Molecular Imaging and Biology

, Volume 14, Issue 2, pp 237–244 | Cite as

18F-FDG PET/CT Imaging Detects Therapy Efficacy of Anti-EMMPRIN Antibody and Gemcitabine in Orthotopic Pancreatic Tumor Xenografts

  • Nemil Shah
  • Guihua Zhai
  • Joseph A. Knowles
  • Cecil R. Stockard
  • William E. Grizzle
  • Naomi Fineberg
  • Tong Zhou
  • Kurt R. Zinn
  • Eben L. Rosenthal
  • Hyunki Kim
Research Article



The objective of this study is to evaluate the therapeutic response to a novel monoclonal antibody targeting human extracellular matrix metalloproteinase inducer (EMMPRIN) in combination with gemcitabine in a pancreatic-tumor xenograft murine model by sequential 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) positron emission tomography/computed tomgraphy (PET/CT) imaging.


Four groups of SCID mice bearing orthotopic pancreatic tumor xenografts were injected with phosphate-buffered saline, gemcitabine (120 mg/kg BW), anti-EMMPRIN antibody (0.2 mg), or combination, respectively, twice weekly for 2 weeks, while 18F-FDG PET/CT imaging was performed weekly for 3 weeks. Changes in mean standardized uptake value (SUVmean) of 18F-FDG and volume of tumors were determined.


The tumor SUVmean change in the group receiving combination therapy was significantly lower than those of the other groups. Tumor-volume changes of groups treated with anti-EMMPRIN monotherapy or combined therapy were significantly lower than that of the control group.


These data provide support for clinical studies of anti-EMMPRIN therapy with gemcitabine for pancreatic cancer treatment.

Key words

FDG-PET CT EMMPRIN Gemcitabine Pancreatic cancer 



Financial support was provided by an HSF-GEF Scholar Award, AACR-PANCAN Career Development Award, National Cancer Institute (R01CA142637 and 5K08CA102154), the Pancreatic SPORE (CA101955), and the UAB small animal imaging shared facility (5P30CA013148). Authors thank Sharon Samuel, Lee Whitworth, and Amber Martin for assistance with growing cells, in vitro assays, animal monitoring, and imaging. All experiments complied will current regulatory and ethical requirements.

Conflict of interest

No authors have conflict of interest to report.


  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249PubMedCrossRefGoogle Scholar
  2. 2.
    Klapman J, Malafa MP (2008) Early detection of pancreatic cancer: why, who, and how to screen. Cancer Control 15:280–287PubMedGoogle Scholar
  3. 3.
    Burris HA, Moore MJ, Andersen J et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413PubMedGoogle Scholar
  4. 4.
    Cardenes HR, Chiorean EG, Dewitt J, Schmidt M, Loehrer P (2006) Locally advanced pancreatic cancer: current therapeutic approach. Oncologist 11:612–623PubMedCrossRefGoogle Scholar
  5. 5.
    Stathis A, Moore MJ (2010) Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol 7:163–172PubMedCrossRefGoogle Scholar
  6. 6.
    Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB (2002) Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 20:3270–3275PubMedCrossRefGoogle Scholar
  7. 7.
    Heinemann V, Quietzsch D, Gieseler F et al (2006) Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 24:3946–3952PubMedCrossRefGoogle Scholar
  8. 8.
    Rocha Lima CM, Green MR, Rotche R et al (2004) Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 22:3776–3783PubMedCrossRefGoogle Scholar
  9. 9.
    Louvet C, Labianca R, Hammel P et al (2005) Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 23:3509–3516PubMedCrossRefGoogle Scholar
  10. 10.
    Abou-Alfa GK, Letourneau R, Harker G et al (2006) Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol 24:4441–4447PubMedCrossRefGoogle Scholar
  11. 11.
    Moore MJ, Goldstein D, Hamm J et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966PubMedCrossRefGoogle Scholar
  12. 12.
    Kindler HL (2007) Pancreatic cancer: an update. Curr Oncol Rep 9:170–176PubMedCrossRefGoogle Scholar
  13. 13.
    Kindler HL (2005) Front-line therapy of advanced pancreatic cancer. Semin Oncol 32:S33–S36PubMedCrossRefGoogle Scholar
  14. 14.
    Biswas C, Zhang Y, DeCastro R et al (1995) The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res 55:434–439PubMedGoogle Scholar
  15. 15.
    Suzuki S, Sato M, Senoo H, Ishikawa K (2004) Direct cell-cell interaction enhances pro-MMP-2 production and activation in co-culture of laryngeal cancer cells and fibroblasts: involvement of EMMPRIN and MT1-MMP. Exp Cell Res 293:259–266PubMedCrossRefGoogle Scholar
  16. 16.
    Ellenrieder V, Alber B, Lacher U et al (2000) Role of MT-MMPs and MMP-2 in pancreatic cancer progression. Int J Cancer 85:14–20PubMedCrossRefGoogle Scholar
  17. 17.
    Tang Y, Nakada MT, Kesavan P et al (2005) Extracellular matrix metalloproteinase inducer stimulates tumor angiogenesis by elevating vascular endothelial cell growth factor and matrix metalloproteinases. Cancer Res 65:3193–3199PubMedGoogle Scholar
  18. 18.
    Bougatef F, Quemener C, Kellouche S et al (2009) EMMPRIN promotes angiogenesis through hypoxia-inducible factor-2alpha-mediated regulation of soluble VEGF isoforms and their receptor VEGFR-2. Blood 114:5547–5556PubMedCrossRefGoogle Scholar
  19. 19.
    Zheng HC, Takahashi H, Murai Y et al (2006) Upregulated EMMPRIN/CD147 might contribute to growth and angiogenesis of gastric carcinoma: a good marker for local invasion and prognosis. Br J Cancer 95:1371–1378PubMedCrossRefGoogle Scholar
  20. 20.
    Riethdorf S, Reimers N, Assmann V et al (2006) High incidence of EMMPRIN expression in human tumors. Int J Cancer 119:1800–1810PubMedCrossRefGoogle Scholar
  21. 21.
    Dandekar M, Tseng JR, Gambhir SS (2007) Reproducibility of 18F-FDG microPET studies in mouse tumor xenografts. J Nucl Med 48:602–607PubMedCrossRefGoogle Scholar
  22. 22.
    Kroep JR, Van Groeningen CJ, Cuesta MA et al (2003) Positron emission tomography using 2-deoxy-2-[18F]-fluoro-D-glucose for response monitoring in locally advanced gastroesophageal cancer; a comparison of different analytical methods. Mol Imaging Biol 5:337–346PubMedCrossRefGoogle Scholar
  23. 23.
    Kelloff GJ, Hoffman JM, Johnson B et al (2005) Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development. Clin Cancer Res 11:2785–2808PubMedCrossRefGoogle Scholar
  24. 24.
    Barber TW, Kalff V, Cherk MH, Yap KS, Evans P, Kelly MJ (2010) (18)F-FDG PET/CT influences management in patients with known or suspected pancreatic cancer. Intern Med J. doi: 10.1111/j.1445-5994.2010.02257.x
