title: Osteoblast-secreted factors enhance the expression of dysadherin and CCL2-dependent migration of renal carcinoma cells.
abstract: Renal cell carcinoma (RCC) frequently metastasizes to the bone marrow. These metastases are characterized by extensive osteolytic lesions. The mechanism, however, by which RCC cells metastasize to bone marrow remains poorly understood. To unravel the role of bone marrow cells in this context, we performed cell adhesion and migration assays using human RCC cell lines to analyze the influence of resident bone marrow cells on renal tumor cells. The strongest adhesion of RCC cells was observed to osteoblasts. Moreover, conditioned medium of osteoblasts (OB-CM) significantly increased RCC cell migration. By gene expression analysis dysadherin was identified as a transcript whose expression could be elevated more than twofold in RCC cells when exposed to OB-CM. Suppression of dysadherin expression in RCC cells by siRNA reduced their ability to migrate in the presence of OB-CM. Furthermore, the RCC cells secreted high amounts of the chemokine CCL2 when tumor cells migrated under the influence of osteoblast-secreted factors. CCL2 neutralization strongly reduced the migratory ability of the RCC cells. Silencing the expression of dysadherin in RCC cells resulted in a twofold reduction of CCL2 protein expression indicating a dysadherin-dependent expression of the chemokine. Taken together, our data show that osteoblasts are the major cell type of the bone marrow that affect RCC cells by secreting factors that increase the expression of dysadherin and CCL2 in the tumor cells leading to enhanced cell migration. These data suggest an osteoblast-induced autocrine mechanism for a facilitated homing of RCC cells to the bone marrow.
authors.affiliation: Section for Transplantation Immunology and Immunohematology, Center for Medical Research, University of Tübingen, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schüler
authors.forename: Cornelia
authors.initials: C
authors.lastname: Lee-Thedieck
authors.forename: Konstanze
authors.initials: K
authors.lastname: Geiger
authors.forename: Tatjana
authors.initials: T
authors.lastname: Kaiser
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ino
authors.forename: Wilhelm K
authors.initials: WK
authors.lastname: Aicher
authors.forename: Gerd
authors.initials: G
authors.lastname: Klein
mesh_terms: D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D017077:Culture Media, Conditioned; D055785:Gene Knockdown Techniques; D006801:Humans; D007473:Ion Channels; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D008840:Microfilament Proteins; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; C451410:FXYD5 protein, human; D007473:Ion Channels; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins