The clinical relevance of cancer cell lines.

Although advances in genomics during the last decade have opened new avenues for translational research and allowed the direct evaluation of clinical samples, there is still a need for reliable preclinical models to test therapeutic strategies. Human cancer-derived cell lines are the most widely used models to study the biology of cancer and to test hypotheses to improve the efficacy of cancer treatment. Since the development of the first cancer cell line, the clinical relevance of these models has been continuously questioned. Based upon recent studies that have fueled the debate, we review the major events in the development of the in vitro models and the emergence of new technologies that have revealed important issues and limitations concerning human cancer cell lines as models. All cancer cell lines do not have equal value as tumor models. Some have been successful, whereas others have failed. However, the success stories should not obscure the growing body of data that motivates us to develop new in vitro preclinical models that would substantially increase the success rate of new in vitro-assessed cancer treatments.

[1]  W. Nelson-Rees The identification and monitoring of cell line specificity. , 1978, Progress in clinical and biological research.

[2]  M. Gottesman,et al.  The Hepatocyte and the Cancer Cell: Dr Jekyll and Mr Hyde , 2009 .

[3]  Jean-Pierre Gillet,et al.  Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance , 2011, Proceedings of the National Academy of Sciences.

[4]  S. Ramaswamy,et al.  Systematic identification of genomic markers of drug sensitivity in cancer cells , 2012, Nature.

[5]  D. Selwood,et al.  Anticancer Drug Development: Preclinical Screening, Clinical Trials and Approval , 2004, British Journal of Cancer.

[6]  Use of the KB cell line for in vitro cytotoxicity assays. , 1983, Cancer treatment reports.

[7]  Jean-Pierre Gillet,et al.  Mechanisms of multidrug resistance in cancer. , 2010, Methods in molecular biology.

[8]  T. Perlmann,et al.  Maintaining differentiated cellular identity , 2012, Nature Reviews Genetics.

[9]  Curt Ga,et al.  Evidence for multidrug-resistant cells in human tumor cell populations. , 1983 .

[10]  Yuri Kotliarov,et al.  Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. , 2006, Cancer cell.

[11]  Paul A Clemons,et al.  The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease , 2006, Science.

[12]  Brendan Borrell,et al.  How accurate are cancer cell lines? , 2010, Nature.

[13]  B. Fleshler,et al.  The Liver: Biology and Pathobiology , 1983 .

[14]  Shuguang Huang,et al.  Comparative analysis and integrative classification of NCI60 cell lines and primary tumors using gene expression profiling data , 2006, BMC Genomics.

[15]  Michael Peyton,et al.  Alterations in Genes of the EGFR Signaling Pathway and Their Relationship to EGFR Tyrosine Kinase Inhibitor Sensitivity in Lung Cancer Cell Lines , 2009, PloS one.

[16]  Adam A. Margolin,et al.  The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity , 2012, Nature.

[17]  W. Nelson-Rees,et al.  Inter- and intraspecies contamination of human breast tumor cell lines HBC and BrCa5 and other cell cultures , 1977, Science.

[18]  W. Nelson-Rees,et al.  Banded Marker Chromosomes as Indicators of Intraspecies Cellular Contamination , 1974, Science.

[19]  Michael R. Boyd,et al.  The NCI In Vitro Anticancer Drug Discovery Screen , 1997 .

[20]  M. Gottesman,et al.  Advances in the molecular detection of ABC transporters involved in multidrug resistance in cancer. , 2011, Current pharmaceutical biotechnology.

[21]  R. Shoemaker The NCI60 human tumour cell line anticancer drug screen , 2006, Nature Reviews Cancer.

[22]  Gemma K. Alderton Stem cells: Marking stem cells , 2012, Nature Reviews Cancer.

[23]  C. Rudin,et al.  Frequent detection of infectious xenotropic murine leukemia virus (XMLV) in human cultures established from mouse xenografts , 2011, Cancer biology & therapy.

[24]  V. Ling,et al.  Multidrug resistance in cancer. , 1989, Scientific American.

[25]  I. Pastan,et al.  Isolation and genetic characterization of human KB cell lines resistant to multiple drugs , 1985, Somatic cell and molecular genetics.

[26]  S. Yamanaka,et al.  Induced pluripotent stem cells: opportunities and challenges , 2011, Philosophical Transactions of the Royal Society B: Biological Sciences.

[27]  American Type Culture Collection Standards Development Orga ASN-0002 Cell line misidentification: the beginning of the end , 2010, Nature Reviews Cancer.

[28]  T. Langmann,et al.  Human ATP-binding cassette transporter TaqMan low-density array: analysis of macrophage differentiation and foam cell formation. , 2006, Clinical chemistry.

