title: The molecular signature of the stroma response in prostate cancer-induced osteoblastic bone metastasis highlights expansion of hematopoietic and prostate epithelial stem cell niches.
abstract: The reciprocal interaction between cancer cells and the tissue-specific stroma is critical for primary and metastatic tumor growth progression. Prostate cancer cells colonize preferentially bone (osteotropism), where they alter the physiological balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, and elicit prevalently an osteoblastic response (osteoinduction). The molecular cues provided by osteoblasts for the survival and growth of bone metastatic prostate cancer cells are largely unknown. We exploited the sufficient divergence between human and mouse RNA sequences together with redefinition of highly species-specific gene arrays by computer-aided and experimental exclusion of cross-hybridizing oligonucleotide probes. This strategy allowed the dissection of the stroma (mouse) from the cancer cell (human) transcriptome in bone metastasis xenograft models of human osteoinductive prostate cancer cells (VCaP and C4-2B). As a result, we generated the osteoblastic bone metastasis-associated stroma transcriptome (OB-BMST). Subtraction of genes shared by inflammation, wound healing and desmoplastic responses, and by the tissue type-independent stroma responses to a variety of non-osteotropic and osteotropic primary cancers generated a curated gene signature ("Core" OB-BMST) putatively representing the bone marrow/bone-specific stroma response to prostate cancer-induced, osteoblastic bone metastasis. The expression pattern of three representative Core OB-BMST genes (PTN, EPHA3 and FSCN1) seems to confirm the bone specificity of this response. A robust induction of genes involved in osteogenesis and angiogenesis dominates both the OB-BMST and Core OB-BMST. This translates in an amplification of hematopoietic and, remarkably, prostate epithelial stem cell niche components that may function as a self-reinforcing bone metastatic niche providing a growth support specific for osteoinductive prostate cancer cells. The induction of this combinatorial stem cell niche is a novel mechanism that may also explain cancer cell osteotropism and local interference with hematopoiesis (myelophthisis). Accordingly, these stem cell niche components may represent innovative therapeutic targets and/or serum biomarkers in osteoblastic bone metastasis.
authors.affiliation: Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Berna C
authors.initials: BC
authors.lastname: Özdemir
authors.affiliation: Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Janine
authors.initials: J
authors.lastname: Hensel
authors.affiliation: Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Secondini
authors.affiliation: Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Wetterwald
authors.affiliation: Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Ruth
authors.initials: R
authors.lastname: Schwaninger
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Fleischmann
authors.affiliation: Institut Génétique Biologie Moléculaire Cellulaire (IGBMC), Strasbourg, France.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Raffelsberger
authors.affiliation: ICube UMR7357, University of Strasbourg, Strasbourg, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Poch
authors.affiliation: Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne and Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: Biomedical Informatics Division, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Ramzi
authors.initials: R
authors.lastname: Temanni
authors.affiliation: Prostate Cancer Research Group, Norway Centre for Molecular Medicine (NCMM), University of Oslo, Oslo, Norway.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
authors.affiliation: Department of Urology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands.
authors.forename: Gabri
authors.initials: G
authors.lastname: van der Pluijm
authors.affiliation: Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: George N
authors.initials: GN
authors.lastname: Thalmann
authors.affiliation: Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Marco G
authors.initials: MG
authors.lastname: Cecchini
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D002454:Cell Differentiation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D006413:Hematopoietic System / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology*; D010012:Osteogenesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055153:Stem Cell Niche / Q000235:genetics*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger