Heterogeneous phenotype of human melanoma cells with in vitro and in vivo features of tumor-initiating cells.
Melanospheres, the melanoma cells that grow as nonadherent colonies and that show in vitro self-renewing capacity and multipotency, were selected from melanoma specimens or from melanoma cell lines. Melanospheres were highly tumorigenic, and intradermal injections in severe combined immunodeficient (SCID) mice of as few as 100 cells generated tumors that maintained tumorigenic potential into subsequent recipients. Primary and serially transplanted xenografts recapitulated the phenotypic features of the original melanoma of the patient. Melanoma cells cultured in the presence of fetal calf serum (FCS) were also tumorigenic in SCID mice, although with lower efficiency; these xenografts showed a homogeneous phenotype for the expression of melanoma-associated markers, Melan-A/Mart-1, HMB45, and MITF, and contained cells with features of fully differentiated cells. Melanospheres were heterogeneous for the expression of stem cell markers and showed a significantly enhanced expression of the Nanog and Oct3/4 transcription factors when compared with adherent melanoma cells. No direct and unique correlation between any of the examined stem cell markers and in vivo tumorigenicity was found. Taken together, our data provide further evidence on the heterogeneous nature of human melanomas and show that melanospheres and their corresponding tumors, which are generated in vivo in immunocompromised mice, represent a model to investigate melanoma biology.
Perego
Michela
M
Department of Experimental Oncology, Fondazione IRCSS, Istituto Nazionale dei Tumori, Milan, Italy.
Tortoreto
Monica
M
Tragni
Gabrina
G
Mariani
Luigi
L
Deho
Paola
P
Carbone
Antonino
A
Santinami
Mario
M
Patuzzo
Roberto
R
Mina
Pamela Della
PD
Villa
Antonello
A
Pratesi
Graziella
G
Cossa
Giacomo
G
Perego
Paola
P
Daidone
Maria G
MG
Alison
Malcolm R
MR
Parmiani
Giorgio
G
Rivoltini
Licia
L
Castelli
Chiara
C
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001798:Blood Proteins / Q000494:pharmacology; D051929:CD146 Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D066298:In Vitro Techniques; D008207:Lymphatic Metastasis; D008545:Melanoma / Q000503:physiopathology / Q000556:secondary*; D051379:Mice; D016513:Mice, SCID; D000071317:Nanog Homeobox Protein; D009368:Neoplasm Transplantation / Q000379:methods*; D014411:Neoplastic Stem Cells / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D012878:Skin Neoplasms / Q000473:pathology* / Q000503:physiopathology; D018874:Spheroids, Cellular; D014183:Transplantation, Heterologous
D014408:Biomarkers, Tumor; D001798:Blood Proteins; D051929:CD146 Antigen; D018398:Homeodomain Proteins; C497902:MCAM protein, human; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse