Bioluminescence Imaging Serves as a Dynamic Marker for Guiding and Assessing Thermal Treatment of Cancer in a Preclinical Model

BackgroundBioluminescence has been harnessed as a dynamic imaging technique in research. This is a proof of principle study examining feasibility of using bioluminescent proteins as a marker to guide therapeutic ablation.MethodsMesothelioma cancer cells (MSTO-Td) were transfected with a retroviral vector bearing firefly luciferase gene, plated in serial dilutions, and imaged to compare bioluminescence signal to cell number, determining threshold of bioluminescence detection. MSTO-Td cells were subjected to thermal treatment in a heated chamber; the bioluminescence signal and number of remaining live cancer cells were determined. Mice with MSTO-Td xenografts underwent electrocautery tumor ablation guided by bioluminescence imaging; bioluminescence signal and tumor size were monitored for 3 weeks.ResultsMSTO-Td cells emitted a bright, clear, bioluminescence signal that amplified with the cell number (P < .001) and was detectable with as few as 10 cells in cell culture. Bioluminescence decreased in a dose-dependent fashion upon thermal treatment as temperature increased from 37 to 70 °C (P < .001) and as treatment duration increased from 5 to 20 min (P < .001). This correlated with the number of remaining live MSTO-Td cells (Pearson coefficient = 0.865; P < .001). In mice, the bioluminescence signal correlated with tumor size posttreatment and effectively guided the ablation procedure to completion, achieving 0 % tumor recurrence.ConclusionsBioluminescence imaging is a sensitive, real-time imaging approach; bioluminescence reporters such as firefly luciferase can assess and guide thermal treatment of cancer. This encourages research into bioluminescence imaging as a molecular technique with potential to target tumors via biomarkers and optimize thermal treatment procedures in a clinical setting.

[1]  B. Rice,et al.  Quantitative comparison of the sensitivity of detection of fluorescent and bioluminescent reporters in animal models. , 2004, Molecular imaging.

[2]  C. Contag,et al.  Visualizing the kinetics of tumor-cell clearance in living animals. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[3]  K. Wood,et al.  Cloning of firefly luciferase cDNA and the expression of active luciferase in Escherichia coli. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[4]  C. Contag,et al.  Noninvasive assessment of tumor cell proliferation in animal models. , 1999, Neoplasia.

[5]  G. Gazelle,et al.  Thermal ablation therapy for focal malignancy: a unified approach to underlying principles, techniques, and diagnostic imaging guidance. , 2000, AJR. American journal of roentgenology.

[6]  E. Hoffman,et al.  In vivo mouse studies with bioluminescence tomography. , 2006, Optics express.

[7]  N. Rubio,et al.  Combined Noninvasive Imaging and Luminometric Quantification of Luciferase-Labeled Human Prostate Tumors and Metastases , 2002, Laboratory Investigation.

[8]  Christopher H Contag,et al.  Revealing lymphoma growth and the efficacy of immune cell therapies using in vivo bioluminescence imaging. , 2003, Blood.

[9]  M. Jacobs,et al.  Choline metabolism in cancer: implications for diagnosis and therapy , 2006, Expert review of molecular diagnostics.

[10]  H. Hricak,et al.  Imaging of hypoxia-driven gene expression in an orthotopic liver tumor model , 2007, Molecular Cancer Therapeutics.

[11]  Robin S. Dothager,et al.  Advances in bioluminescence imaging of live animal models. , 2009, Current opinion in biotechnology.

[12]  H. Hricak,et al.  Escherichia coli Nissle 1917 Facilitates Tumor Detection by Positron Emission Tomography and Optical Imaging , 2008, Clinical Cancer Research.

[13]  T. Ochiya,et al.  Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[14]  T. Smith,et al.  Towards detecting the HER-2 receptor and metabolic changes induced by HER-2-targeted therapies using medical imaging. , 2010, The British journal of radiology.

[15]  S. Lyons,et al.  Noninvasive bioluminescence imaging of normal and spontaneously transformed prostate tissue in mice. , 2006, Cancer research.

[16]  J. Benlloch,et al.  Molecular Imaging in Breast Cancer , 2012, Journal of oncology.

[17]  C. V. van Noorden,et al.  Validity of bioluminescence measurements for noninvasive in vivo imaging of tumor load in small animals. , 2007, BioTechniques.

[18]  J. Massagué,et al.  Multimodality imaging of TGFβ signaling in breast cancer metastases , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  Hyunsuk Shim,et al.  Metabolic positron emission tomography imaging in cancer detection and therapy response. , 2011, Seminars in oncology.

[20]  Atsushi B. Tsuji,et al.  C-kit-targeted imaging of gastrointestinal stromal tumor using radiolabeled anti-c-kit monoclonal antibody in a mouse tumor model. , 2010, Nuclear medicine and biology.

[21]  Peter G. Schultz,et al.  Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK , 2007, Proceedings of the National Academy of Sciences.

[22]  Ivo Que,et al.  Optical imaging of cancer metastasis to bone marrow: a mouse model of minimal residual disease. , 2002, The American journal of pathology.

[23]  Jie Tian,et al.  In vivo quantitative bioluminescence tomography using heterogeneous and homogeneous mouse models. , 2010, Optics express.

[24]  J. Trachtenberg,et al.  Image guidance for focal therapy of prostate cancer , 2010, World Journal of Urology.

[25]  M. Gönen,et al.  Genetically Engineered Oncolytic Newcastle Disease Virus Effectively Induces Sustained Remission of Malignant Pleural Mesothelioma , 2010, Molecular Cancer Therapeutics.

[26]  K. Shah Current advances in molecular imaging of gene and cell therapy for cancer , 2005, Cancer biology & therapy.

[27]  P. Low,et al.  Tumor detection using folate receptor-targeted imaging agents , 2008, Cancer and Metastasis Reviews.

[28]  Yuman Fong,et al.  Local Surgical, Ablative, and Radiation Treatment of Metastases , 2009, CA: a cancer journal for clinicians.

[29]  M. Al-Dhaheri,et al.  Selenium disrupts estrogen receptor α signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells , 2005, Molecular Cancer Therapeutics.

[30]  W. Gerald,et al.  Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. , 2005, The Journal of clinical investigation.

[31]  W. Lau,et al.  Percutaneous Local Ablative Therapy for Hepatocellular Carcinoma: A Review and Look Into the Future , 2003, Annals of surgery.

[32]  Shenmin Zhang,et al.  Use of the ODD-Luciferase Transgene for the Non-Invasive Imaging of Spontaneous Tumors in Mice , 2011, PloS one.

[33]  Y. Fong,et al.  Real‐time intraoperative detection of melanoma lymph node metastases using recombinant vaccinia virus GLV‐1h68 in an immunocompetent animal model , 2009, International journal of cancer.