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Tumor-specific imaging through progression elevated gene-3 promoter-driven gene expression


Molecular-genetic imaging is advancing from a valuable preclinical tool to a guide for patient management. The strategy involves pairing an imaging reporter gene with a complementary imaging agent in a system that can be used to measure gene expression or protein interaction or track gene-tagged cells in vivo. Tissue-specific promoters can be used to delineate gene expression in certain tissues, particularly when coupled with an appropriate amplification mechanism. Here we show that the progression elevated gene-3 (PEG-3) promoter, derived from a rodent gene mediating tumor progression and metastatic phenotypes, can be used to drive imaging reporters selectively to enable detection of micrometastatic disease in mouse models of human melanoma and breast cancer using bioluminescence and radionuclide-based molecular imaging techniques. Because of its strong promoter activity, tumor specificity and capacity for clinical translation, PEG-3 promoter–driven gene expression may represent a practical, new system for facilitating cancer imaging and therapy.

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Figure 1: Cancer-specific PEG-3 promoter activity shown by bioluminescence imaging in experimental metastasis models of human melanoma (Mel) and breast cancer (BCa).
Figure 2: Correlation between PEG-3 promoter–driven Luc expression and microscopic metastatic sites shown by histopathological analysis in a mouse model of melanoma metastasis.
Figure 3: Histological confirmation of the microscopic metastatic sites detected by the PEG-3 promoter–driven bioluminescence imaging system in a human breast cancer metastasis model.
Figure 4: Cancer-specific expression of HSV1-TK driven by PEG-3 promoter shown by SPECT-CT imaging in an experimental model of human melanoma metastasis.
Figure 5: Detection and localization of metastatic masses by SPECT-CT imaging after the systemic administration of pPEG-HSV1tk.


  1. Blasberg, R.G. & Tjuvajev, J.G. Molecular-genetic imaging: current and future perspectives. J. Clin. Invest. 111, 1620–1629 (2003).

    CAS  Article  Google Scholar 

  2. Zhang, Y. et al. ABCG2/BCRP expression modulates D-luciferin based bioluminescence imaging. Cancer Res. 67, 9389–9397 (2007).

    CAS  Article  Google Scholar 

  3. Uhrbom, L., Nerio, E. & Holland, E.C. Dissecting tumor maintenance requirements using bioluminescence imaging of cell proliferation in a mouse glioma model. Nat. Med. 10, 1257–1260 (2004).

    CAS  Article  Google Scholar 

  4. Kishimoto, H. et al. In vivo imaging of lymph node metastasis with telomerase-specific replication-selective adenovirus. Nat. Med. 12, 1213–1219 (2006).

    CAS  Article  Google Scholar 

  5. Padmanabhan, P. et al. Visualization of telomerase reverse transcriptase (hTERT) promoter activity using a trimodality fusion reporter construct. J. Nucl. Med. 47, 270–277 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Freytag, S.O. et al. Phase I trial of replication-competent adenovirus–mediated suicide gene therapy combined with IMRT for prostate cancer. Mol. Ther. 15, 1016–1023 (2007).

    CAS  Article  Google Scholar 

  7. Yaghoubi, S.S. et al. Noninvasive detection of therapeutic cytolytic T cells with 18F-FHBG PET in a patient with glioma. Nat. Clin. Pract. Oncol. 6, 53–58 (2009).

    CAS  Article  Google Scholar 

  8. Su, Z.Z., Shi, Y. & Fisher, P.B. Subtraction hybridization identifies a transformation progression-associated gene PEG-3 with sequence homology to a growth arrest and DNA damage–inducible gene. Proc. Natl. Acad. Sci. USA 94, 9125–9130 (1997).

    CAS  Article  Google Scholar 

  9. Su, Z.Z. et al. Targeting gene expression selectively in cancer cells by using the progression-elevated gene-3 promoter. Proc. Natl. Acad. Sci. USA 102, 1059–1064 (2005).

    CAS  Article  Google Scholar 

  10. Sarkar, D. et al. Eradication of therapy-resistant human prostate tumors using a cancer terminator virus. Cancer Res. 67, 5434–5442 (2007).

    CAS  Article  Google Scholar 

  11. Sarkar, D. et al. Targeted virus replication plus immunotherapy eradicates primary and distant pancreatic tumors in nude mice. Cancer Res. 65, 9056–9063 (2005).

    CAS  Article  Google Scholar 

  12. Sarkar, D. et al. A cancer terminator virus eradicates both primary and distant human melanomas. Cancer Gene Ther. 15, 293–302 (2008).

