The S100A4 protein stimulates metastatic spread of tumor cells. However, the actual mechanism by which S100A4 promotes tumor progression remains unclear. Recent findings suggest that S100A4 contributes to tumor progression when released into the extracellular compartment. To assess the role of S100A4 at the stroma site in tumorigenesis Grum-Schwensen et al. transplanted highly metastatic mammary carcinoma cells into mice lacking the S100A4 gene. Using this model they observed a significant delay in tumor uptake and decreased tumor incidences in the S100A4(-/-) mice compared to the wild type controls (survival curve). Immunohistochemical analyses of these tumors revealed abnormal distribution of host-derived stroma cells (here illustrated by specific staining of myofibroblasts in tumor sections). The retardation of tumor development could be surmounted by addition of S100A4 (+/+) fibroblasts to the tumor transplants. These fibroblasts were characterized by an enhanced motility and invasiveness (as shown by the ability of the cells to invade 3D Matrigel) in comparison with the S100A4(-/-) fibroblasts. Taken together, our results point to a determinative role of host-derived stroma cells expressing S100A4 in tumor progression and metastasis. Blocking of S100A4 activity in the tumor microenvironment will open new possibilities for the development of new anticancer therapies. For details, see the article by Grum-Schwensen et al. on page 3772 of this issue.

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