TSU-68 ameliorates hepatocellular carcinoma growth by inhibiting microenvironmental platelet-derived growth factor signaling.
BACKGROUND
TSU-68 is a multikinase inhibitor that targets platelet-derived growth factor receptors (PDGFRs). In the present study, we evaluated the effect of TSU-68 on the tumor-microenvironment interaction in hepatocellular carcinoma (HCC).


METHODS
HCC and fibroblast cell lines (HuH7, Hep3B, HuH1 and WI-38) were used to evaluate their interactions. Cancer characteristics were evaluated by spheroid formation and tumorigenicity in immunodeficient mice. Time-lapse image analysis was performed to monitor cell motility.


RESULTS
Although PDGFA was abundantly expressed, PDGFR-α was predominantly located in the cytoplasm and was not functional in HuH7 cells. Co-culture experiments demonstrated that HCC cells induced phosphorylation of PDGFR-α in WI-38 fibroblasts and that stimulated fibroblasts, in turn, boosted the spheroid formation capacity of HCC cells. TSU-68 inhibited phosphorylation of PDGFR-α in WI-38 cells and suppressed the growth of subcutaneously co-injected HuH7/WI-38 tumor xenografts.


CONCLUSIONS
TSU-68 inhibits stromal PDGF signaling activated by cancer cells and suppresses HCC growth.
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Yasumasa
Y
Hara
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan taroy@m-kanazawa.jp.
Taro
T
Yamashita
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Naoki
N
Oishi
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Kouki
K
Nio
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Takehiro
T
Hayashi
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Yoshimoto
Y
Nomura
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Mariko
M
Yoshida
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Tomoyuki
T
Hayashi
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Tomomi
T
Hashiba
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Yoshiro
Y
Asahina
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Mitsumasa
M
Kondo
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Hikari
H
Okada
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Hajime
H
Sunagozaka
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Masao
M
Honda
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Shuichi
S
Kaneko
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D000078183:Oxindoles; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D011422:Propionates / Q000494:pharmacology*; D011758:Pyrroles; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D015398:Signal Transduction / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
D007211:Indoles; D000078183:Oxindoles; D010982:Platelet-Derived Growth Factor; D011422:Propionates; D011758:Pyrroles; D053773:Transforming Growth Factor beta1; C412603:orantinib; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta
Hepatocellular carcinoma; TSU-68; platelet-derived growth factors