A gene expression signature associated with survival in metastatic melanoma

BACKGROUND: Current clinical and histopathological criteria used to define the prognosis of melanoma patients are inadequate for accurate prediction of clinical outcome. We investigated whether genome screening by means of high-throughput gene microarray might provide clinically useful information on patient survival. METHODS: Forty-three tumor tissues from 38 patients with stage III and stage IV melanoma were profiled with a 17,500 element cDNA microarray. Expression data were analyzed using significance analysis of microarrays (SAM) to identify genes associated with patient survival, and supervised principal components (SPC) to determine survival prediction. RESULTS: SAM analysis revealed a set of 80 probes, corresponding to 70 genes, associated with survival, i.e. 45 probes characterizing longer and 35 shorter survival times, respectively. These transcripts were included in a survival prediction model designed using SPC and cross-validation which allowed identifying 30 predicting probes out of the 80 associated with survival. CONCLUSION: The longer-survival group of genes included those expressed in immune cells, both innate and acquired, confirming the interplay between immunological mechanisms and the natural history of melanoma. Genes linked to immune cells were totally lacking in the poor-survival group, which was instead associated with a number of genes related to highly proliferative and invasive tumor cells

Functional Roles for CSPG4/NG2 in Chondrosarcoma

CSPG4/NG2 is a multifunctional transmembrane protein with limited distribution in adult tissues including articular cartilage. The purpose of this study was to investigate the possible roles of CSPG4/NG2 in chondrosarcomas and to establish whether this molecule may have potential for targeted therapy. Stable knock‐down of CSPG4/NG2 in the JJ012 chondrosarcoma cell line by shRNA resulted in decreased cell proliferation and migration as well as a decrease in gene expression of the MMP (matrix metalloproteinase) 3 protease and ADAMTS4 (aggrecanase). Chondrosarcoma cells in which CSPG4/NG2 was knocked down were more sensitive to doxorubicin than wild‐type cells. The results indicate that CSPG4/NG2 has roles in regulating chondrosarcoma cell function in relation to growth, spread and resistance to chemotherapy and that anti‐CSPG4/NG2 therapies may have potential in the treatment of surgically unresectable chondrosarcoma

Unique glycoprotein-proteoglycan complex defined by monoclonal antibody on human melanoma cells.

A monoclonal antibody, 9.2.27, with a high specificity for human melanoma cell surfaces has been utilized for biosynthetic studies in M21 human melanoma cells to define a unique antigenic complex consisting of a 250-kilodalton N-linked glycoprotein and a high molecular weight proteoglycan component larger than 400 kilodaltons. The 250-kilodalton glycoprotein has endoglycosidase H-sensitive precursors and shows a lower apparent molecular weight after treatment with neuraminidase. The biosynthesis of the proteoglycan component is inhibited by exposure of M21 cells to the monovalent ionophore monensin, this component can be labeled biosynthetically with 35SO4, is sensitive to beta-elimination in dilute base, and is degraded by both chondroitinase AC and ABC lyases, suggesting that it is a chondroitin sulfate proteoglycan. These data demonstrate that the antigenic determinant recognized by monoclonal antibody 9.2.27 is located on a glycoprotein-proteoglycan complex which may have unique implications for the interaction of glycoconjugates at the human melanoma tumor cell surface

Monoclonal antibody-directed effector cells selectively lyse human melanoma cells in vitro and in vivo.

Monoclonal antibody 9.2.27 (mAb 9.2.27) directed to a chondroitin sulfate proteoglycan on human melanoma cells was able to suppress tumor growth in athymic (nu/nu) mice more effectively when bound with polyethylene glycol to murine effector cells than when injected alone. These "armed" effector cells also proved more effective than the monoclonal antibody in eliciting antibody-dependent cellular cytotoxicity against human melanoma target cells in vitro