RESUMEN
The huge cadre of genes regulated by Myc has obstructed the identification of critical effectors that are essential for Myc-driven tumorigenesis. Here, we describe how only the lack of the receptor Fzd9, previously identified as a Myc transcriptional target, impairs sustained tumor expansion and ß-cell dedifferentiation in a mouse model of Myc-driven insulinoma, allows pancreatic islets to maintain their physiological structure and affects Myc-related global gene expression. Importantly, Wnt signaling inhibition in Fzd9-competent mice largely recapitulates the suppression of proliferation caused by Fzd9 deficiency upon Myc activation. Together, our results indicate that the Wnt signaling receptor Fzd9 is essential for Myc-induced tumorigenesis in pancreatic islets.
Asunto(s)
Adenoma de Células de los Islotes Pancreáticos/fisiopatología , Carcinogénesis/metabolismo , Receptores Frizzled/metabolismo , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Animales , Movimiento Celular , Proliferación Celular , Femenino , Receptores Frizzled/genética , Receptores Frizzled/fisiología , Genes myc/genética , Genes myc/fisiología , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Vía de Señalización Wnt/genética , Vía de Señalización Wnt/fisiología , beta Catenina/metabolismoRESUMEN
The cellular origin of sporadic pancreatic neuroendocrine tumors (PNETs) is obscure. Hormone expression suggests that these tumors arise from glucagon-producing alpha cells or insulin-producing ß cells, but instability in hormone expression prevents linage determination. We utilize loss of hepatic glucagon receptor (GCGR) signaling to drive alpha cell hyperproliferation and tumor formation to identify a cell of origin and dissect mechanisms that drive progression. Using a combination of genetically engineered Gcgr knockout mice and GCGR-inhibiting antibodies, we show that elevated plasma amino acids drive the appearance of a proliferative population of SLC38A5+ embryonic progenitor-like alpha cells in mice. Further, we characterize tumors from patients with rare bi-allelic germline GCGR loss-of-function variants and find prominent tumor-cell-associated expression of the SLC38A5 paralog SLC7A8 as well as markers of active mTOR signaling. Thus, progenitor cells arise from adult alpha cells in response to metabolic signals and, when inductive signals are chronically present, drive tumor initiation.
Asunto(s)
Aminoácidos/sangre , Células Secretoras de Glucagón/metabolismo , Células Secretoras de Glucagón/patología , Tumores Neuroendocrinos/sangre , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/patología , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Adenoma de Células de los Islotes Pancreáticos/patología , Animales , Glucemia/metabolismo , Femenino , Glucagón/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Glucosa/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Tumores Neuroendocrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores de Glucagón/metabolismo , Transducción de Señal/fisiologíaRESUMEN
OBJECTIVES: Pancreatic cancer (PC) is a lethal malignancy that lacks specific diagnostic markers. The present study explores the diagnostic potential of the most differentially overexpressed secretory mucin MUC5AC alone and in combination with CA19-9 using multi-center training and validation sets. METHODS: The expression of MUC5AC in benign pancreatic pathologies, PC precursor lesions, primary PC tissues and metastatic lesions was evaluated by immunohistochemistry. Circulating MUC5AC levels were measured using sandwich ELISA assay developed in-house, and CA19-9 was measured using radioimmunoassay. A combined training set (n=346) was used to evaluate the diagnostic (n=241) and predictive (n=105, total samples 201 from pre- and post-surgical and chemotherapy set) significance of MUC5AC. Results were further validated with a pre-defined cut-off value using independent sets from the Mayo Clinic (n=94) and the University of Pittsburgh Medical Center (n=321). RESULTS: Tissue expression analyses indicated the de novo expression of MUC5AC in pancreatic intraepithelial precursor lesions 1A (PanIN1A); the expression was maintained through all stages of progression to invasive adenocarcinoma. The median circulating MUC5AC levels in patients with resectable early-stage PC (EPC) (stage 1/2; 67.2 ng/ml, IQR: 23.9-382.1) and unresectable late-stage PC (LPC) (stage 3/4; 389.7 ng/ml, IQR: 87.7-948.6) were significantly higher compared with (P-value ≤0.0001) benign controls (BC) (7.2 ng/ml, IQR: 0.4-26.5) and (P-value ≤0.0001) chronic pancreatitis (CP) controls (8.4 ng/ml, IQR: 1.5-19.2). In the diagnostic training set (n=241), MUC5AC efficiently differentiated EPC from healthy controls (HC) (83%/80% sensitive (SN)/specific (SP)), BC (67%/87% SN/SP), and CP (83%/77% SN/SP). Independent validation sets from the Mayo Clinic and UPMC confirmed the diagnostic potential of MUC5AC to differentiate EPC from BC (68%/73%; 65%/83%) and CP (68%/79%; 65%/72%). Furthermore, MUC5AC and CA19-9 combination significantly improved (p-value < 0.001) the diagnostic accuracy for differentiating resectable cases from controls. CONCLUSIONS: MUC5AC is a valuable diagnostic biomarker, either alone or in combination with CA19-9, to differentiate PC from CP and benign controls.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Antígeno CA-19-9/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Mucina 5AC/metabolismo , Neoplasias Pancreáticas/metabolismo , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunohistoquímica , Análisis Multivariante , Neoplasias Pancreáticas/diagnóstico , Pancreatitis Crónica/metabolismo , Radioinmunoensayo , Sensibilidad y EspecificidadRESUMEN
Insulin-like growth factor type II (IGF-II) is the main cause of non-islet cell tumour hypoglycaemia (NICTH) and insulin is thought to be the only factor causing hypoglycaemia in insulinomas. However, two case reports of pancreatic neuroendocrine tumours (PNETs) producing IGF-II have been previously published: a human and a canine patient. In this study, we investigated clinical, histopathological, immunohistochemical and ultrastructural features, and biological behaviour of canine pancreatic IGF-II-omas, a subgroup of PNETs that has not been previously characterized. Case records of 58 dogs with confirmed PNETs and hypoglycaemia were reviewed: six patients were affected by IGF-II-omas. Surgery was performed in all cases and two dogs had metastases. Four patients remained alive and in remission at 370, 440, 560 and 890 days post-diagnosis; two died of non-tumour-related causes. IGF-II-omas can be differentiated from insulinomas through hypoinsulinaemia, IGF-II positive and insulin negative immunostaining. The prevalence of this neoplasia is low, accounting for just 6% of PNETs.
Asunto(s)
Adenoma de Células de los Islotes Pancreáticos/veterinaria , Enfermedades de los Perros/metabolismo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Neoplasias Pancreáticas/veterinaria , Adenoma de Células de los Islotes Pancreáticos/genética , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Animales , Enfermedades de los Perros/genética , Perros , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Factor II del Crecimiento Similar a la Insulina/genética , Masculino , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Estudios RetrospectivosRESUMEN
Accurate visualization and quantification of ß-cell mass is critical for the improved understanding, diagnosis, and treatment of both type 1 diabetes (T1D) and insulinoma. Here, we describe the synthesis of a bimodal imaging probe (PET/fluorescence) for imaging GLP-1R expression in the pancreas and in pancreatic islet cell tumors. The conjugation of a bimodal imaging tag containing a near-infrared fluorescent dye, and the copper chelator sarcophagine to the GLP-1R targeting peptide exendin-4 provided the basis for the bimodal imaging probe. Conjugation was performed via a novel sequential one-pot synthetic procedure including (64)Cu radiolabeling and copper-catalyzed click-conjugation. The bimodal imaging agent (64)Cu-E4-Fl was synthesized in good radiochemical yield and specific activity (RCY = 36%, specific activity: 141 µCi/µg, >98% radiochemical purity). The agent showed good performance in vivo and ex vivo, visualizing small xenografts (<2 mm) with PET and pancreatic ß-cell mass by phosphor autoradiography. Using the fluorescent properties of the probe, we were able to detect individual pancreatic islets, confirming specific binding to GLP-1R and surpassing the sensitivity of the radioactive label. The use of bimodal PET/fluorescent imaging probes is promising for preoperative imaging and fluorescence-assisted analysis of patient tissues. We believe that our procedure could become relevant as a protocol for the development of bimodal imaging agents.
Asunto(s)
Adenoma de Células de los Islotes Pancreáticos/metabolismo , Radioisótopos de Cobre , Imagen Multimodal/métodos , Imagen Óptica/métodos , Páncreas/metabolismo , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Receptores de Glucagón/metabolismo , Adenoma de Células de los Islotes Pancreáticos/diagnóstico por imagen , Adenoma de Células de los Islotes Pancreáticos/tratamiento farmacológico , Secuencia de Aminoácidos , Animales , Rastreo Celular/métodos , Células Cultivadas , Exenatida , Femenino , Técnica del Anticuerpo Fluorescente , Receptor del Péptido 1 Similar al Glucagón , Humanos , Hipoglucemiantes/administración & dosificación , Ratones , Ratones Desnudos , Datos de Secuencia Molecular , Páncreas/diagnóstico por imagen , Páncreas/efectos de los fármacos , Péptidos/administración & dosificación , Receptores de Glucagón/análisis , Ponzoñas/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Foregut neuroendocrine tumors [NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor (EGFR) by growth factors, gastrointestinal (GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid,BON, the somatostatinoma QGP-1 and the rat islet tumor,Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr(1068) EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs.
