The Role of Hedgehog Signaling in the Melanoma Tumor Bone Microenvironment

• Published in: International journal of molecular sciences Vol. 24; no. 10; p. 8862
• Main Authors: Shamsoon, Karnoon, Hiraki, Daichi, Yoshida, Koki, Takabatake, Kiyofumi, Takebe, Hiroaki, Yokozeki, Kenji, Horie, Naohiro, Fujita, Naomasa, Nasrun, Nisrina Ekayani, Okui, Tatsuo, Nagatsuka, Hitoshi, Abiko, Yoshihiro, Hosoya, Akihiro, Saito, Takashi, Shimo, Tsuyoshi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16.05.2023; MDPI
• Subjects: Angiogenesis; Animals; Apoptosis; B7-H1 Antigen; Bone marrow; Bone remodeling; Cancer; Cancer therapies; Care and treatment; Cell Line, Tumor; Chemotherapy; Cortical bone; Destruction; Development and progression; Female; Flow cytometry; Gene set enrichment analysis; Gli; Health aspects; Hedgehog; Hedgehog protein; Hedgehog Proteins - metabolism; Immunosuppression; malignant melanoma; Melanoma; Melanoma - drug therapy; Melanoma - metabolism; Metaphysis; Mice; Mice, Inbred C57BL; Oral cancer; Osteoclasts; Patients; PD-L1 protein; Scientific equipment and supplies industry; Skin cancer; Therapeutic targets; Transcription factors; tumor bone microenvironment; Tumor cells; Tumor Microenvironment; Tumors; Vemurafenib; Zinc Finger Protein GLI1 - metabolism; Zinc Finger Protein Gli2 - metabolism; United States; Japan; tumor bone microenvironment; Hedgehog; malignant melanoma; Gli
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24108862

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.