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  • Review Article
  • Published:

Molecular imaging in gastroenterology

Key Points

  • Molecular imaging uses fluorescently labelled probes to specifically highlight neoplastic lesions

  • Probes include labelled antibodies, oligopeptides, affibodies, aptamers, nanoparticles and activatable probes, and are usually labelled with fluorescein or indocyanine green derivatives

  • Molecular imaging in gastrointestinal endoscopy aims to improve detection and characterization of lesions, and to assess the likelihood of response to molecular targeted therapy

  • The first translational studies in patients have shown promising results; however, thorough analysis of patient benefits and safety issues needs to be advanced before widespread clinical use can be promoted

Abstract

Molecular imaging is a novel field in gastroenterology that uses fluorescently labelled probes to specifically highlight neoplastic lesions on the basis of their molecular signature. The development of molecular imaging has been driven by the need to improve endoscopic diagnosis and by progress in targeted therapies in gastrointestinal oncology to provide individualized treatment, which coincides with progress in endoscopy techniques and further miniaturization of detection devices. Different exogenous molecular probes for imaging include labelled antibodies, oligopeptides, affibodies (Affibody AB, Bromma, Sweden), aptamers and activatable probes. Molecular imaging has been evaluated in two major indications: many trials have studied molecular imaging as a red flag technique to improve detection of lesions in wide-field imaging; on the other hand, microscopic analysis has been investigated for in vivo characterization of the molecular fingerprint of tumours with the ultimate goal of assessing the likelihood of response to targeted therapy. This Review focusses on the applications of molecular imaging that have immediate potential for translational science or imminent transition into clinical practice of gastrointestinal endoscopy.

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Figure 1: Principle of molecular imaging in the gastrointestinal tract.
Figure 2
Figure 3: Wide field detection of colonic adenomas in a mouse model of colitis-associated cancer.
Figure 4: Molecular imaging with therapeutic antibodies.

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References

  1. Yalamarthi, S., Witherspoon, P., McCole, D. & Auld, C. D. Missed diagnoses in patients with upper gastrointestinal cancers. Endoscopy 36, 874–879 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Rex, D. K. et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 112, 24–28 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. van Rijn, J. C. et al. Polyp miss rate determined by tandem colonoscopy: a systematic review. Am. J. Gastroenterol. 101, 343–350 (2006).

    Article  PubMed  Google Scholar 

  4. Murthy, S., Goetz, M., Hoffman, A. & Kiesslich, R. Novel colonoscopic imaging. Clin. Gastroenterol. Hepatol. 10, 984–987 (2012).

    Article  PubMed  Google Scholar 

  5. Brown, S. R. & Baraza, W. Chromoscopy versus conventional endoscopy for the detection of polyps in the colon and rectum. Cochrane Database of Systematic Reviews. Issue 10. Art No.: CD006439 http://dx.doi.org/10.1002/14651858.CD006439.pub3.

  6. Tanaka, S. & Sano, Y. Aim to unify the narrow band imaging (NBI) magnifying classification for colorectal tumors: current status in Japan from a summary of the consensus symposium in the 79th Annual Meeting of the Japan Gastroenterological Endoscopy Society. Dig. Endosc. 23 (Suppl 1), 131–139 (2011).

    Article  PubMed  Google Scholar 

  7. Hoffman, A. et al. High definition colonoscopy combined with i-Scan is superior in the detection of colorectal neoplasias compared with standard video colonoscopy: a prospective randomized controlled trial. Endoscopy 42, 827–833 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Goetz, M., Malek, N. & Kiesslich, R. Microscopic imaging in endoscopy: endomicroscopy and endocytoscopy. Nat. Rev. Gastroenterol. Hepatol. http://dx.doi.org/10.1038/nrgastro.2013.134.

  9. Therasse, P. et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl Cancer Inst. 92, 205–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Takao, M. et al. Endoscopic evaluation of primary tumor response in patients with metastatic colorectal cancer treated by systemic chemotherapy. Int. J. Clin. Oncol. http://dx.doi.org/10.1007/s10147-012-0452-2.

  11. Wang, T. D. Targeted imaging of neoplasia in the digestive tract. Cancer Biomark. 4, 285–286 (2008).

    Article  PubMed  Google Scholar 

  12. Rex, D. K. et al. The American Society for Gastrointestinal Endoscopy PIVI (Preservation and Incorporation of Valuable Endoscopic Innovations) on real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest. Endosc. 73, 419–422 (2011).

    Article  PubMed  Google Scholar 

  13. Goetz, M., Hoetker, M. S., Diken, M., Galle, P. R. & Kiesslich, R. In vivo molecular imaging with cetuximab, an anti-EGFR antibody, for prediction of response in xenograft models of human colorectal cancer. Endoscopy 45, 469–477 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Goetz, M. & Wang, T. D. Molecular imaging in gastrointestinal endoscopy. Gastroenterology 138, 828–833.e1 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Mahmood, U. & Wallace, M. B. Molecular imaging in gastrointestinal disease. Gastroenterology 132, 11–14 (2007).

    Article  PubMed  Google Scholar 

  16. Vogelstein, B. & Kinzler, K. W. Cancer genes and the pathways they control. Nat. Med. 10, 789–799 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Goetz, M. et al. In vivo molecular imaging of colorectal cancer with confocal endomicroscopy by targeting epidermal growth factor receptor. Gastroenterology 138, 435–446 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Keller, R., Winde, G., Terpe, H. J., Foerster, E. C. & Domschke, W. Fluorescence endoscopy using a fluorescein-labeled monoclonal antibody against carcinoembryonic antigen in patients with colorectal carcinoma and adenoma. Endoscopy 34, 801–807 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Fottner, C. et al. In vivo molecular imaging of somatostatin receptors in pancreatic islet cells and neuroendocrine tumors by miniaturized confocal laser-scanning fluorescence microscopy. Endocrinology 151, 2179–2188 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Tung, C. H., Mahmood, U., Bredow, S. & Weissleder, R. In vivo imaging of proteolytic enzyme activity using a novel molecular reporter. Cancer Res. 60, 4953–4958 (2000).

    CAS  PubMed  Google Scholar 

  21. Bremer, C., Bredow, S., Mahmood, U., Weissleder, R. & Tung, C. H. Optical imaging of matrix metalloproteinase-2 activity in tumors: feasibility study in a mouse model. Radiology 221, 523–529 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Kang, H. W., Torres, D., Wald, L., Weissleder, R. & Bogdanov, A. A. Jr. Targeted imaging of human endothelial-specific marker in a model of adoptive cell transfer. Lab. Invest. 86, 599–609 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Wallace, M. B. et al. The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract. Aliment. Pharmacol. Ther. 31, 548–552 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Li, M. & Wang, T. D. Targeted endoscopic imaging. Gastrointest. Endosc. Clin. N. Am. 19, 283–298 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Hoetker, M. S. et al. Molecular in vivo imaging of gastric cancer in a human-murine xenograft model: targeting epidermal growth factor receptor. Gastrointest. Endosc. 76, 612–620 (2012).

    Article  PubMed  Google Scholar 

  26. Kwon, Y. S., Cho, Y. S., Yoon, T. J., Kim, H. S. & Choi, M. G. Recent advances in targeted endoscopic imaging: Early detection of gastrointestinal neoplasms. World J. Gastrointest. Endosc. 4, 57–64 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kelly, K., Alencar, H., Funovics, M., Mahmood, U. & Weissleder, R. Detection of invasive colon cancer using a novel, targeted, library-derived fluorescent peptide. Cancer Res. 64, 6247–6251 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Hsiung, P. L. et al. Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy. Nat. Med. 14, 454–458 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shangguan, D. et al. Aptamers evolved from live cells as effective molecular probes for cancer study. Proc. Natl Acad. Sci. USA 103, 11838–11843 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Meng, L. et al. Using live cells to generate aptamers for cancer study. Methods Mol. Biol. 629, 355–367 (2010).

    PubMed  Google Scholar 

  31. Sefah, K. et al. DNA aptamers as molecular probes for colorectal cancer study. PLoS ONE 5, e14269 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Tolmachev, V. et al. Affibody molecules: potential for in vivo imaging of molecular targets for cancer therapy. Expert Opin. Biol. Ther. 7, 555–568 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Baum, R. P. et al. Molecular imaging of HER2-expressing malignant tumors in breast cancer patients using synthetic 111In- or 68Ga-labeled affibody molecules. J. Nucl. Med. 51, 892–897 (2010).

    Article  PubMed  Google Scholar 

  34. Santra, S., Xu, J., Wang, K. & Tan, W. Luminescent nanoparticle probes for bioimaging. J. Nanosci. Nanotechnol. 4, 590–599 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Choi, H. S. & Frangioni, J. V. Nanoparticles for biomedical imaging: fundamentals of clinical translation. Mol. Imaging 9, 291–310 (2010).

    CAS  PubMed  Google Scholar 

  36. Schmidt, C. et al. Nano- and microscaled particles for drug targeting to inflamed intestinal mucosa: a first in vivo study in human patients. J. Control Release 165, 139–145 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Weissleder, R., Tung, C. H., Mahmood, U. & Bogdanov, A. Jr. In vivo imaging of tumors with protease-activated near-infrared fluorescent probes. Nat. Biotechnol. 17, 375–378 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Marten, K. et al. Detection of dysplastic intestinal adenomas using enzyme-sensing molecular beacons in mice. Gastroenterology 122, 406–414 (2002).

    Article  PubMed  Google Scholar 

  39. Urano, Y. et al. Selective molecular imaging of viable cancer cells with pH-activatable fluorescence probes. Nat. Med. 15, 104–109 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Pavlinkova, G. et al. Effects of humanization and gene shuffling on immunogenicity and antigen binding of anti-TAG-72 single-chain Fvs. Int. J. Cancer 94, 717–726 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Uetrecht, J. & Naisbitt, D. J. Idiosyncratic adverse drug reactions: current concepts. Pharmacol. Rev. 65, 779–808 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Hardman, R. A toxicologic review of quantum dots: toxicity depends on physicochemical and environmental factors. Environ. Health Perspect. 114, 165–172 (2006).

    Article  PubMed  Google Scholar 

  43. Alford, R. et al. Toxicity of organic fluorophores used in molecular imaging: literature review. Mol. Imaging 8, 341–354 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Messmann, H. et al. Fluorescence endoscopy for the detection of low and high grade dysplasia in ulcerative colitis using systemic or local 5-aminolaevulinic acid sensitisation. Gut 52, 1003–1007 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu, Z., Miller, S. J., Joshi, B. P. & Wang TD. In vivo targeting of colonic dysplasia on fluorescence endoscopy with near-infrared octapeptide. Gut 62, 395–403 (2013).

    Article  PubMed  Google Scholar 

  46. Alencar, H. et al. Colonic adenocarcinomas: near-infrared microcatheter imaging of smart probes for early detection—study in mice. Radiology 244, 232–238 (2007).

    Article  PubMed  Google Scholar 

  47. Mitsunaga, M. et al. Fluorescence endoscopic detection of murine colitis-associated colon cancer by topically applied enzymatically rapid-activatable probe. Gut http://dx.doi.org/10.1136/gutjnl-2011-301795.

  48. Zhang, H. et al. Biochromoendoscopy: molecular imaging with capsule endoscopy for detection of adenomas of the GI tract. Gastrointest. Endosc. 68, 520–527 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Goetz, M., Watson, A. & Kiesslich, R. Confocal laser endomicroscopy in gastrointestinal diseases. J. Biophotonics 4, 498–508 (2011).

    Article  PubMed  Google Scholar 

  50. Wallace, M. B. & Fockens, P. Probe-based confocal laser endomicroscopy. Gastroenterology 136, 1509–1513 (2009).

    Article  PubMed  Google Scholar 

  51. Goetz, M. et al. Near-infrared confocal imaging during mini-laparoscopy: a novel rigid endomicroscope with increased imaging plane depth. J. Hepatol. 53, 84–90 (2010).

    Article  PubMed  Google Scholar 

  52. Endlicher, E. et al. Endoscopic fluorescence detection of low and high grade dysplasia in Barrett's oesophagus using systemic or local 5-aminolaevulinic acid sensitisation. Gut 48, 314–319 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mayinger, B., Neidhardt, S., Reh, H., Martus, P. & Hahn, E. G. Fluorescence induced with 5-aminolevulinic acid for the endoscopic detection and follow-up of esophageal lesions. Gastrointest. Endosc. 54, 572–578 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Kuiper, T. et al. Endoscopic trimodal imaging detects colonic neoplasia as well as standard video endoscopy. Gastroenterology 140, 1887–1894 (2011).

    Article  PubMed  Google Scholar 

  55. Habibollahi, P. et al. Optical imaging with a cathepsin B activated probe for the enhanced detection of esophageal adenocarcinoma by dual channel fluorescent upper GI endoscopy. Theranostics 2, 227–234 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wong, G. S. et al. Optical imaging of periostin enables early endoscopic detection and characterization of esophageal cancer in mice. Gastroenterology http://dx.doi.org/10.1053/j.gastro.2012.10.030.

  57. Curvers, W. L. et al. Endoscopic tri-modal imaging for detection of early neoplasia in Barrett's oesophagus: a multi-centre feasibility study using high-resolution endoscopy, autofluorescence imaging and narrow band imaging incorporated in one endoscopy system. Gut 57, 167–172 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Li, M. et al. Affinity peptide for targeted detection of dysplasia in Barrett's esophagus. Gastroenterology 139, 1472–1480 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Joshi, B. P., Liu, Z., Elahi, S. F., Appelman, H. D. & Wang, T. D. Near-infrared-labeled peptide multimer functions as phage mimic for high affinity, specific targeting of colonic adenomas in vivo (with videos). Gastrointest. Endosc. 76, 1197–1206 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  60. van Dam, G. M. et al. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-alpha targeting: first in-human results. Nat. Med. 17, 1315–1319 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Bird-Lieberman, E. L. et al. Molecular imaging using fluorescent lectins permits rapid endoscopic identification of dysplasia in Barrett's esophagus. Nat. Med. 18, 315–321 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Goetz, M. et al. In-vivo confocal real-time mini-microscopy in animal models of human inflammatory and neoplastic diseases. Endoscopy 39, 350–356 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Foersch, S. et al. Molecular imaging of VEGF in gastrointestinal cancer in vivo using confocal laser endomicroscopy. Gut 59, 1046–1055 (2010).

    Article  PubMed  Google Scholar 

  64. Liu, J. et al. In vivo molecular imaging of epidermal growth factor receptor in patients with colorectal neoplasia using confocal laser endomicroscopy. Cancer Lett. 330, 200–207 (2013).

    Article  CAS  PubMed  Google Scholar 

  65. Li, Z. et al. In vivo molecular imaging of gastric cancer by targeting MG7 antigen with confocal laser endomicroscopy. Endoscopy 45, 79–85 (2013).

    Article  PubMed  Google Scholar 

  66. Froehlich, F., Wietlisbach, V., Gonvers, J. J., Burnand, B. & Vader, J. P. Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study. Gastrointest. Endosc. 61, 378–384 (2005).

    Article  PubMed  Google Scholar 

  67. Kaminski, M. F. et al. Quality indicators for colonoscopy and the risk of interval cancer. N. Engl. J. Med. 362, 1795–1803 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Barclay, R. L., Vicari, J. J., Doughty, A. S., Johanson, J. F. & Greenlaw, R. L. Colonoscopic withdrawal times and adenoma detection during screening colonoscopy. N. Engl. J. Med. 355, 2533–2541 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Pox, C. P. et al. Efficacy of a nationwide screening colonoscopy program for colorectal cancer. Gastroenterology 142, 1460–1467 e2 (2012).

    Article  PubMed  Google Scholar 

  70. Jain, V. K., Hawkes, E. A. & Cunningham, D. Integration of biologic agents with cytotoxic chemotherapy in metastatic colorectal cancer. Clin. Colorectal Cancer. 10, 245–257 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. Pirker, R. & Filipits, M. Monoclonal antibodies against EGFR in non-small cell lung cancer. Crit. Rev. Oncol. Hematol. 80, 1–9 (2011).

    Article  PubMed  Google Scholar 

  72. Lievre, A. et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J. Clin. Oncol. 26, 374–379 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Bang, Y. J. et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376, 687–697 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Hoetker, M. S. et al. Molecular in vivo imaging of gastric cancer in a human-murine xenograft model: targeting epidermal growth factor receptor (EGFR). Gastrointest. Endosc. 76, 612–620 (2012).

    Article  PubMed  Google Scholar 

  75. Kwekkeboom, D. J. et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: peptide receptor radionuclide therapy with radiolabeled somatostatin analogs. Neuroendocrinology 90, 220–226 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Boudreaux, J. P. et al. The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the Jejunum, Ileum, Appendix, and Cecum. Pancreas 39, 753–766 (2010).

    Article  PubMed  Google Scholar 

  77. Helman, E. E. et al. Optical imaging predicts tumor response to anti-EGFR therapy. Cancer Biol. Ther. 10, 166–171 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Both authors contributed equally to all aspects of the preparation of this manuscript.

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Correspondence to Martin Goetz.

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M. Goetz declares that he receives research support from Pentax and Optiscan. R. Atreya declares no competing interests.

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Atreya, R., Goetz, M. Molecular imaging in gastroenterology. Nat Rev Gastroenterol Hepatol 10, 704–712 (2013). https://doi.org/10.1038/nrgastro.2013.125

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