title: Acute Tumor Lactate Perturbations as a Biomarker of Genotoxic Stress: Development of a Biochemical Model.
abstract: Ionizing radiation is the primary nonsurgical treatment modality for solid tumors. Its effectiveness is impacted by temporal constraints such as fractionation, hypoxia, and development of radioresistant clones. Biomarkers of acute radiation response are essential to developing more effective clinical algorithms. We hypothesized that acute perturbations in tumor lactate levels act as a surrogate marker of radiation response. In vitro experiments were carried out using validated human-derived cell lines from three histologies: anaplastic thyroid carcinoma (ATC), head and neck squamous cell carcinoma (HNSCC), and papillary thyroid carcinoma (PTC). Cellular metabolic activity was measured using standard biochemical assays. In vivo validation was performed using both an orthotopic and a flank derivative of a previously established ATC xenograft murine model. Irradiation of cells and tumors triggered a rapid, dose-dependent, transient decrease in lactate levels that was reversed by free radical scavengers. Acute lactate perturbations following irradiation could identify hypoxic conditions and correlated with hypoxia-induced radioresistance. Mutant TP53 cells and cells in which p53 activity was abrogated (shRNA) demonstrated a blunted lactate response to irradiation, consistent with a radioresistant phenotype. Lactate measurements therefore rapidly detected both induced (i.e., hypoxia) and intrinsic (i.e., mutTP53-driven) radioresistance. We conclude that lactate is a quantitative biomarker of acute genotoxic stress, with a temporal resolution that can inform clinical decision making. Combined with the spatial resolution of newly developed metabolic imaging platforms, this biomarker could lead to the development of truly individualized treatment strategies.
authors.affiliation: Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas. Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vlad C
authors.initials: VC
authors.lastname: Sandulache
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Heath D
authors.initials: HD
authors.lastname: Skinner
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Tongtong
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lei
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Laurence E
authors.initials: LE
authors.lastname: Court
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Meyn
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Clifton D
authors.initials: CD
authors.lastname: Fuller
authors.affiliation: Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: James A
authors.initials: JA
authors.lastname: Bankson
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. sylai@mdanderson.org.
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Lai
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D002291:Carcinoma, Papillary; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000528:radiation effects; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D051379:Mice; D011836:Radiation Tolerance / Q000235:genetics; D011839:Radiation, Ionizing; D000077195:Squamous Cell Carcinoma of Head and Neck; D000077273:Thyroid Cancer, Papillary; D065646:Thyroid Carcinoma, Anaplastic / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019344:Lactic Acid