Altered Biological Potential and Radioresponse of Murine Tumors in Different Microenvironments.
OBJECTIVE
This study was conducted to evaluate the biological features of murine hepatocarcinoma according to different tumor microenvironmental models and to determine the change in molecular and immunologic responses after radiation.


METHODS
Tumor models were established in the liver (orthotopic) and thigh (heterotopic) of male C3H/HeN mice. Tumor growth and lung metastasis were assessed in these models. To evaluate the radiation effect, the tumors were irradiated with 10 Gy. Factors associated with tumor microenvironment including vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), transforming growth factor beta1 (TGF-β1), CD31, and serum interleukin-6 (IL-6) were evaluated. Tumor-infiltrating regulatory immune cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) were also analyzed.


RESULTS
A higher number of lung metastases were observed in the orthotopic tumor model than in the heterotopic tumor model. VEGF, CD31, COX-2, and TGF-β1 expression was more prominent in the orthotopic tumor model than in the heterotopic tumor model. Expression of the angiogenic factor VEGF and key regulatory molecules (TGF-β1 and COX-2) decreased following radiation in the orthotopic tumor model, while the serum IL-6 level increased after radiation. In the orthotopic tumor model, the number of both Tregs and MDSCs in the tumor burden decreased after radiation.


CONCLUSIONS
The orthotopic tumor model showed higher metastatic potential and more aggressive molecular features than the heterotopic tumor model. These findings suggest that the orthotopic tumor mouse model may be more reflective of the tumor microenvironment and suitable for use in the translational research of radiation treatment.
Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea.
Ik Jae
IJ
Lee
Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea.
Eun Jeong
EJ
Lee
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Hyojin
H
Park
Department of Radiation Treatment Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Wonwoo
W
Kim
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Sang-Jun
SJ
Ha
Cancer Metastasis Research Center, Yonsei Institute for Cancer Research, Seoul, Korea.
You Keun
YK
Shin
Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea.
Jinsil
J
Seong
D000818:Animals; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology* / Q000532:radiotherapy*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology / Q000528:radiation effects; D009368:Neoplasm Transplantation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000528:radiation effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D059016:Tumor Microenvironment / Q000528:radiation effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D015850:Interleukin-6; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2
Hepatocarcinoma; Radiation; Tumor microenvironment