The 72 kDa type IV collagenase is modulated via differential expression of alpha v beta 3 and alpha 5 beta 1 integrins during human melanoma cell invasion.
We have recently reported that concomitant with an increase in invasiveness, there is an increase in the expression and secretion of the matrix-degrading 72 kDa gelatinase A/type IV collagenase (MMP-2) in a moderately invasive human melanoma cell line (A375M) upon perturbation of the alpha v beta 3 classic vitronectin receptor. In the present study, we have extended these observations to include a highly invasive and metastatic melanoma cell line (C8161) which expresses a comparable amount of the alpha 5 beta 1 integrin (classic fibronectin receptor), but very little alpha v beta 3 integrin on its surface. When perturbed with an anti-alpha 5 beta 1 antibody, C8161 cells are 89% more invasive in vitro, and express and secrete increased levels of the gelatinase A. These changes were not elicited using antibodies to the alpha v beta 3 integrin. In addition, a 73% increase in invasion of C8161 cells through a fibronectin-enhanced matrix occurred, which could be abrogated by neutralizing antibodies to gelatinase A. Furthermore, we attempted to transiently mimic the invasive phenotype of the C8161 cells by diminishing the alpha v beta 3 integrin from the A375M cell surface through fluorescence-activated cell sorting selection or deoxynojirimycin treatment, and found these cells to be 30-50% more invasive than the parental population. These data suggest that alternative modulation and signaling events could be involved in melanoma tumor cell invasion as a result of the differential expression of integrins, and strictly cataloging the presence of these integrins is but an initial step in the analysis of their functional activity.
Seftor
R E
RE
Department of Ophthalmology, University of Arizona, Tucson 85724.
Seftor
E A
EA
Stetler-Stevenson
W G
WG
Hendrix
M J
MJ
D000906:Antibodies / Q000008:administration & dosage; D017364:Collagenases / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000032:analysis / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D016024:Receptors, Cytoadhesin / Q000032:analysis / Q000378:metabolism*; D017469:Receptors, Fibronectin; D019030:Receptors, Vitronectin
D000906:Antibodies; D016023:Integrins; D016024:Receptors, Cytoadhesin; D017469:Receptors, Fibronectin; D019030:Receptors, Vitronectin; D017364:Collagenases; D020780:Matrix Metalloproteinase 9