Tracking Tumor Colonization in Xenograft Mouse Models Using Accelerator Mass Spectrometry [Tracking Tumor Colonization in vivo Using Accelerator Mass Spectrometry]

Hum, Nicholas R.; Martin, Kelly A.; Malfatti, Michael A.; Haack, Kurt; Buchholz, Bruce A.; Loots, Gabriela G.

doi:10.1038/s41598-018-33368-0

Title: Tracking Tumor Colonization in Xenograft Mouse Models Using Accelerator Mass Spectrometry [Tracking Tumor Colonization in vivo Using Accelerator Mass Spectrometry]

Journal Article · 08 October 2018 · Scientific Reports

DOI: https://doi.org/10.1038/s41598-018-33368-0 · OSTI ID:1527297

Hum, Nicholas R. ^[1]; Martin, Kelly A. ^[2]; Malfatti, Michael A. ^[1]; Haack, Kurt ^[1]; Buchholz, Bruce A. ^[1]; Loots, Gabriela G. ^[3]

Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Georgetown Univ., Washington, DC (United States)
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California Merced, Merced, CA (United States)

Here we propose an Accelerator Mass Spectrometry (AMS)-based high precision method for quantifying the number of cancer cells that initiate metastatic tumors, in xenograft mice. Quantification of ¹⁴C per cell prior to injection into animals, and quantification of ¹⁴C in whole organs allows us to extrapolate the number of cancer cells available to initiate metastatic tumors. The ¹⁴C labeling was optimized such that 1 cancer cell was detected among 1 million normal cells. We show that ~1–5% of human cancer cells injected into immunodeficient mice form subcutaneous tumors, and even fewer cells initiate metastatic tumors. Comparisons of metastatic site colonization between a highly metastatic (PC3) and a non-metastatic (LnCap) cell line showed that PC3 cells colonize target tissues in greater quantities at 2 weeks post-delivery, and by 12 weeks post-delivery no ¹⁴C was detected in LnCap xenografts, suggesting that all metastatic cells were cleared. The ¹⁴C-signal correlated with the presence and the severity of metastatic tumors. AMS measurements of ¹⁴C-labeled cells provides a highly-sensitive, quantitative assay to experimentally evaluate metastasis and colonization of target tissues in xenograft mouse models. This method can potentially be used to evaluate tumor aggressiveness and assist in making informed decisions regarding treatment.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1527297

Report Number(s):: LLNL-JRNL-730778; 881776

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 8; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (62)

