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Translational pancreatic cancer research:a comparative study on patient-derived xenograft models

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World Journal of Gastroenterology 2018年第7期24卷 794-809页

作者： Mercedes Rubio-Manzanares Dorado Luis Miguel Marín Gómez Daniel Aparicio Sánchez Sheila Pereira Arenas Juan Manuel Praena-Fernández Juan Jose Borrero Martín Francisco Farfán López Miguel ángel Gómez Bravo Jordi Muntané Relat Javier Padillo Ruiz Department of Hepatobiliary and Pancreatic Surgery Virgen del Rocio University Hospital Oncology Surgery Cell Therapy and Organ Transplantation Group Institute of Biomedicine of Seville (IBiS) Virgen del Rocio University Hospital University of Seville Statistics Methodology and Evaluation of Research Unit Virgen del Rocio University Hospital Pathology Department Virgen del Rocio University Hospital

AIM To assess the viability of orthotopic and heterotopic patient-derived pancreatic cancer xenografts implanted into nude *** This study presents a prospective experimental analytical follow-up of the development of tumours in mice upon implantation of human pancreatic adenocarcinoma samples. Specimens were obtained surgically from patients with a pathological diagnosis of pancreatic adenocarcinoma. Tumour samples from pancreatic cancer patients were transplanted into nude mice in three different locations(intraperitoneal, subcutaneous and pancreatic). Histological analysis(haematoxylin-eosin and Masson's trichrome staining) and immunohistochemical assessment of apoptosis(TUNEL), proliferation(Ki-67), angiogenesis(CD31) and fibrogenesis(α-SMA) were performed. When a tumour xenograft reached the target size, it was reimplanted in a new nude mouse. Three sequential tumour xenograft generations were generated(F1, F2 and F3).RESULTS The overall tumour engraftment rate was 61.1%. The subcutaneous model was most effective in terms of tissue growth(69.9%), followed by intraperitoneal(57.6%) and pancreatic(55%) models. Tumour development was faster in the subcutaneous model(17.7 ± 2.6 wk) compared with the pancreatic(23.1 ± 2.3 wk) and intraperitoneal(25.0 ± 2.7 wk) models(P = 0.064). There was a progressive increase in the tumour engraftment rate over successive generations for all three models(F1 28.1% vs F2 71.4% vs F3 80.9%, P patient-derived xenograft models presented similar histological and immunohistochemical *** In our experie

关键词： Immunohistological analysis Pancreatic cancer patient-derived xenograft Animal model Nude mice

Generation and application of patient-derived xenograft models in pancreatic cancer research

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Chinese Medical Journal 2019年第22期132卷 2729-2736页

作者： Cheng-Fang Wang Xian-Jie Shi Department of Hepato-Biliary Surgery The General Hospital of People's Liberation Army(301 hospital)Beijing 100853China

Objective:Pancreatic ductal adenocarcinoma cancer(PDAC)is one of the leading causes of cancer-related death ***,the development of effective anti-PDAC therapies is urgently ***-derived xenograft(PDX)models are useful models for developing anti-cancer therapies and screening drugs for pre&sion *** review aimed to provide an updated summary of using PDX models in *** sources:The author retrieved information from the PubMed database up to June 2019 using various combinations of search terms,including PDAC,pancreatic carcinoma,pancreatic cancer,patient-derived xenografts or PDX,and patient-derived tumor xenografts or *** selection:Original articles and review articles relevant to the review's theme were ***:PDX models are better than cell line-derived xenograft and other *** models consistently demonstrate retained tumor morphology and genetic stability,are benefi&al in cancer research,could enhance drug discovery and oncologic mechanism development of PDAC,allow an improved understanding of human cancer cell biology,and help guide personalized ***:In this review,we outline the status and application of PDX models in both basic and pre-clinical pancreatic cancer *** model is one of the most appropriate pre-clinical tools that can improve the prognosis of patients with pancreatic cancer in the future.

关键词： Cancer research Pancreatic ductal adenocarcinoma patient-derived xenografts Precision medicine

Advantages and limitations in the establishment and utilization of patient-derived xenografts in gastric cancer

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Oncology and Translational Medicine 2017年第1期3卷 3-9页

作者： Zuhua Chen Lin Shen Department of Gastrointestinal Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer Hospital&InstituteBeijing 100142China

Owing to the high genetic heterogeneity of tumors, small number of therapeutic strategies available, and frequent presentation of drug resistance, the prognosis for patients with advanced gastric cancer(AGC) are unsatisfactory. The utility of traditional cancer cell lines in translational research is limited by their poor correspondence to the genomic alterations and expression profiles that occur in actual patient tumors. In the last decade, increasing attention has been given to patient-derived tumor xenografts(PDTXs), which can faithfully recapitulate the histopathology, molecular characteristics, and therapeutic responses of the patient's tumor. However, the widespread development and utilization of PDTXs is restricted by factors such as the timeframe of establishment, lymphoma transformation during passaging, the immunodeficient microenvironment, and pharmacokinetic differences between mice and humans. In this review, we summarize the establishment and characterization of PDTX models for gastric cancer(GC). We then weigh the advantages and limitations of PDTXs when used to evaluate novel compounds, identify effective biomarkers, demonstrate resistance mechanisms, and predict clinical outcomes.

关键词： patient-derived tumor xenograft (PDTX) gastric cancer (GC) preclinical research

Mouse models of colorectal cancer: Past, present and future perspectives

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World Journal of Gastroenterology 2020年第13期26卷 1394-1426页

作者： Florian Bürtin Christina S Mullins Michael Linnebacher Department of General VisceralVascular and Transplantation SurgeryUniversity Medical Center RostockUniversity of RostockRostock 18057Germany Department of Thoracic Surgery University Medical Center RostockUniversity of RostockRostock 18057Germany Molecular Oncology and Immunotherapy Department of GeneralVisceralVascular and Transplantation SurgeryUniversity Medical Center RostockRostock 18057Germany

Colorectal cancer(CRC)is the third most common diagnosed malignancy among both sexes in the United States as well as in the European *** the incidence and mortality rates in western,high developed countries are declining,reflecting the success of screening programs and improved treatment regimen,a rise of the overall global CRC burden can be observed due to lifestyle changes paralleling an increasing human development *** a growing insight into the biology of CRC and many therapeutic improvements in the recent decades,preclinical in vivo models are still indispensable for the development of new treatment *** the development of carcinogen-induced rodent models for CRC more than 80 years ago,a plethora of animal models has been established to study colon cancer *** tenuous invasiveness and metastatic behavior,these models are useful for chemoprevention studies and to evaluate colitis-related *** engineered mouse models(GEMM)mirror the pathogenesis of sporadic as well as inherited CRC depending on the specific molecular pathways activated or *** the vast majority of CRC GEMM lack invasiveness,metastasis and tumor heterogeneity,they still have proven useful for examination of the tumor microenvironment as well as systemic immune responses;thus,supporting development of new therapeutic *** of metastatic disease by orthotopic injection of CRC cell lines is possible,but the so generated models lack genetic diversity and the number of suited cell lines is very ***-derived xenografts,in contrast,maintain the pathological and molecular characteristics of the individual patient's CRC after subcutaneous implantation into immunodeficient mice and are therefore most reliable for preclinical drug development–even in comparison to GEMM or cell line-based ***,subcutaneous patient-derived xenograft models are less suitable for studying most aspects of the tumor micr

关键词： Colorectal cancer Mouse models patient-derived xenografts Carcinogen-induced models Genetically engineered mouse models Preclinical drug development

Establishment,functional and genetic characterization of a colon derived large cell neuroendocrine carcinoma cell line

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World Journal of Gastroenterology 2018年第33期24卷 3749-3759页

