC risk on multigene panels, the associated evidence, and currently recommended management strategies.


Assuntos
Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Genética , Humanos , Medição de Risco/métodos , Fatores de Risco
13.
J Natl Compr Canc Netw ; 14(8): 1010-30, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27496117

RESUMO

This is a focused update highlighting the most current NCCN Guidelines for diagnosis and management of Lynch syndrome. Lynch syndrome is the most common cause of hereditary colorectal cancer, usually resulting from a germline mutation in 1 of 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2), or deletions in the EPCAM promoter. Patients with Lynch syndrome are at an increased lifetime risk, compared with the general population, for colorectal cancer, endometrial cancer, and other cancers, including of the stomach and ovary. As of 2016, the panel recommends screening all patients with colorectal cancer for Lynch syndrome and provides recommendations for surveillance for early detection and prevention of Lynch syndrome-associated cancers.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Gerenciamento Clínico , Detecção Precoce de Câncer/métodos , Mutação em Linhagem Germinativa , Humanos , Vigilância da População , Medição de Risco
14.
J Natl Compr Canc Netw ; 13(8): 959-68; quiz 968, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26285241

RESUMO

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colorectal Cancer Screening provide recommendations for selecting individuals for colorectal cancer screening, and for evaluation and follow-up of colon polyps. These NCCN Guidelines Insights summarize major discussion points of the 2015 NCCN Colorectal Cancer Screening panel meeting. Major discussion topics this year were the state of evidence for CT colonography and stool DNA testing, bowel preparation procedures for colonoscopy, and guidelines for patients with a positive family history of colorectal cancer.


Assuntos
Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer , Neoplasias Colorretais/mortalidade , Detecção Precoce de Câncer/métodos , Humanos , Fatores de Risco
15.
Adv Sci (Weinh) ; 11(6): e2308537, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38110836

RESUMO

Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, it is reported that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating roles in the activation of MAPK pathways and the acquisition of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. The findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.


Assuntos
Carcinoma Ductal Pancreático , Proteínas de Homeodomínio , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/genética , Regulação da Expressão Gênica , Neoplasias Pancreáticas/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo
16.
Nat Cell Biol ; 26(4): 613-627, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38429478

RESUMO

The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Pancreáticas , Animais , Camundongos , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Acetatos/farmacologia , Acetatos/metabolismo , Neoplasias Pancreáticas/genética , Poliaminas , Microambiente Tumoral
17.
Mod Pathol ; 26(6): 881-7, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23348901

RESUMO

The aim of this study is to examine the clinical and pathologic characteristics of collagenous colitis (CC) in children and adolescents. Seven patients (five females and two males, median age: 13 years, ranging from 4 to 16) were included. Four (of 7, 57%) patients presented with non-bloody watery diarrhea, one with alternating constipation and diarrhea with rectal prolapse, one with constipation, and one with normal bowel movement. Abdominal pain and weight loss were manifested in 80 and 40% patients, respectively. Two patients had celiac disease in remission. None of the patients took non-steroidal antiinflammatory agents. All patients had normal colonoscopy, but had typical histologic features of CC in colon biopsies. Four patients had clinical follow-up (24-75 months duration, median 54 months): three patients had no gastrointestinal symptoms upon follow-up, but one patient had continued symptoms of alternating diarrhea and constipation. Two patients had follow-up biopsies: one showed persistence of CC, and one had complete histologic resolution. We conclude that while CC is rare in children and adolescents, the clinical presentation is similar to adults, with a female preponderance, presentation with diarrhea and abdominal pain, and an association with celiac disease and other autoimmune disorders. However, compared with adults, children and adolescents are more likely to have weight loss and an atypical presentation including alternating constipation and diarrhea, constipation alone or normal bowel movements. Treatment is less standardized in children and adolescents with CC.


Assuntos
Colite Colagenosa/patologia , Colo/patologia , Adolescente , Fatores Etários , Anti-Inflamatórios/uso terapêutico , Biópsia , Criança , Pré-Escolar , Colite Colagenosa/complicações , Colite Colagenosa/tratamento farmacológico , Colo/diagnóstico por imagem , Colo/efeitos dos fármacos , Colonoscopia , Feminino , Fármacos Gastrointestinais/uso terapêutico , Humanos , Masculino , Valor Preditivo dos Testes , Radiografia Abdominal , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento
18.
J Natl Compr Canc Netw ; 11(12): 1538-75, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24335688

RESUMO

Mortality from colorectal cancer can be reduced by early diagnosis and by cancer prevention through polypectomy. These NCCN Guidelines for Colorectal Cancer Screening describe various colorectal screening modalities and recommended screening schedules for patients at average or increased risk of developing colorectal cancer. In addition, the guidelines provide recommendations for the management of patients with high-risk colorectal cancer syndromes, including Lynch syndrome. Screening approaches for Lynch syndrome are also described.


Assuntos
Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Detecção Precoce de Câncer/métodos , Humanos
19.
Dis Model Mech ; 16(1)2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36579622

RESUMO

The 5-year survival of pancreatic cancer (PC) remains low. Murine models may not adequately mimic human PC and can be too small for medical device development. A large-animal PC model could address these issues. We induced and characterized pancreatic tumors in Oncopigs (transgenic swine containing KRASG12D and TP53R167H). The oncopigs underwent injection of adenovirus expressing Cre recombinase (AdCre) into one of the main pancreatic ducts. Resultant tumors were characterized by histology, cytokine expression, exome sequencing and transcriptome analysis. Ten of 14 Oncopigs (71%) had gross tumor within 3 weeks. At necropsy, all of these subjects had gastric outlet obstruction secondary to pancreatic tumor and phlegmon. Oncopigs with injections without Cre recombinase and wild-type pigs with AdCre injection did not show notable effect. Exome and transcriptome analysis of the porcine pancreatic tumors revealed similarity to the molecular signatures and pathways of human PC. Although further optimization and validation of this porcine PC model would be beneficial, it is anticipated that this model will be useful for focused research and development of diagnostic and therapeutic technologies for PC. This article has an associated First Person interview with the joint first authors of the paper.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Camundongos , Humanos , Suínos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Neoplasias Pancreáticas/patologia , Animais Geneticamente Modificados , Perfilação da Expressão Gênica , Carcinoma Ductal Pancreático/patologia , Proteína Supressora de Tumor p53 , Neoplasias Pancreáticas
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