Bioluminescent imaging: a critical tool in pre-clinical oncology research O'Neill, Karen; Lyons, Scott K.; Gallagher, William M. The Journal of Pathology https://doi.org/10.1002/path.2656	journal	January 2009
Efficacy of cell proliferation imaging with 4DST PET/CT for predicting the prognosis of patients with esophageal cancer: a comparison study with FDG PET/CT Hotta, Masatoshi; Minamimoto, Ryogo; Toyohara, Jun European Journal of Nuclear Medicine and Molecular Imaging, Vol. 48, Issue 8 https://doi.org/10.1007/s00259-020-05179-x	journal	January 2021
Characterization of two mouse models of metastatic pheochromocytoma using bioluminescence imaging Giubellino, Alessio; Woldemichael, Girma M.; Sourbier, Carole Cancer Letters, Vol. 316, Issue 1 https://doi.org/10.1016/j.canlet.2011.10.019	journal	March 2012
Research Techniques Made Simple: Techniques to Assess Cell Proliferation Romar, George A.; Kupper, Thomas S.; Divito, Sherrie J. Journal of Investigative Dermatology, Vol. 136, Issue 1 https://doi.org/10.1016/j.jid.2015.11.020	journal	January 2016
Operation of the “Small” BioAMS spectrometers at CAMS: Past and future prospects Ognibene, T. J.; Haack, K. W.; Bench, G. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, Vol. 361 https://doi.org/10.1016/j.nimb.2015.05.019	journal	October 2015
The Usefulness of Bone Biomarkers for Monitoring Treatment Disease: A Comparative Study in Osteolytic and Osteosclerotic Bone Metastasis Models Martín-Fernández, Marta; Valencia, Karmele; Zandueta, Carolina Translational Oncology, Vol. 10, Issue 2 https://doi.org/10.1016/j.tranon.2016.12.001	journal	April 2017
A High-Throughput Method for the Conversion of CO ₂ Obtained from Biochemical Samples to Graphite in Septa-Sealed Vials for Quantification of ¹⁴ C via Accelerator Mass Spectrometry Ognibene, Ted J.; Bench, Graham; Vogel, John S. Analytical Chemistry, Vol. 75, Issue 9 https://doi.org/10.1021/ac026334j	journal	May 2003
Isotope-labeled immunoassays without radiation waste Shan, G.; Huang, W.; Gee, S. J. Proceedings of the National Academy of Sciences, Vol. 97, Issue 6 https://doi.org/10.1073/pnas.040575997	journal	March 2000
GABAA receptor target of tetramethylenedisulfotetramine Zhao, C.; Hwang, S. H.; Buchholz, B. A. Proceedings of the National Academy of Sciences, Vol. 111, Issue 23 https://doi.org/10.1073/pnas.1407379111	journal	May 2014
Post-transcriptional Inhibition of Luciferase Reporter Assays by the Nod-like Receptor Proteins NLRX1 and NLRC3 Ling, Arthur; Soares, Fraser; Croitoru, David O. Journal of Biological Chemistry, Vol. 287, Issue 34 https://doi.org/10.1074/jbc.m111.333146	journal	June 2012
Non-Invasive in vivo Imaging in Small Animal Research Koo, V.; Hamilton, P. W.; Williamson, K. Analytical Cellular Pathology, Vol. 28, Issue 4 https://doi.org/10.1155/2006/245619	journal	January 2006
Vandetanib Restores Head and Neck Squamous Cell Carcinoma Cells' Sensitivity to Cisplatin and Radiation In Vivo and In Vitro Sano, D.; Matsumoto, F.; Valdecanas, D. R. Clinical Cancer Research, Vol. 17, Issue 7 https://doi.org/10.1158/1078-0432.ccr-10-2120	journal	February 2011
Tumor Microenvironment Regulates Metastasis and Metastasis Genes of Mouse MMTV-PymT Mammary Cancer Cells In Vivo Werbeck, J. L.; Thudi, N. K.; Martin, C. K. Veterinary Pathology, Vol. 51, Issue 4 https://doi.org/10.1177/0300985813505116	journal	September 2013
Animal Models of Bone Metastasis Simmons, J. K.; Hildreth, B. E.; Supsavhad, W. Veterinary Pathology, Vol. 52, Issue 5 https://doi.org/10.1177/0300985815586223	journal	May 2015
Estrogen Receptors β1 and β2 Have Opposing Roles in Regulating Proliferation and Bone Metastasis Genes in the Prostate Cancer Cell Line PC3 Dey, Prasenjit; Jonsson, Philip; Hartman, Johan Molecular Endocrinology, Vol. 26, Issue 12 https://doi.org/10.1210/me.2012.1227	journal	December 2012