    CAS  Article  Google Scholar 

  13. Su, Z., Shi, Y. & Fisher, P.B. Cooperation between AP1 and PEA3 sites within the progression elevated gene-3 (PEG-3) promoter regulate basal and differential expression of PEG-3 during progression of the oncogenic phenotype in transformed rat embryo cells. Oncogene 19, 3411–3421 (2000).

    CAS  Article  Google Scholar 

  14. Sarkar, D. et al. Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice. Proc. Natl. Acad. Sci. USA 102, 14034–14039 (2005).

    CAS  Article  Google Scholar 

  15. Wood, M. et al. Biodistribution of an adenoviral vector carrying the luciferase reporter gene following intravesical or intravenous administration to a mouse. Cancer Gene Ther. 6, 367–372 (1999).

    CAS  Article  Google Scholar 

  16. Peng, K.W. et al. Organ distribution of gene expression after intravenous infusion of targeted and untargeted lentiviral vectors. Gene Ther. 8, 1456–1463 (2001).

    CAS  Article  Google Scholar 

  17. Evans, K.D., Tulloss, T.A. & Hall, N. 18FDG uptake in brown fat: potential for false positives. Radiol. Technol. 78, 361–366 (2007).

    PubMed  Google Scholar 

  18. Shreve, P.D., Anzai, Y. & Wahl, R.L. Pitfalls in oncologic diagnosis with FDG PET imaging: physiologic and benign variants. Radiographics 19, 61–77, quiz 150–151 (1999).

    CAS  Article  Google Scholar 

  19. Ray, S. et al. Noninvasive imaging of therapeutic gene expression using a bidirectional transcriptional amplification strategy. Mol. Ther. 16, 1848–1856 (2008).

    CAS  Article  Google Scholar 

  20. Qiao, J. et al. Tumor-specific transcriptional targeting of suicide gene therapy. Gene Ther. 9, 168–175 (2002).

    CAS  Article  Google Scholar 

  21. Iyer, M. et al. Two-step transcriptional amplification as a method for imaging reporter gene expression using weak promoters. Proc. Natl. Acad. Sci. USA 98, 14595–14600 (2001).

    CAS  Article  Google Scholar 

  22. Sadowski, I., Ma, J., Triezenberg, S. & Ptashne, M. GAL4–VP16 is an unusually potent transcriptional activator. Nature 335, 563–564 (1988).

    CAS  Article  Google Scholar 

  23. Burton, J.B. et al. Adenovirus-mediated gene expression imaging to directly detect sentinel lymph node metastasis of prostate cancer. Nat. Med. 14, 882–888 (2008).

    CAS  Article  Google Scholar 

  24. Iyer, M. et al. Noninvasive imaging of enhanced prostate-specific gene expression using a two-step transcriptional amplification-based lentivirus vector. Mol. Ther. 10, 545–552 (2004).

    CAS  Article  Google Scholar 

  25. Huyn, S.T. et al. A potent, imaging adenoviral vector driven by the cancer-selective mucin-1 promoter that targets breast cancer metastasis. Clin. Cancer Res. 15, 3126–3134 (2009).

    CAS  Article  Google Scholar 

  26. Jacobs, A. et al. Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas. Lancet 358, 727–729 (2001).

    CAS  Article  Google Scholar 

  27. Immonen, A. et al. AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. Mol. Ther. 10, 967–972 (2004).

    CAS  Article  Google Scholar 

  28. Klatzmann, D. et al. A phase I/II study of herpes simplex virus type 1 thymidine kinase “suicide” gene therapy for recurrent glioblastoma. Study Group on Gene Therapy for Glioblastoma. Hum. Gene Ther. 9, 2595–2604 (1998).

    CAS  PubMed  Google Scholar 

  29. Trask, T.W. et al. Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors. Mol. Ther. 1, 195–203 (2000).

    CAS  Article  Google Scholar 

  30. Bonnet, M.E., Erbacher, P. & Bolcato-Bellemin, A.L. Systemic delivery of DNA or siRNA mediated by linear polyethylenimine (L-PEI) does not induce an inflammatory response. Pharm. Res. 25, 2972–2982 (2008).

    CAS  Article  Google Scholar 

  31. Coelho-Castelo, A.A. et al. Tissue distribution of a plasmid DNA encoding Hsp65 gene is dependent on the dose administered through intramuscular delivery. Genet. Vaccines Ther. 4, 1 (2006).

    CAS  Article  Google Scholar 

  32. Kang, K.K. et al. Safety evaluation of GX-12, a new HIV therapeutic vaccine: investigation of integration into the host genome and expression in the reproductive organs. Intervirology 46, 270–276 (2003).

