title: Metastatic outgrowth encompasses COL-I, FN1, and POSTN up-regulation and assembly to fibrillar networks regulating cell adhesion, migration, and growth.
abstract: Although the outgrowth of micrometastases into macrometastases is the rate-limiting step in metastatic progression and the main determinant of cancer fatality, the molecular mechanisms involved have been little studied. Here, we compared the gene expression profiles of melanoma lymph node micro- and macrometastases and unexpectedly found no common up-regulation of any single growth factor/cytokine, except for the cytokine-like SPP1. Importantly, metastatic outgrowth was found to be consistently associated with activation of the transforming growth factor-beta signaling pathway (confirmed by phospho-SMAD2 staining) and concerted up-regulation of POSTN, FN1, COL-I, and VCAN genes-all inducible by transforming growth factor-beta. The encoded extracellular matrix proteins were found to together form intricate fibrillar networks around tumor cell nests in melanoma and breast cancer metastases from various organs. Functional analyses suggested that these newly synthesized protein networks regulate adhesion, migration, and growth of tumor cells, fibroblasts, and endothelial cells. POSTN acted as an anti-adhesive molecule counteracting the adhesive functions of FN1 and COL-I. Further, cellular FN and POSTN were specifically overexpressed in the newly forming/formed tumor blood vessels. Transforming growth factor-beta receptors and the metastasis-related matrix proteins, POSTN and FN1, in particular, may thus provide attractive targets for development of new therapies against disseminated melanoma, breast cancer, and possibly other tumors, by affecting key processes of metastasis: tumor/stromal cell migration, growth, and angiogenesis.
authors.affiliation: Department of Pathology, Haartman Institute, P.O. Box 21 (Haartmaninkatu 3), FI-00014 Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Soikkeli
authors.forename: Piotr
authors.initials: P
authors.lastname: Podlasz
authors.forename: Miao
authors.initials: M
authors.lastname: Yin
authors.forename: Pirjo
authors.initials: P
authors.lastname: Nummela
authors.forename: Tiina
authors.initials: T
authors.lastname: Jahkola
authors.forename: Susanna
authors.initials: S
authors.lastname: Virolainen
authors.forename: Leena
authors.initials: L
authors.lastname: Krogerus
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkilä
authors.forename: Karl
authors.initials: K
authors.lastname: von Smitten
authors.forename: Olli
authors.initials: O
authors.lastname: Saksela
authors.forename: Erkki
authors.initials: E
authors.lastname: Hölttä
mesh_terms: D002448:Cell Adhesion / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046228:Microarray Analysis; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D053675:Versicans / Q000235:genetics / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; C512835:POSTN protein, human; D053675:Versicans