Functional significance of metastasis-inducing S100A4(Mts1) in tumor-stroma interplay.
Causal implication of S100A4 in inducing metastases was convincingly shown previously. However, the mechanisms that associate S100A4 with tumor progression are not well understood. S100A4 protein, as a typical member of the S100 family, exhibits dual, intracellular and extracellular, functions. This work is focused on the extracellular function of S100A4, in particular its involvement in tumor-stroma interplay in VMR (mouse adenocarcinoma cell line) tumor cells, which exhibit stroma-dependent metastatic phenotype. We demonstrated the reciprocal influence of tumor and stroma cells where tumor cells stimulate S100A4 secretion from fibroblasts in culture. In turn, extracellular S100A4 modifies the cytoskeleton and focal adhesions and triggers several other events in tumor cells. We found stabilization of the tumor suppressor protein p53 and modulation of its function. In particular, extracellular S100A4 down-regulates the pro-apoptotic bax and the angiogenesis inhibitor thrombospondin-1 genes. For the first time, we demonstrate here that the S100A4 protein added to the extracellular space strongly stimulates proteolytic activity of VMR cells. This activity most probably is associated with matrix metalloproteinases and, in particular, with matrix metalloproteinase-13. Finally, the application of the recombinant S100A4 protein confers stroma-independent metastatic phenotype on VMR tumor cells. In conclusion, our results indicate that metastasis-inducing S100A4 protein plays a pivotal role in the tumor-stroma environment. S100A4 released either by tumor or stroma cells triggers pro-metastatic cascades in tumor cells.
Schmidt-Hansen
Birgitte
B
Department of Molecular Cancer Biology, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
Klingelhöfer
Jörg
J
Grum-Schwensen
Birgitte
B
Christensen
Annette
A
Andresen
Susanne
S
Kruse
Charlotte
C
Hansen
Thomas
T
Ambartsumian
Noona
N
Lukanidin
Eugene
E
Grigorian
Mariam
M
D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D017364:Collagenases / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D051379:Mice; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism; D010641:Phenotype; D011233:Precipitin Tests; D011994:Recombinant Proteins / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000737:chemistry / Q000502:physiology*; D019700:Thrombospondin 1 / Q000096:biosynthesis; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D011994:Recombinant Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D019700:Thrombospondin 1; D016159:Tumor Suppressor Protein p53; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse