title: Differential mechanisms of tumor progression in clones from a single heterogeneous human melanoma.
abstract: We used vertical growth phase (VGP) human VMM5 melanoma cells to ask whether the tumor microenvironment could induce matrix metalloproteinase-1 (MMP-1) in vivo, and whether this induction correlated with metastasis. We isolated two clones from parental VMM5 cells: a low MMP-1 producing clone (C4) and high producing clone (C9). When these clones were injected orthotopically (intradermally) into nude mice, both were equally tumorigenic and produced equivalent and abundant amounts of MMP-1. However, the tumors from the C4 clones displayed different growth kinetics and distinct profiles of gene expression from the C9 population. The C4 tumors, which had low MMP-1 levels in vitro, appeared to rely on growth factors and cytokines in the microenvironment to increase MMP-1 expression in vivo, while MMP-1 levels remained constant in the C9 tumors. C9 cells, but not C4 cells, grew as spheres in culture and expressed higher levels of JARID 1B, a marker associated with melanoma initiating cells. We conclude that VMM5 melanoma cells exhibit striking intra-tumor heterogeneity, and that the tumorigenicity of these clones is driven by different molecular pathways. Our data suggest that there are multiple mechanisms for melanoma progression within a tumor, which may require different therapeutic strategies.
authors.affiliation: Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA.
authors.forename: Walburga
authors.initials: W
authors.lastname: Croteau
authors.forename: Molly H
authors.initials: MH
authors.lastname: Jenkins
authors.forename: Siying
authors.initials: S
authors.lastname: Ye
authors.forename: David W
authors.initials: DW
authors.lastname: Mullins
authors.forename: Constance E
authors.initials: CE
authors.lastname: Brinckerhoff
mesh_terms: D000818:Animals; D002999:Clone Cells; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D020781:Matrix Metalloproteinase 1