ROR2: A Potential Therapeutic Target in Soft Tissue Tumors.
Badreddin Edris, Inigo Espinosa, Andrew H Beck, Cheng-Han Lee, Alexander J Lazar, Dina Lev, Jonathan A Fletcher, Robert B West, Roel Nusse, Matt van de Rijn. Stanford University School of Medicine, CA; Universitat Autònoma de Barcelona, Spain; Vancouver General Hospital, BC, Canada; MD Anderson Cancer Center, Houston, TX; Harvard Medical School, Boston, MA
Background: Receptor tyrosine kinases (RTKs) are a family of cell surface receptors that regulate a range of normal cellular processes and that can play critical roles in cancer development and progression. Receptor Tyrosine Kinase-Like Orphan Receptor 2 (ROR2) is activated by its ligand Wnt5A during the course of normal bone and cartilage development. ROR2 has been shown to have pro-tumorigenic effects in osteosarcoma, renal cell carcinoma, and melanoma. However, the prognostic significance of ROR2 expression in mesenchymal tumors has yet to be shown.
Design: Gene expression profiling data from a series of soft tissue tumors were analyzed for ROR2 gene expression. Next, we performed an immunohistochemistry analysis using a novel ROR2 antibody on tissue microarrays that contained leiomyosarcoma (LMS), gastrointestinal stromal tumor (GIST), and desmoid-type fibromatosis (DTF) tumors with known clinical outcome. To interrogate the functional significance of ROR2 expression in tumor proliferation and metastasis, we performed in vitro cell proliferation and matrigel invasion assays with LMS cells using small interfering RNAs to down-regulate ROR2 expression.
Results: Gene expression profiling revealed high levels of ROR2 mRNA expression in a subset of LMS, GIST, and DTF samples. These finds were confirmed by ROR2 immunostaining of tissue arrays containing 147 primary LMS, 417 GIST, and 195 DTF tumors. Kaplan-Meier survival curve analysis showed that high expression of ROR2 was associated with poor patient outcome in LMS (p=0.017) and GIST (p= 0.039) but no statistical significance was reached in DTF. In vitro experiments demonstrated that reductions in ROR2 expression levels did not affect the proliferative capacity of LMS cells but did decrease their ability to invade through a matrigel matrix.
Conclusions: ROR2 is highly expressed in a subset of LMS, GIST, and DTF cases and high ROR2 protein expression is significantly associated with poor clinical outcome in patients with LMS and GIST. ROR2 expression is important for LMS cells to successfully migrate through a matrigel matrix, which implies an important role for ROR2 in mediating invasive ability. Taken together, these results suggest that ROR2 may represent a novel therapeutic target for the treatment of GIST, LMS, and possibly DTF.
Category: Bone & Soft Tissue
Monday, February 28, 2011 1:00 PM
Poster Session II # 12, Monday Afternoon