title: 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: Department of Tumor Microenvironment and Metastasis, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
authors: Henrik Devitt
authors: HD
authors: Møller
authors: Ulrik
authors: U
authors: Ralfkjær
authors: Natascha
authors: N
authors: Cremers
authors: Mika
authors: M
authors: Frankel
authors: Rune Troelsgaard
authors: RT
authors: Pedersen
authors: Jörg
authors: J
authors: Klingelhöfer
authors: Hiromi
authors: H
authors: Yanagisawa
authors: Mariam
authors: M
authors: Grigorian
authors: Per
authors: P
authors: Guldberg
authors: Jonathan
authors: J
authors: Sleeman
authors: Eugene
authors: E
authors: Lukanidin
authors: Noona
authors: N
authors: Ambartsumian
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000187:drug effects / Q000378:metabolism; D015820:Cadherins / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D055513:Connective Tissue Growth Factor / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000187:drug effects / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary*; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary*; D019278:Matrix Metalloproteinase 3 / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism*; D051379:Mice
chemical_list: D000950:Antigens, Ly; C526318:CCN2 protein, mouse; D015820:Cadherins; C491946:Cdh16 protein, mouse; D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; C526827:Ly6 protein, mouse; D055513:Connective Tissue Growth Factor; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9