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Cancer stem cells in colorectal cancer from pathogenesis to therapy: Controversies and perspectives

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World Journal of Gastroenterology 2014年第4期20卷 923-942页

作者： Caterina Fanali Donatella Lucchetti Marisa Farina Maddalena Corbi Valerio Cufino Achille Cittadini Alessandro sgambato Istituto di Patologia Generale Università Cattolica del Sacro Cuore

Colorectal cancer remains one of the most common and lethal malignancies worldwide despite the use of various therapeutic strategies. A better understanding of the mechanisms responsible for tumor initiation and progression is essential for the development of novel, more powerful therapies. The traditional, so-called “stochastic model” of tumor development, which assumes that each cancer cell is tumorigenic, has been deeply challenged during the past decade by the identification of cancer stem cells (CSCs), a biologically distinct subset of cells within the bulk of tumor mass. This discovery led to the development of the hierarchical model of tumorigenesis which assumes that only CSCs have the ability to initiate tumor growth, both at primary and metastatic sites. This model implies that the elimination of all CSCs is fundamental to eradicate tumors and that failure to do so might be responsible for the occurrence of relapses and/or metastases frequently observed in the clinical management of colorectal cancer patients. Identification and isolation of CSCs is essential for a better understanding of their role in the tumorigenetic process and for the development of CSC-specific therapies. Several methods have been used for this purpose and many efforts have been focused on the identification of specific CSC-surface markers. This review provides an overview of the proposed roles of CSC in human colorectal tumorigenesis focusing on the most important molecules identified as CSC-specific markers in colorectal cancer and on the potential strategies for the development of CSC-targeted therapy.

关键词： Colorectal cancer Cancer stem cells Tumorigenesis Cancer therapy Prognostic marker

Propionyl-L-carnitine hydrochloride for treatment of mild to moderate colonic inflammatory bowel diseases

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World Journal of Gastroenterology 2012年第36期18卷 5065-5071页

作者： Giuseppe Merra Giovanni Gasbarrini Lucrezia Laterza Marco Pizzoferrato Andrea Poscia Franco Scaldaferri Vincenzo Arena Francesca Fiore Achille Cittadini Alessandro sgambato Francesco Franceschi Antonio Gasbarrini Emergency Department Catholic University of Sacred Heart00168 RomeItaly Medical Research Foundation and nonprofit organization 40123 BolognaItaly Department of Internal Medicine and Gastroenterology Catholic University of Sacred Heart00168 RomeItaly Institute of Hygiene Catholic University of Sacred Heart00168 RomeItaly Institute of Pathology Catholic University of Sacred Heart00168 RomeItaly Department of Internal Medicine and Geriatry Catholic University of Sacred Heart00168 RomeItaly Institute of General Pathology Catholic University of Sacred Heart00168 RomeItaly

AIM:To assess clinical and endoscopic response to propionyl-L-carnitine hydrochloride(PLC) in colonic inflammatory bowel ***:Patients suffering from mild to moderate ulcerative colitis(UC) or Crohn's disease(CD) colitis,with disease activity index(DAI) between 3 and 10 and under stable therapy with oral aminosalicylates,mercaptopurine or azathioprine,for at least 8 wk prior to baseline assessments,were considered suitable for *** patients were enrolled to assume PLC 2 g/d(two active tablets twice daily) ***-endoscopic and histological activity were assessed by DAI and histological index(HI),respectively,following a colonoscopy performed immediately before and after 4 wk *** response was defined as a lowering of at least 3 points in DAI and clinical remission as a DAI score ≤ *** response was defined as an improvement of HI of at least 1 *** used median values for the *** pre-and post-treatment were analyzed by Wilcoxon signed rank ***:All patients enrolled completed the *** patient,despite medical advice,took deflazacort 5 d before follow-up colonoscopy *** side effects were reported by patients during the *** treatment,71%(SE 12%) of patients achieved clinical response,while 64%(SE 13%) obtained *** UC from CD patients,we observed a clinical response in 60%(SE 16%) and 100%,*** 60%(SE 16%) of UC patients and 75%(SE 25%) of CD patients were in clinical remission after *** median DAI was 7 [interquartile range(IQR):4-8] before treatment and decreased to 2(IQR:1-3)(P < 0.01) after *** patients with UC showed a significant reduction of DAI,from a median 6.5(IQR:4-9) before treatment to 2(IQR:1-3) after treatment(P < 0.01).Conversely,in CD patients,although displaying a clear reduction of DAI from 7(IQR:5.5-7.5) before therapy to 1.5(IQR:0.5-2.5) after therapy,differences observed were not sign

关键词： PropionyI-L-carnitine Ulcerative colitis Crohn's disease Inflammatory bowel disease therapy PropionyI-L-carnitine hydrochloride

Bone alterations in inflammatory bowel diseases

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World Journal of Clinical Cases 2019年第15期7卷 1908-1925页

作者： Dolores sgambato Francesca Gimigliano Cristiana De Musis Antimo Moretti Giuseppe Toro Emanuele Ferrante Agnese Miranda Domenico De Mauro Lorenzo Romano Giovanni Iolascon Marco Romano Departments of Precision Medicine and Polyspecialistic Internal Medicine University of Campania "Luigi Vanvitelli" and University HospitalNaples 80131Italy Department of Physical and Mental Health University of Campania“Luigi Vanvitelli”Naples 80131Italy Department of Medical and Surgical Specialties and Dentistry University of Campania“Luigi Vanvitelli”Naples 80131Italy Surgical Digestive Endoscopy Department of Clinical Medicine and SurgeryFederico Ⅱ UniversityNaples 80131Italy

Inflammatory bowel diseases(IBDs)are characterized by a multifactorial partially unknown etiology that involves genetic,immunological and environmental *** to 50%of IBD patients experience at least one extraintestinal manifestation;among them is the involvement of bone density which is referred to as metabolic bone disease(MBD),including osteopenia and *** alterations in IBDs population appear to have a multifactorial etiology:Decreased physical activity,inflammation-related bone resorption,multiple intestinal resections,dietary malabsorption of minerals and vitamin D deficiency,genetic factors,gut-bone immune signaling interaction,steroid treatment,microbiota and pathogenic micro-organisms interaction,and dietary malabsorption of minerals,that,all together or individually,may contribute to the alteration of bone mineral *** review aims to summarize the prevalence and pathophysiology of metabolic bone alterations in IBD subjects outlining the main risk factors of bone *** also want to underline the role of the screening and prophylaxis of bone alterations in Crohn’s disease and ulcerative colitis patients and the importance of treating appropriately MBD.

关键词： Inflammatory bowel diseases Bone alterations Bone mineral density Osteoporosis Osteopenia Ulcerative colitis Crohn’s disease

Infliximab does not increase colonic cancer risk associated to murine chronic colitis

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World Journal of Gastroenterology 2016年第44期22卷 9727-9733页

作者： Loris R Lopetuso Valentina Petito Tiziano Zinicola Cristina Graziani Viviana Gerardi Vincenzo Arena Maria Emiliana Caristo Andrea Poscia Giovanni Cammarota Alfredo Papa Valerio Cufino Alessandro sgambato Antonio Gasbarrini Franco Scaldaferri Gastroenterology Division Catholic University of Sacred Heart Institute of Pathology Catholic University of Sacred Heart Experimental Center Catholic University of Sacred Heart Institute of Hygiene Catholic University of Sacred Heart Institute of General Pathology Catholic University of Sacred Heart

AIM To explore the influence of Infliximab(IFX) on cancer progression in a murine model of colonic cancer associated to chronic *** AOM/DSS model was induced in C57BL/6 mice. Mice were injected with IFX(5 mg/kg) during each DSS cycle while control mice received saline. Body weight, occult blood test and stool consistency were measured to calculate the disease activity index(DAI). Mice were sacrificed at week 10 and colons were analyzed macroscopically and microscopically for number of cancers and degree of inflammation. MTT assay was performed on CT26 to evaluate the potential IFX role on metabolic activity and proliferation. Cells were incubated with TNF-α or IFX or TNF-α plus IFX, and cell vitality was evaluated after 6, 24 and 48 h. The same setting was used after pre-incubation with TNF-α for 24 *** IFX significantly reduced DAI and body weight loss in mice compared with controls, preserving also colon length at sacrifice. Histological score was also reduced in treated mice. At macroscopic analysis, IFX treated mice showed a lower number of tumor lesions compared to controls. This was confirmed at microscopic analysis, although differences were not statistically significant. In vitro, IFX treated CT26 maintained similar proliferation ability at MTT test, both when exposed to IFX alone and when associated to TNF-α.CONCLUSION IFX did not increase colonic cancer risk in AOM-DSS model of cancer on chronic colitis nor influence directly the proliferation of murine colon cancer epithelial cells.

