Abstract
Mucosal melanoma represents one of the most highly metastatic and aggressive subtypes of melanoma. The biology of mucosal melanoma is poorly documented, and the lack of experimental models makes it difficult to design and test new therapies. Dogs are frequently affected by melanomas of the oral cavity, making spontaneous canine melanoma a potentially predictable model for their human counterpart. We recently established and characterized two new canine mucosal melanoma cell lines named OCR_OCMM1 and OCR_OCMM2. Here, we identified quiescent cancer stem cell (CSC) subpopulations in both canine cell lines that displayed similarities to human quiescent CSCs: canine melanoma CSCs had the ability to self-renew, produced nonstem cell (SC) progeny, and formed melanospheres that recapitulated the phenotypic profile of the parental tumor. These CSCs also formed melanoma in immunodeficient mice, and the inhibition of PI3K/AKT signaling expanded the CSC pool. A subset of non-CSCs transitioned to become CSCs. OCR_OCMM1 and OCR_OCMM2 displayed different CSC compartment behaviors in regard to their initial size and expansion abilities. Collectively, this study showed that the OCR_OCMM1 and OCR_OCMM2 canine melanoma cell lines are powerful cellular tools to study melanoma SCs, not only for mucosal but also for the more common human cutaneous melanoma.
Highlights
Increasing evidence suggests that melanoma cancer stem cells (CSCs) play an essential role in the resistance as well as in the relapse of this disease [1,2,3]
We previously showed that the PI3K/AKT signaling pathway controls the oscillation between the active and quiescent states of Rh123low cells with SC-like characteristics; this signaling pathway controls the size of the Rh123low melanoma SC compartment in human melanoma [4]
We demonstrated that our canine melanoma cell lines contain a small subset of cells with SC-like activities, including a superior ability to self-renew and to regenerate tumor-like spheres with progeny that recapitulated the phenotypic heterogeneity of the parental tumors
Summary
Increasing evidence suggests that melanoma cancer stem cells (CSCs) play an essential role in the resistance as well as in the relapse of this disease [1,2,3]. We highlighted the regulation of human melanoma CSCs through the PI3K/AKT pathway [4]. We observed in a mouse model of melanoma dormancy that long-term persistent cancer cells showed characteristics of CSC [5]. Despite these important findings, the relevance of the currently available preclinical melanoma mouse models is questioned, notably because of the size and life span differences between rodents and humans. Mucosal melanoma of the oral cavity is rare but is highly aggressive and metastatic [9], with frequent relapse and
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