1. Differential mechanisms of tumor progression in clones from a single heterogeneous human melanoma
- Author
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Constance E. Brinckerhoff, Siying Ye, Walburga Croteau, David W. Mullins, and Molly H. Jenkins
- Subjects
Physiology ,Clinical Biochemistry ,Population ,Clone (cell biology) ,Gene Expression ,Mice, Nude ,Biology ,Article ,Metastasis ,Mice ,In vivo ,Tumor Cells, Cultured ,Tumor Microenvironment ,medicine ,Animals ,Humans ,RNA, Messenger ,Neoplasm Metastasis ,education ,Melanoma ,education.field_of_study ,Tumor microenvironment ,Cell Biology ,medicine.disease ,In vitro ,Clone Cells ,Tumor progression ,Immunology ,Disease Progression ,Neoplastic Stem Cells ,Cancer research ,Cytokines ,Female ,Matrix Metalloproteinase 1 - 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.
- Published
- 2012