作者： Michael Gock Christina S Mullins Christine Harnack Friedrich Prall Robert Ramer Anja Goder Oliver H Kramer Ernst Klar Michael Linnebacher Department of General Surgery University of RostockRostock 18055Germany Department of General Surgery Section of Molecular Oncology and ImmunotherapyUniversity of RostockRostock 18055Germany Institute of Pathology University of RostockRostock 18055Germany Institute of Pharmacology University of RostockRostock 18055Germany Institute of Toxicology University Medical Center MainzMainz 55131Germany

AIM To establish cell line and patient-derived xenograft(PDX) models for neuroendocrine carcinomas(NEC) which is highly desirable for gaining insight into tumor development as well as preclinical research includingbiomarker testing and drug response *** Cell line establishment was conducted from direct in vitro culturing of colonic NEC tissue(HROC57). A PDX could also successfully be established from vitally frozen tumor samples. Morphological features, invasive and migratory behavior of the HROC57 cells as well as expression of neuroendocrine markers were vastly analyzed. Phenotypic analysis was done by microscopy and multicolor flow cytometry. The extensive molecular-pathological profiling included mutation analysis, assessment of chromosomal and microsatellite instability; and in addition, fingerprinting(i.e., STR analysis) was performed from the cell line in direct comparison to primary patient-derived tissues and the PDX model established. Drug responsiveness was examined for a panel of chemotherapeutics in clinical use for the treatment of solid *** The established cell line HROC57 showed distinct morphological and molecular features of a poorly differentiated large-cell NEC with KI-67 > 50%. Molecular-pathological analysis revealed a Cp G island promoter methylation positive cell line with microsatellite instability being absent. The following mutation profile was observed: KRAS(wt), BRAF(mut). A high sensitivity to etoposide, cisplatin and 5-FU could be demonstrated while it was more resistant towards rapamycin. CONCLUSION We successfully established and characterized a novel patient-derived NEC cell line in parallel to a PDX model as a useful tool for further analysis of the biological characteristics and for development of novel diagnostic and therapeutic options for NEC.

关键词： patient-derived tumor model Large cell neuroendocrine carcinoma Individualized medicine

Establishment and characterization of cell lines from chromosomal instable colorectal cancer

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World Journal of Gastroenterology 2015年第1期21卷 164-176页

作者： Claudia Maletzki Michael Gock Martin Randow Ernst Klar Maja Huehns Friedrich Prall Michael Linnebacher Section of Molecular Oncology and Immunotherapy University of RostockD-18057 RostockGermany Department of General Surgery University of RostockD-18057 RostockGermany Institute of Pathology University of RostockD-18057 RostockGermany

AIM: To generate novel tumor models for preclinicalvalidation of biomarkers that allow drug response prediction and individual therapeutic ***: Cell line establishment was conducted by both direct in vitro culturing and in vivo xenografting followed by in vitro culturing procedure.A comprehensive characterization was subsequently *** included quality control,consisting of the confirmation of human and colorectal cancer(CRC) origin by DNA fingerprint and epithelial cell adhesion molecule(EpC AM) staining,as well as mycoplasma and human virus *** analysis was done by light microscopy and multicolor flow *** examination(β-catenin and cytokeratin staining) was conducted in direct comparison to parental tumor *** molecular-pathological profiling included mutation analysis for CRC-associated driver mutations,assessment of chromosomal and microsatellite instability,and the grade of CpG island ***,an arraybased comparative genomic hybridization analysis was *** responsiveness was assessed for a panel of classical and novel substances in clinical use for the treatment of solid ***,tumorigenicity of the cell lines was tested by xenografting into immunocompromised nude ***: Herein we describe the establishment of three ultra-low passage cell lines from two individual patients suffering from sporadic *** cell line was derived directly from an early stage case(HROC18),whereas two cell lines could be established both direct from patient material and after xenografting from a late stage tumor(HROC32).All cell lines were free of contaminating mycoplasma and *** analysis allowed all cell lines to be classified as chromosomal instable(CIN+).They were aneuploid,with CpG island promoter methylation and microsatellite instability being *** following mutational profile was observed both in the cell lines and the parental t