Enhanced Beetle Luciferase for High-Resolution Bioluminescence Imaging Nakajima, Yoshihiro; Yamazaki, Tomomi; Nishii, Shigeaki PLoS ONE, Vol. 5, Issue 4 https://doi.org/10.1371/journal.pone.0010011	journal	April 2010
SOST Inhibits Prostate Cancer Invasion Hudson, Bryan D.; Hum, Nicholas R.; Thomas, Cynthia B. PLOS ONE, Vol. 10, Issue 11 https://doi.org/10.1371/journal.pone.0142058	journal	November 2015
Molecular Dissection of Induced Platinum Resistance through Functional and Gene Expression Analysis in a Cell Culture Model of Bladder Cancer Wang, Sisi; Zhang, Hongyong; Scharadin, Tiffany M. PLOS ONE, Vol. 11, Issue 1 https://doi.org/10.1371/journal.pone.0146256	journal	January 2016
68Ga and 188Re Starch-Based Microparticles as Theranostic Tool for the Hepatocellular Carcinoma: Radiolabeling and Preliminary In Vivo Rat Studies Verger, Elise; Drion, Pierre; Meffre, Geneviève PLOS ONE, Vol. 11, Issue 10 https://doi.org/10.1371/journal.pone.0164626	journal	October 2016
The use of accelerator mass spectrometry to obtain early human ADME/PK data Lappin, Graham; Garner, R. Colin Expert Opinion on Drug Metabolism & Toxicology, Vol. 1, Issue 1 https://doi.org/10.1517/17425255.1.1.23	journal	June 2005
Noninvasive Imaging Reveals Inhibition of Ovarian Cancer by Targeting CXCL12-CXCR4 Ray, Paramita; Lewin, Sarah A.; Mihalko, Laura Anne Neoplasia, Vol. 13, Issue 12 https://doi.org/10.1593/neo.111076	journal	December 2011
The IGR-CaP1 Xenograft Model Recapitulates Mixed Osteolytic/Blastic Bone Lesions Observed in Metastatic Prostate Cancer Al Nakouzi, Nader; Bawa, Olivia; Le Pape, Alain Neoplasia, Vol. 14, Issue 5 https://doi.org/10.1593/neo.12308	journal	May 2012
Proof-of-Concept Study of Monitoring Cancer Drug Therapy with Cerenkov Luminescence Imaging Xu, Y.; Chang, E.; Liu, H. Journal of Nuclear Medicine, Vol. 53, Issue 2 https://doi.org/10.2967/jnumed.111.094623	journal	January 2012
Cancer Cell Colonisation in the Bone Microenvironment Kan, Casina; Vargas, Geoffrey; Pape, François International Journal of Molecular Sciences, Vol. 17, Issue 10 https://doi.org/10.3390/ijms17101674	journal	October 2016
In Vivo Imaging of Human Malignant Mesothelioma Grown Orthotopically in the Peritoneal Cavity of Nude Mice Feng, Mingqian; Zhang, Jingli; Anver, Miriam Journal of Cancer, Vol. 2 https://doi.org/10.7150/jca.2.123	journal	January 2011
Establishing human prostate cancer cell xenografts in bone: Induction of osteoblastic reaction by prostate-specific antigen-producing tumors in athymic and SCID/bg mice using LNCaP and lineage-derived metastatic sublines Wu, Tony T.; Sikes, Robert A.; Cui, Quanjun International Journal of Cancer, Vol. 77, Issue 6 https://doi.org/10.1002/(SICI)1097-0215(19980911)77:6<887::AID-IJC15>3.0.CO;2-Z	journal	September 1998
Characterization of tumor cell dissemination patterns in preclinical models of cancer metastasis using flow cytometry and laser scanning cytometry Goodale, David; Phay, Carolina; Postenka, Carl O. Cytometry Part A, Vol. 75A, Issue 4 https://doi.org/10.1002/cyto.a.20657	journal	April 2009
Bioluminescent imaging: a critical tool in pre-clinical oncology research O'Neill, Karen; Lyons, Scott K.; Gallagher, William M. The Journal of Pathology https://doi.org/10.1002/path.2656	journal	January 2009
Intrinsic Erythrocyte Labeling and Attomole Pharmacokinetic Tracing of14C-Labeled Folic Acid with Accelerator Mass Spectrometry Buchholz, Bruce A.; Arjomand, Ali; Dueker, Stephen R. Analytical Biochemistry, Vol. 269, Issue 2 https://doi.org/10.1006/abio.1999.4041	journal	May 1999
[18F]FLT-PET in oncology: current status and opportunities Been, Lukas B.; Suurmeijer, Albert J. H.; Cobben, David C. P. European Journal of Nuclear Medicine and Molecular Imaging, Vol. 31, Issue 12 https://doi.org/10.1007/s00259-004-1687-6	journal	November 2004
Tips and traps in the 14C bio-AMS preparation laboratory Buchholz, Bruce A.; Freeman, Stewart P. H. T.; Haack, Kurt W. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, Vol. 172, Issue 1-4 https://doi.org/10.1016/S0168-583X(00)00142-7	journal	October 2000
