TY - JOUR
T1 - 'Proteolytic switching'
T2 - Opposite patterns of regulation of gelatinase B and its inhibitor TIMP-1 during human melanoma progression and consequences of gelatinase B overexpression
AU - MacDougall, J. R.
AU - Bani, M. R.
AU - Lin, Y.
AU - Muschel, R. J.
AU - Kerbel, R. S.
PY - 1999
Y1 - 1999
N2 - Although it is generally accepted that proleolytic degradation is an important mechanism used by malignant cells in the process of metastasis, comparatively little is known about the regulation of molecules responsible for proteolysis and how they become de-regulated during human tumour progression. Using a genetically related pair of human melanoma cell lines, derived from the same patient at different stages of disease, we analysed differences in the cytokine-mediated regulation of gelatinase B (MMP-9), an enzyme thought to play an important role in cellular invasiveness, and TIMP-1, a physiological inhibitor of this enzyme. Whereas the advanced stage (i.e. metastatic) partner of this pair (WM 239) could produce gelatinase B upon induction with interleukin (IL)-1β or tumour necrosis factor alpha (TNF-α), the early stage (i.e. primary) partner (WM 115) could not. In sharp contrast, we found that TIMP-1 displayed an opposite pattern of induction in these cell lines. Specifically, the early stage cell line, WM 115, demonstrated a marked increase in the production of TIMP-1 when treated with IL-1β or TNF-α whereas the advanced cell line, WM 239, showed no such increase. Treatment with the DNA demethylating agent, 2-deoxy-5-azacytidine, resulted in a marked up-regulation of both gelatinase B and TIMP-1 in both cell lines. It was further found that constitutive overexpression of gelatinase B in WM 239 cells and an additional melanoma cell line (MeWo), derived from a metastatic lesion, was able to greatly enhance lung colonization in an experimental metastasis assay while we did not observe differences in tumorigenicity. From these results we conclude that an altered responsiveness of gelatinase B and TIMP-1 to induction by similar agents is associated with disease progression in human melanoma and that this altered responsiveness can have consequences to the aggressive nature of the disease.
AB - Although it is generally accepted that proleolytic degradation is an important mechanism used by malignant cells in the process of metastasis, comparatively little is known about the regulation of molecules responsible for proteolysis and how they become de-regulated during human tumour progression. Using a genetically related pair of human melanoma cell lines, derived from the same patient at different stages of disease, we analysed differences in the cytokine-mediated regulation of gelatinase B (MMP-9), an enzyme thought to play an important role in cellular invasiveness, and TIMP-1, a physiological inhibitor of this enzyme. Whereas the advanced stage (i.e. metastatic) partner of this pair (WM 239) could produce gelatinase B upon induction with interleukin (IL)-1β or tumour necrosis factor alpha (TNF-α), the early stage (i.e. primary) partner (WM 115) could not. In sharp contrast, we found that TIMP-1 displayed an opposite pattern of induction in these cell lines. Specifically, the early stage cell line, WM 115, demonstrated a marked increase in the production of TIMP-1 when treated with IL-1β or TNF-α whereas the advanced cell line, WM 239, showed no such increase. Treatment with the DNA demethylating agent, 2-deoxy-5-azacytidine, resulted in a marked up-regulation of both gelatinase B and TIMP-1 in both cell lines. It was further found that constitutive overexpression of gelatinase B in WM 239 cells and an additional melanoma cell line (MeWo), derived from a metastatic lesion, was able to greatly enhance lung colonization in an experimental metastasis assay while we did not observe differences in tumorigenicity. From these results we conclude that an altered responsiveness of gelatinase B and TIMP-1 to induction by similar agents is associated with disease progression in human melanoma and that this altered responsiveness can have consequences to the aggressive nature of the disease.
KW - Cytokines
KW - Gelatinase B
KW - Melanoma
KW - TIMP-1
KW - Tumour progression
UR - http://www.scopus.com/inward/record.url?scp=0032927440&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032927440&partnerID=8YFLogxK
U2 - 10.1038/sj.bjc.6690385
DO - 10.1038/sj.bjc.6690385
M3 - Article
C2 - 10408860
AN - SCOPUS:0032927440
VL - 80
SP - 504
EP - 512
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 3-4
ER -