    CAS  Article  Google Scholar 

  33. Manam, S. et al. Plasmid DNA vaccines: tissue distribution and effects of DNA sequence, adjuvants and delivery method on integration into host DNA. Intervirology 43, 273–281 (2000).

    CAS  Article  Google Scholar 

  34. Ramirez, K. et al. Preclinical safety and biodistribution of Sindbis virus measles DNA vaccines administered as a single dose or followed by live attenuated measles vaccine in a heterologous prime-boost regimen. Hum. Gene Ther. 19, 522–531 (2008).

    CAS  Article  Google Scholar 

  35. Dwyer, R.M., Bergert, E.R., O'Connor, M.K., Gendler, S.J. & Morris, J.C. In vivo radioiodide imaging and treatment of breast cancer xenografts after MUC1-driven expression of the sodium iodide symporter. Clin. Cancer Res. 11, 1483–1489 (2005).

    CAS  Article  Google Scholar 

  36. Tsuruta, Y. et al. A fiber-modified mesothelin promoter-based conditionally replicating adenovirus for treatment of ovarian cancer. Clin. Cancer Res. 14, 3582–3588 (2008).

    CAS  Article  Google Scholar 

  37. Su, Z.Z. et al. Potential molecular mechanism for rodent tumorigenesis: mutational generation of Progression Elevated Gene-3 (PEG-3). Oncogene 24, 2247–2255 (2005).

    CAS  Article  Google Scholar 

  38. Loening, A.M. & Gambhir, S.S. AMIDE: a free software tool for multimodality medical image analysis. Mol. Imaging 2, 131–137 (2003).

    Article  Google Scholar 

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We appreciate the technical support provided by S. Dhara, S. Nimmagadda, M. Goggins and M. Griffith. We are grateful to J. Fox and G. Green for providing [125I]FIAU and assisting in the SPECT-CT and PET-CT imaging studies. We also thank C. Endres, B. Tsui, J. Yu and J. Fox for help with SPECT and PET data processing. The MDA-MB-231 cell line and pCMV-Tri construct were generous gifts from Z. Bhujwalla (Johns Hopkins University) and S. Gambhir (Stanford University), respectively. Funding was provided by US National Institutes of Health grant U24 CA92871 (to M.G.P.), by the Predoctoral Molecular Imaging Scholar Program from the Society of Nuclear Medicine and the Korea Science and Engineering Foundation Fellowship Program (to H.C.B.) and by the US National Institutes of Health grant P01 CA104177 and the US National Foundation for Cancer Research (to P.B.F.). P.B.F. holds the Thelma Newmeyer Corman Chair in Cancer Research at the Virginia Commonwealth University Massey Cancer Center.

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Authors and Affiliations



H.-e.C.B. designed and performed the experiments, analyzed data and prepared the manuscript. K.L.G. provided technical support in histopathology. J.L., K.L.G. and P.B.F. gave conceptual advice and edited the manuscript. M.G.P. and P.B.F. conceived of the project. M.G.P. supervised the project and prepared the manuscript.

Corresponding author

Correspondence to Martin G Pomper.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Methods and Supplementary Figures 1–8 (PDF 1603 kb)

Supplementary Video 1

Detection of metastatic melanoma after systemic administration of pPEG-HSV1tk/PEI polyplex using SPECT-CT. Movie of a representative melanoma metastasis model, Mel-2 from Figure 4b and Figure 5a,b. The image was acquired at 24 h post injection of [125I]FIAU (1.4 mCi), which was 70 h after the pPEG-HSV1tk delivery. Multiple metastatic sites are predicted in the lung and upper dorsal area of the animal by [125I]FIAU SPECT. Melanoma masses were confirmed under the brown adipose tissue in the corresponding area (Fig. 5b) as well as in its lung by the gross pathological analysis. (MOV 3009 kb)

Supplementary Video 2

Movie of a representative control animal, Ctrl-3 from Figure 4a. This whole body SPECT-CT image was acquired at 24 h post injection of 1.4 mCi of [125I]FIAU, which was 70 h after the IV injection of pPEG-HSV1tk/PEI polyplex. Accumulated radioactivity was only detected in the urinary bladder and intestines of the animal. The same pseudo color scale used for Mel-2 in Supplementary Video 1 was applied. (MOV 2835 kb)

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Bhang, He., Gabrielson, K., Laterra, J. et al. Tumor-specific imaging through progression elevated gene-3 promoter-driven gene expression. Nat Med 17, 123–129 (2011).

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