title: BMP-2 inhibits tumor-initiating ability in human renal cancer stem cells and induces bone formation.
abstract: OBJECTIVE
  We have previously shown that BMP-2 induces bone formation and inhibits tumorigenicity of cancer stem cells (CSCs) in a human osteosarcoma OS99-1 cell line. In this study, we sought to determine whether BMP-2 can similarly induce bone formation and inhibit the tumorigenicity of renal CSCs identified based on aldehyde dehydrogenase (ALDH) activity in renal cell carcinoma (RCC) cell lines and primary tumors.
  
  
  METHODS
  Using a xenograft model in which cells from human RCC cell lines ACHN, Caki-2, and primary tumors were grown in NOD/SCID mice, renal CSCs were identified as a subset of ALDH(br) cells. The ALDH(br) cells possessed a greater colony-forming efficiency, higher proliferative output, increased expression of stem cell marker genes Oct3/4A, Nanog, renal embryonic marker Pax-2, and greater tumorigenicity compared to cells with low ALDH activity (ALDH(lo) cells), generating new tumors with as few as 25 cells in mice.
  
  
  RESULTS
  In vitro, BMP-2 was found to inhibit the ALDH(br) cell growth, down-regulate the expression of embryonic stem cell markers, and up-regulate the transcription of osteogenic markers. In vivo, all animals receiving a low number of ALDH(br) cells (5 × 10(3)) from ACHN, Caki-2, and primary tumor xenografts treated with 30 µg BMP-2 per animal showed limited tumor growth with significant bone formation, while untreated cells developed large tumor masses without bone formation.
  
  
  CONCLUSIONS
  These results suggest that BMP-2 inhibits the tumor-initiating ability of renal CSCs and induces osseous bone formation. BMP-2 may therefore provide a beneficial strategy for human RCC treatment by targeting the CSC-enriched population.
authors.affiliation: Spine Research Laboratory, Department of Neurosurgery, University of Michigan Medical School, 1500 E. Medical Center Drive, Room 3552 TC, Ann Arbor, MI, 48109-5338, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Paul
authors.initials: P
authors.lastname: Park
authors.forename: Frank
authors.initials: F
authors.lastname: La Marca
authors.forename: Khoi D
authors.initials: KD
authors.lastname: Than
authors.forename: Chia-Ying
authors.initials: CY
authors.lastname: Lin
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism* / Q000494:pharmacology; D001859:Bone Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D015536:Down-Regulation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis; D012516:Osteosarcoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D000444:Aldehyde Dehydrogenase