Molecular-Genetic Imaging Based on Reporter Gene Expression

Molecular imaging includes proteomic, metabolic, cellular biologic process, and genetic imaging. In a narrow sense, molecular imaging means genetic imaging and can be called molecular-genetic imaging. Imaging reporter genes play a leading role in molecular-genetic imaging. There are 3 major methods of molecular-genetic imaging, based on optical, MRI, and nuclear medicine modalities. For each of these modalities, various reporter genes and probes have been developed, and these have resulted in successful transitions from bench to bedside applications. Each of these imaging modalities has its unique advantages and disadvantages. Fluorescent and bioluminescent optical imaging modalities are simple, less expensive, more convenient, and more user friendly than other imaging modalities. Another advantage, especially of bioluminescence imaging, is its ability to detect low levels of gene expression. MRI has the advantage of high spatial resolution, whereas nuclear medicine methods are highly sensitive and allow data from small-animal imaging studies to be translated to clinical practice. Moreover, multimodality imaging reporter genes will allow us to choose the imaging technologies that are most appropriate for the biologic problem at hand and facilitate the clinical application of reporter gene technologies. Reporter genes can be used to visualize the levels of expression of particular exogenous and endogenous genes and several intracellular biologic phenomena, including specific signal transduction pathways, nuclear receptor activities, and protein–protein interactions. This technique provides a straightforward means of monitoring tumor mass and can visualize the in vivo distributions of target cells, such as immune cells and stem cells. Molecular imaging has gradually evolved into an important tool for drug discovery and development, and transgenic mice with an imaging reporter gene can be useful during drug and stem cell therapy development. Moreover, instrumentation improvements, the identification of novel targets and genes, and imaging probe developments suggest that molecular-genetic imaging is likely to play an increasingly important role in the diagnosis and therapy of cancer.

[1]  C. Moonen,et al.  Gene expression and gene therapy imaging , 2007, European Radiology.

[2]  J Vijg,et al.  Efficient rescue of integrated shuttle vectors from transgenic mice: a model for studying mutations in vivo. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[3]  C. Contag,et al.  Advances in in vivo bioluminescence imaging of gene expression. , 2002, Annual review of biomedical engineering.

[4]  W. Gerald,et al.  Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. , 2005, The Journal of clinical investigation.

[5]  Lily Wu,et al.  Transcriptionally targeted gene therapy to detect and treat cancer. , 2003, Trends in molecular medicine.

[6]  Michal Neeman,et al.  Ferritin as an endogenous MRI reporter for noninvasive imaging of gene expression in C6 glioma tumors. , 2005, Neoplasia.

[7]  S. Larson,et al.  Imaging TCR-dependent NFAT-mediated T-cell activation with positron emission tomography in vivo. , 2001, Neoplasia.

[8]  J. S. Lee,et al.  Performance Measurement of the microPET Focus 120 Scanner , 2007, Journal of Nuclear Medicine.

[9]  J Humm,et al.  Imaging transcriptional regulation of p53-dependent genes with positron emission tomography in vivo , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Kevin P. Francis,et al.  Rapid Direct Method for Monitoring Antibiotics in a Mouse Model of Bacterial Biofilm Infection , 2003, Antimicrobial Agents and Chemotherapy.

[11]  Konstantin A Lukyanov,et al.  Fluorescent proteins as a toolkit for in vivo imaging. , 2005, Trends in biotechnology.

[12]  E. Ahrens,et al.  A new transgene reporter for in vivo magnetic resonance imaging , 2005, Nature Medicine.

[13]  Dong Soo Lee,et al.  Noninvasive in vivo monitoring of neuronal differentiation using reporter driven by a neuronal promoter , 2007, European Journal of Nuclear Medicine and Molecular Imaging.

[14]  Simon R Cherry,et al.  Simultaneous molecular and anatomical imaging of the mouse in vivo , 2002, Physics in medicine and biology.

[15]  C. Contag,et al.  It's not just about anatomy: In vivo bioluminescence imaging as an eyepiece into biology , 2002, Journal of magnetic resonance imaging : JMRI.

[16]  S. Lyons,et al.  Noninvasive bioluminescence imaging of normal and spontaneously transformed prostate tissue in mice. , 2006, Cancer research.

[17]  C. Contag,et al.  Use of reporter genes for optical measurements of neoplastic disease in vivo. , 2000, Neoplasia.

[18]  R. Blasberg,et al.  Multi-modality molecular imaging of tumors. , 2006, Hematology/oncology clinics of North America.