关键词： Inflammatory bowel disease Ulcerative colitis Colorectal cancer Infliximab AOM-DSS model Cancer on chronic colitis

Anti-tumor necrosis factor α therapy associates to type 17 helper T lymphocytes immunological shift and significant microbial changes in dextran sodium sulphate colitis

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World Journal of Gastroenterology 2019年第12期25卷 1465-1477页

作者： Valentina Petito Cristina Graziani Loris R Lopetuso Marco Fossati Alessandra Battaglia Vincenzo Arena Domenico Scannone Gianluca Quaranta Andrea Quagliariello Federica Del Chierico Lorenza Putignani Luca Masucci Maurizio Sanguinetti Alessandro sgambato Antonio Gasbarrini Franco Scaldaferri Istituto di Patologia Speciale Medica Università Cattolica del Sacro Cuore UOC di Medicina Interna e Gastroenterologia Area di Gastroenterologia e Oncologia Medica Dipartimento di Scienze Gastroenterologiche Endocrino-Metaboliche e Nefro-Urologiche Fondazione Policlinico Universitario "A. Gemelli" IRCCS Dipartimento delle Scienze della Salute della Donna e del Bambino Fondazione Policlinico Universitario "A. Gemelli" IRCCS Istituto di Clinica Ostetrica e Ginecologica Università Cattolica del Sacro Cuore U.O.S.A. Gineco-Patologia e Patologia Mammaria Fondazione Policlinico Universitario "A. Gemelli" IRCCS Istituto di Anatomia Patologica Università Cattolica del Sacro Cuore Dipartimento di Anatomia Patologica e Istologia Fondazione Policlinico Universitario "A. Gemelli" IRCCS Dipartimento di Microbiologia Fondazione Policlinico Universitario "A. Gemelli" IRCCS Istituto di Microbiologia Università Cattolica del Sacro Cuore Unità di Microbioma Umano Ospedale Pediatrico Bambino Gesù IRCCS Unità di Parassitologia Ospedale Pediatrico Bambino Gesù IRCCS Istituto di Patologia Generale Università Cattolica del Sacro Cuore

BACKGROUND Anti-tumor necrosis factor α(TNFα) represents the best therapeutic option to induce mucosal healing and clinical remission in patients with moderate-severe ulcerative colitis. On the other side gut microbiota plays a crucial role in pathogenesis of ulcerative colitis but few information exists on how microbiota changes following anti-TNFα therapy and on microbiota role in mucosal *** To elucidate whether gut microbiota and immune system changes appear following anti TNFα therapy during dextran sulfate sodium(DSS) *** Eighty C57 BL/6 mice were divided into four groups: "No DSS", "No DSS + antiTNFα", "DSS" and "DSS + anti-TNFα". "DSS" and "DSS + anti-TNFα" were treated for 5 d with 3% DSS. At day 3, mice whithin "No DSS+anti-TNFα" and"DSS+anti-TNFα" group received 5 mg/kg of an anti-TNFα agent. Forty mice were sacrificed at day 5, forty at day 12, after one week of recovery post DSS. The severity of colitis was assessed by a clinical score(Disease Activity Index), colon length and histology. Bacteria such as Bacteroides, Clostridiaceae, Enterococcaceae and Fecalibacterium prausnitzii(F. prausnitzii) were evaluated by quantitative *** 1 helper T lymphocytes(Th1), type 17 helper T lymphocytes(Th17) and CD4+ regulatory T lymphocytes(Treg) distributions in the mesenteric lymph node(MLN) were studied by flow *** Bacteria associated with a healthy state(i.e., such as Bacteroides, Clostridiaceae and F. prausnitzii) decreased during colitis and increased in course of anti-TNFαtreatment. Conversely, microorganisms belonging to Enterococcaceae genera,which are linked to inflammatory processes, showed an opposite ***, in colitic mice treated with anti-TNFα microbial changes were associated with an initial increase(day 5 of the colitis) in Treg cells and a consequent decrease(day 12 post DSS) in Th1 and Th17 frequency cells. Healthy mice treated with anti-TNFα showed the same histological, microbial and immune featur

关键词： Gut microbiota Dextran sodium sulphate colitis Immune system T cells Mesenchymal lymphnode Tumor necrosis factor α

Liver failure in an obese middle-aged woman after biliointestinal bypass

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World Journal of Clinical Cases 2013年第1期1卷 52-55页

作者： Dolores sgambato Gaetano Cotticelli Ilario de Sio Annalisa Funaro Anna Del Prete Chiara de Sio Lorenzo Romano Alessandro Federico Antonietta Gravina Agnese Miranda Carmelina Loguercio Marco Romano Department of Clinical and Experimental Medicine "Magrassi-Lanzara" Gastroenterology Unit Second University of Naples 80131 Naples Italy

Obesity is considered an emerging epidemic that is often associated with non-alcoholic fatty liver disease. Among the therapeutic options for morbid obesity, bariatric surgery plays an important role when conventional therapies fail. The effects of bariatric surgery on liver function and morphology are controversial in the literature. Liver failure has been reported after jejunoileal bypass(JIB), biliopancreatic diversion and gastric bypass. Biliointestinal bypass(BIB) is considered an effective procedure among recently introduced bariatric surgery techniques. It is a clinically safe, purely malabsorptive operation in which the blind intestinal loop of the JIB is anastomosed to the gallbladder, allowing a portion of bile to transit into excluded intestinal tract. BIB is the only procedure, to our knowledge, to have no liver side effects reported in the literature. We report the case of a young obese woman who developed liver failure 8 mo after BIB. She had a rapid weight loss(70 kg) with a reduction in body mass index of 41% from January to September 2012. Because of a severe hepatic decompensation, she was referred to a transplantation centre. We strongly believe that the most important pathogenetic mechanism involved in the development of liver injury is the rapid weight loss that produced a signif icant fatty liver inf iltration.

