title: Secreted Gaussia luciferase as a biomarker for monitoring tumor progression and treatment response of systemic metastases.
abstract: BACKGROUND
  Currently, only few techniques are available for quantifying systemic metastases in preclinical model. Thus techniques that can sensitively detect metastatic colonization and assess treatment response in real-time are urgently needed. To this end, we engineered tumor cells to express a naturally secreted Gaussia luciferase (Gluc), and investigated its use as a circulating biomarker for monitoring viable metastatic or primary tumor growth and their treatment responses.
  
  
  RESULTS
  We first developed orthotopic primary and metastatic breast tumors with derivative of MDA-MB-231 cells expressing Gluc. We then correlated tumor burden with Gluc activity in the blood and urine along with bioluminescent imaging (BLI). Second, we utilized blood Gluc assay to monitor treatment response to lapatinib in an experimental model of systemic metastasis. We observed good correlation between the primary tumor volume and Gluc concentration in blood (R(2) = 0.84) and urine (R(2) = 0.55) in the breast tumor model. The correlation deviated as a primary tumor grew due to a reduction in viable tumor fraction. This was also supported by our mathematical models for tumor growth to compare the total and viable tumor burden in our model. In the experimental metastasis model, we found numerous brain metastases as well as systemic metastases including bone and lungs. Importantly, blood Gluc assay revealed early growth of metastatic tumors before BLI could visualize their presence. Using secreted Gluc, we localized systemic metastases by BLI and quantitatively monitored the total viable metastatic tumor burden by blood Gluc assay during the course of treatment with lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2.
  
  
  CONCLUSIONS
  We demonstrated secreted Gluc assay accurately reflects the amount of viable cancer cells in primary and metastatic tumors. Blood Gluc activity not only tracks metastatic tumor progression but also serves as a longitudinal biomarker for tumor response to treatments.
authors.affiliation: Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Euiheon
authors.initials: E
authors.lastname: Chung
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamashita
authors.forename: Patrick
authors.initials: P
authors.lastname: Au
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000097:blood / Q000473:pathology* / Q000628:therapy / Q000652:urine; D045744:Cell Line, Tumor; D033342:Copepoda / Q000201:enzymology*; D018450:Disease Progression; D057075:Enzyme Assays; D005260:Female; D021621:Imaging, Three-Dimensional; D008156:Luciferases / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008163:Luminescent Measurements; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000628:therapy*; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; D008156:Luciferases