| RRC ID |
78163
|
| 著者 |
Shamsoon K, Hiraki D, Yoshida K, Takabatake K, Takebe H, Yokozeki K, Horie N, Fujita N, Nasrun NE, Okui T, Nagatsuka H, Abiko Y, Hosoya A, Saito T, Shimo T.
|
| タイトル |
The Role of Hedgehog Signaling in the Melanoma Tumor Bone Microenvironment.
|
| ジャーナル |
Int J Mol Sci
|
| Abstract |
A crucial regulator in melanoma progression and treatment resistance is tumor microenvironments, and Hedgehog (Hh) signals activated in a tumor bone microenvironment are a potential new therapeutic target. The mechanism of bone destruction by melanomas involving Hh/Gli signaling in such a tumor microenvironment is unknown. Here, we analyzed surgically resected oral malignant melanoma specimens and observed that Sonic Hedgehog, Gli1, and Gli2 were highly expressed in tumor cells, vasculatures, and osteoclasts. We established a tumor bone destruction mouse model by inoculating B16 cells into the bone marrow space of the right tibial metaphysis of 5-week-old female C57BL mice. An intraperitoneal administration of GANT61 (40 mg/kg), a small-molecule inhibitor of Gli1 and Gli2, resulted in significant inhibition of cortical bone destruction, TRAP-positive osteoclasts within the cortical bone, and endomucin-positive tumor vessels. The gene set enrichment analysis suggested that genes involved in apoptosis, angiogenesis, and the PD-L1 expression pathway in cancer were significantly altered by the GANT61 treatment. A flow cytometry analysis revealed that PD-L1 expression was significantly decreased in cells in which late apoptosis was induced by the GANT61 treatment. These results suggest that molecular targeting of Gli1 and Gli2 may release immunosuppression of the tumor bone microenvironment through normalization of abnormal angiogenesis and bone remodeling in advanced melanoma with jaw bone invasion.
|
| 巻・号 |
24(10)
|
| 公開日 |
2023-5-16
|
| DOI |
10.3390/ijms24108862
|
| PII |
ijms24108862
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| PMID |
37240209
|
| PMC |
PMC10218521
|
| MeSH |
Animals
B7-H1 Antigen
Cell Line, Tumor
Female
Hedgehog Proteins* / metabolism
Melanoma* / drug therapy
Melanoma* / metabolism
Mice
Mice, Inbred C57BL
Tumor Microenvironment
Zinc Finger Protein GLI1 / metabolism
Zinc Finger Protein Gli2 / metabolism
|
| リソース情報 |
| ヒト・動物細胞 |
B16 mouse melanoma |
