Functional role of S100A4 in tumor stroma interaction
Abstract:S100A4(Mts1) is a typical member of the S100 family of Ca2+-binding proteins with dual, intra- and extracellular functions. The S100A4 protein stimulates metastatic spread of tumor cells.
Studies in the laboratory revealed that possible mechanism of S100A4 action as a metastasis-promoting protein is connected with its extracellular function. When secreted S100A4 interacts with endothelial cells and tumor cells itself stimulating production of matrix degrading proteases leading to extracellular matrix remodeling (Schmidt-Hansen et al, 2004a, Schmidt-Hansen et al, 2004b).
To assess the role of S100A4 at the stroma site in tumorigenesis we transplanted highly metastatic tumor cells into mice lacking the S100A4 gene. Using this model we observed a significant delay in tumor uptake and decreased tumor incidences in the S100A4 (−/−) mice compared to the wild type controls. Moreover, tumors developed in the S100A4 (−/−) mice never metastasize. Co-injection of CSML100 cells with S100A4-positive fibroblasts partially restored the dynamics of tumor development and the ability to form metastasis. These results points to a determinative role of host-derived stroma cells expressing S100A4 in tumor progression and metastasis (Grum-Schwensen et al., 2005).
To study the consequences of S100A4 deficiency in the development and progression of a spontaneous tumor, we have generated a double transgenic PymT S100A4 (−/−) mouse model. In this model, the Polyomavirus middle T antigen (PymT) under control of a mouse mammary tumor virus long terminal repeat promoter (MMTV-LTR) induces metastatic breast tumors with 100% penetrance. We will determine which stroma components express S100A4 and how the S100A4-null mutation affects these cells in course of spontaneous tumor development. These data will allow us to clarify the mechanisms by which S100A4 promotes metastasis and open the possibilities for therapeutic intervention that will prevent metastatic spread of the tumor.
Schmidt-Hansen B, Ornas D, Grigorian M, Klingelhofer J, Tulchinsky E, Lukanidin E, Ambartsumian N. Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity. Oncogene. 2004a Jul 15; 23 (32): 5487–95.
Schmidt-Hansen B, Klingelhofer J, Grum-Schwensen B, Christensen A, Andresen S, Kruse C, Hansen T, Ambartsumian N, Lukanidin E, Grigorian M. Functional significance of metastasis-inducing S100A4(Mts1) in tumor-stroma interplay. J Biol Chem. 2004b Jun 4; 279 (23): 24498–508.
Grum-Schwensen B, Klingelhofer J, Berg CH, El-Naaman C, Grigorian M, Lukanidin E, Ambartsumian N. Suppression of tumor development and metastasis formation in mice lacking the S100A4 (mts1) gene. Cancer Res. 2005 May 1; 65 (9): 3772–3780.
Document Type: Abstract
Publication date: 2008-05-01