Metastatic Outgrowth Encompasses COL-I, FN1, and POSTN Up-Regulation and Assembly to Fibrillar Networks Regulating Cell Adhesion, Migration, and Growth

• Published in: The American journal of pathology Vol. 177; no. 1; pp. 387 - 403
• Main Authors: Soikkeli, Johanna, Podlasz, Piotr, Yin, Miao, Nummela, Pirjo, Jahkola, Tiina, Virolainen, Susanna, Krogerus, Leena, Heikkilä, Päivi, von Smitten, Karl, Saksela, Olli, Hölttä, Erkki
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.07.2010; American Society for Investigative Pathology
• Subjects: Biological and medical sciences; Cell Adhesion - physiology; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Movement - physiology; Collagen Type I - genetics; Collagen Type I - metabolism; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Fibronectins - genetics; Fibronectins - metabolism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Investigative techniques, diagnostic techniques (general aspects); Lymphatic Metastasis; Medical sciences; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Microarray Analysis; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Regular; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Tumor Cells, Cultured; Up-Regulation; Versicans - genetics; Versicans - metabolism; Cell proliferation; Malignant tumor; Metastasis; Adhesion; Cell motility; Anatomic pathology; Regulation(control); Network; Advanced stage; Metastatic; Cell migration; Assembly; Cancer
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2010.090748

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-β 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-β. 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-β 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.