title: Functional Characterization and Drug Response of Freshly Established Patient-Derived Tumor Models with CpG Island Methylator Phenotype.
abstract: Patient-individual tumor models constitute a powerful platform for basic and translational analyses both in vitro and in vivo. However, due to the labor-intensive and highly time-consuming process, only few well-characterized patient-derived cell lines and/or corresponding xenografts exist. In this study, we describe successful generation and functional analysis of novel tumor models from patients with sporadic primary colorectal carcinomas (CRC) showing CpG island methylator phenotype (CIMP). Initial DNA fingerprint analysis confirmed identity with the patient in all four cases. These freshly established cells showed characteristic features associated with the CIMP-phenotype (HROC40: APCwt, TP53 mut, KRAS mut; 3/8 marker methylated; HROC43: APC mut, TP53 mut, KRAS mut; 4/8 marker methylated; HROC60: APCwt, TP53 mut, KRASwt; 4/8 marker methylated; HROC183: APC mut, TP53 mut, KRAS mut; 6/8 marker methylated). Cell lines were of epithelial origin (EpCAM+) with distinct morphology and growth kinetics. Response to chemotherapeutics was quite individual between cells, with stage I-derived cell line HROC60 being most susceptible towards standard clinically approved chemotherapeutics (e.g. 5-FU, Irinotecan). Of note, most cell lines were sensitive towards "non-classical" CRC standard drugs (sensitivity: Gemcitabin > Rapamycin > Nilotinib). This comprehensive analysis of tumor biology, genetic alterations and assessment of chemosensitivity towards a broad range of (chemo-) therapeutics helps bringing forward the concept of personalized tumor therapy.
authors.affiliation: Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Maletzki
authors.affiliation: Institute of Pathology, University of Rostock, Rostock, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Huehns
authors.affiliation: Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Knapp
authors.affiliation: Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany.
authors.forename: Nancy
authors.initials: N
authors.lastname: Waukosin
authors.affiliation: Department of General Surgery, University of Rostock, Rostock, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Klar
authors.affiliation: Institute of Pathology, University of Rostock, Rostock, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Prall
authors.affiliation: Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebacher
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D057285:Precision Medicine; D061251:Primary Cell Culture
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor