title: Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-β-deficient mouse mammary carcinomas.
abstract: The tumor stromal environment can dictate many aspects of tumor progression. A complete understanding of factors driving stromal activation and their role in tumor metastasis is critical to furthering research with the goal of therapeutic intervention. Polyoma middle T-induced mammary carcinomas lacking the type II TGF-β receptor (PyMT(mgko)) are highly metastatic compared with control PyMT-induced carcinomas (PyMT(fl/fl)). We hypothesized that the PyMT(mgko)-activated stroma interacts with carcinoma cells to promote invasion and metastasis. We show that the extracellular matrix associated with PyMT(mgko) tumors is stiffer and has more fibrillar collagen and increased expression of the collagen crosslinking enzyme lysyl oxidase (LOX) compared with PyMT(fl/fl) mammary carcinomas. Inhibition of LOX activity in PyMT(mgko) mice had no effect on tumor latency and size, but significantly decreased tumor metastasis through inhibition of tumor cell intravasation. This phenotype was associated with a decrease in keratin 14-positive myoepithelial cells in PyMT(mgko) tumors following LOX inhibition as well as a decrease in focal adhesion formation. Interestingly, the primary source of LOX was found to be activated fibroblasts. LOX expression in these fibroblasts can be driven by myeloid cell-derived TGF-β, which is significantly linked to human breast cancer. Overall, stromal expansion in PyMT(mgko) tumors is likely caused through the modulation of immune cell infiltrates to promote fibroblast activation. This feeds back to the epithelium to promote metastasis by modulating phenotypic characteristics of basal cells. Our data indicate that epithelial induction of microenvironmental changes can play a significant role in tumorigenesis and attenuating these changes can inhibit metastasis. Cancer Res; 73(17); 5336-46. ©2013 AACR.
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine and Vanderbilt-Ingram Cancer Center, Nashville, TN 37212, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pickup
authors.forename: Hanane
authors.initials: H
authors.lastname: Laklai
authors.forename: Irene
authors.initials: I
authors.lastname: Acerbi
authors.forename: Philip
authors.initials: P
authors.lastname: Owens
authors.forename: Agnieszka E
authors.initials: AE
authors.lastname: Gorska
authors.forename: Anna
authors.initials: A
authors.lastname: Chytil
authors.forename: Mary
authors.initials: M
authors.lastname: Aakre
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D003094:Collagen / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D053547:Keratin-14 / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D018625:Microscopy, Atomic Force; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D015398:Signal Transduction; D017154:Stromal Cells / Q000201:enzymology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D053547:Keratin-14; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II