  25. 25.
    Mataki Y, Shinchi H, Kurahara H et al (2009) Clinical usefulness of FDG-PET for pancreatic cancer. Gan To Kagaku Ryoho 36:2516–2520PubMedGoogle Scholar
  26. 26.
    Maisey NR, Webb A, Flux GD et al (2000) FDG-PET in the prediction of survival of patients with cancer of the pancreas: a pilot study. Br J Cancer 83:287–293PubMedCrossRefGoogle Scholar
  27. 27.
    Higashi T, Sakahara H, Torizuka T et al (1999) Evaluation of intraoperative radiation therapy for unresectable pancreatic cancer with FDG PET. J Nucl Med 40:1424–1433PubMedGoogle Scholar
  28. 28.
    Kuwatani M, Kawakami H, Eto K et al (2009) Modalities for evaluating chemotherapeutic efficacy and survival time in patients with advanced pancreatic cancer: comparison between FDG-PET, CT, and serum tumor markers. Intern Med 48:867–875PubMedCrossRefGoogle Scholar
  29. 29.
    Schellenberg D, Quon A, Minn AY et al (2010) 18Fluorodeoxyglucose PET is prognostic of progression-free and overall survival in locally advanced pancreas cancer treated with stereotactic radiotherapy. Int J Radiat Oncol Biol Phys 77:1420–1425PubMedCrossRefGoogle Scholar
  30. 30.
    Schneiderhan W, Diaz F, Fundel M et al (2007) Pancreatic stellate cells are an important source of MMP-2 in human pancreatic cancer and accelerate tumor progression in a murine xenograft model and CAM assay. J Cell Sci 120:512–519PubMedCrossRefGoogle Scholar
  31. 31.
    Larsen SK, Solomon HF, Caldwell G, Abrams MJ (1995) [99mTc]tricine: a useful precursor complex for the radiolabeling of hydrazinonicotinate protein conjugates. Bioconjug Chem 6:635–638PubMedCrossRefGoogle Scholar
  32. 32.
    Lowry O, Rosebrough N, Farr L, Randall R (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  33. 33.
    Prasad R, Ratib O, Zaidi H (2010) Performance evaluation of the FLEX triumph X-PET scanner using the national electrical manufacturers association NU-4 standards. J Nucl Med 51:1608–1615PubMedCrossRefGoogle Scholar
  34. 34.
    Kim H, Morgan DE, Buchsbaum DJ et al (2008) Early therapy evaluation of combined anti-death receptor 5 antibody and gemcitabine in orthotopic pancreatic tumor xenografts by diffusion-weighted magnetic resonance imaging. Cancer Res 68:8369–8376PubMedCrossRefGoogle Scholar
  35. 35.
    Neter J, Kutner MH, Nachtsheim JC, Wasserman W (1996) Applied linear statistical models. McGraw-Hill, ColumbusGoogle Scholar
  36. 36.
    Hertzog C, Rovine M (1985) Repeated-measures analysis of variance in developmental research: selected issues. Child Dev 56:787–809PubMedCrossRefGoogle Scholar
  37. 37.
    Rodgers JL, Nicewander WA (1988) Thirteen ways to look at the correlation coefficient. Am Stat 42:59–66CrossRefGoogle Scholar
  38. 38.
    Escorcia FE, Henke E, McDevitt MR et al (2010) Selective killing of tumor neovasculature paradoxically improves chemotherapy delivery to tumors. Cancer Res 70:9277–9286PubMedCrossRefGoogle Scholar
  39. 39.
    Dean NR, Newman JR, Helman EE et al (2009) Anti-EMMPRIN monoclonal antibody as a novel agent for therapy of head and neck cancer. Clin Cancer Res 15:4058–4065PubMedCrossRefGoogle Scholar

Copyright information

© Academy of Molecular Imaging and Society for Molecular Imaging 2011

Authors and Affiliations

  • Nemil Shah
    • 1
  • Guihua Zhai
    • 2
  • Joseph A. Knowles
    • 4
  • Cecil R. Stockard
    • 5
  • William E. Grizzle
    • 5
    • 7
  • Naomi Fineberg
    • 6
  • Tong Zhou
    • 1
  • Kurt R. Zinn
    • 1
    • 2
    • 7
  • Eben L. Rosenthal
    • 4
    • 7
  • Hyunki Kim
    • 2
    • 3
    • 7
  1. 1.Department of MedicineUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Department of RadiologyUniversity of Alabama at BirminghamBirminghamUSA
  3. 3.Department of Biomedical EngineeringUniversity of Alabama at BirminghamBirminghamUSA
  4. 4.Department of SurgeryUniversity of Alabama at BirminghamBirminghamUSA
  5. 5.Department of PathologyUniversity of Alabama at BirminghamBirminghamUSA
  6. 6.Department of BiostatisticsUniversity of Alabama at BirminghamBirminghamUSA
  7. 7.Department of Comprehensive Cancer CenterUniversity of Alabama at BirminghamBirminghamUSA

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