Abstract
Inappropriate kinase expression and subsequent promiscuous activity defines the transformation of many solid tumors including renal cell carcinoma (RCC). Thus, the expression of novel tumor-associated kinases has the potential to dramatically shape tumor cell behavior. Further, identifying tumor-associated kinases can lend insight into patterns of tumor growth and characteristics. Here, we report the identification of the RTK-like orphan receptor 2 (Ror2), a new tumor-associated kinase in RCC cell lines and primary tumors. Ror2 is an orphan receptor tyrosine kinase with physiological expression normally seen in the embryonic kidney. However, in RCC, Ror2 expression correlated with expression of genes involved at the extracellular matrix, including Twist and matrix metalloprotease-2 (MMP2). Expression of MMP2 in RCC cells was suppressed by Ror2 knockdown, placing Ror2 as a mediator of MMP2 regulation in RCC and a potential regulator of extracellular matrix remodeling. The suppression of Ror2 not only inhibited cell migration, but also inhibited anchorage-independent growth in soft agar and growth in an orthotopic xenograft model. These findings suggest a novel pathway of tumor-promoting activity by Ror2 within a subset of renal carcinomas, with significant implications for unraveling the tumorigenesis of RCC.
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References
Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR et al. (2004). Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22: 909–918.
Billiard J, Way DS, Seestaller-Wehr LM, Moran RA, Mangine A, Bodine PV . (2005). The orphan receptor tyrosine kinase Ror2 modulates canonical Wnt signaling in osteoblastic cells. Mol Endocrinol 19: 90–101.
Cancer Facts and Figures (2008). American Cancer Society Inc.: Atlanta, GA.
Coombs GS, Covey TM, Virshup DM . (2008). Wnt signaling in development, disease and translational medicine. Curr Drug Targets 9: 513–531.
Cowey CL, Rathmell WK . (2008). Using molecular biology to develop drugs for renal cell carcinoma. Expert Opin Drug Discov 3: 311–327.
Davies JA . (1996). Mesenchyme to epithelium transition during development of the mammalian kidney tubule. Acta Anat (Basel) 156: 187–201.
de Castro-Carpeno J, Belda-Iniesta C, Casado Saenz E, Hernandez Agudo E, Feliu Batlle J, Gonzalez Baron M . (2008). EGFR and colon cancer: a clinical view. Clin Transl Oncol 10: 6–13.
De Luca A, Carotenuto A, Rachiglio A, Gallo M, Maiello MR, Aldinucci D et al. (2008). The role of the EGFR signaling in tumor microenvironment. J Cell Physiol 214: 559–567.
Deloukas P, Schuler GD, Gyapay G, Beasley EM, Soderlund C, Rodriguez-Tome P et al. (1998). A physical map of 30 000 human genes. Science 282: 744–746.
Hosack DA, Dennis Jr G, Sherman BT, Lane HC, Lempicki RA . (2003). Identifying biological themes within lists of genes with EASE. Genome Biol 4: R70.
Irwin MS, Kondo K, Marin MC, Cheng LS, Hahn WC, Kaelin Jr WG . (2003). Chemosensitivity linked to p73 function. Cancer Cell 3: 403–410.
Kurban G, Hudon V, Duplan E, Ohh M, Pause A . (2006). Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. Cancer Res 66: 1313–1319.
Linehan WM, Walther MM, Zbar B . (2003). The genetic basis of cancer of the kidney. J Urol 170: 2163–2172.
Liotta LA, Kohn EC . (2001). The microenvironment of the tumour-host interface. Nature 411: 375–379.
Masiakowski P, Carroll RD . (1992). A novel family of cell surface receptors with tyrosine kinase-like domain. J Biol Chem 267: 26181–26190.
Matsuda T, Nomi M, Ikeya M, Kani S, Oishi I, Terashima T et al. (2001). Expression of the receptor tyrosine kinase genes, Ror1 and Ror2, during mouse development. Mech Dev 105: 153–156.
Nakagawara A . (2001). Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett 169: 107–114.
Oishi I, Sugiyama S, Liu ZJ, Yamamura H, Nishida Y, Minami Y . (1997). A novel Drosophila receptor tyrosine kinase expressed specifically in the nervous system. Unique structural features and implication in developmental signaling. J Biol Chem 272: 11916–11923.
Oldridge M, Fortuna AM, Maringa M, Propping P, Mansour S, Pollitt C et al. (2000). Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B. Nat Genet 24: 275–278.
Racusen LC, Monteil C, Sgrignoli A, Lucskay M, Marouillat S, Rhim JG et al. (1997). Cell lines with extended in vitro growth potential from human renal proximal tubule: characterization, response to inducers, and comparison with established cell lines. J Lab Clin Med 129: 318–329.
Rathmell WK, Wright TM, Rini BI . (2005). Molecularly targeted therapy in renal cell carcinoma. Expert Rev Anticancer Ther 5: 1031–1040.
Saxen L, Sariola H . (1987). Early organogenesis of the kidney. Pediatr Nephrol 1: 385–392.
Schwabe GC, Trepczik B, Suring K, Brieske N, Tucker AS, Sharpe PT et al. (2004). Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome. Dev Dyn 229: 400–410.
Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R et al. (2007). Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318: 287–290.
Takeuchi S, Takeda K, Oishi I, Nomi M, Ikeya M, Itoh K et al. (2000). Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation. Genes Cells 5: 71–78.
Tusher VG, Tibshirani R, Chu G . (2001). Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98: 5116–5121.
van Amerongen R, Mikels A, Nusse R . (2008). Alternative Wnt signaling is initiated by distinct receptors. Sci Signal 1: re9.
Yoda A, Oishi I, Minami Y . (2003). Expression and function of the Ror-family receptor tyrosine kinases during development: lessons from genetic analyses of nematodes, mice, and humans. J Recept Signal Transduct Res 23: 1–15.
Zhang X, Yamashita M, Uetsuki H, Kakehi Y . (2002). Angiogenesis in renal cell carcinoma: evaluation of microvessel density, vascular endothelial growth factor and matrix metalloproteinases. Int J Urol 9: 509–514.
Acknowledgements
We thank the Rathmell Lab members and the Lineberger Cancer Center community for thoughtful insights/advice. Additional thanks to the Microscopy Services Laboratory for use of their facilities, the Lineberger Animal Core Studies Facility and the Baldwin Lab for use of reagents. We also thank Dr H Shelton Earp, Dr Ian Davis and Dr Jon Serody for paper critiques. Funding for this project was provided in part by the Doris Duke Charitable Fund and the V foundation (WKR), Initiative for Maximizing Student Diversity Training Grant NIH-R25GM055336 (TMW and CM) and NCI-F31CA132543 (TMW). Funding for JDG was provided by a MSTP grant and a T32 grant in hemostasis and thrombosis. Human tumor samples were collected by the UNC Tumor Procurement Facility, supported by the UNC Lineberger Comprehensive Cancer Center.
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Wright, T., Brannon, A., Gordan, J. et al. Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma. Oncogene 28, 2513–2523 (2009). https://doi.org/10.1038/onc.2009.116
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DOI: https://doi.org/10.1038/onc.2009.116
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