title: Mesenchymal stem cell-derived CCL-9 and CCL-5 promote mammary tumor cell invasion and the activation of matrix metalloproteinases.
abstract: Stromal chemokine gradients within the breast tissue microenvironment play a critical role in breast cancer cell invasion, a prerequisite to metastasis. To elucidate which chemokines and mechanisms are involved in mammary cell migration we determined whether mesenchymal D1 stem cells secreted specific chemokines that differentially promoted the invasion of mammary tumor cells in vitro. Results indicate that mesenchymal D1 cells produced concentrations of CCL5 and CCL9 4- to 5-fold higher than the concentrations secreted by 4T1 tumor cells (P < 0.01). Moreover, 4T1 tumor cell invasion toward D1 mesenchymal stem cell conditioned media (D1CM), CCL5 alone, CCL9 alone or a combination CCL5 and CCL9 was observed. The invasion of 4T1 cells toward D1 mesenchymal stem CM was dose-dependently suppressed by pre-incubation with the CCR1/CCR5 antagonist met-CCL5 (P < 0.01). Furthermore, the invasion of 4T1 cells toward these chemokines was prevented by incubation with the broad-spectrum MMP inhibitor GM6001. Additionally, the addition of specific MMP9/MMP13 and MMP14 inhibitors prevented the MMP activities of supernatants collected from 4T1 cells incubated with D1CM, CCL5 or CCL9. Taken together these data highlight the role of CCL5 and CCL9 produced by mesenchymal stem cells in mammary tumor cell invasion.
authors.affiliation: Cell and Molecular Division; Department of Biology, University of North Carolina, Charlotte, Charlotte, NC, USA.
authors.forename: Muthulekha
authors.initials: M
authors.lastname: Swamydas
authors.forename: Krista
authors.initials: K
authors.lastname: Ricci
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Rego
authors.forename: Didier
authors.initials: D
authors.lastname: Dréau
mesh_terms: D000818:Animals; D065100:CCR5 Receptor Antagonists; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D054402:Chemokine CCL1 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000378:metabolism*; D019742:Chemokines, CC / Q000096:biosynthesis / Q000378:metabolism*; D017077:Culture Media, Conditioned; D004151:Dipeptides / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D054388:Receptors, CCR / Q000037:antagonists & inhibitors
chemical_list: C119309:CC chemokine receptor 9; D065100:CCR5 Receptor Antagonists; C502258:Ccl1 protein, mouse; C503460:Ccl5 protein, mouse; C095218:Ccl9 protein, mouse; D054402:Chemokine CCL1; D018946:Chemokine CCL5; D019742:Chemokines, CC; D017077:Culture Media, Conditioned; D004151:Dipeptides; D019402:Macrophage Inflammatory Proteins; C507096:Mmp14 protein, mouse; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D054388:Receptors, CCR; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D053511:Matrix Metalloproteinase 14
keywords: MMPs; breast tumor; cell migration; chemokine; chemokine receptor; mesenchymal stem cell