Real-time imaging of trail-induced apoptosis of glioma tumors in vivo

ABSTRACT Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in neoplastic cells. While many previous studies have been performed in cell

culture, the delivery and efficiency of TRAIL variants _in vivo_ is less well established. Using dual substrate/reporter bioluminescence imaging (Fluc: firefly luciferase – luciferin and

Rluc: _Renilla_ luciferase – coelenterazine), we tested the efficacy of TRAIL using replication-deficient herpes simplex virus (HSV) type 1 amplicon vectors in gliomas. The cDNA for complete

TRAIL and the extracellular domain of TRAIL (aa 114–281) were cloned into HSV amplicons and packaged into helper virus-free vectors. Both forms of TRAIL induced similar degrees of apoptosis

in human glioma cells (Gli36) in culture within 24 h of infection with TRAIL amplicon vectors. Growth of tumors stably transfected with Fluc (Gli36fluc+) was readily monitored _in vivo_ by

bioluminescence imaging following luciferin administration. HSV amplicon vectors bearing the genes for TRAIL and Rluc injected directly into Gli36fluc+-expressing subcutaneous gliomas

revealed peak Rluc activity 36 h after intratumoral injection as determined by coelenterazine injection followed by imaging. TRAIL-treated gliomas regressed in size over a period of 4 weeks

as compared to the mock-injected gliomas. These results show the efficacy of vector delivered TRAIL in treating tumors _in vivo_ and offer a unique way to monitor both gene delivery and

efficacy of TRAIL-induced apoptosis in tumors _in vivo_ in real time by dual enzyme substrate (Rluc/Fluc) imaging. Access through your institution Buy or subscribe This is a preview of

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BIOLUMINESCENCE IMAGING OF ORTHOTOPIC PATIENT-DERIVED GLIOBLASTOMA XENOGRAFTS Article Open access 21 September 2020 NOVEL NANOLUC SUBSTRATES ENABLE BRIGHT TWO-POPULATION BIOLUMINESCENCE

IMAGING IN ANIMALS Article 13 July 2020 ELEVATED CELLULAR PPIX POTENTIATES SONODYNAMIC THERAPY IN A MOUSE GLIOMA STEM CELL-BEARING GLIOMA MODEL BY DOWNREGULATING THE AKT/NF-ΚB/MDR1 PATHWAY

Article Open access 23 July 2021 CHANGE HISTORY * _ 20 FEBRUARY 2024 Editor's note: Readers are alerted that concerns have been raised regarding the reliability of data presented in

this article. Further editorial action will be taken if appropriate once the investigation into the concerns is complete and all parties have been given an opportunity to respond in full. _

* _ 23 JULY 2024 A Correction to this paper has been published: https://doi.org/10.1038/s41388-024-03109-x _ REFERENCES * Ashkenazi A and Dixit VM . (1998). _Science_, 281, 1305–1308. *

Ashkenazi A and Dixit VM . (1999). _Curr. Opin. Cell Biol._, 11, 255–260 (Review). * Bhumik S and Gambhir SS . (2002). _Proc. Natl. Acad. Sci. USA_, 99, 377–382. * Boviatsis EJ, Scharf JM,

Chase M, Harrington K, Kowall NW, Breakefield XO and Chiocca EA . (1994). _Gene Ther._, 1, 323–331. * Chinnaiyan AM, Prasad U, Shankar S, Hamstra DA, Shanaiah M, Chenevert TL, Ross BD and

Rehemtulla A . (2000). _Proc. Natl. Acad. Sci. USA_, 97, 1754–1759. * Contag PR, Olomu IN, Stevenson DK and Contag CH . (1998). _Nat. Med._, 4, 245–247. * Contag CH and Buchmann MH . (2002).

_Ann. Rev. Biomed. Eng._, 4, 235–260. * Contag CH, Jenkins D, Contag PR and Negrin RS . (2000). _Neoplasia_, 2, 41–52 (Review). * Di X, Nishizaki T, Harada K, Kajiwara K, Nakayama H and Ito

H . (1997). _J. Exp. Clin. Cancer Res._, 16, 389–394. * Evan S and Littlewood V . (1998). _Science_, 281, 1317–1322 (Review). * Evan GL, Brown L, Whyte M and Harrington E . (1995). _Curr.

Opin. Cell Biol._, 7, 825–834 (Review). * Fraefel C, Jacoby DR and Breakefield XO . (2000). _Adv. Virus Res._, 55, 425–452. * Fulci G and Chiocca EA . (2003). _Front Bioscience,_ 8, 346–360

(Review). * Gambhir S . (2002). _Nat. Rev. Cancer_, 2, 683–693 (Review). * Gliniak B and Le T . (1999). _Cancer Res._, 59, 6153–6158. * Griffith TS and Broghammer FL . (2001). _Mol. Ther._,

4, 257–266. * Griffith TS, Anderson RD, Davidson BL, Williams RD and Ratliff TL . (2000). _J. Immunol._, 165, 2886–2894. * Gruss HJ and Dower SK . (1995). _Blood_, 85, 3378–3404 (Review). *

Jo M, Kim TH, Seol DW, Esplen JE, Dorko K, Billiar TR and Strom SC . (2000). _Nat. Med._, 6, 564–567. * Kagawa S, He C, Gu J, Koch P, Rha SJ, Roth JA, Curley SA, Stephens LC and Fang B .

