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Recent advances in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms

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World Journal of Gastrointestinal Surgery 2022年第5期14卷 383-396页

作者： Meng Dai Christina S Mullins Lili Lu Guido Alsfasser michael linnebacher Clinic of General Surgery Molecular Oncology and ImmunotherapyRostock University Medical Center18057 RostockGermany Clinic of General Surgery Rostock University Medical Center18057 RostockGermany

Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)are a rare group of tumors originating from neuroendocrine cells of the digestive system.Their incidence has increased over the last decades.The specific pathogenetic mechanisms underlying GEP-NEN development have not been completely revealed.Unfunctional GEP-NENs are usually asymptomatic;some grow slowly and thus impede early diagnosis,which ultimately results in a high rate of misdiagnosis.Therefore,many GEP-NEN patients present with later staged tumors.Motivated hereby,research attention for diagnosis and treatment for GEP-NENs increased in recent years.The result of which is great progress in clinical diagnosis and treatment.According to the most recent clinical guidelines,improved grading standards can accurately define poorly differentiated grade 3 neuroendocrine tumors and neuroendocrine carcinomas(NECs),which are subclassified into large and small cell NECs.Combining different functional imaging methods facilitates precise diagnosis.The expression of somatostatin receptors helps to predict prognosis.Genetic analyses of mutations affecting death domain associated protein(DAXX),multiple endocrine neoplasia type 1(MEN 1),alpha thalassemia/intellectual disability syndrome X-linked(ATRX),retinoblastoma transcriptional corepressor 1(RB 1),and mothers against decapentaplegic homolog 4(SMAD 4)help distinguishing grade 3 NENs from poorly differentiated NECs.The aim of this review is to summarize the latest research progress on diagnosis and treatment of GEP-NENs.

关键词： GEP-NENs Functional imaging Peptide receptor radionuclide therapy Targeting agents Immune checkpoint inhibitors Genetic mutations

Human endogenous retroviruses and cancer:Causality and therapeutic possibilities

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World Journal of Gastroenterology 2012年第42期18卷 6027-6035页

作者： Christina S Mullins michael linnebacher Department of General ThoracicVascular and Transplantation SurgerySection Molecular Oncology and ImmunotherapyUniversity of RostockSchillingallee 3518057 RostockGermany

A substantial part of the human genome is derived from transposable elements;remnants of ancient retroviral infections.Conservative estimates set the percentage of human endogenous retroviruses(HERVs) in the genome at 8%.For the most part,the interplay between mutations,epigenetic mechanisms and posttranscriptional regulations silence HERVs in somatic cells.We first highlight mechanisms by which activation of members of several HERV families may be associated with tumor development before discussing the arising chances for both diagnosis and therapy.It has been shown that at least in some cases,tumor cells expressing HERV open reading frames(ORFs) thus gain tumor-promoting functions.However,since these proteins are not expressed in healthy tissues,they become prime target structures.Of potential pharmacological interest are the prevention of HERV transposition,the inhibition of HERV-encoded protein expression and the interference with these proteins' activities.Evidence from recent studies unequivocally proves that HERV ORFs represent a very interesting source of novel tumor-specific antigens with even the potential to surpass entity boundaries.The development of new tumor(immune-) therapies is a very active field and true tumor-specific targets are of outstanding interest since they minimize the risk of autoimmunity and could reduce side effects.Finally,we postulate on main future research streams in order to stimulate discussion on this hot topic.

关键词：内源性逆转录病毒人类基因组因果关系治疗自身免疫性疾病癌症开放阅读框特异性抗原

Tumor-infiltrating B cells come into vogue

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World Journal of Gastroenterology 2013年第1期19卷 8-11页

作者： michael linnebacher Division of Molecular Oncology and Immunotherapy Department of General SurgeryUniversity of RostockD-18057 RostockGermany

Lymphocyte infiltration into solid tumors has been recognized as a main determinator of positive prognosis.For the most part this is attributed to cytotoxic T cells capable of directly destroying malignant cells.However,when considering the complex composition of the human immune system,recent findings of Nielsenet al on a potentially central role of tumor-infiltrating B cells is not really surprising.In this commentary article,I want to highlight the enormous potential impact of this observation for basic and translational research,prognostic procedures and ultimately for the development of future therapeutic concepts.

关键词： CD20 + tumor-infiltrating lymphocytes Tumorinfiltrating B cells Prognosis Immunotherapy Functional immunology

Bacteriolytic therapy of experimental pancreatic carcinoma

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World Journal of Gastroenterology 2010年第28期16卷 3546-3552页

作者： Claudia Maletzki michael Gock Ulrike Klier Ernst Klar michael linnebacher Department of General VascularThoracic and Transplantation SurgerySection of Molecular Oncology and ImmunotherapyUniversity of Rostock18057 RostockGermany

AIM:To investigate the effectiveness of Clostridium novyi(C.novyi)-NT spores for the treatment of established subcutaneous pancreatic tumor in the syngeneic,immunocompetent Panc02/C57Bl/6 model. METHODS:C.novyi-NT spores were applied intravenously to animals carrying established pancreatic tumors of three different sizes.Systemic immune responses in peripheral blood and spleen were examined by flow cytometry.Supplementary,cytotoxic activity of lymphocytes against syngeneic tumor targets was analyzed. RESULTS:Application of spores identified,that(1) small tumors(450 mm3)responded with substantial necrosis followed by shrinkage and significant lethality most likely due to tumor lysis syndrome (n=6);and(3)an optimal treatment window exists for tumors of approximately 250 mm 3 (n=21).In this latter group,all tumor-bearing animals had complete tu-mor regression and remained free of tumor recurrence. In subsequent tumor rechallenge experiments a significant delay in tumor growth compared to the initial tumor cell inoculation was observed(tumor volume at day 28:197.8±87.3 mm 3 vs 500.1±50.9 mm3,P<0.05). These effects were accompanied by systemic activation of immune response mechanisms predominantly mediated by the innate arm of the immune system. CONCLUSION:The observed complete tumor regression is encouraging and shows that immunotherapy with C.novyi-NT is an interesting strategy for the treatment of pancreatic carcinomas of defined sizes.

关键词： Bacteriolytic immunotherapy Clostridium novyi-NT Immune response Pancreatic carcinoma

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 Union.While 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 index.Despite 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 approaches.Since 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 biology.Despite tenuous invasiveness and metastatic behavior,these models are useful for chemoprevention studies and to evaluate colitis-related carcinogenesis.Genetically engineered mouse models(GEMM)mirror the pathogenesis of sporadic as well as inherited CRC depending on the specific molecular pathways activated or inhibited.Although 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 avenues.Induction 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 limited.Patient-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 analyses.However,subcutaneous patient-derived xenograft models are less suitable for studying most aspects of the tumor microenvironment and anti-tumoral immune responses.T

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

Colorectal cancer vaccines: Tumor-associated antigens vs neoantigens

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World Journal of Gastroenterology 2018年第48期24卷 5418-5432页

作者： Sandra Wagner Christina S Mullins michael linnebacher Section of Molecular Oncology and Immunotherapy General SurgeryUniversity Medical Center

Therapeutic options for the treatment of colorectal cancer(CRC) are diverse but still not always satisfying. Recent success of immune checkpoint inhibition treatment for the subgroup of CRC patients suffering from hypermutated tumors suggests a permanent role of immune therapy in the clinical management of CRC. Substantial improvement in treatment outcome could be achieved by development of efficient patient-individual CRC vaccination strategies. This mini-review summarizes the current knowledge on the two general classes of targets: tumor-associated antigens(TAAs) and tumorspecific antigens. TAAs like carcinoembryonic antigen and melanoma associated antigen are present in and shared by a subgroup of patients and a variety of clinical studies examined the efficacy of different TAA-derived peptide vaccines. Combinations of several TAAs as the next step and the development of personalized TAA-based peptide vaccines are discussed. Improvements of peptidebased vaccines achievable by adjuvants and immunestimulatory chemotherapeutics are highlighted. Finally, we sum up clinical studies using tumor-specific antigens-in CRC almost exclusively neoantigens-which revealed promising results; particularly no severe adverse events were reported so far. Critical progress for clinical outcomes can be expected by individualizing neoantigen-based peptide vaccines and combining them with immunestimulatory chemotherapeutics and immune checkpoint inhibitors. In light of these data and latest developments, truly personalized neoantigen-based peptide vaccines can be expected to fulfill modern precision medicine's requirements and will manifest as treatment pillar for routine clinical management of CRC.

关键词： Cancer vaccines Colorectal neoplasm Immunotherapy Neoplasm antigen tumor-associated antigens tumor-specific antigens Neoantigen(s)

A global assessment of recent trends in gastrointestinal cancer and lifestyle-associated risk factors

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Cancer Communications 2021年第11期41卷 1137-1151页

作者： Lili Lu Christina S.Mullins Clemens Schafmayer Sebastian Zeißig michael linnebacher Department of General Surgery Molecular Oncology and ImmunotherapyRostock University Medical CenterRostock 18057Germany Department of Medicine I University Hospital Carl Gustav CarusTechnische Universität(TU)DresdenDresden 01307Germany

Background:Gastrointestinal(GI)cancers were responsible for 26.3%of cancer cases and 35.4%of deaths worldwide in 2018.This study aimed to analyze the global incidence,mortality,prevalence,and contributing risk factors of the 6 major GI cancer entities[esophageal cancer(EC),gastric cancer(GC),liver cancer(LC),pancreatic cancer(PC),colon cancer,and rectal cancer].Methods:Using the Global Cancer Observatory and the Global Health Observatory databases,we reviewed the current GI cancer incidence,prevalence,and mortality,analyzed the association of GI cancer prevalence with national human development indices(HDIs),identified the contributing risk factors,and estimated developing age-and sex-specific trends in incidence and mortality.Results:In 2020,the trend in age-standardized rate of incidence of GI cancers closely mirrored that of mortality,with the highest rates of LC,EC,and GC in Asia and of colorectal cancer(CRC)and PC mainly in Europe.Incidence and mortality were positively,but the mortality-to-incidence ratio(MIR)was inversely correlated with the national HDI levels.High MIRs in developing countries likely reflected the lack of preventive strategies and effective treatments.GI cancer prevalence was highest in Europe and was also positively correlated with HDIs and lifestyle-associated risk factors,such as alcohol consumption,smoking,obesity,insufficient physical activity,and high blood cholesterol level,but negatively correlated with hypertension and diabetes.Incidences of EC were consistently and those of GC mostly decreasing,whereas incidences of CRC were increasing in most countries/regions,especially in the younger populations.Incidences of LC and PC were also increasing in all age-gender populations except for younger males.Mortalities were decreasing for EC,GC,and CRC in most countries/regions, and age-specific trends were observed in PC and LC with adecrease in the younger but an increase in the older population.Conclusions: On the global scale, higher GI cancer burden was accompanied,for the most part,

关键词： annual percentage change(APC) diabetes gastrointestinal(GI)cancer high blood cholesterol human development indices(HDI) hypertension incidence lifestyle mortality prevalence

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 prediction.METHODS 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 cancers.RESULTS 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,functional and genetic characterization of three novel patient-derived rectal cancer cell lines

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World Journal of Gastroenterology 2018年第43期24卷 4880-4892页

作者： michael Gock Christina S Mullins Carina Bergner Friedrich Prall Robert Ramer Anja Goder Oliver H Kramer Falko Lange Bernd J Krause Ernst Klar michael linnebacher Department of General Surgery University Medical CenterRostock 18055Germany Section of Molecular Oncology and Immunotherapy University MedicalCenterRostock 18055Germany Department of NuclearMedicine University Medical CenterRostock 18055Germany Institute of Pathology University MedicalCenterRostock 18055Germany Institute of Pharmacology University Medical CenterRostock 18055Germany Institute of Toxicology University Medical Center MainzMainz 55131Germany Oscar-Langendorff-Institute of Physiology University Medical CenterRostock 18055Germany

AIM To establish patient-individual tumor models of rectal cancer for analyses of novel biomarkers, individual response prediction and individual therapy regimens.METHODS Establishment of cell lines was conducted by direct in vitro culturing and in vivo xenografting with subsequent in vitro culturing. Cell lines were in-depth characterized concerning morphological features, invasive and migratory behavior, phenotype, molecular profile including mutational analysis, protein expression, and confirmation of origin by DNA fingerprint. Assessment of chemosensitivity towards an extensive range of current chemotherapeutic drugs and of radiosensitivity was performed including analysis of a combined radioand chemotherapeutic treatment. In addition, glucose metabolism was assessed with 18 F-fluorodeoxyglucose(FDG) and proliferation with 18 F-fluorothymidine.RESULTS We describe the establishment of ultra-low passage rectal cancer cell lines of three patients suffering from rectal cancer. Two cell lines(HROC126, HROC284 Met) were established directly from tumor specimens while HROC239 T0 M1 was established subsequent to xenografting of the tumor. Molecular analysis classified all three cell lines as CIMP-0/non-MSI-H(sporadic standard) type. Mutational analysis revealed following mutational profiles: HROC126: APC^(wt), TP53^(wt), KRAS^(wt), BRAF^(wt), PTEN^(wt); HROC239 T0 M1: APC^(mut), P53^(wt), KRAS^(mut), BRAF^(wt), PTEN^(mut) and HROC284 Met: APC^(wt), P53^(mut), KRAS^(mut), BRAF^(wt), PTEN^(mut). All cell lines could be characterized as epithelial(EpCAM+) tumor cells with equivalent morphologic features and comparable growth kinetics. The cell lines displayed a heterogeneous response toward chemotherapy, radiotherapy and their combined application. HROC126 showed a highly radio-resistant phenotype and HROC284 Met was more susceptible to a combined radiochemotherapy than HROC126 and HROC239 T0 M1. Analysis of 18 F-FDG uptake displayed a markedly reduced FDG uptake of all three cell lines after combined radiochemotherapy.

关键词： Patient-derived tumor model Rectal cancer ^(18)F-fluorodeoxyglucose ^(18)F-fluorothymidine FOLFOX FOLFIRI Personalized medicine