Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene.
The S100A4(mts1) protein stimulates metastatic spread of tumor cells. An elevated expression of S100A4 is associated with poor prognosis in many human cancers. Dynamics of tumor development were studied in S100A4-deficient mice using grafts of CSML100, highly metastatic mouse mammary carcinoma cells. A significant delay in tumor uptake and decreased tumor incidences were observed in S100A4(-/-) mice compared with the wild-type controls. Moreover, tumors developed in S100A4(-/-) mice never metastasize. Immunohistochemical analyses of these tumors revealed reduced vascularity and abnormal distribution of host-derived stroma cells. Coinjection of CSML100 cells with immortalized S100A4(+/+) fibroblasts partially restored the dynamics of tumor development and the ability to form metastasis. These fibroblasts were characterized by an enhanced motility and invasiveness in comparison with S100A4(-/-) fibroblasts, as well as by the ability to release S100A4 into the tumor environment. Taken together, our results point to a determinative role of host-derived stroma cells expressing S100A4 in tumor progression and metastasis.
Grum-Schwensen
Birgitte
B
Department of Molecular Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.
Klingelhofer
Jörg
J
Berg
Christian Hededam
CH
El-Naaman
Christina
C
Grigorian
Mariam
M
Lukanidin
Eugene
E
Ambartsumian
Noona
N
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D007178:Inbreeding; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000172:deficiency / Q000235:genetics*; D017154:Stromal Cells / Q000473:pathology
D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse