Bcl-2 overexpression in melanoma cells increases tumor progression-associated properties and in vivo tumor growth.
In this study, we demonstrated that bcl-2 overexpression in human melanoma cells consistently enhanced the activity of multiple metastasis-related proteinases, in vitro cell invasion, and in vivo tumor growth. In particular, by using the M14 parental cell line, the MN8 control clone, and two bcl-2 overexpressing derivatives, we found that bcl-2 overexpressing cells exposed to hypoxia, when compared to parental cells, expressed higher level of several metalloproteases (MMPs) such as MMP-2, MMP-7, MT1-MMP, and tissue inhibitors of metalloproteases-1 and -2. Moreover, bcl-2 overexpression in melanoma cells enhanced in vitro invasion on matrigel and, in vivo tumor growth. The more aggressive behavior of bcl-2 transfectants tumors is significantly associated to an increase in MMP-2 expression as well as in a more elevated microvessel density as compared to the parental line. Taken together, our data suggest that bcl-2 plays a pivotal role in the regulation of molecules associated with the migratory and invasive phenotype, contributing, in cooperation to hypoxia, to tumor progression.
Trisciuoglio
Daniela
D
Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy.
Desideri
Marianna
M
Ciuffreda
Ludovica
L
Mottolese
Marcella
M
Ribatti
Domenico
D
Vacca
Angelo
A
Del Rosso
Mario
M
Marcocci
Lucia
L
Zupi
Gabriella
G
Del Bufalo
Donatella
D
D000818:Animals; D017209:Apoptosis; D001672:Biocompatible Materials; D002455:Cell Division; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003094:Collagen; D018450:Disease Progression; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism; D007797:Laminin; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011509:Proteoglycans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014183:Transplantation, Heterologous
D001672:Biocompatible Materials; D004338:Drug Combinations; D016023:Integrins; D007797:Laminin; D011509:Proteoglycans; D019253:Proto-Oncogene Proteins c-bcl-2; D019714:Tissue Inhibitor of Metalloproteinases; C059485:matrigel; D003094:Collagen; D020782:Matrix Metalloproteinases