Cancer Modeling in the Modern Era Progress and Challenges

Genetically engineered mouse models have contributed extensively to the field of cancer research. The ability to manipulate the mouse germline affords numerous approaches toward understanding the complexities of this disease, possibly providing accurate preclinical models for therapeutic and diagnostic advances. This review highlights some of the current strategies for modeling cancer in the mouse, recent accomplishments, and key remaining challenges.

[1]  J. Blenis,et al.  An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Krzysztof P Bobinski,et al.  Seeing is believing: Non‐invasive, quantitative and repetitive imaging of reporter gene expression in living animals, using positron emission tomography , 2000, Journal of neuroscience research.

[3]  G. Lozano,et al.  Mouse models dissect the role of p53 in cancer and development. , 1998, Seminars in cancer biology.

[4]  Scott W. Lowe,et al.  Apoptosis A Link between Cancer Genetics and Chemotherapy , 2002, Cell.

[5]  M J Paulus,et al.  High resolution computed tomography and MRI for monitoring lung tumor growth in mice undergoing radioimmunotherapy: correlation with histology. , 2000, Medical physics.

[6]  G. Christofori,et al.  N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling , 2001, Nature Cell Biology.

[7]  H. Varmus,et al.  Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. , 2001, Genes & development.

[8]  S. Dudley,et al.  Mlh1 deficiency enhances several phenotypes of ApcMin/+ mice , 2000, Oncogene.

[9]  Shigeyoshi Itohara,et al.  Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis , 2000, Nature Cell Biology.

[10]  S. Lowe,et al.  INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. , 1999, Genes & development.

[11]  L. Chin,et al.  Essential role for oncogenic Ras in tumour maintenance , 1999, Nature.

[12]  F. Wórum,et al.  [Islet cell carcinoma]. , 1987, Orvosi hetilap.

[13]  Thomas Ried,et al.  Multicolour spectral karyotyping of mouse chromosomes , 1996, Nature Genetics.

[14]  C. Contag,et al.  Visualizing the kinetics of tumor-cell clearance in living animals. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  K. Pienta,et al.  Longitudinal cohort analysis of lethal prostate cancer progression in transgenic mice. , 1998, The Journal of urology.

[16]  A. Lenferink,et al.  Blockade of the epidermal growth factor receptor tyrosine kinase suppresses tumorigenesis in MMTV/Neu + MMTV/TGF-alpha bigenic mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[17]  A. Berns.  Cancer: Improved mouse models , 2001, Nature.

[18]  A. Bradley,et al.  Cancer predisposition caused by elevated mitotic recombination in Bloom mice , 2000, Nature Genetics.

[19]  Lynda Chin,et al.  Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice , 2000, Nature.

[20]  G. Magrane,et al.  Selective Inactivation of p53 Facilitates Mouse Epithelial Tumor Progression without Chromosomal Instability , 2001, Molecular and Cellular Biology.

[21]  D. Hanahan,et al.  Angiogenesis and apoptosis are cellular parameters of neoplastic progression in transgenic mouse models of tumorigenesis. , 1998, The International journal of developmental biology.

[22]  T. Jacks,et al.  Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. , 2001, Genes & development.

[23]  R. Kucherlapati,et al.  Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice. , 1999, Cancer research.

[24]  D. Louis,et al.  PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. , 2001, Genes & development.

[25]  A. Berns,et al.  Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer , 2001, Nature Genetics.

[26]  R Weissleder,et al.  In vivo imaging of proteolytic enzyme activity using a novel molecular reporter. , 2000, Cancer research.

[27]  Ashok R Venkitaraman,et al.  Cancer Susceptibility and the Functions of BRCA1 and BRCA2 , 2002, Cell.

[28]  R. Hoffman,et al.  Visualization of GFP-expressing tumors and metastasis in vivo. , 2001, BioTechniques.

[29]  T. Jacks,et al.  Insights into cancer from transgenic mouse models , 1999, The Journal of pathology.

[30]  Thomas Ried,et al.  Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation , 1999, Nature Genetics.