[19]  V. Ponomarev,et al.  A Human-Derived Reporter Gene for Noninvasive Imaging in Humans: Mitochondrial Thymidine Kinase Type 2 , 2007, Journal of Nuclear Medicine.

[20]  D. Lee,et al.  Doxorubicin Enhances the Expression of Transgene Under Control of the CMV Promoter in Anaplastic Thyroid Carcinoma Cells , 2007, Journal of Nuclear Medicine.

[21]  Gabriela Chiosis,et al.  Molecular imaging of the efficacy of heat shock protein 90 inhibitors in living subjects. , 2008, Cancer research.

[22]  S. Larson,et al.  Positron emission tomography-based imaging of transgene expression mediated by replication-conditional, oncolytic herpes simplex virus type 1 mutant vectors in vivo. , 2001, Cancer research.

[23]  B. Rice,et al.  Quantitative comparison of the sensitivity of detection of fluorescent and bioluminescent reporters in animal models. , 2004, Molecular imaging.

[24]  S. Gambhir,et al.  Applications of molecular imaging in cancer gene therapy. , 2005, Current gene therapy.

[25]  G. Chiesa,et al.  A transgenic mouse model for the detection of cellular stress induced by toxic inorganic compounds , 1997, Nature Biotechnology.

[26]  Bernard Bendriem,et al.  In vivo imaging of oligonucleotides with positron emission tomography , 1998, Nature Medicine.

[27]  A. Müller-Taubenberger Application of fluorescent protein tags as reporters in live-cell imaging studies. , 2006, Methods in molecular biology.

[28]  J. Barrio,et al.  Positron emission tomography imaging of adenoviral-mediated transgene expression in liver cancer patients. , 2005, Gastroenterology.

[29]  R. Blasberg,et al.  Imaging the expression of transfected genes in vivo. , 1995, Cancer research.

[30]  U. Haberkorn,et al.  Increased MIBG uptake after transfer of the human norepinephrine transporter gene in rat hepatoma. , 2003, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[31]  J. Bulte,et al.  Developing MR reporter genes: promises and pitfalls , 2007, NMR in biomedicine.

[32]  G. Lucignani,et al.  Techniques: reporter mice - a new way to look at drug action. , 2004, Trends in pharmacological sciences.

[33]  R. Blasberg,et al.  Imaging hNET Reporter Gene Expression with 124I-MIBG , 2007, Journal of Nuclear Medicine.

[34]  J. Dumont,et al.  Anion selectivity by the sodium iodide symporter. , 2003, Endocrinology.

[35]  R Weissleder,et al.  MR imaging and scintigraphy of gene expression through melanin induction. , 1997, Radiology.

[36]  D. Kohn,et al.  Immune response to green fluorescent protein: implications for gene therapy , 1999, Gene Therapy.

[37]  M. Resnick,et al.  Molecular imaging of NF‐kappaB in prostate tissue after systemic administration of IL‐1β , 2008, The Prostate.

[38]  June-Key Chung,et al.  Sodium iodide symporter: its role in nuclear medicine. , 2002, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[39]  Sanjiv S Gambhir,et al.  Reporter gene imaging of protein-protein interactions in living subjects. , 2007, Current opinion in biotechnology.

[40]  Fang Jia,et al.  Antisense imaging: And miles to go before we sleep? , 2003, Journal of cellular biochemistry.

[41]  C. Ginter,et al.  N-linked Glycosylation of the Thyroid Na+/I− Symporter (NIS) , 1998, The Journal of Biological Chemistry.

[42]  M. Mayo,et al.  In vivo localization of [(111)In]-DTPA-D-Phe1-octreotide to human ovarian tumor xenografts induced to express the somatostatin receptor subtype 2 using an adenoviral vector. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[43]  Qing-Rong Liu,et al.  Cloning of the human sodium lodide symporter. , 1996, Biochemical and biophysical research communications.

[44]  Irving L. Weissman,et al.  Shifting foci of hematopoiesis during reconstitution from single stem cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[45]  David W Townsend,et al.  PET/CT today and tomorrow. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[46]  Kwang Il Kim,et al.  Evaluation of transcriptional activity of the oestrogen receptor with sodium iodide symporter as an imaging reporter gene , 2006, Nuclear medicine communications.

[47]  Wei He,et al.  Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[48]  S. Gambhir,et al.  Visualization of advanced human prostate cancer lesions in living mice by a targeted gene transfer vector and optical imaging , 2002, Nature Medicine.

[49]  Masafumi Oshiro,et al.  Visualizing Gene Expression in Living Mammals Using a Bioluminescent Reporter , 1997, Photochemistry and photobiology.

