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TSU-68 ameliorates hepatocellular carcinoma growth by inhibiting microenvironmental platelet-derived growth factor
Yasumasa Hara1, Taro Yamashita2, Naoki Oishi1
1Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
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).
Materials And 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.
Conclusion:
TSU-68 inhibits stromal PDGF signaling activated by cancer cells and suppresses HCC growth.
Insights
TSU-68, a multikinase inhibitor, targets platelet-derived growth factor receptors (PDGFRs). It was found to inhibit stromal PDGF signaling and suppress hepatocellular carcinoma (HCC) growth by impacting tumor-microenvironment interactions.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Hepatocellular carcinoma (HCC) is a complex disease influenced by tumor-microenvironment interactions.
- TSU-68 is a multikinase inhibitor targeting platelet-derived growth factor receptors (PDGFRs).
Purpose of the Study:
- To investigate the effect of TSU-68 on tumor-microenvironment interactions in HCC.
- To elucidate the role of PDGFR signaling in HCC progression.
Main Methods:
- Utilized HCC and fibroblast cell lines (HuH7, Hep3B, HuH1, WI-38) for interaction studies.
- Assessed cancer characteristics via spheroid formation and tumorigenicity in immunodeficient mice.
- Employed time-lapse imaging to analyze cell motility and PDGFR phosphorylation.
Main Results:
- HCC cells induced PDGFR-α phosphorylation in fibroblasts, which in turn enhanced HCC spheroid formation.
- TSU-68 inhibited PDGFR-α phosphorylation in fibroblasts.
- TSU-68 suppressed the growth of HCC/fibroblast co-injected tumor xenografts.
Conclusions:
- TSU-68 effectively inhibits cancer cell-activated stromal PDGF signaling.
- TSU-68 demonstrates therapeutic potential in suppressing HCC growth by modulating the tumor microenvironment.
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