Asunto(s)
Adenoma de Células de los Islotes Pancreáticos/patología , Proliferación Celular/efectos de los fármacos , Receptores ErbB/metabolismo , Hormonas Gastrointestinales/farmacología , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/patología , Somatostatinoma/patología , Adenoma de Células de los Islotes Pancreáticos/tratamiento farmacológico , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Animales , Western Blotting , Factor de Crecimiento Epidérmico/farmacología , Humanos , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Somatostatinoma/tratamiento farmacológico , Somatostatinoma/metabolismo , Activación Transcripcional , Factor de Crecimiento Transformador alfa/farmacología , Células Tumorales Cultivadas , Tirosina/metabolismoRESUMEN
CONTEXT: Glucagon-like peptide-1 (GLP-1) is a gut peptide that promotes insulin release from pancreatic ß-cells and stimulates ß-cell hyperplasia. GLP-1 secretion causing hypoglycemia has been described once from an ovarian neuroendocrine tumor (NET) but has not been reported from a pancreatic NET (pNET). OBJECTIVE: A 56-yr-old male with a previous diagnosis of diabetes presented with fasting hypoglycemia and was found to have a metastatic pNET secreting glucagon. Neither the primary tumor nor metastases stained for insulin, whereas the resected normal pancreas showed histological evidence of islet cell hyperplasia. We provide evidence that GLP-1 secretion from the tumor was the cause of hyperinsulinemic hypoglycemia. METHODS: GLP-1 levels were determined in the patient, and immunohistochemistry for GLP-1 was performed on the tumor metastases. Ex vivo tissue culture and a bioassay constructed by transplantation of tumor into nude mice were performed to examine the tumor secretory products and their effects on islet cell function. RESULTS: The patient had high levels of glucagon and GLP-1 with an exaggerated GLP-1 response to oral glucose. Immunohistochemistry and primary tissue culture demonstrated secretion of glucagon and GLP-1 from the tumor metastases, whereas insulin secretion was almost undetectable. Ex vivo coculture of the tumor with normal human islets resulted in inhibition of insulin release, and transplanted mice developed impaired glucose tolerance. CONCLUSIONS: This is the first description of glucagon and GLP-1 secretion from a metastatic pNET causing sequential diabetes and hypoglycemia. Hypoglycemia was caused by insulin secretion from hyperplastic ß-cells stimulated by tumor-derived GLP-1.
Asunto(s)
Diabetes Mellitus/etiología , Péptido 1 Similar al Glucagón/sangre , Hiperinsulinismo/etiología , Hipoglucemia/etiología , Tumores Neuroendocrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Adenoma de Células de los Islotes Pancreáticos/complicaciones , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Adenoma de Células de los Islotes Pancreáticos/cirugía , Animales , Células Cultivadas , Glucagón/sangre , Hepatectomía , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Tumores Neuroendocrinos/complicaciones , Tumores Neuroendocrinos/cirugía , Pancreatectomía , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/cirugía , Reacción en Cadena en Tiempo Real de la Polimerasa , EsplenectomíaRESUMEN
BACKGROUND: This study was designed to evaluate the role of the hedgehog pathway in tumor progression of murine islet cell tumors. Blockade of aberrant hedgehog activation has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with a new orally bioavailable Smoothened (Smo) antagonist LDE225 have not been examined. MATERIAL AND METHODS: To assess in vivo effects, transgenic Rip1Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or LDE225 (80 mg/kg/d) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by iummohistochemsistry. Quantitative real-time polymerase chain reaction was performed for hedgehog target genes with RNA from islet, isolated from treated and untreated Rip1Tag2 mice. RESULTS: LDE225 significantly reduced tumor volume by 95% compared with untreated control mice. Hedgehog inhibition with LDE225 significantly prolonged median survival in the used transgenic mouse model (105 vs 116 days; P = 0.02). Quantitative real-time polymerase chain reaction for downstream hedgehog target genes demonstrated significant downregulation in the islet cell tumors of Rip1Tag2 mice treated with LDE225, confirming the ability to achieve effective pharmacologic levels of LDE225 within the desired tissue site, in vivo. CONCLUSION: This is the first study to show that the orally bioavailable Smo antagonist LDE225 may provide a new option for therapy of islet cell neoplasms.
Asunto(s)
Adenoma de Células de los Islotes Pancreáticos/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Compuestos de Bifenilo/administración & dosificación , Proteínas Hedgehog/antagonistas & inhibidores , Neoplasias Pancreáticas/tratamiento farmacológico , Piridinas/administración & dosificación , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Adenoma de Células de los Islotes Pancreáticos/mortalidad , Adenoma de Células de los Islotes Pancreáticos/patología , Administración Oral , Animales , Animales Modificados Genéticamente , Disponibilidad Biológica , Modelos Animales de Enfermedad , Regulación hacia Abajo/fisiología , Femenino , Masculino , Ratones , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor SmoothenedRESUMEN
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder associated mainly with tumors of multiple endocrine organs. Mutations in the MEN1 gene that encodes for the menin protein are the predominant cause for hereditary MEN1 syndrome. Though menin is a tumor suppressor, its molecular mechanism of action has not been defined. Here, we report that menin interacts with AKT1 in vitro and in vivo. Menin downregulates the level of active AKT and its kinase activity. Through interaction with AKT1, menin suppresses both AKT1-induced proliferation and antiapoptosis in nonendocrine and endocrine cells. Confocal microscopy analysis revealed that menin regulates AKT1 in part by reducing the translocation of AKT1 from the cytoplasm to the plasma membrane during growth factor stimulation. Our findings may be generalizable to other cancers, insofar as we found that loss of menin expression was also associated with AKT activation in a mouse model of pancreatic islet adenoma. Together, our results suggest menin as an important novel negative regulator of AKT kinase activity.
Asunto(s)
Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Animales , Procesos de Crecimiento Celular , Membrana Celular/enzimología , Membrana Celular/metabolismo , Activación Enzimática , Células HEK293 , Humanos , Ratones , Microscopía Confocal , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , TransfecciónRESUMEN
A 14-year-old female spayed Golden Retriever was presented to the University of Florida's Veterinary Medical Center with history of lymphoplasmacytic gastroenteritis, intermittent vomiting, watery diarrhea, and weight loss for over a year. CBC, biochemical profile, and urinalysis were within reference intervals. Abdominal ultrasonographic examination revealed mesenteric and jejunal lymphadenopathy and hyperechoic hepatic nodules. Cytologic examination of the enlarged lymph nodes revealed loosely cohesive cells with moderate nuclear pleomorphism and rare punctate eosinophilic cytoplasmic granules. The cytologic interpretation was metastatic neuroendocrine neoplasia. On surgical exploration, a mass was detected in the right lobe of the pancreas. Histologic evaluation determined the mass to be an islet cell tumor. Approximately 98% of cells were positive by immunolabeling for pancreatic polypeptide (PP), and only rare cells were positive for insulin or somatostatin. All cells were negative for glucagon, gastrin, vasoactive intestinal polypeptide, protein gene product 9.5, synaptophysin, and chromogranins A and B. Pancreatic tumors that primarily produce PP are rare in dogs, and this is the first report of both the cytologic and histologic features of an islet cell tumor predominantly secreting PP. Clinical signs for these tumors are typically absent or nonspecific; signs may include watery diarrhea, as noted in this dog, although the diarrhea may have resulted from lymphoplasmacytic gastroenteritis. Additional case studies are needed to further characterize the cytomorphologic features and clinical presentation of PP-secreting islet cell tumor, or polypeptidoma, in dogs.
Asunto(s)
Adenoma de Células de los Islotes Pancreáticos/veterinaria , Enfermedades de los Perros/patología , Neoplasias Pancreáticas/veterinaria , Polipéptido Pancreático/metabolismo , Adenoma de Células de los Islotes Pancreáticos/diagnóstico , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Adenoma de Células de los Islotes Pancreáticos/patología , Animales , Enfermedades de los Perros/diagnóstico , Perros , Femenino , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Metástasis Linfática , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologíaAsunto(s)
Adenoma de Células de los Islotes Pancreáticos/patología , Hipoglucemia/patología , Factor II del Crecimiento Similar a la Insulina/metabolismo , Neoplasias Gástricas/patología , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Humanos , Hipoglucemia/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/metabolismoRESUMEN
PAX (paired box) genes encode a family of transcription factors that regulate organogenesis and cell-lineage specification in multiple organ systems. In the pancreas, PAX proteins play a critical role in islet cell differentiation. We recently observed that islet cells show strong, diffuse staining for PAX8 by immunohistochemistry. However, PAX8 expression has not previously been examined in pancreatic endocrine tumors (PETs). The purpose of this study was to evaluate PAX8 expression in PETs, and to correlate expression with clinical and pathologic features and behavior. PAX8 expression in other well-differentiated neuroendocrine tumors (WDNETs) was also studied. In total, 190 tumors were evaluated: 156 primary WDNETs (63 PETs, 31 ileal, 5 duodenal, 5 gastric, 19 appendiceal, 13 rectal, and 20 pulmonary carcinoid tumors) and 34 liver metastases (18 PETs and 16 ileal carcinoid tumors). PAX8 was positive in 42/63 (67%) primary PETs. Expression of PAX8 was significantly associated with WHO category 1.1 ("benign" behavior) compared with category 1.2 (uncertain behavior) or 2 (well-differentiated endocrine carcinoma) (positive in 100%, 64%, and 52% of tumors, respectively; P<0.05). PAX8-positive PETs were also significantly smaller and more often clinically functional; PAX8-negative tumors were more frequently associated with liver metastases. PAX8 expression was not associated with patient age, gender, MIB1 index, or lymph node metastases. PAX8 expression was detected in 0/20 (0%) pulmonary, 1/5 (20%) gastric, 5/5 (100%) duodenal, 0/31 (0%) ileal, 4/19 (21%) appendiceal, and 11/13 (85%) rectal carcinoid tumors. Among the liver metastases, PAX8 was positive in 9/18 (50%) metastatic PETs compared with 0/16 (0%) metastatic ileal carcinoid tumors. In summary, PAX8 is expressed in normal pancreatic islet cells and in a high proportion of primary and metastatic PETs. In the GI tract, PAX8 is positive in the majority of duodenal and rectal carcinoid tumors, and in a minor subset of appendiceal and gastric carcinoids. PAX8 expression is absent in ileal and pulmonary carcinoid tumors. PAX8 immunostaining may be helpful in determining the primary site for a WDNET metastatic to the liver, as ileal (PAX8 negative) and pancreatic (PAX8 positive) tumors most often present as a metastasis from an occult primary. PAX8 may also be a prognostic marker in PETs, as loss of expression is associated with malignant behavior.
Asunto(s)
Adenoma de Células de los Islotes Pancreáticos/patología , Tumor Carcinoide/patología , Carcinoma de Células de los Islotes Pancreáticos/secundario , Neoplasias Gastrointestinales/patología , Neoplasias Pulmonares/patología , Factores de Transcripción Paired Box/metabolismo , Neoplasias Pancreáticas/patología , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Tumor Carcinoide/metabolismo , Carcinoma de Células de los Islotes Pancreáticos/metabolismo , Femenino , Neoplasias Gastrointestinales/metabolismo , Humanos , Inmunohistoquímica , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/metabolismo , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Factor de Transcripción PAX8 , Neoplasias Pancreáticas/metabolismoRESUMEN
Pancreatic endocrine tumors are rare neoplasms accounting for less than 5% of pancreatic malignancies. They are broadly classified into either functioning tumors (insulinomas, gastrinomas, glucagonomas, VIPomas, and somatostatinomas) or nonfunctioning tumors. The diagnosis of these tumors is difficult and requires a careful history and examination combined with laboratory tests and radiologic imaging. Signs and symptoms are usually related to hormone hypersecretion in the case of functioning tumors and to tumor size or metastases with nonfunctioning tumors. Surgical resection remains the treatment of choice even in the face of metastatic disease. Further development of novel diagnostic and treatment modalities offers potential to greatly improve quality of life and prolong disease-free survival for patients with pancreatic endocrine tumors.
Asunto(s)
Adenoma de Células de los Islotes Pancreáticos , Carcinoma de Células de los Islotes Pancreáticos , Neoplasias Pancreáticas , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Adenoma de Células de los Islotes Pancreáticos/patología , Adenoma de Células de los Islotes Pancreáticos/terapia , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células de los Islotes Pancreáticos/metabolismo , Carcinoma de Células de los Islotes Pancreáticos/patología , Carcinoma de Células de los Islotes Pancreáticos/terapia , Ablación por Catéter , Quimioembolización Terapéutica/métodos , Medicina Basada en la Evidencia , Gastrinas/metabolismo , Glucagón/metabolismo , Humanos , Insulina/metabolismo , Secreción de Insulina , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Calidad de Vida , Somatostatina/metabolismo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Currently used histopathologic criteria for the diagnosis of pancreatic endocrine tumors are still under discussion as far as to their capacity to identify prognostically different tumor subsets, which are potentially helpful for patient management. A recently developed TNM staging system and a variety of proposed histologic and clinicopathologic parameters still need to be fully validated. One hundred fifty-five pancreatic endocrine tumors encompassing all the main histologic types and stages, operated with intention to cure and then followed up for a median 126 months, were carefully investigated histologically to identify prognostically informative parameters at univariable, bivariable, and multivariable analysis. Ki67 index, mitotic rate, neuroinvasion with or without vascular, peritumoral or stromal infiltrative patterns, as well as tumor size, and association with endocrine syndromes other than insulinoma proved effective in predicting recurrence and disease-specific death among well-differentiated tumors. Poorly differentiated histologic features, more than 10 mitoses/10 high power fields, and necrosis were helpful in the identification of high-grade cancers with an invariably poor prognosis. The TNM system proved to be highly predictive of patient outcome and easy to combine with histologic and clinicopathologic parameters to classify pancreatic endocrine tumors into groups of increasing malignant potential.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patología , Adenoma de Células de los Islotes Pancreáticos/diagnóstico , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Adenoma de Células de los Islotes Pancreáticos/patología , Carcinoma de Células de los Islotes Pancreáticos/diagnóstico , Carcinoma de Células de los Islotes Pancreáticos/metabolismo , Carcinoma de Células de los Islotes Pancreáticos/patología , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Humanos , Insulinoma/diagnóstico , Insulinoma/metabolismo , Insulinoma/patología , Antígeno Ki-67/análisis , Índice Mitótico , Necrosis/patología , Invasividad Neoplásica , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Pancreáticas/metabolismo , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Carga TumoralRESUMEN
Menin is a tumor suppressor protein mutated in patients with multiple endocrine neoplasia type 1. We show that menin is essential for canonical Wnt/beta-catenin signaling in cultured rodent islet tumor cells. In these cells, overexpression of menin significantly enhances TCF gene assay reporter activity in response to beta-catenin activation. Contrastingly, inhibition of menin expression with Men1 siRNA decreases TCF reporter gene activity. Likewise, multiple endocrine neoplasia type 1 disease associated missense mutations of menin abrogate the ability to increase TCF reporter gene activity. We show that menin physically interacts with proteins involved in the canonical Wnt signaling pathway, including beta-catenin, TCF3 (TCFL1), and weakly with TCF4 (TCFL2). Menin overexpression increases expression of the Wnt/beta-catenin downstream target gene Axin2, which is associated with increased H3K4 trimethylation of the Axin2 gene promoter. Moreover, inhibition of menin expression by siRNA abrogates H3K4 trimethylation and Axin2 gene expression. Based on these studies, we hypothesized that Wnt signaling could inhibit islet cell proliferation because loss of menin function is thought to increase endocrine tumor cell proliferation. TGP61 rodent islet tumor cells treated with a glycogen synthase kinase 3beta inhibitor that increases Wnt pathway signaling had decreased cell proliferation compared with vehicle-treated cells. Collectively, these data suggest that menin has an essential role in Wnt/beta-catenin signaling through a mechanism that eventually affects histone trimethylation of the downstream target gene Axin2, and activation of Wnt/beta-catenin signaling inhibits islet tumor cell proliferation.