Characterization of two mouse models of metastatic pheochromocytoma using bioluminescence imaging Giubellino, Alessio; Woldemichael, Girma M.; Sourbier, Carole Cancer Letters, Vol. 316, Issue 1 https://doi.org/10.1016/j.canlet.2011.10.019	journal	March 2012
Research Techniques Made Simple: Techniques to Assess Cell Proliferation Romar, George A.; Kupper, Thomas S.; Divito, Sherrie J. Journal of Investigative Dermatology, Vol. 136, Issue 1 https://doi.org/10.1016/j.jid.2015.11.020	journal	January 2016
Operation of the “Small” BioAMS spectrometers at CAMS: Past and future prospects Ognibene, T. J.; Haack, K. W.; Bench, G. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, Vol. 361 https://doi.org/10.1016/j.nimb.2015.05.019	journal	October 2015
Preclinical evaluation of destruxin B as a novel Wnt signaling target suppressing proliferation and metastasis of colorectal cancer using non-invasive bioluminescence imaging Yeh, Chi-Tai; Rao, Yerra Koteswara; Ye, Min Toxicology and Applied Pharmacology, Vol. 261, Issue 1 https://doi.org/10.1016/j.taap.2012.03.007	journal	May 2012
The Usefulness of Bone Biomarkers for Monitoring Treatment Disease: A Comparative Study in Osteolytic and Osteosclerotic Bone Metastasis Models Martín-Fernández, Marta; Valencia, Karmele; Zandueta, Carolina Translational Oncology, Vol. 10, Issue 2 https://doi.org/10.1016/j.tranon.2016.12.001	journal	April 2017
A High-Throughput Method for the Conversion of CO ₂ Obtained from Biochemical Samples to Graphite in Septa-Sealed Vials for Quantification of ¹⁴ C via Accelerator Mass Spectrometry Ognibene, Ted J.; Bench, Graham; Vogel, John S. Analytical Chemistry, Vol. 75, Issue 9 https://doi.org/10.1021/ac026334j	journal	May 2003
Bioaccumulation of Multiwall Carbon Nanotubes in Tetrahymena thermophila by Direct Feeding or Trophic Transfer Mortimer, Monika; Petersen, Elijah J.; Buchholz, Bruce A. Environmental Science & Technology, Vol. 50, Issue 16 https://doi.org/10.1021/acs.est.6b01916	journal	July 2016
Cisplatin plus paclitaxel and maintenance of bevacizumab on tumour progression, dissemination, and survival of ovarian carcinoma xenograft models Oliva, P.; Decio, A.; Castiglioni, V. British Journal of Cancer, Vol. 107, Issue 2 https://doi.org/10.1038/bjc.2012.261	journal	June 2012
Strategies for the discovery and development of therapies for metastatic breast cancer Eckhardt, Bedrich L.; Francis, Prudence A.; Parker, Belinda S. Nature Reviews Drug Discovery, Vol. 11, Issue 6 https://doi.org/10.1038/nrd2372	journal	June 2012
Luciferase Expression Allows Bioluminescence Imaging But Imposes Limitations on the Orthotopic Mouse (4T1) Model of Breast Cancer Baklaushev, V. P.; Kilpeläinen, A.; Petkov, S. Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-07851-z	journal	August 2017
Isotope-labeled immunoassays without radiation waste Shan, G.; Huang, W.; Gee, S. J. Proceedings of the National Academy of Sciences, Vol. 97, Issue 6 https://doi.org/10.1073/pnas.040575997	journal	March 2000
GABAA receptor target of tetramethylenedisulfotetramine Zhao, C.; Hwang, S. H.; Buchholz, B. A. Proceedings of the National Academy of Sciences, Vol. 111, Issue 23 https://doi.org/10.1073/pnas.1407379111	journal	May 2014
Post-transcriptional Inhibition of Luciferase Reporter Assays by the Nod-like Receptor Proteins NLRX1 and NLRC3 Ling, Arthur; Soares, Fraser; Croitoru, David O. Journal of Biological Chemistry, Vol. 287, Issue 34 https://doi.org/10.1074/jbc.M111.333146	journal	June 2012
Mesenchymal-to-Epithelial Transition Facilitates Bladder Cancer Metastasis: Role of Fibroblast Growth Factor Receptor-2 Chaffer, C. L.; Brennan, J. P.; Slavin, J. L. Cancer Research, Vol. 66, Issue 23 https://doi.org/10.1158/0008-5472.CAN-06-2044	journal	November 2006
Vandetanib Restores Head and Neck Squamous Cell Carcinoma Cells' Sensitivity to Cisplatin and Radiation In Vivo and In Vitro Sano, D.; Matsumoto, F.; Valdecanas, D. R. Clinical Cancer Research, Vol. 17, Issue 7 https://doi.org/10.1158/1078-0432.CCR-10-2120	journal	February 2011
