title: ROR2 is a novel prognostic biomarker and a potential therapeutic target in leiomyosarcoma and gastrointestinal stromal tumour.
abstract: Soft-tissue sarcomas are a group of malignant tumours whose clinical management is complicated by morphological heterogeneity, inadequate molecular markers and limited therapeutic options. Receptor tyrosine kinases (RTKs) have been shown to play important roles in cancer, both as therapeutic targets and as prognostic biomarkers. An initial screen of gene expression data for 48 RTKs in 148 sarcomas showed that ROR2 was expressed in a subset of leiomyosarcoma (LMS), gastrointestinal stromal tumour (GIST) and desmoid-type fibromatosis (DTF). This was further confirmed by immunohistochemistry (IHC) on 573 tissue samples from 59 sarcoma tumour types. Here we provide evidence that ROR2 expression plays a role in the invasive abilities of LMS and GIST cells in vitro. We also show that knockdown of ROR2 significantly reduces tumour mass in vivo using a xenotransplantation model of LMS. Lastly, we show that ROR2 expression, as measured by IHC, predicts poor clinical outcome in patients with LMS and GIST, although it was not independent of other clinico-pathological features in a multivariate analysis, and that ROR2 expression is maintained between primary tumours and their metastases. Together, these results show that ROR2 is a useful prognostic indicator in the clinical management of these soft-tissue sarcomas and may represent a novel therapeutic target.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, CA, USA.
authors.forename: Badreddin
authors.initials: B
authors.lastname: Edris
authors.forename: Iñigo
authors.initials: I
authors.lastname: Espinosa
authors.forename: Thomas
authors.initials: T
authors.lastname: Mühlenberg
authors.forename: Amanda
authors.initials: A
authors.lastname: Mikels
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.forename: Sonja E
authors.initials: SE
authors.lastname: Steigen
authors.forename: Shirley
authors.initials: S
authors.lastname: Zhu
authors.forename: Kelli D
authors.initials: KD
authors.lastname: Montgomery
authors.forename: Alexander J F
authors.initials: AJ
authors.lastname: Lazar
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
authors.forename: Robert B
authors.initials: RB
authors.lastname: West
authors.forename: Roel
authors.initials: R
authors.lastname: Nusse
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018572:Disease-Free Survival; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D020869:Gene Expression Profiling / Q000379:methods; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007890:Leiomyosarcoma / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D014594:Uterine Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors