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Aspirin inhibits cell viability and mTOR downstream signaling in gastroenteropancreatic and bronchopulmonary neuroendocrine tumor cells

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World Journal of Gastroenterology 2014年第29期20卷 10038-10049页

作者： matilde spampatti George Vlotides Gerald Spttl Julian Maurer Burkhard Gke Christoph J Auernhammer Department of Internal Medicine Ⅱ University-Hospital Campus GrosshadernInterdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System (GEPNET-KUM)Ludwig-Maximilians-University of Munich U.O.C.Gastroenterologia 2 Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Università degli Studi di Milano

AIM:To investigate the effect of aspirin on neuroendocrine tumor(NET)cell growth and signaling in vitro.METHODS:Human pancreatic BON1,bronchopulmonary NCI-H727 and midgut GOT1 neuroendocrine tumor cells were treated with different concentrations of aspirin(from 0.001 to 5 mmol/L),and the resulting effects on metabolic activity/cell proliferation were measured using cell proliferation assays and SYBR-DNAlabeling after 72,144 and 216 h of incubation.The effects of aspirin on the expression and phosphorylation of several critical proteins that are involved in the most common intracellular growth factor signaling pathways(especially Akt protein kinase B)and mammalian target of rapamycin(mTOR)were determined by Western blot analyses.Propidium iodide staining and flow cytometry were used to evaluate changes in cell cycle distribution and apoptosis.Statistical analysis was performed using a 2-tailed Student’s t-test to evaluate the proliferation assays and cell cycle analyses.The results are expressed as the mean±SD of 3 or 4 independently performed experiments.Statistical significance was set at P<0.05.RESULTS:Treatment with aspirin suppressed the viability/proliferation of BON1,NCI-H727 and GOT1 cells in a time-and dose-dependent manner.Significant effects were observed at starting doses of 0.5-1 mmol/L and peaked at 5 mmol/L.For instance,after treatment with 1 mmol/L aspirin for 144 h,the viability of pancreatic BON1 cells decreased to 66%±13%(P<0.05),the viability of bronchopulmonary NCI-H727 cells decreased to 53%±8%(P<0.01)and the viability of midgut GOT1 cells decreased to 89%±6%(P<0.01).These effects were associated with a decreased entry into the S phase,the induction of the cyclin-dependent kinase inhibitor p21 and reduced expression of cyclindependent kinase 4 and cyclin D3.Aspirin suppressed mTOR downstream signaling,evidenced by the reduced phosphorylation of the mTOR substrates 4E binding protein 1,serine/threonine kinase P70S6K and S6 ribosomal protein and inhibited glycogen synthase kinase3 activity.We o

关键词： Neuroendocrine tumors Aspirin Cell Viability Mamma

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Gastric carcinoids:Between underestimation and overtreatment

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World Journal of Gastroenterology 2009年第18期15卷 2177-2183页

作者： Sara Massironi Valentina Sciola matilde Pia spampatti Maddalena Peracchi Dario Conte Gastroenterology UnitⅡ Fondazione IRCCS Ospedale Maggiore PoliclinicoMangiagalli e Regina Elenaand Postgraduate School of GastroenterologyUniversity of Milan20122 MilanItaly

Gastric carcinoids(GCs),which originate from gastric enterochromaffin-like(ECL) mucosal cells and account for 2.4% of all carcinoids,are found increasingly in the course of upper gastrointestinal tract endoscopy.Current nosography includes those occurring in chronic conditions with hypergastrinemia,as the type 1 associated with chronic atrophic gastritis,and the type 2 associated with Zollinger-Ellison syndrome in multiple endocrine neoplasia type 1,and type 3,which is unrelated to hypergastrinemia and is frequently malignant,with distant metastases.The optimal clinical approach to GCs remains to be elucidated,depending upon type,size and number of carcinoids.While there is agreement concerning the treatment of type 3 carcinoids,for types 1 and 2,current possibilities include simple surveillance,endoscopic polypectomy,surgical excision,associated or not with surgical antrectomy,or total gastrectomy.Moreover,the recent introduction of somatostatin analogues represents a therapeutic option of possibly outstanding relevance.

关键词：胃类癌多发性内分泌腺瘤病高胃泌素血症慢性萎缩性胃炎生长抑素类似物消化道内窥镜手术切除息肉切除术

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Neuroendocrine tumors of the gastro-entero-pancreatic system

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World Journal of Gastroenterology 2008年第35期14卷 5377-5384页

作者： Sara Massironi Valentina Sciola Maddalena Peracchi Clorinda Ciafardini matilde Pia spampatti Dario Conte Gastroenterology Unit Ⅱ Fondazione IRCCS Ospedale Maggiore PoliclinicoMangiagalli e Regina ElenaMilan 20122Italy

Gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs) are rare neoplasms, although their prevalence has increased substantially over the past three decades. Moreover, there has been an increased clinical recognition and characterization of these neoplasms. They show extremely variable biological behavior and clinical course. Most NETs have endocrine function and secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome; however, many are clinically silent until late presentation with mass effects. Investigation and management should be individualized for each patient, taking into account the likely natural history of the tumor and general health of the patient. Management strategies include surgery for cure or palliation, and a variety of other cytoreductive techniques, and medical treatment including chemotherapy, and biotherapy to control symptoms due to hormone release and tumor growth, with somatostatin analogues (SSAs) and alphainterferon. New biological agents and somatostatintagged radionuclides are under investigation. Advances in the therapy and development of centers of excellence which coordinate multicenter studies, are needed to improve diagnosis, treatment and therefore survival of patients with GEP NETs.

关键词：神经内分泌瘤良性肿瘤胃肠胰腺消化系统肿瘤

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