title: Expression of LDL receptor-related protein 5 (LRP5) as a novel marker for disease progression in high-grade osteosarcoma.
abstract: The Wingless-type (Wnt) family of proteins and its coreceptor LRP5 have recently been implicated in human skeletal development. Wnt pathway modulates cell fate and cell proliferation during embryonic development and carcinogenesis through activation of receptor-mediated signaling. Osteosarcoma (OS) is a bone-forming tumor of mesenchymal origin whose growth control has been linked to autocrine or paracrine stimulation by several growth factor families. We examined 4 OS cell lines for WNT1, WNT4, WNT5A, WNT7A, WNT11, FZD1-10 and LRP5 expression by reverse transcription polymerase chain reaction (RT-PCR). In addition, RT-PCR for LRP5 expression was performed in 44 OS patient samples and the findings were correlated with clinical data. Expression profiling of Wnts and their receptors revealed the presence of several isoforms in OS cell lines. Overall, 22/44 (50%) of OS patient samples showed evidence of LRP5 expression. Presence of LRP5 correlated significantly with tumor metastasis (p = 0.005) and the chondroblastic subtype of OS (p = 0.045). In addition, patients whose tumors were positive for LRP5 showed a trend toward decreased event-free survival (p = 0.066). No significant association was found between LRP5 expression and age, gender, site of disease, site of metastasis or degree of chemotherapy-induced tumor necrosis. Sequencing of exon 3 of LRP5 in 10 OS patient-derived cell cultures showed no activating mutation of LRP5. These results showed that expression of LRP5 is a common event in OS and strongly suggest a role for LRP and Wnt signaling in the pathobiology and progression of this disease.
authors.affiliation: Department of Surgery, Orthopaedic Surgery Service, affiliated with Weill Medical College of Cornell University, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Bang H
authors.initials: BH
authors.lastname: Hoang
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Kubo
authors.forename: John H
authors.initials: JH
authors.lastname: Healey
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sowers
authors.forename: BethAnne
authors.initials: B
authors.lastname: Mazza
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Huvos
authors.forename: Paul A
authors.initials: PA
authors.lastname: Meyers
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002455:Cell Division; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002648:Child; D002675:Child, Preschool; D019902:Chondrocytes / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D018450:Disease Progression; D005091:Exons; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology*; D020033:Protein Isoforms; D011973:Receptors, LDL / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D016896:Treatment Outcome; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D005819:Genetic Markers; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D020033:Protein Isoforms; D011973:Receptors, LDL; D015534:Trans-Activators; D051176:beta Catenin