[31]  Gerhard Christofori,et al.  A causal role for E-cadherin in the transition from adenoma to carcinoma , 1998, Nature.

[32]  G. Evan,et al.  Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. , 1999, Molecular cell.

[33]  D. Troyer,et al.  Genetic determinants of response to chemotherapy in transgenic mouse mammary and salivary tumors , 2000, Oncogene.

[34]  G. Glatting,et al.  In vivo evaluation of 5-[(18)F]fluoro-2'-deoxyuridine as tracer for positron emission tomography in a murine pancreatic cancer model. , 2001, Cancer research.

[35]  D A Benaron,et al.  Imaging brain structure and function, infection and gene expression in the body using light. , 1997, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[36]  A. Clarke.  Manipulating the germline: its impact on the study of carcinogenesis. , 2000, Carcinogenesis.

[37]  M. Roussel,et al.  Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. , 1999, Genes & development.

[38]  C. Barlow,et al.  Atm Is Dispensable for p53 Apoptosis and Tumor Suppression Triggered by Cell Cycle Dysfunction , 1999, Molecular and Cellular Biology.

[39]  T. Jacks,et al.  Somatic activation of the K-ras oncogene causes early onset lung cancer in mice , 2001, Nature.

[40]  Gerhard Christofori,et al.  Molecular Mechanisms of Tumor Angiogenesis and Tumor Progression , 2000, Journal of Neuro-Oncology.

[41]  Eric C. Holland,et al.  Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice , 2000, Nature Genetics.

[42]  T. Jacks.  Tumor suppressor gene mutations in mice. , 1999, Annual review of genetics.

[43]  L. Donehower,et al.  Transgenic mouse models for tumour‐suppressor genes , 1995, Journal of internal medicine.

[44]  T. Jacks,et al.  Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors. , 1998, Genes & development.

[45]  S. Lowe,et al.  p53-Dependent apoptosis suppresses tumor growth and progression in vivo , 1994, Cell.

[46]  A. Berns.  Turning on tumors to study cancer progression , 1999, Nature Medicine.

[47]  S. Kogan,et al.  Retinoic Acid and Arsenic Synergize to Eradicate Leukemic Cells in a Mouse Model of Acute Promyelocytic Leukemia , 1999, The Journal of experimental medicine.

[48]  D. Hanahan,et al.  DNA copy number changes associated with characteristic LOH in islet cell carcinomas of transgenic mice , 1997, Genes, chromosomes & cancer.

[49]  P. Pandolfi,et al.  Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RARalpha and PLZF-RARalpha oncoproteins. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[50]  J. Green,et al.  2-difluoromethylornithine and dehydroepiandrosterone inhibit mammary tumor progression but not mammary or prostate tumor initiation in C3(1)/SV40 T/t-antigen transgenic mice. , 2001, Cancer research.

[51]  B. O’Malley,et al.  Development of gene-switch transgenic mice that inducibly express transforming growth factor beta1 in the epidermis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[52]  G. Daley,et al.  Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in P190 transgenic mice with the farnesyl transferase inhibitor SCH66336. , 2001, Blood.

[53]  Joe W. Gray,et al.  Genome scanning with array CGH delineates regional alterations in mouse islet carcinomas , 2001, Nature Genetics.

[54]  M. Black,et al.  A mutant herpes simplex virus type 1 thymidine kinase reporter gene shows improved sensitivity for imaging reporter gene expression with positron emission tomography. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[55]  D. Hanahan,et al.  MMP-9 Supplied by Bone Marrow–Derived Cells Contributes to Skin Carcinogenesis , 2000, Cell.

[56]  H. Varmus,et al.  Development of a flexible and specific gene delivery system for production of murine tumor models , 1999, Oncogene.

[57]  E. Lander,et al.  Tumor suppressor loci on mouse chromosomes 9 and 16 are lost at distinct stages of tumorigenesis in a transgenic model of islet cell carcinoma. , 1995, Cancer research.

