This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rocks, N. Articles by Cataldo, D. D. Search for Related Content PubMed PubMed Citation Articles by Rocks, N. Articles by Cataldo, D. D.

ADAMTS-1 Metalloproteinase Promotes Tumor Development through the Induction of a Stromal Reaction In vivo

Laboratory of Biology of Tumors and Development, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-Research, GIGA-Cancer and GIGA-I³, University of Liege and CHU of Liège, Liège, Belgium

Requests for reprints: Agnès Noel, University of Liege, Tower of Pathology (B23), 4th Floor, 4000 Liege, Belgium. Phone: 32-4-366-24-53; Fax: 32-4-366-29-36; E-mail: agnes.noel{at}ulg.ac.be.

Key Words: ADAMTS • lung cancer • tumor stroma • myofibroblast • MMP-13

ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motifs), the first described member of the ADAMTS family, is differentially expressed in various tumors. However, its exact role in tumor development and progression is still unclear. The aim of this study was to investigate the effects of ADAMTS-1 transfection in a bronchial epithelial tumor cell line (BZR) and its potential to modulate tumor development. ADAMTS-1 overexpression did not affect in vitro cell properties such as (a) proliferation in two-dimensional culture, (b) proliferation in three-dimensional culture, (c) anchorage-independent growth in soft agar, (d) cell migration and invasion in modified Boyden chamber assay, (e) angiogenesis in the aortic ring assay, and (f) cell apoptosis. In contrast, ADAMTS-1 stable transfection in BZR cells accelerated the in vivo tumor growth after s.c. injection into severe combined immunodeficient mice. It also promoted a stromal reaction characterized by myofibroblast infiltration and excessive matrix deposition. These features are, however, not observed in tumors derived from cells overexpressing a catalytically inactive mutant of ADAMTS-1. Conditioned media from ADAMTS-1–overexpressing cells display a potent chemotactic activity toward fibroblasts. ADAMTS-1 overexpression in tumors was associated with increased production of matrix metalloproteinase-13, fibronectin, transforming growth factor β (TGF-β), and interleukin-1β (IL-1β). Neutralizing antibodies against TGF-β and IL-1β blocked the chemotactic effect of medium conditioned by ADAMTS-1–expressing cells on fibroblasts, showing the contribution of these factors in ADAMTS-1–induced stromal reaction. In conclusion, we propose a new paradigm for catalytically active ADAMTS-1 contribution to tumor development, which consists of the recruitment of fibroblasts involved in tumor growth and tumor-associated stroma remodeling. [Cancer Res 2008;68(22):9541–50]