Phenotypical and functional studies on putative cancer stem cells of human melanoma

Perego, Michela (2011). Phenotypical and functional studies on putative cancer stem cells of human melanoma. PhD thesis The Open University.



Several lines of evidence obtained in a variety of human tumours support the theory of cancer stem cells (CSCs). The aim of this thesis was the isolation and the biomolecular characterization of the tumorigenic subpopulation of melanoma cells. Melanoma cells growing in stem cell medium as non-adherent colonies, here named 'melanospheres', were successfully isolated from melanoma specimens or from melanoma cell lines. Melanospheres displayed a self-renewal capacity and multipotency in vitro and were highly tumorigenic in vivo. Remarkably, melanosphere-derived xenografts maintained tumorigenic potential in subsequent recipients and mirrored the original melanoma of the patient. Melanospheres expressed a heterogeneous assortment of stem cell markers, and no direct and unique correlation between any of their phenotypes and in vivo tumorigenicity was found. Conversely, melanoma cells cultured in the presence of fetal calf serum displayed a lower tumorigenicity in SCID mice with limited engraftment capacity in secondary recipient animals. Moreover, adherent cell xenografts displayed a homogeneous phenotype for the expression of melanoma associated markers and contained cells with markers of full differentiation. Taken together our data provide further evidence on the heterogeneous nature of human melanomas and show that melanospheres and their xenografted tumours represent a useful model to investigate melanoma biology. The parent-to-progeny relationship between CSCs and tumour bulk does not necessarily reflect the well conserved and predictable rules operating in normal tissue development. CSCs may thus not be a static compartment but rather stemness features can be acquired by tumour cells in response to environmental signals. Thus, in this thesis, experiments have been performed to define the role of tumour environmental factors produced by melanoma cells themselves or by cells composing the tumour stroma in modulating the acquisition of sternness properties. The results provided in this thesis indicated that melanospheres display an extensive secretory capacity quantitatively and qualitatively different from that of melanoma cells growing as adherent monolayer. The roles of these immunerelated factors in shaping melanoma heterogeneity, plasticity and tumour maintenance are discussed.

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