关键词： Bariatric surgery Biliointestinal bypass Liver failure Non-alcoholic fatty liver disease Obesity Rapid weight loss

Nature：研究鉴定出侵袭性胰腺癌细胞及其弱点

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现代生物医学进展 2017年第14期17卷 I0002-I0003页

作者： Genovese, Giannicola Carugo, Alessandro Tepper, James Robinson, Frederick Scott Li, Liren Svelto, Maria Nezi, Luigi Corti, Denise Minelli, Rosalba Pettazzoni, Piergiorgio Gutschner, Tony Wu, Chia-Chin Seth, Sahil Akdemir, Kadir Caner Leo, Elisabetta Amin, Samirkumar Dal Molin, Marco Ying, Haoqiang Kwong, Lawrence N. Colla, Simona Takahashi, Koichi Ghosh, Papia Giuliani, Virginia Muller, Florian Dey, Prasenjit Jiang, Shan Garvey, Jill Liu, Chang-Gong Zhang, Jianhua Heffernan, Timothy P. Toniatti, Carlo Fleming, Jason B. Goggins, Michael G. Wood, Laura D. sgambato, Alessandro Agaimy, Abbas Maitra, Anirban Roberts, Charles W. M. Wang, Huamin Viale, Andrea DePinho, Ronald A. Draetta, Giulio F. Chin, Lynda Univ Texas MD Anderson Canc Ctr Dept Genom Med Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Inst Appl Canc Sci Houston TX 77030 USA European Inst Oncol I-20141 Milan Italy Sun Yat Sen Univ Ctr Canc State Key Lab Oncol South China Guangzhou 510060 Guangdong Peoples R China Univ Cattolica Sacro Cuore Ist Patol Gen I-00168 Rome Italy Baylor Coll Med Grad Program Struct & Computat Biol & Mol Biophys Houston TX 77030 USA Johns Hopkins Univ Sol Goldman Pancreat Canc Res Ctr Dept Pathol Baltimore MD 21287 USA Univ Texas MD Anderson Canc Ctr Dept Mol & Cellular Oncol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Translat Mol Pathol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Leukemia Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Off Technol Commercializat Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Canc Syst Imaging Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Canc Biol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Expt Therapeut Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr ORBIT Platform Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Surg Oncol Houston TX 77030 USA Friedrich Alexander Univ Erlangen Nuremberg Univ Hosp Dept Pathol D-91054 Erlangen Germany Friedrich Alexander Univ Erlangen Nuremberg Dept Pathol D-91054 Erlangen Germany Friedrich Alexander Univ Erlangen Nuremberg Sheikh Ahmed Bin Zayed Nahyan Ctr Pancreat Canc R D-91054 Erlangen Germany St Jude Childrens Res Hosp Ctr Comprehens Canc Memphis TN 77027 USA St Jude Childrens Res Hosp Dept Oncol Memphis TN 77027 USA C4 Therapeut Cambridge MA 02142 USA Univ Texas Syst Inst Hlth Transformat Austin TX 78701 USA

在一项新的研究中，来自美国德州大学MD安德森癌症中心的研究人员利用患者源性肿瘤异种移植（patient—derived tumorxenograft,PDx）和模式小鼠开展一系列临床前实验，鉴定出一种门卫蛋白（gatekee Perprotein）阻止胰腺癌细胞转化为... 详细信息

在一项新的研究中，来自美国德州大学MD安德森癌症中心的研究人员利用患者源性肿瘤异种移植（patient—derived tumorxenograft,PDx）和模式小鼠开展一系列临床前实验，鉴定出一种门卫蛋白（gatekee Perprotein）阻止胰腺癌细胞转化为一种极具侵袭性的细胞类型，并且也发现剔除这种门卫蛋白的疗法能够阻止这些癌细胞。这些发现有助为携带这种进展迅速的治疗抵抗性的胰腺癌细胞亚群的患者开发出潜在的疗法。

关键词：胰腺癌癌细胞侵袭性鉴定异种移植研究人员细胞类型细胞转化