title: Stromal fibroblasts facilitate cancer cell invasion by a novel invadopodia-independent matrix degradation process.
abstract: Metastatic invasion of tumors into peripheral tissues is known to rely upon protease-mediated degradation of the surrounding stroma. This remodeling process uses complex, actin-based, specializations of the plasma membrane termed invadopodia that act both to sequester and release matrix metalloproteinases. Here we report that cells of mesenchymal origin, including tumor-associated fibroblasts, degrade substantial amounts of surrounding matrix by a mechanism independent of conventional invadopodia. These degradative sites lack the punctate shape of conventional invadopodia to spread along the cell base and are reticular and/or fibrous in character. In marked contrast to invadopodia, this degradation does not require the action of Src kinase, Cdc42 or Dyn2. Rather, inhibition of Dyn2 causes a marked upregulation of stromal matrix degradation. Further, expression and activity of matrix metalloproteinases are differentially regulated between tumor cells and stromal fibroblasts. This matrix remodeling by fibroblasts increases the invasive capacity of tumor cells, thereby illustrating how the tumor microenvironment can contribute to metastasis. These findings provide evidence for a novel matrix remodeling process conducted by stromal fibroblasts that is substantially more effective than conventional invadopodia, distinct in structural organization and regulated by disparate molecular mechanisms.
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota USA.|Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota USA.
authors.forename: Robbin D
authors.initials: RD
authors.lastname: Eppinga
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota USA.|Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota USA.
authors.forename: Gina L
authors.initials: GL
authors.lastname: Razidlo
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota USA.
authors.forename: Eugene W
authors.initials: EW
authors.lastname: Krueger
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qiang
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota USA.|Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: McNiven
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D034285:Dynamin II; D034281:Dynamins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D000069261:Podosomes / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D020764:cdc42 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D019061:src-Family Kinases; D020782:Matrix Metalloproteinases; D020764:cdc42 GTP-Binding Protein; C000593490:DNM2 protein, human; D034285:Dynamin II; D034281:Dynamins