Tumor Microenvironment Regulates Metastasis and Metastasis Genes of Mouse MMTV-PymT Mammary Cancer Cells In Vivo Werbeck, J. L.; Thudi, N. K.; Martin, C. K. Veterinary Pathology, Vol. 51, Issue 4 https://doi.org/10.1177/0300985813505116	journal	September 2013
Animal Models of Bone Metastasis Simmons, J. K.; Hildreth, B. E.; Supsavhad, W. Veterinary Pathology, Vol. 52, Issue 5 https://doi.org/10.1177/0300985815586223	journal	May 2015
Mouse models of breast cancer metastasis Fantozzi, Anna; Christofori, Gerhard Breast Cancer Research, Vol. 8, Issue 4 https://doi.org/10.1186/bcr1530	journal	July 2006
Estrogen Receptors β1 and β2 Have Opposing Roles in Regulating Proliferation and Bone Metastasis Genes in the Prostate Cancer Cell Line PC3 Dey, Prasenjit; Jonsson, Philip; Hartman, Johan Molecular Endocrinology, Vol. 26, Issue 12 https://doi.org/10.1210/me.2012.1227	journal	December 2012
Enhanced Beetle Luciferase for High-Resolution Bioluminescence Imaging Nakajima, Yoshihiro; Yamazaki, Tomomi; Nishii, Shigeaki PLoS ONE, Vol. 5, Issue 4 https://doi.org/10.1371/journal.pone.0010011	journal	April 2010
SOST Inhibits Prostate Cancer Invasion Hudson, Bryan D.; Hum, Nicholas R.; Thomas, Cynthia B. PLOS ONE, Vol. 10, Issue 11 https://doi.org/10.1371/journal.pone.0142058	journal	November 2015
Molecular Dissection of Induced Platinum Resistance through Functional and Gene Expression Analysis in a Cell Culture Model of Bladder Cancer Wang, Sisi; Zhang, Hongyong; Scharadin, Tiffany M. PLOS ONE, Vol. 11, Issue 1 https://doi.org/10.1371/journal.pone.0146256	journal	January 2016
68Ga and 188Re Starch-Based Microparticles as Theranostic Tool for the Hepatocellular Carcinoma: Radiolabeling and Preliminary In Vivo Rat Studies Verger, Elise; Drion, Pierre; Meffre, Geneviève PLOS ONE, Vol. 11, Issue 10 https://doi.org/10.1371/journal.pone.0164626	journal	October 2016
The use of accelerator mass spectrometry to obtain early human ADME/PK data Lappin, Graham; Garner, R. Colin Expert Opinion on Drug Metabolism & Toxicology, Vol. 1, Issue 1 https://doi.org/10.1517/17425255.1.1.23	journal	June 2005
Noninvasive Imaging Reveals Inhibition of Ovarian Cancer by Targeting CXCL12-CXCR4 Ray, Paramita; Lewin, Sarah A.; Mihalko, Laura Anne Neoplasia, Vol. 13, Issue 12 https://doi.org/10.1593/neo.111076	journal	December 2011
The IGR-CaP1 Xenograft Model Recapitulates Mixed Osteolytic/Blastic Bone Lesions Observed in Metastatic Prostate Cancer Al Nakouzi, Nader; Bawa, Olivia; Le Pape, Alain Neoplasia, Vol. 14, Issue 5 https://doi.org/10.1593/neo.12308	journal	May 2012
Development of a Novel Preclinical Pancreatic Cancer Research Model: Bioluminescence Image- Guided Focal Irradiation and Tumor Monitoring of Orthotopic Xenografts Tuli, Richard; Surmak, Andrew; Reyes, Juvenal Translational Oncology, Vol. 5, Issue 2 https://doi.org/10.1593/tlo.11316	journal	April 2012
Proof-of-Concept Study of Monitoring Cancer Drug Therapy with Cerenkov Luminescence Imaging Xu, Y.; Chang, E.; Liu, H. Journal of Nuclear Medicine, Vol. 53, Issue 2 https://doi.org/10.2967/jnumed.111.094623	journal	January 2012
Cancer Cell Colonisation in the Bone Microenvironment Kan, Casina; Vargas, Geoffrey; Pape, François International Journal of Molecular Sciences, Vol. 17, Issue 10 https://doi.org/10.3390/ijms17101674	journal	October 2016
In vivo Bioluminescence Imaging of Tumor Hypoxia Dynamics of Breast Cancer Brain Metastasis in a Mouse Model Saha, Debabrata; Dunn, Henry; Zhou, Heling Journal of Visualized Experiments, Issue 56 https://doi.org/10.3791/3175	journal	January 2011
In Vivo Imaging of Human Malignant Mesothelioma Grown Orthotopically in the Peritoneal Cavity of Nude Mice Feng, Mingqian; Zhang, Jingli; Anver, Miriam Journal of Cancer, Vol. 2 https://doi.org/10.7150/jca.2.123	journal	January 2011