(2001). _Cancer Res._, 61, 3330–3338. * Kashima T, Vinters HV and Campagnoni AT . (1995). _J. Neuropathol. Exp. Neurol._, 54, 23–31. * Lawrence D, Shahrokh Z, Marsters S, Achilles K, Shih D,

Mounho B, Hillan K, Totpal K, DeForge L, Schow P, Hooley J, Sherwood S, Pai R, Leung S, Khan L, Gliniak B, Bussiere J, Smith CA, Strom SS, Kelley S, Fox JA, Thomas D and Ashkenazi A .

(2001). _Nat. Med._, 7, 383–385. * LeBlanc HN and Ashkenazi A . (2003). _Cell Death Differ._, 10, 66–75. * Luker GD, Bardill JP, Prior JL, Pica CM, Piwnica-Worms D and Leib DA . (2002). _J.

Virol._, 76, 12149–12161. * Marsters SA, Pitti RM, Donahue CJ, Ruppert S, Bauer KD and Ashkenazi A . (1996). _Curr. Biol._, 6, 750–752. * Morgenstern JP and Land H . (1990). _Nucleic Acids

Res._, 18, 3587–3596. * Nagata S . (1997). _Cell_, 88, 355–365. * Nitsch R, Bechmann I, Deisz RA, Haas D, Lehmann TN, Wendling U and Zipp F . (2000). _Lancet_, 356, 827–828. * Pitti RM,

Marsters SA, Ruppert S, Donahue CJ, Moore A and Ashkenazi A . (1996). _J. Biol. Chem._, 271, 12687–12690. * Pulkkanen KJ, Parkkinen JJ, Laukkanen JM, Kettunen MI, Tyynela K, Kauppinen RA,

Ala-Opas MY and Yla-Herttuala S . (2001). _Cancer Gene Ther._, 8, 529–536. * Rehemtulla A, Stegman LD, Cardozo SJ, Gupta S, Hall DE, Contag CH and Ross BD . (2000). _Neoplasia_, 2, 491–495.

* Rieger J, Naumann U, Glaser T, Ashkenazi A and Weller M . (1998). _FEBS Lett._, 427, 124–129. * Saeki Y, Fraefel C, Ichikawa T, Breakefield XO and Chiocca EA . (2001). _Mol. Ther._, 3,

591–601. * Shen Y and Shenk TE . (1995). _Curr. Opin. Genet. Dev._, 5, 105–111 (Review). * Tjuvajev JG, Doubrovin M, Akhurst T, Cai S, Balatoni J, Alauddin MM, Finn R, Bornmann W, Thaler H,

Conti PS and Blasberg RG . (2002). _J. Nucl. Med._, 43, 1072–1083. * Vaux DL . (1993). _Proc. Natl. Acad. Sci. USA_, 90, 786–789 (Review). * Voelkel-Johnson C, King DL and Norris JS .

(2002). _Cancer Gene Ther._, 9, 164–172. * Wajant H, Pfizenmaier K and Scheurich P . (2002). _Apoptosis_, 7, 449–459. * Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin

W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC and Lynch DH . (1999a). _Nat. Med._, 5, 157–163. * Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS,

Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC and Lynch DH . (1999b). _Nat. Med._, 5, 157–163. * Weissleder R . (2002). _Nat. Rev. Cancer_, 2,

11–18 (Review). Download references ACKNOWLEDGEMENTS We thank Sara Camp for helping with viral DNA preparations and Deb Schuback for interesting discussions. We also thank Dr Edward Graves

for providing us with the image analysis program and its regular upgrades and Dr Vasilis Nziachristos for help with the imaging system installation and CCD camera calibration. This work is

supported in part by American Brain Tumor Association grant, Gene therapy for brain tumors (GTBT) CA6924 grant, a P50 center grant (CA86355), Goldhirsh Medical Foundation of Massachusetts

and small animal imaging resource grant (SAIRG) (R24-CA92782). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard

Medical School, Boston, MA, USA Khalid Shah, Yi Tang & Ralph Weissleder * Department of Neurology Massachusetts General Hospital, Molecular Neurogenetics Unit, Harvard Medical School,

Boston, MA, USA Khalid Shah & Xandra Breakefield Authors * Khalid Shah View author publications You can also search for this author inPubMed Google Scholar * Yi Tang View author

publications You can also search for this author inPubMed Google Scholar * Xandra Breakefield View author publications You can also search for this author inPubMed Google Scholar * Ralph

Weissleder View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Khalid Shah. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Shah, K., Tang, Y., Breakefield, X. _et al._ Real-time imaging of TRAIL-induced apoptosis of glioma tumors _in vivo_. _Oncogene_ 22,

6865–6872 (2003). https://doi.org/10.1038/sj.onc.1206748 Download citation * Received: 14 January 2003 * Revised: 21 April 2003 * Accepted: 23 April 2003 * Published: 09 October 2003 * Issue

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a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * TRAIL * bioluminescence *

apoptosis