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Deciphering PDT-induced inflammatory responses using real-time FDG-PET in a mouse tumour model

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Abstract

Dynamic positron emission tomography (PET), combined with constant infusion of 2-deoxy-2-[18F]fluoro-d-glucose (FDG), enables real-time monitoring of transient metabolic changes in vivo, which can serve to understand the underlying physiology. Here we investigated characteristic changes in the tumour FDG-uptake profiles in relation to acute localized inflammatory responses induced by photodynamic therapy (PDT). Dynamic PET imaging with constant FDG infusion was used with EMT-6 tumour bearing mice. FDG time-activity uptake curves were measured simultaneously, in treated and reference tumours, for 3 hours, before, during and after PDT light treatment. Inflammation was studied when evoked, either by PDT using a trisulfonated porphyrazine photosensitizer, or lipopolysaccharide (LPS), and inhibited using indomethacin. The distinct transient patterns, characterized by drops and subsequent recovery of tumour FDG uptake rates, were also analysed using immunohistochemical markers for apoptosis, necrosis, and inflammation. Typical profiles for tumour FDG-uptake, consisted of a drop during PDT, followed by a gradual recovery period. Tumours treated with LPS, but not with light, showed a continuous increase in FDG-uptake during the 3 h experimental period. Treatment with indomethacin, inhibited the rise in FDG-uptake observed with either LPS or PDT. Tumour FDG-uptake profiles correlated with necrosis markers during PDT, and inflammatory response markers post-PDT, but not with an apoptosis marker at any time during or after PDT. Dynamic FDG-PET imaging combined with indomethacin reveals that, the drop in the tumour FDG-uptake rate during the PDT illumination phase reflects vascular collapse and necrosis, while the increased tumour FDG-uptake rate immediately post-illumination involves an acute localized inflammatory response. Dynamic FDG infusion and PET imaging, combined with the use of selective inhibitors, provides unique insight for deciphering the complex underlying processes leading to tumour response in PDT, and allows for rapid as well as cost effective optimization of PDT protocols.

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Notes and references

  1. N. Cauchon, E. Turcotte, R. Lecomte, H. M. Hasséssian, J. E. van Lier, Predicting efficacy of photodynamic therapy by real-time FDG-PET in a mouse tumour model, Photochem. Photobiol. Sci., 2012, 11, 364–370.

    Article  CAS  PubMed  Google Scholar 

  2. V. Bérard, J. A. Rousseau, J. Cadorette, L. Hubert, M. Bentourkia, J. E. van Lier, R. Lecomte, Dynamic imaging of transient metabolic processes by small-animal PET for the evaluation of photosensitizers in photodynamic therapy of cancer, J. Nucl. Med., 2006, 47, 1119–1126.

    PubMed  Google Scholar 

  3. A. T. Byrne, A. E. O’Connor, M. Hall, J. Murtagh, K. O’Neill, K. M. Curran, K. Mongrain, J. A. Rousseau, R. Lecomte, S. McGee, J. J. Calanan, D. F. O’Shea, W. M. Gallagher, Vascular-targeted photodynamic therapy with BF2-chelated Tetraaryl-Azadipyrromethene agents: a multi-modality molecular imaging approach to therapeutic assessment, Br. J. Cancer, 2009, 101, 1565–1573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. M. Koberlik, PDT-associated host response and its role in the therapy outcome, Laser Surg. Med., 2006, 38, 500–508.

    Article  Google Scholar 

  5. M. Firczuk, D. Nowisa, J. Goła, PDT-induced inflammatory and host responses, Photochem. Photobiol. Sci., 2011, 10, 653–663.

    Article  CAS  PubMed  Google Scholar 

  6. N. L. Oleinick, R. Morris, I. Belichenko, The role of apoptosis in response to photodynamic therapy: what, where, why, and how, Photochem. Photobiol. Sci., 2002, 1, 1–21.

    Article  CAS  PubMed  Google Scholar 

  7. N. Cauchon, R. Langlois, J. A. Rousseau, G. Tessier, J. Cadorette, R. Lecomte, D. J. Hunting, R. A. Pavan, S. K. Zeisler, J. E. van Lier, PET imaging of apoptosis with 64Cu-labeled streptavidin following pretargeting of phosphatidylserine with biotinylated annexin-V. Eur, J. Nucl. Med. Mol. Imaging, 2007, 34, 247–258.

    Article  CAS  Google Scholar 

  8. C. B. Oberdanner, T. Kiesslich, B. Krammer, K. Plaetzer, Glucose is required to maintain high ATP levels for the energy utilizing steps during PDT-induced apoptosis, Photochem. Photobiol., 2002, 76, 695–703.

    Article  CAS  PubMed  Google Scholar 

  9. A. van Waarde, P. H. Elsinga, Proliferation markers for the differential diagnosis of tumour and inflammation, Curr. Pharm. Des., 2008, 14, 3326–3339.

    Article  PubMed  Google Scholar 

  10. A. P. Castano, P. Mroz, M. R. Hamblin, Photodynamic therapy and anti-tumour immunity, Nat. Rev. Cancer, 2006, 6, 535–545.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. R. Kubota, S. Yamamda, K. Kubota, K. Ishiwata, N. Tamahashi, T. Ido, Intratumoural distribution of fluorin-18-fluorodeoxyglucose in vivo; high accumulation in macrophages and granulation tissues studied by microauto-radiography, J. Nucl. Med., 1992, 33, 1972–1980.

    CAS  PubMed  Google Scholar 

  12. V. H. Fingar, T. J. Wieman, K. W. Doak, Role of thromboxane and prostacyclin release on photodynamic therapy-induced tumour destruction, Cancer Res., 1990, 50, 2599–2603.

    CAS  PubMed  Google Scholar 

  13. J. Kleban, J. Mikes, B. Szilardiova, J. Koval, V. Sackova, P. Solar, Modulation of hypericin photodynamic therapy by pretreatment with various inhibitors of arachidonic acid metabolism in colon adenocarcinoma HT-29 cells, Photochem. Photobiol., 2007, 83, 1174–1185.

    Article  CAS  PubMed  Google Scholar 

  14. M. Fujiharaa, M. Muroib, K. I. Tanamotob, T. Suzukic, H. Azumaa, H. Ikedaa, Molecular mechanisms of macrophage activation and deactivation by lipopolysaccharide: roles of the receptor complex, Pharmacol. Ther., 2003, 100, 171–194.

    Article  Google Scholar 

  15. S. Nagano, T. Otsuka, H. Niiro, K. Yamaoka, Y. Arinobu, E. Ogami, M. Akahoshi, Y. Inoue, K. Miyake, H. Nakashima, Y. Niho, M. Harada, Molecular mechanisms of lipopolysaccharide-induced cyclooxygenase-2 expression in human neutrophils: involvement of the mitogen-activated protein kinase pathway and regulation by anti-inflammatory cytokines, Int. Immunol., 2002, 14, 733–740.

    Article  CAS  PubMed  Google Scholar 

  16. W. G. Bessler, K. Mittenbühler, U. Esche, M. Huber, Lipopeptide adjuvants in combination treatment, Int. Immunopharmacol., 2003, 3, 1217–1224.

    Article  CAS  PubMed  Google Scholar 

  17. M. R. Chicoine, M. Zahner, E. K. Won, R. R. Kalra, T. Kitamura, A. Perry, R. Higashikubo, The in vivo antitumoural effects of lipopolysaccharide against glioblastoma multiforme are mediated in part by Toll-like receptor 4, Neurosurgery, 2007, 60, 372–381.

    Article  PubMed  Google Scholar 

  18. S. Basith, B. Manavalan, G. Lee, S. Geon Kim, S. Choi, Toll-like receptor modulators: a patent review (2006-2010), Expert Opin. Ther. Pat., 2011, 21, 927–944.

    Article  CAS  PubMed  Google Scholar 

  19. J. E. van Lier, H. Tian, H. Ali, N. Cauchon, H. M. Hasséssian, Trisulfonated porphyrazines: new photosensitizers for the treatment of retinal and sub-retinal oedema, J. Med. Chem., 2009, 52, 4107–4110.

    Article  PubMed  Google Scholar 

  20. K. Hamacher, H. H. Coenen, G. Stocklin, Efficient stereo-specific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-d-glucose using aminopolyether supported nucleophilic substitution, J. Nucl. Med., 1986, 27, 235–238.

    CAS  PubMed  Google Scholar 

  21. M. Bergeron, J. Cadorette, J. F. Beaudoin, M. D. Lepage, G. Robert, V. Selivanov, M. A. Tétrault, N. Viscogliosi, J. P. Noremberg, R. Fontaine, R. Lecomte, Performance evaluation of the LabPET™ APD-based digital PET scanner, IEEE Trans. Nucl. Sci., 2009, 56, 10–16.

    Article  Google Scholar 

  22. S. Girard, G. Sébire, H. Kadhim, Proinflammatory orientation of the interleukin 1 system and downstream induction of matrix metalloproteinase 9 in the pathophysiology of human perinatal white matter damage, J. Neuropathol. Exp. Neurol., 2010, 69, 1116–1129.

    Article  CAS  PubMed  Google Scholar 

  23. D. Lapointe, N. Brasseur, J. Cadorette, C. La Madeleine, S. Rodrigue, J. E. van Lier, R. Lecomte, High-resolution PET imaging for in vivo monitoring of tumour response after photodynamic therapy in mice, J. Nucl. Med., 1999, 40, 876–882.

    CAS  PubMed  Google Scholar 

  24. C. P. Bleeker-Rovers, F. J. Vos, W. T. A. van der Graaf, J. G. Oyen, Nuclear medicine imaging of infection in cancer patients (with emphasis on FDG-PET), Oncologist, 2011, 16, 980–991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. J. Liu, M. Ogawa, T. Sakai, M. Takashima, S. Okazaki, Y. Magata, Differentiation of tumour sensitivity to photodynamic therapy and early evaluation of treatment effect by nuclear medicine techniques, Ann. Nucl. Med., 2013, 27, 669–675.

    Article  CAS  PubMed  Google Scholar 

  26. N. V. Chandrasekharan, H. Dai, L. T. Roos, N. K. Evanson, J. Tomsik, T. S. Elton, Simmons DL. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression, Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 13926–13931.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. I. Morita, Distinct functions of COX-1 and COX-2, Prostaglandins Other Lipid Mediat, 2002, 69, 165–175.

    Article  Google Scholar 

  28. K. J. Sales, H. N. Jabbour, Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium, Reproduction, 2003, 126, 559–567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. B. J. Tong, J. Tan, L. Tajeda, S. K. Das, J. A. Chapman, R. N. DuBois, S. K. Dey, Heightened expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor in human endometrial adenocarcinoma, Neoplasia, 2000, 2, 482–490.

    Article  Google Scholar 

  30. G. Ferrandina, F. Legge, F. O. Ranelletti, G. F. Zannoni, N. Maggiano, A. Evangelisti, S. Mancuso, G. Scambia, L. Lauriola, Cyclooxygenase-2 expression in endometrial carcinoma correlation with clinicopathologic parameters and clinical outcome, Cancer, 2002, 95, 801–807.

    Article  CAS  PubMed  Google Scholar 

  31. K. Watenabe, T. Kawamori, S. Nakatsugi, Inhibitory effect of a prostaglandin E receptor subtype EPI selective antagonist: ONO-8713, on development of azoxymethane-induced aberrant crypt foci in mice, Cancer Lett., 2000, 156, 57–61.

    Article  Google Scholar 

  32. H. Sheng, J. Shao, M. K. Washington, R. N. DuBois, Prostaglandin E2 increases growth and motility of colorectal carcinoma cells, J. Biol. Chem., 2001, 276, 18075–18081.

    Article  CAS  PubMed  Google Scholar 

  33. S. Narumiya, Y. Sugimoto, F. Ushikubi, Prostanoid receptors: Structures: properties and functions, Physiol. Rev., 1999, 79, 1193–1226.

    Article  CAS  PubMed  Google Scholar 

  34. F. Kamachi, H. S. Ban, N. Hirasawa, K. Ohuchi, Inhibition of lipopolysaccharide-induced prostaglandin E2 production and inflammation by the Na+/H+ exchanger inhibitors, J. Pharmacol. Exp. Ther., 2007, 321, 345–352.

    Article  CAS  PubMed  Google Scholar 

  35. B. W. Henderson, J. M. Donovan, Release of prostaglandin E2 from cells by photodynamic treatment in vitro, Cancer Res., 1989, 49, 6896–6900.

    CAS  PubMed  Google Scholar 

  36. L. C. Penning, M. J. Keirse, J. van Steveninck, T. M. Dubbelman, Ca(2+)-mediated prostaglandin E2 induction reduces haematoporphyrin-derivative-induced cytotoxicity of T24 human bladder transitional carcinoma cells in vitro, Biochem. J., 1993, 292, 237–240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. M. T. Foultier, T. Patrice, S. Yactayo, Y. Lajat, F. Resche, Photodynamic treatment of normal endothelial cells or glioma cells in vitro, Surg. Neurol., 1992, 37, 83–88.

    Article  CAS  PubMed  Google Scholar 

  38. A. J. Lonigro, M. H. Hagemann, A. H. Stephenson, C. L. Fry, Inhibition of protaglandin synthesis by indomethacin augments the renal vasodilator response to bradykinin in the anesthetized dog, Circ. Res., 1978, 43, 447–455.

    Article  CAS  PubMed  Google Scholar 

  39. C. W. Leffler, R. Mirro, L. J. Pharris, M. Shibata, Permissive role of prostacyclin in cerebral vasodilation to hypercapnia in new-born pigs, Am. J. Physiol., 1994, 267, H285–H291.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Sherbrooke Molecular Imaging Centre, CRCHUS, and Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada

    Nicole Cauchon, Eric Turcotte, Roger Lecomte & Johan E. van Lier

  2. Departments of Ophthalmology and Biomedical Sciences, Université de Montréal, Centre de Recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, 5415 Boul. de l’Assomption, Montréal, QC, H1T 2M4, Canada

    Haroutioun M. Hasséssian

  3. NorVision Therapeutics Inc., 1 Place Ville-Marie, Montréal, Québec, H3B 2C4, Canada

    Haroutioun M. Hasséssian

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  1. Nicole Cauchon
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  3. Eric Turcotte
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  4. Roger Lecomte
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  5. Johan E. van Lier
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Correspondence to Johan E. van Lier.

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Cauchon, N., Hasséssian, H.M., Turcotte, E. et al. Deciphering PDT-induced inflammatory responses using real-time FDG-PET in a mouse tumour model. Photochem Photobiol Sci 13, 1434–1443 (2014). https://doi.org/10.1039/c4pp00140k

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