关键词： patient-derived tumor model Colorectal cancer Indi

Modeling diseases of noncoding unstable repeat expansions using mutant pluripotent stem cells

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World Journal of Stem Cells 2015年第5期7卷 823-838页

作者： Shira Yanovsky-Dagan Hagar Mor-Shaked Rachel Eiges Stem Cell Research Laboratory Medical Genetics Institute Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine

Pathogenic mutations involving DNA repeat expansions are responsible for over 20 different neuronal and neuromuscular diseases. All result from expanded tracts of repetitive DNA sequences(mostly microsatellites) that become unstable beyond a critical length whentransmitted across generations. Nearly all are inherited as autosomal dominant conditions and are typically associated with anticipation. Pathologic unstable repeat expansions can be classified according to their length, repeat sequence, gene location and underlying pathologic mechanisms. This review summarizes the current contribution of mutant pluripotent stem cells(diseased human embryonic stem cells and patient-derived induced pluripotent stem cells) to the research of unstable repeat pathologies by focusing on particularly large unstable noncoding expansions. Among this class of disorders are Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome, myotonic dystrophy type 1 and myotonic dystrophy type 2, Friedreich ataxia and C9 related amyotrophic lateral sclerosis and/or frontotemporal dementia, Facioscapulohumeral Muscular Dystrophy and potentially more. Common features that are typical to this subclass of conditions are RNA toxic gain-of-function, epigenetic loss-of-function, toxic repeat-associated non-ATG translation and somatic instability. For each mechanism we summarize the currently available stem cell based models, highlight how they contributed to better understanding of the related mechanism, and discuss how they may be utilized in future investigations.

关键词： Unstable repeat associated disorders Human embryonic stem cells patient-derived inducedpluripotent stem cells Disease modeling Epigenetics repeat-associated non-ATG translation RNA toxicity Repeat somatic instability

AMPK promotes the survival of colorectal cancer stem cells

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Animal Models and Experimental Medicine 2018年第2期1卷 134-142页

作者： Bing Guo Xin Han Diane Tkach Shu-Guang Huang Dong Zhang Pfizer Research Novartis Pharmaceuticals Department of Biomedical Sciences College of Osteopathic Medicine New York Institute of Technology

Background: Colorectal cancer(CRC) is the third most commonly diagnosed cancer in males and the second in females worldwide in 2012. In the past 20 years, strong evidence suggests that cancer stem cells are the main culprit of cancer metastasis,chemotherapy resistance, and ***: To further understand the unique biological properties of cancer stem cells and uncover novel molecular targets to eradicate them, we first established a panel of patient-derived xenograft(PDX) tumor models using tumors surgically removed from human colorectal cancer patients. We then isolated CRC cancer stem cells based on their ALDH activity using fluorescent-activated cell sorting(FACS)and characterized their metabolic ***: Interestingly, we found that the CRC cancer stem cells(ie, CRC cells with higher ALDH activity, or ALDH+) express higher level of antioxidant genes and have lower level of reactive oxygen species(ROS) than non-CRC cancer stem cells(ie, CRC cells with lower ALDH activity, or ALDHà). The CRC cancer stem cells also possess more mitochondria mass and show higher mitochondrial activity. More intriguingly,we observed higher AMP-activated protein kinase(AMPK) activities in these CRC cancer stem cells. Inhibition of the AMPK activity using 2 AMPK inhibitors, Compound C and Iodotubercidin, preferentially induces cell death in CRC cancer stem ***: We propose that AMPK inhibitors may help to eradicate the CRC cancer stem cells and prevent the relapse of CRCs.

关键词： AMP-activated protein kinase cancer metabolism colorectal cancer stem cells patient-derived xenograft