[50]  C. Contag,et al.  Adoptive Immunotherapy of Experimental Autoimmune Encephalomyelitis Via T Cell Delivery of the IL-12 p40 Subunit1 , 2001, The Journal of Immunology.

[51]  W. Heiss,et al.  Switching on the Lights for Gene Therapy , 2007, PloS one.

[52]  Alnawaz Rehemtulla,et al.  Molecular imaging of Akt kinase activity , 2007, Nature Medicine.

[53]  R. Tsien,et al.  Construction and validation of improved triple fusion reporter gene vectors for molecular imaging of living subjects. , 2007, Cancer research.

[54]  D. Piwnica-Worms,et al.  Molecular imaging strategies for drug discovery and development. , 2006, Current opinion in chemical biology.

[55]  Non-invasive imaging of a transgenic mouse model using a prostate-specific two-step transcriptional amplification strategy , 2005, Transgenic Research.

[56]  J. Foidart,et al.  Differential heat shock gene hsp70-1 response to toxicants revealed by in vivo study of lungs in transgenic mice , 2002, Cell stress & chaperones.

[57]  R. Senekowitsch-Schmidtke,et al.  α-Fetoprotein promoter-targeted sodium iodide symporter gene therapy of hepatocellular carcinoma , 2008, Gene Therapy.

[58]  M. J. Cormier,et al.  Isolation and expression of a cDNA encoding Renilla reniformis luciferase. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[59]  D. Lee,et al.  Noninvasive imaging for monitoring of viable cancer cells using a dual-imaging reporter gene. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[60]  K. Zinn,et al.  Gene transfer strategies for improving radiolabeled peptide imaging and therapy. , 2000, The quarterly journal of nuclear medicine : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology.

[61]  Talakad G. Lohith,et al.  Potential of the FES-hERL PET reporter gene system -- basic evaluation for gene therapy monitoring. , 2006, Nuclear medicine and biology.

[62]  S. Gambhir,et al.  Molecular Imaging of Cardiac Cell Transplantation in Living Animals Using Optical Bioluminescence and Positron Emission Tomography , 2003, Circulation.

[63]  S. Larson,et al.  Positron emission tomography imaging for herpes virus infection: Implications for oncolytic viral treatments of cancer , 2001, Nature Medicine.

[64]  G. Lucignani,et al.  Molecular imaging: A new way to study molecular processes in vivo , 2006, Molecular and Cellular Endocrinology.

[65]  Ciprian Catana,et al.  Performance test of an LSO-APD detector in a 7-T MRI scanner for simultaneous PET/MRI. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[66]  D. Lee,et al.  Immune response to firefly luciferase as a naked DNA , 2007, Cancer biology & therapy.

[67]  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.

[68]  S S Gambhir,et al.  Noninvasive imaging of protein–protein interactions in living subjects by using reporter protein complementation and reconstitution strategies , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[69]  S. Cherry,et al.  Repetitive, non-invasive imaging of the dopamine D2 receptor as a reporter gene in living animals , 1999, Gene Therapy.

[70]  Kevin C. Chen,et al.  A transgenic mouse model with a luciferase reporter for studying in vivo transcriptional regulation of the human CYP3A4 gene. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[71]  Vasilis Ntziachristos,et al.  Three-Dimensional in Vivo Imaging of Green Fluorescent Protein-Expressing T Cells in Mice with Noncontact Fluorescence Molecular Tomography , 2007, Molecular imaging.

[72]  E. Galun,et al.  Imaging transgene expression in live animals. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[73]  D. Lee,et al.  In Vivo Imaging of Retinoic Acid Receptor Activity using a Sodium/Iodide Symporter and Luciferase Dual Imaging Reporter Gene , 2004, Molecular imaging.

[74]  Wei Li,et al.  Noninvasive imaging of protein–protein interactions in living animals , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[75]  D. Lee,et al.  In Vivo Bioluminescence Visualization of Antitumor Effects by Human MUC1 Vaccination , 2007, Molecular imaging.

[76]  Michel Sadelain,et al.  Serial in vivo imaging of the targeted migration of human HSV-TK-transduced antigen-specific lymphocytes , 2003, Nature Biotechnology.

[77]  H. Choy,et al.  Noninvasive Real-time Imaging of Tumors and Metastases Using Tumor-targeting Light-emitting Escherichia coli , 2007, Molecular Imaging and Biology.

[78]  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.

[79]  K Wienhard,et al.  Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas , 2001, The Lancet.

[80]  Sanjiv S Gambhir,et al.  Quantitative imaging of the T cell antitumor response by positron-emission tomography , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[81]  R. Blasberg,et al.  Reporter gene imaging: potential impact on therapy. , 2005, Nuclear medicine and biology.

