title: Effect of Irradiation on Tumor Microenvironment and Bone Marrow Cell Migration in a Preclinical Tumor Model.
abstract: To characterize the tumor microenvironment after standard radiation therapy (SRT) and pulsed radiation therapy (PRT) in Lewis lung carcinoma (LLC) allografts.
  
  
  
  Subcutaneous LLC tumors were established in C57BL/6 mice. Standard RT or PRT was given at 2 Gy/d for a total dose of 20 Gy using a 5 days on, 2 days off schedule to mimic clinical delivery. Radiation-induced tumor microenvironment changes were examined after treatment using flow cytometry and antibody-specific histopathology. Normal tissue effects were measured using noninvasive (18)F-fluorodeoxyglucose positron emission tomography/computed tomography after naïve animals were given whole-lung irradiation to 40 Gy in 4 weeks using the same 2-Gy/d regimens.
  
  
  
  Over the 2 weeks of therapy, PRT was more effective than SRT at reducing tumor growth rate (0.31 ± 0.02 mm(3)/d and 0.55 ± 0.04 mm(3)/d, respectively; P<.007). Histopathology showed a significant comparative reduction in the levels of Ki-67 (14.5% ± 3%), hypoxia (10% ± 3.5%), vascular endothelial growth factor (2.3% ± 1%), and stromal-derived factor-1α (2.5% ± 1.4%), as well as a concomitant decrease in CD45(+) bone marrow-derived cell (BMDC) migration (7.8% ± 2.2%) after PRT. The addition of AMD3100 also decreased CD45(+) BMDC migration in treated tumors (0.6% ± 0.1%). Higher vessel density was observed in treated tumors. No differences were observed in normal lung tissue after PRT or SRT.
  
  
  
  Pulsed RT-treated tumors exhibited slower growth and reduced hypoxia. Pulsed RT eliminated initiation of supportive mechanisms utilized by tumors in low oxygen microenvironments, including angiogenesis and recruitment of BMDCs.
authors: Department of Biological Sciences, Oakland University, Rochester, Michigan; Department of Radiation Oncology, William Beaumont Health System, Royal Oak, Michigan.
authors: Jonathan L
authors: JL
authors: Kane
authors: Department of Radiation Oncology, William Beaumont Health System, Royal Oak, Michigan.
authors: Sarah A
authors: SA
authors: Krueger
authors: Department of Radiation Oncology, William Beaumont Health System, Royal Oak, Michigan.
authors: Alaa
authors: A
authors: Hanna
authors: Department of Biological Sciences, Oakland University, Rochester, Michigan.
authors: Thomas R
authors: TR
authors: Raffel
authors: Department of Radiation Oncology, William Beaumont Health System, Royal Oak, Michigan.
authors: George D
authors: GD
authors: Wilson
authors: Department of Biological Sciences, Oakland University, Rochester, Michigan.
authors: Gerard J
authors: GJ
authors: Madlambayan
authors: Department of Radiation Oncology, William Beaumont Health System, Royal Oak, Michigan. Electronic address: Brian.Marples@beaumont.edu.
authors: Brian
authors: B
authors: Marples
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000528:radiation effects*; D018827:Carcinoma, Lewis Lung / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D008297:Male; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000473:pathology / Q000532:radiotherapy*; D000069473:Radiation Dose Hypofractionation; D016896:Treatment Outcome; D047368:Tumor Burden / Q000528:radiation effects; D059016:Tumor Microenvironment / Q000528:radiation effects*