Cancer stem cells and the SHH pathway in malignant melanoma: Therapeutic implications

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Melanoma is an aggressive skin cancer arising from melanocytes. Melanoma is a complex disease, sourced from genetic and environmental factors. Within melanoma, cancer stem cells (CSCs) play a crucial role in tumor progression, therapeutic resistance, and recurrence due to their capabilities for self-renewal and differentiation. The Sonic Hedgehog (SHH) signaling pathway is an important regulator of CSCs and is essential for cell differentiation and proliferation. Due to the known role in embryonic development and involvement in cancers, SHH pathway significantly affects CSC behavior in malignant melanoma, promoting tumorigenicity, metastasis, and resistance to therapies. This pathway coordinates canonical mechanisms involving Gli transcription factors and non-canonical mechanisms affecting cell migration and cytoskeletal organization. Targeting the SHH pathway has emerged as a promising therapeutic strategy, with inhibitors focusing on components like Smoothened (Smo) and Gli proteins. However, resistance to these inhibitors necessitates further exploration of novel therapeutic combinations. Current research focuses on combining SHH inhibitors with immunotherapies for more effective, long-lasting responses. Targeted medicines, which disrupt SHH processes, attempt to eliminate the fundamental causes of carcinogenesis and increase melanoma patient survival rates.