Aldehyde Dehydrogenase (ALDH) Activity Does Not Select for Cells with Enhanced Aggressive Properties in Malignant Melanoma

Malignant melanoma is an exceptionally aggressive, drug-resistant and heterogeneous cancer. Recently it has been shown that melanoma cells with high clonogenic and tumourigenic abilities are common, but markers distinguishing such cells from cells lacking these abilities have not been identified. There is therefore no definite evidence that an exclusive cell subpopulation, i.e. cancer stem cells (CSC), exists in malignant melanoma. Rather, it is suggested that multiple cell populations are implicated in initiation and progression of the disease, making it of importance to identify subpopulations with elevated aggressive properties.. Furthermore, both subpopulations showed similar sensitivity to the anti-melanoma drugs, dacarbazine and lexatumumab.These findings suggest that ALDH does not distinguish tumour-initiating and/or therapy-resistant cells, implying that the ALDH phenotype is not associated with more-aggressive subpopulations in malignant melanoma, and arguing against ALDH as a “universal” marker. Besides, it was shown that the ability to reestablish tumour heterogeneity is not necessarily linked to the more aggressive phenotype

Mapping the expression of anti-apoptotic proteins and evaluation of the therapeutic potential of TRAIL receptor antibodies in “close-to-patient” melanoma models.

Malignant melanoma is a very metastatic and therapy resistant disease, with few therapeutic options in advanced stages. An abnormal apoptosis pathway is considered to contribute substantially to the resistance observed in melanoma patients. In this study, “close-to-patient” melanoma cell models: adherent monolayers in serum-containing media and non-adherent spheroids in stem cell media (which supposedly selects for stem-like melanoma initiating cells), were compared with respect to: the expression of anti-apoptotic molecules from the Inhibitors of Apoptosis Proteins (IAP) family; and sensitivity to the treatment with Tumor Necrosis Factor (TNF) - Related Apoptosis Inducing Ligand (TRAIL), acting through death receptor 4 and 5 (DR4 and DR5), alone or in combination with siRNA-mediated down-regulation of IAPs. Spheroids demonstrated a higher expression of IAPs (in 8 from 15 studied cases), where the IAP livin was up-regulated the most. Also a tendency for up-regulation of DR5 was shown, and the spheroid cells were more sensitive to the DR5-mediated treatment than the monolayer cells, indicating that this strategy might affect tumor initiating cells present in melanoma spheres. The treatment via DR4 had only a negligible effect. Although down-regulation of XIAP showed a small additive effect, the contribution of the XIAP or survivin knock-down to the reduced cell viability or spheroid forming capacity, was very low