[58]  A. Berns,et al.  Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. , 2000, Genes & development.

[59]  D. Katzenstein,et al.  Primary subtype C HIV-1 infection in Harare, Zimbabwe. , 1999, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[60]  S. Korsmeyer,et al.  Bax suppresses tumorigenesis and stimulates apoptosis in vivo , 1997, Nature.

[61]  L. Hennighausen,et al.  Time-Sensitive Reversal of Hyperplasia in Transgenic Mice Expressing SV40 T Antigen , 1996, Science.

[62]  Y. Geng,et al.  Specific protection against breast cancers by cyclin D1 ablation , 2001, Nature.

[63]  David K. Stevenson,et al.  Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression , 2001, Transgenic Research.

[64]  D. Tenen,et al.  Reversibility of acute B-cell leukaemia induced by BCR–ABL1 , 2000, Nature Genetics.

[65]  H. Bujard,et al.  Tet repressor-based system for regulated gene expression in eukaryotic cells: principles and advances. , 2000, Methods in enzymology.

[66]  J. Shaughnessy,et al.  Leukaemia disease genes: large-scale cloning and pathway predictions , 1999, Nature Genetics.

[67]  R. Coffey,et al.  Treatment with farnesyl-protein transferase inhibitor induces regression of mammary tumors in transforming growth factor (TGF) alpha and TGF alpha/neu transgenic mice by inhibition of mitogenic activity and induction of apoptosis. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[68]  M. A. Green.  Seeing is believing , 1987 .

[69]  A. Balmain,et al.  Building 'validated' mouse models of human cancer. , 2001, Current opinion in cell biology.

[70]  P. Farnham,et al.  Expression profiling and identification of novel genes in hepatocellular carcinomas , 2001, Oncogene.

[71]  A. Balmain.  Cancer as a Complex Genetic Trait Tumor Susceptibility in Humans and Mouse Models , 2002, Cell.

[72]  T. Jacks,et al.  In vitro and in vivo effects of a farnesyltransferase inhibitor on Nf1-deficient hematopoietic cells. , 1999, Blood.

[73]  R. DePinho,et al.  Telomere dysfunction and evolution of intestinal carcinoma in mice and humans , 2001, Nature Genetics.

[74]  A. Berns,et al.  Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. , 2000, Genes & development.

[75]  T. Jacks,et al.  The role of p53 in tumour suppression: lessons from mouse models , 1999, Cellular and Molecular Life Sciences CMLS.

[76]  P. Pandolfi,et al.  Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. , 2001, The Journal of clinical investigation.

[77]  H. Varmus,et al.  Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. , 2002, Cancer cell.

[78]  T. van Dyke,et al.  p19ARF Is Dispensable for Oncogenic Stress-Induced p53-Mediated Apoptosis and Tumor Suppression In Vivo , 2002, Molecular and Cellular Biology.

[79]  Hong Wu,et al.  Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[80]  A. Kral,et al.  Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice , 1995, Nature Medicine.

[81]  J. Tichelaar,et al.  Conditional Expression of Fibroblast Growth Factor-7 in the Developing and Mature Lung* , 2000, The Journal of Biological Chemistry.

[82]  Karlyne M. Reilly,et al.  Mouse models of tumor development in neurofibromatosis type 1. , 1999, Science.

[83]  S. Cory,et al.  Transgenic models of tumor development. , 1991, Science.

[84]  J. Alexander.  Use of transgenic mice in identifying chemopreventive agents. , 2000, Toxicology letters.

[85]  D. Hanahan,et al.  Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. , 1999, Science.

[86]  S. Linn,et al.  Mouse model for lung tumorigenesis through Cre/lox controlled sporadic activation of the K-Ras oncogene , 2001, Oncogene.

[87]  D. Felsher,et al.  Reversible tumorigenesis by MYC in hematopoietic lineages. , 1999, Molecular cell.

[88]  A. Wynshaw-Boris,et al.  Unraveling human cancer in the mouse: recent refinements to modeling and analysis. , 2001, Human molecular genetics.