[82]  Ronald G Blasberg,et al.  In vivo molecular‐genetic imaging , 2002, Journal of cellular biochemistry. Supplement.

[83]  Rika Takikawa,et al.  [In-vivo visualization of gene expression using magnetic resonance imaging]. , 2007, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[84]  S. Cherry,et al.  Imaging adenoviral-directed reporter gene expression in living animals with positron emission tomography. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[85]  C. Contag,et al.  Antigen-specific T cell-mediated gene therapy in collagen-induced arthritis. , 2001, The Journal of clinical investigation.

[86]  R. Weissleder Scaling down imaging: molecular mapping of cancer in mice , 2002, Nature Reviews Cancer.

[87]  Piotr Walczak,et al.  Artificial reporter gene providing MRI contrast based on proton exchange , 2007, Nature Biotechnology.

[88]  D. Lee,et al.  Development of a sodium/iodide symporter (NIS)-transgenic mouse for imaging of cardiomyocyte-specific reporter gene expression. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[89]  U. Haberkorn,et al.  Gene therapy with sodium/iodide symporter in hepatocarcinoma , 2001, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[90]  Johannes T. Heverhagen,et al.  In vitro MR imaging of regulated gene expression. , 2003, Radiology.

[91]  D. Lee,et al.  In vivo long-term imaging and radioiodine therapy by sodium-iodide symporter gene expression using a lentiviral system containing ubiquitin C promoter , 2007, Cancer biology & therapy.

[92]  W D McElroy,et al.  Complementary DNA coding click beetle luciferases can elicit bioluminescence of different colors. , 1989, Science.

[93]  W. Heiss,et al.  Multitracer Positron Emission Tomographic Imaging of Exogenous Gene Expression Mediated by a Universal Herpes Simplex Virus 1 Amplicon Vector , 2007, Molecular imaging.

[94]  S. Shabahang,et al.  Renilla luciferase-Aequorea GFP (Ruc-GFP) fusion protein, a novel dual reporter for real-time imaging of gene expression in cell cultures and in live animals , 2002, Molecular Genetics and Genomics.

[95]  D. Rottenberg,et al.  Quantitative autoradiographic mapping of herpes simplex virus encephalitis with a radiolabeled antiviral drug. , 1982, Science.

[96]  N. Carrasco,et al.  Cloning and characterization of the thyroid iodide transporter , 1996, Nature.

[97]  G. Sfakianakis,et al.  Noninvasive imaging of c-myc oncogene messenger RNA with indium-111-antisense probes in a mammary tumor-bearing mouse model. , 1994, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[98]  U. Haberkorn,et al.  Impact of functional genomics and proteomics on radionuclide imaging. , 2004, Seminars in nuclear medicine.

[99]  Kwang Il Kim,et al.  Visualization of endogenous p53-mediated transcription in vivo using sodium iodide symporter. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[100]  Jos Jonkers,et al.  Noninvasive imaging of spontaneous retinoblastoma pathway-dependent tumors in mice. , 2002, Cancer research.

[101]  D. Lee,et al.  Feasibility of sodium/iodide symporter gene as a new imaging reporter gene: comparison with HSV1-tk , 2004, European Journal of Nuclear Medicine and Molecular Imaging.

[102]  S. Gambhir,et al.  Noninvasive imaging of lentiviral-mediated reporter gene expression in living mice. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[103]  R. Blasberg,et al.  Cytoplasmically retargeted HSV1-tk/GFP reporter gene mutants for optimization of noninvasive molecular-genetic imaging. , 2003, Neoplasia.

[104]  A. Jacobs,et al.  Functional coexpression of HSV-1 thymidine kinase and green fluorescent protein: implications for noninvasive imaging of transgene expression. , 1999, Neoplasia.

[105]  D. Lee,et al.  Human sodium iodide symporter gene adjunctive radiotherapy to enhance the preventive effect of hMUC1 DNA vaccine , 2007, International journal of cancer.

[106]  H. Herschman Noninvasive imaging of reporter gene expression in living subjects. , 2004, Advances in cancer research.

[107]  P. Acton,et al.  Imaging reporter genes for cell tracking with PET and SPECT. , 2005, The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of....

[108]  M. Iyer,et al.  Two-step transcriptional amplification as a method for imaging reporter gene expression using weak promoters , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[109]  S. Gambhir,et al.  Imaging androgen receptor function during flutamide treatment in the LAPC9 xenograft model , 2005, Molecular Cancer Therapeutics.