Asunto(s)
Adenoma de Células de los Islotes Pancreáticos/metabolismo , Neoplasia Endocrina Múltiple Tipo 1/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Wnt/metabolismo , Adenoma de Células de los Islotes Pancreáticos/genética , Animales , Proteína Axina , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Cricetinae , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Proteínas de Unión al ADN/genética , Histonas/metabolismo , Humanos , Riñón/citología , Metilación , Ratones , Ratones Noqueados , Neoplasia Endocrina Múltiple Tipo 1/genética , Mutación Missense , Neoplasias Pancreáticas/genética , Regiones Promotoras Genéticas/fisiología , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas/genética , ARN Interferente Pequeño , Transducción de Señal/fisiología , Factor de Transcripción 4 , Factores de Transcripción/genética , beta Catenina/metabolismoRESUMEN
PURPOSE: Tumor hypoxia is associated with poor prognosis and resistance to treatment. Our aim was to assess the expression of proteins that act as cellular oxygen sensors, directly regulating the hypoxia inducible factor (HIF) pathway, i.e., prolyl hydroxylase domain proteins (PHD)-1, PHD-2, PHD-3, and FIH in pancreatic endocrine tumors (PET). EXPERIMENTAL DESIGN: Immunohistochemical expression of these markers was examined in 109 PET included in tissue microarrays and representing various stages of tumorigenesis. The results were correlated with histoprognostic factors including Ki-67 index, presence of a fibrotic focus, and microvascular density (MVD). RESULTS: The cytoplasmic and nuclear expressions of the three PHD isoforms were associated, and their expression was significantly higher in aggressive PETS, malignant, with lymph node metastases or with lower MVD. High nuclear expression of the three isoforms highly correlated with HIF-1alpha nuclear expression (P = 0.02, 0.003, and 0.006, respectively). Moreover, high nuclear PHD-1 or PHD-3 expression was associated with a poorer survival (P = 0.01). Cytoplasmic FIH was significantly higher in malignant PETs (P = 0.05) and in PETs with lymph node metastases (P = 0.02), and its expression correlated positively with those of cytoplasmic PHD isoforms (P < 0001). FIH stromal expression was found in 23% of PETs and correlated with higher FIH nuclear expression (P = 0.0004) and poorer disease-free survival (P = 0.0018). CONCLUSION: HIF regulatory proteins are highly expressed in PET and their expression is correlated with tumor metastases, tumor recurrence, and prognosis. These molecules that play an important role in the control of hypoxia-induced genes may have a function in the regulation of cellular proliferation and differentiation during endocrine tumorigenesis.
Asunto(s)
Hipoxia de la Célula , Dioxigenasas/metabolismo , Neoplasias Pancreáticas/metabolismo , Procolágeno-Prolina Dioxigenasa/metabolismo , Proteínas Represoras/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/secundario , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Adenoma de Células de los Islotes Pancreáticos/patología , Adulto , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/secundario , Diferenciación Celular , Proliferación Celular , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Técnicas para Inmunoenzimas , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Metástasis Linfática , Masculino , Microcirculación , Oxigenasas de Función Mixta , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/metabolismo , Neovascularización Patológica , Neoplasias Pancreáticas/patología , Análisis de Matrices TisularesRESUMEN
Even though the cytologic criteria for pancreatic ductal adenocarcinoma (PDA) on fine-needle aspiration biopsy (FNAB) specimens have been well defined, a diagnostic challenge is still present. We immunohistochemically evaluated the diagnostic value of S100P on cell-block and/or smear preparations in 58 cases of FNAB specimens of the pancreas. The 58 cases were divided into 4 groups: 1, 32 cases of PDA; 2, 6 cases with an atypical or "suspicious" diagnosis; 3, 14 cases of benign or reactive ductal epithelium; and 4, 6 cases of endocrine tumor. Positive immunoreactivity for S100P was observed in all cases in groups 1 and 2, whereas only 1 of 14 cases in group 3 was positive for S100P. All cases in group 4 were negative for S100P. S100P is a sensitive and specific marker for the detection of PDA on FNAB specimens on cell-block and smear preparations.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Proteínas Portadoras/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/diagnóstico , Adenoma de Células de los Islotes Pancreáticos/diagnóstico , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Biopsia con Aguja Fina , Carcinoma de Células de los Islotes Pancreáticos/diagnóstico , Carcinoma de Células de los Islotes Pancreáticos/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Diagnóstico Diferencial , Células Epiteliales/metabolismo , Células Epiteliales/patología , Humanos , Técnicas para Inmunoenzimas , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Conductos Pancreáticos/metabolismo , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/metabolismoRESUMEN
Tumors develop through multiple stages, implicating multiple effectors, but the tools to assess how candidate genes contribute to stepwise tumor progression have been limited. We have developed a novel system in which progression of phenotypes in a mouse model of pancreatic islet cell tumorigenesis can be used to measure the effects of genes introduced by cell-type-specific infection with retroviral vectors. In this system, bitransgenic mice, in which the rat insulin promoter (RIP) drives expression of both the SV40 T antigen (RIP-Tag) and the receptor for subgroup A avian leukosis virus (RIP-tva), are infected with avian viral vectors carrying cDNAs encoding candidate progression factors. Like RIP-Tag mice, RIP-Tag; RIP-tva bitransgenic mice develop isolated carcinomas by approximately 14 wk of age, after progression through well-defined stages that are similar to aspects of human tumor progression, including hyperplasia, angiogenesis, adenoma, and invasive carcinoma. When avian retroviral vectors carrying a green fluorescent protein marker were introduced into RIP-Tag; RIP-tva mice by intra-cardiac injection at the hyperplastic or early dysplastic stage of tumorigenesis, approximately 20% of the TVA-positive cells were infected and expressed green fluorescent proteins as measured by flow cytometry. Similar infection with vectors carrying cDNA encoding either of two progression factors, a dominant-negative version of cadherin 1 (dnE-cad) or Bcl-xL, accelerated the formation of islet tumors with invasive properties and pancreatic lymph node metastasis. To begin studying the mechanism by which Bcl-xL, an anti-apoptotic protein, promotes invasion and metastasis, RIP-Tag; RIP-tva pancreatic islet tumor cells were infected in vitro with RCASBP-Bcl-xL. Although no changes were observed in rates of proliferation or apoptosis, Bcl-xL altered cell morphology, remodeled the actin cytoskeleton, and down-regulated cadherin 1; it also induced cell migration and invasion, as evaluated using two-chamber transwell assays. In addition, myosin Va was identified as a novel Bcl-xL-interacting protein that might mediate the effects of Bcl-xL on tumor cell migration and invasion.
