Role of fibulin-5 in metastatic organ colonization.

Abstract

The tumor microenvironment is now recognized as a major factor in determining the survival and growth of disseminated tumor cells at potential metastatic sites. Tumor cells send signals to stroma cells and stimulate them to produce factors that in turn create favorable conditions for tumor cell metastasis. Activated fibroblasts constitute an important component of the tumor-associated stroma. We have previously shown that S100A4 protein produced by stromal fibroblasts in the primary tumor stimulates metastasis formation. Here we show that activated fibroblasts also stimulate the formation of metastases independently of S100A4 expression during organ colonization. To identify genes that could potentially interfere with fibroblast-driven metastasis, we used gene expression profiling of S100A4-deficient fibroblasts treated with and without tumor cell-conditioned media. Five differentially expressed genes encoding cell surface and secreted proteins with potential metastasis-modulating activity were selected. Expression of lymphocyte antigen 6 complex (Ly6c) and matrix metalloproteinase 3 (Mmp3) was upregulated in fibroblasts in response to tumor-conditioned medium, whereas expression of cadherin-16 (Cdh16), Ccn2, and fibulin-5 (Fbln5) was downregulated. Further analysis showed that Fibulin-5 is able to suppress the metastatic colonization of lungs and liver. Additional studies suggest a mechanism in which Fibulin-5 suppresses metastasis formation by inhibiting production of matrix metalloproteinase 9 (MMP9) and reducing the invasive behavior of fibroblasts. Together our data are consistent with the notion that tumors secrete factors that downregulate expression of Fbln5 in fibroblasts at sites of metastatic colonization, in turn upregulating Mmp9 expression and stimulating metastatic organ colonization.

• Authors: Henrik Devitt Møller, Ulrik Ralfkjær, Natascha Cremers, Mika Frankel, Rune Troelsgaard Pedersen, Jörg Klingelhöfer, Hiromi Yanagisawa, Mariam Grigorian, Per Guldberg, Jonathan Sleeman, Eugene Lukanidin, Noona Ambartsumian
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 9 Issue 5 Pg. 553-63 (May 2011) ISSN: 1557-3125 [Electronic] United States
• PMID: 21454378 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Ly
• CCN2 protein, mouse
• Cadherins
• Cdh16 protein, mouse
• Culture Media, Conditioned
• Extracellular Matrix Proteins
• FBLN5 protein, human
• Ly6 protein, mouse
• Connective Tissue Growth Factor
• Matrix Metalloproteinase 3
• Matrix Metalloproteinase 9

Topics

• Animals
• Antigens, Ly (drug effects, metabolism)
• Cadherins (drug effects, metabolism)
• Cell Line, Tumor
• Connective Tissue Growth Factor (drug effects, metabolism)
• Culture Media, Conditioned (pharmacology)
• Down-Regulation
• Extracellular Matrix Proteins (drug effects, metabolism)
• Fibroblasts (drug effects, metabolism)
• Gene Expression Regulation, Neoplastic
• Liver Neoplasms (genetics, secondary)
• Lung Neoplasms (genetics, secondary)
• Matrix Metalloproteinase 3 (drug effects, metabolism)
• Matrix Metalloproteinase 9 (drug effects, metabolism)
• Mice