title: Bone Metastasis in Renal Cell Carcinoma is Preprogrammed in the Primary Tumor and Caused by AKT and Integrin α5 Signaling.
abstract: OBJECTIVE
  Bone metastasis develops in 30% of all patients with renal cell carcinoma. We elucidated the mechanisms that lead to and predict bone metastasis of renal cell carcinoma.
  
  
  METHODS
  Nine renal cell carcinoma primary cell lines and 30 renal cell carcinoma tissue specimens (normal and tumor tissue) were collected from 3 patients with no metastasis and 10 with lung or bone metastasis within 5 years after nephrectomy. Cell migration was analyzed in a Boyden chamber and proliferation was assessed by bromodeoxyuridine incorporation. Adhesion to fibronectin, and collagen I and IV was determined after cell staining. The expression and/or activity of cellular signaling molecules was quantified by Western blot.
  
  
  RESULTS
  Compared to renal cell carcinoma cells from patients without metastasis, the migration of cells from patients with bone metastasis was enhanced 13.5-fold (p = 0.034), and adhesion to fibronectin and collagen I was enhanced 5.8-fold and 6.1-fold (p = 0.002 and 0.014, respectively). In general proliferation was decreased in metastasizing cells. In accordance with these results we detected higher activity of AKT (p = 0.011) and FAK (p = 0.054), higher integrin α5 expression (p = 0.052) and lower PTEN expression in primary cells from patients with bone metastasis compared to nonmetastasizing cells. An almost similarly altered expression pattern was also observed in the renal cell carcinoma tissue specimens and the normal renal tissue of patients with bone metastasis.
  
  
  CONCLUSIONS
  We describe evidence that molecular predispositions determine the potential for bone metastasis to develop in renal cell carcinoma, which may serve as prognostic markers after initial tumor detection.
authors.affiliation: Department of Urology, University Medical Center, University of Mainz, Mainz, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Haber
authors.affiliation: Department of Urology, University Medical Center, University of Mainz, Mainz, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Jöckel
authors.affiliation: Department of Urology, University Medical Center, University of Mainz, Mainz, Germany.
authors.forename: Frederik C
authors.initials: FC
authors.lastname: Roos
authors.affiliation: Department of Urology, University Homburg/Saar, Homburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Junker
authors.affiliation: Center for Pediatrics and Adolescent Medicine, Johannes Gutenberg University Medical Center, Mainz, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Prawitt
authors.affiliation: Department of Urology, University Medical Center, University of Mainz, Mainz, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hampel
authors.affiliation: Department of Urology, University Medical Center, University of Mainz, Mainz, Germany.
authors.forename: Joachim W
authors.initials: JW
authors.lastname: Thüroff
authors.affiliation: Department of Urology, University Medical Center, University of Mainz, Mainz, Germany. Electronic address: brenner@uni-mainz.de.
authors.forename: Walburgis
authors.initials: W
authors.lastname: Brenner
mesh_terms: D015153:Blotting, Western; D001859:Bone Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000556:secondary*; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000235:genetics / Q000556:secondary*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004273:DNA, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039482:Integrin alpha5 / Q000096:biosynthesis / Q000235:genetics*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins
chemical_list: D004273:DNA, Neoplasm; D039482:Integrin alpha5; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: bone and bones; carcinoma; kidney; neoplasm metastasis; renal cell; signal transduction