Asunto(s)
Adenoma de Células de los Islotes Pancreáticos , Progresión de la Enfermedad , Técnicas de Transferencia de Gen , Invasividad Neoplásica , Proteína bcl-X/metabolismo , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Adenoma de Células de los Islotes Pancreáticos/patología , Animales , Cadherinas/genética , Cadherinas/metabolismo , Movimiento Celular/fisiología , Forma de la Célula , Modelos Animales de Enfermedad , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Humanos , Islotes Pancreáticos/citología , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Metástasis de la Neoplasia , Ratas , Proteína bcl-X/genéticaRESUMEN
Insulinoma is considered the most common endocrine tumour of the pancreas with an annual prevalence of 4 cases per million people. Contrary to the other endocrine tumours of this organ, over 90% of the insulinomas are benign in nature. The clinical presentation of this neoplasm depends on excessive production of insulin and pro-insulin and is characterised by the symptoms of neuroglycopenia and catecholamine response. Effective management requires directed biochemical testing, careful choice of preoperative imaging tests, and complete pancreatic exploration by an experienced endocrine surgeon utilising intraoperative ultrasound. The only curative treatment for insulinoma is complete resection of the tumour. The aim of this paper is to critically discuss contemporary diagnosis and treatment of this neoplasm on the basis of progress made in recent years.
Asunto(s)
Adenoma de Células de los Islotes Pancreáticos/complicaciones , Adenoma de Células de los Islotes Pancreáticos/diagnóstico , Insulinoma/complicaciones , Insulinoma/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Adenoma de Células de los Islotes Pancreáticos/cirugía , Diagnóstico Diferencial , Procedimientos Quirúrgicos Endocrinos/métodos , Gastrinoma/complicaciones , Gastrinoma/diagnóstico , Gastrinoma/metabolismo , Gastrinoma/cirugía , Humanos , Hipoglucemia/complicaciones , Insulina/metabolismo , Insulinoma/metabolismo , Insulinoma/cirugía , Pancreatectomía/métodos , Neoplasias Pancreáticas/clasificación , Neoplasias Pancreáticas/cirugía , Pronóstico , Enfermedades RarasRESUMEN
Altered expression of recently described claudins (CLDNs) as members of tight junction (TJ) transmembrane proteins was noted in several malignancies. We aimed to analyze protein and messenger RNA (mRNA) expressions of different CLDNs in human pancreatic endocrine tumors (PET) and ductal adenocarcinomas. A total of 45 formalin-fixed, paraffin-embedded samples were studied. Immunohistochemistry and real-time reverse transcriptase polymerase chain reaction analysis were carried out for quantification of CLDN 1, -2, -3, -4, and -7 expressions. Normal acini and ducts showed strong CLDNs 1, -3, -4, and -7 and scattered CLDN 2 protein expressions, while Langerhans islands revealed only CLDN 3 and -7 expressions. CLDN 2 expression was found in the half of ductal adenocarcinomas, while the vast majority of endocrine tumors were negative. CLDN 1, -4, and -7 immunohistochemistry was positive in all adenocarcinomas, whereas endocrine tumors were completely negative for CLDNs 1 and -4. CLDN 3 and -7 proteins were detected in all endocrine tumors, while CLDN 3 in ductal adenocarcinomas was negative. The mRNA expression of CLDNs showed differences between endocrine tumors and ductal adenocarcinomas, similar as found for protein expression. Our findings support that PET and ductal carcinomas are specifically characterized by different expression pattern of CLDNs. High expressions of CLDN 3 in endocrine tumors and CLDN 4 in ductal carcinomas might attract them as targets for adjuvant therapy.