Recruitment of Cancer-Associated Fibroblasts and Blood Vessels by Orthotopic Liver Tumors Imaged in Red Fluorescent Protein (RFP) Transgenic Nude Mice.
OBJECTIVE
The tumor microenvironment (TME) is critical for tumor growth and progression. We report here an imageable model of the TME of orthotopic liver cancer.


METHODS
The transgenic red fluorescent protein (RFP)-expressing nude mouse was used as the host. The RFP nude mouse expresses RFP in all organs. Non-colored Huh-7 human hepatoma cells were injected in the spleen of RFP nude mice to establish an orthotopic liver cancer model. TME formation resulting from the orthotopic liver tumor was observed using the Olympus OV100 small animal fluorescence imaging system.


RESULTS
Non-colored liver cancer cells formed tumor colonies in the liver 28 days after cell transplantation to the spleen. RFP-expressing host cells and blood vessels were recruited by the liver tumors as visualized by fluorescence imaging. A desmin- and sirus-red-positive area increased around and within the liver tumor over time.


CONCLUSIONS
These results indicate cancer-associated fibroblasts (CAFs) were recruited by the liver tumors suggesting that CAFs, along with the angiogenic tumor blood vessels, were necessary for liver-tumor growth and could serve as visible therapeutic targets.
Gifu University Graduate School of Medicine, Gifu, Japan AntiCancer, Inc. San Diego, CA, U.S.A Department of Surgery, University of California, San Diego, CA, U.S.A.
Atsushi
A
Suetsugu
AntiCancer, Inc. San Diego, CA, U.S.A Department of Surgery, University of California, San Diego, CA, U.S.A.
Yukihiko
Y
Hiroshima
Gifu University Graduate School of Medicine, Gifu, Japan.
Takuro
T
Matsumoto
Gifu University Graduate School of Medicine, Gifu, Japan.
Kosuke
K
Hasagawa
Gifu University Graduate School of Medicine, Gifu, Japan.
Miki
M
Nakamura
Gifu University Graduate School of Medicine, Gifu, Japan.
Masahito
M
Shimizu
Gifu University Graduate School of Medicine, Gifu, Japan.
Shigetoyo
S
Saji
Gifu University Graduate School of Medicine, Gifu, Japan.
Hisataka
H
Moriwaki
Department of Surgery, University of California, San Diego, CA, U.S.A.
Michael
M
Bouvet
AntiCancer, Inc. San Diego, CA, U.S.A Department of Surgery, University of California, San Diego, CA, U.S.A. all@anticancer.com.
Robert M
RM
Hoffman
D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D003952:Diagnostic Imaging; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008164:Luminescent Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment; D000097573:Red Fluorescent Protein
D008164:Luminescent Proteins; D000097573:Red Fluorescent Protein
RFP; Tumor microenvironment; blood vessels; cancer-associated fibroblasts; color-coded imaging; fluorescence; liver metastasis