Cited By (2)

Radiocarbon Tracers in Toxicology and Medicine: Recent Advances in Technology and Science Malfatti, Michael A.; Buchholz, Bruce A.; Enright, Heather A. Toxics, Vol. 7, Issue 2 https://doi.org/10.3390/toxics7020027	journal	May 2019
Radiocarbon Tracers in Toxicology and Medicine: Recent Advances in Technology and Science Malfatti, Michael A.; Buchholz, Bruce A.; Enright, Heather A. Toxics, Vol. 7, Issue 2 https://doi.org/10.3390/toxics7020027	journal	May 2019

Similar Records

Accelerator Mass Spectrometry Allows for Cellular Quantification of Doxorubicin at Femtomolar Concentrations

Journal Article · 2005 · Cancer Chemotherapy and Pharmacology · OSTI ID:877773

DeGregorio, M W; Dingley, K H; Wurz, G T; +2 more

Adenovirus E2F1 Overexpression Sensitizes LNCaP and PC3 Prostate Tumor Cells to Radiation In Vivo

Journal Article · 2011 · International Journal of Radiation Oncology, Biology and Physics · OSTI ID:21491595

Udayakumar, Thirupandiyur S; Stoyanova, Radka; Hachem, Paul; +2 more

Radioimmunoscintigraphy of human colon cancer xenografts in mice with radioiodinated monoclonal antibody B72. 3

Journal Article · 1984 · J. Nucl. Med.; (United States) · OSTI ID:5989843

Keenan, A M; Colcher, D; Larson, S M; +1 more

Related Subjects

60 APPLIED LIFE SCIENCES

Title: Tracking Tumor Colonization in Xenograft Mouse Models Using Accelerator Mass Spectrometry [Tracking Tumor Colonization in vivo Using Accelerator Mass Spectrometry]

Citation Formats

References (62)

Cited By (2)

Similar Records

Related Subjects