[29]  J. T. Syverton,et al.  STUDIES ON THE PROPAGATION IN VITRO OF POLIOMYELITIS VIRUSES , 1952, The Journal of experimental medicine.

[30]  Nelson Wa The identification and monitoring of cell line specificity. , 1978 .

[31]  J. T. Syverton,et al.  STUDIES ON THE PROPAGATION IN VITRO OF POLIOMYELITIS VIRUSES , 1952, The Journal of experimental medicine.

[32]  D. Haber,et al.  Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents , 2010, Nature Reviews Cancer.

[33]  J. Minna,et al.  Lung cancer cell lines: Useless artifacts or invaluable tools for medical science? , 2010, Lung cancer.

[34]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

[35]  Luc Girard,et al.  Lung cancer cell lines as tools for biomedical discovery and research. , 2010, Journal of the National Cancer Institute.

[36]  R. E. Purdue KB cell culture I. Role in discovery of antitumor agents from higher plants. , 1982 .

[37]  E. D. de Vries,et al.  Prognostic versus predictive value of biomarkers in oncology. , 2008, European journal of cancer.

[38]  H. Parkinson,et al.  A global map of human gene expression , 2010, Nature Biotechnology.

[39]  R. Shoemaker,et al.  Evidence for multidrug-resistant cells in human tumor cell populations. , 1983, Cancer treatment reports.

[40]  R. E. Perdue KB cell culture I. Role in discovery of antitumor agents from higher plants. , 1982, Journal of natural products.

[41]  M. Volm,et al.  Human tumor xenografts as model for drug testing , 1988, Cancer and Metastasis Reviews.

[42]  T. Yamori,et al.  Panel of human cancer cell lines provides valuable database for drug discovery and bioinformatics , 2003, Cancer Chemotherapy and Pharmacology.

[43]  Masters,et al.  Cell line misidentification: the beginning of the end , 2010 .

[44]  N. McCarthy Mouse models: Of mice and men , 2012, Nature Reviews Cancer.

[45]  M. Gottesman,et al.  Clinical relevance of multidrug resistance gene expression in ovarian serous carcinoma effusions. , 2011, Molecular pharmaceutics.

[46]  Ultan McDermott,et al.  High-throughput lung cancer cell line screening for genotype-correlated sensitivity to an EGFR kinase inhibitor. , 2008, Methods in enzymology.

[47]  P. Arnstein,et al.  Source, alterations, characteristics and use of a new dog cell line (Cf2Th) , 1976, In Vitro.

[48]  J. Weinstein Drug discovery: Cell lines battle cancer , 2012, Nature.

[49]  Justin Lamb,et al.  The Connectivity Map: a new tool for biomedical research , 2007, Nature Reviews Cancer.

[50]  A. Cebrián,et al.  Approaches for the study of cancer: towards the integration of genomics, proteomics and metabolomics , 2011, Clinical and Translational Oncology.

[51]  K. Garber From human to mouse and back: 'tumorgraft' models surge in popularity. , 2009, Journal of the National Cancer Institute.

[52]  L. Wessels,et al.  Do predictive signatures really predict response to cancer chemotherapy? , 2010, Cell cycle.

[53]  P. Ikonomi,et al.  Short tandem repeat profiling: part of an overall strategy for reducing the frequency of cell misidentification , 2010, In Vitro Cellular & Developmental Biology - Animal.

[54]  T. Tsuruo,et al.  Potent antitumor activity of MS-247, a novel DNA minor groove binder, evaluated by an in vitro and in vivo human cancer cell line panel. , 1999, Cancer research.

[55]  Amanda Capes-Davis,et al.  Recommendation of short tandem repeat profiling for authenticating human cell lines, stem cells, and tissues , 2010, In Vitro Cellular & Developmental Biology - Animal.

[56]  Gabriel S. Eichler,et al.  Evaluation of current methods used to analyze the expression profiles of ATP-binding cassette transporters yields an improved drug-discovery database , 2009, Molecular Cancer Therapeutics.

[57]  L. Chin,et al.  Non-germline genetically engineered mouse models for translational cancer research , 2010, Nature Reviews Cancer.

[58]  A N Desai,et al.  Next‐generation sequencing: ready for the clinics? , 2012, Clinical genetics.

[59]  Olivier Toussaint,et al.  Artefactual effects of oxygen on cell culture models of cellular senescence and stem cell biology , 2011, Journal of cellular physiology.

[60]  P. Borst,et al.  Drug resistance in the mouse cancer clinic. , 2012, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[61]  Wen-Lin Kuo,et al.  A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. , 2006, Cancer cell.

[62]  Jean-Pierre Gillet,et al.  Multidrug Resistance–Linked Gene Signature Predicts Overall Survival of Patients with Primary Ovarian Serous Carcinoma , 2012, Clinical Cancer Research.