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RON, a Tyrosine Kinase Receptor Involved in Tumor Progression and Metastasis

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Abstract

Tyrosine kinase receptors mediate many critical cellular functions that contribute to tumor progression and metastasis and thus are potential targets for molecular-based cancer therapy. As has been found for many receptor tyrosine kinases, RON (recepteur d’origine nantais) and its ligand, macrophage-stimulating protein, have recently been implicated in the progression and metastasis of tumors. In in vitro experiments using colon and breast cancer cell lines, overexpression of RON led to increased invasion and migration of cancer cells and prevented apoptosis and anoikis. In addition, transgenic mice engineered to overexpress RON in the lung epithelium developed multiple pulmonary tumors, suggesting a role for RON in tumorigenesis. In human cancer specimens, increased RON expression has been demonstrated in colon, breast, ovarian, and lung tumors. Therefore, therapies designed to inhibit RON activation may hinder critical tumor survival mechanisms and play a role in the treatment of advanced disease.

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References

  1. J Mendelsohn (2002) ArticleTitleTargeting the epidermal growth factor receptor for cancer therapy J Clin Oncol 20 IssueID18 Suppl 1S–13S Occurrence Handle12235219 Occurrence Handle1:CAS:528:DC%2BD38Xot1Ghs70%3D

    PubMed  CAS  Google Scholar 

  2. J Baselga (2001) ArticleTitleThe EGFR as a target for anticancer therapy—focus on cetuximab Eur J Cancer 37 IssueIDSuppl 4 S16–22 Occurrence Handle11597400 Occurrence Handle1:CAS:528:DC%2BD3MXntlOku70%3D

    PubMed  CAS  Google Scholar 

  3. YQ Chen YQ Zhou D Angeloni et al. (2000) ArticleTitleOverexpression and activation of the RON receptor tyrosine kinase in a panel of human colorectal carcinoma cell lines Exp Cell Res 261 229–38 Occurrence Handle11082293 Occurrence Handle1:CAS:528:DC%2BD3cXotVyntrg%3D

    PubMed  CAS  Google Scholar 

  4. MH Wang D Wang YQ Chen (2003) ArticleTitleOncogenic and invasive potentials of human macrophage-stimulating protein receptor, the RON receptor tyrosine kinase Carcinogenesis 24 1291–300 Occurrence Handle12807733 Occurrence Handle1:CAS:528:DC%2BD3sXmtFKktbc%3D

    PubMed  CAS  Google Scholar 

  5. AL Hughes (2000) ArticleTitleModes of evolution in the protease and kringle domains of the plasminogen-prothrombin family Mol Phylogenet Evol 14 469–78 Occurrence Handle10712851 Occurrence Handle1:CAS:528:DC%2BD3cXhsFyltrw%3D

    PubMed  CAS  Google Scholar 

  6. C Ronsin F Muscatelli MG Mattei R Breathnach (1993) ArticleTitleA novel putative receptor protein tyrosine kinase of the met family Oncogene 8 1195–202 Occurrence Handle8386824 Occurrence Handle1:CAS:528:DyaK3sXks1ClsL4%3D

    PubMed  CAS  Google Scholar 

  7. D Angeloni A Danilkovitch-Miagkova A Miagkov et al. (2004) ArticleTitleThe soluble sema domain of the RON receptor inhibits macrophage-stimulating protein-induced receptor activation J Biol Chem 279 3726–32 Occurrence Handle14597639 Occurrence Handle1:CAS:528:DC%2BD2cXmtlCrsQ%3D%3D

    PubMed  CAS  Google Scholar 

  8. PM Comoglio L Tamagnone C Boccaccio (1999) ArticleTitlePlasminogen-related growth factor and semaphorin receptors: a gene superfamily controlling invasive growth Exp Cell Res 253 88–99 Occurrence Handle10579914 Occurrence Handle1:CAS:528:DyaK1MXnsF2it74%3D

    PubMed  CAS  Google Scholar 

  9. RS Muraoka WY Sun MC Colbert et al. (1999) ArticleTitleThe Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse J Clin Invest 103 1277–85 Occurrence Handle10.1172/JCI6091 Occurrence Handle10225971 Occurrence Handle1:CAS:528:DyaK1MXivFans7w%3D

    Article  PubMed  CAS  Google Scholar 

  10. SE Waltz L Eaton K Toney-Earley et al. (2001) ArticleTitleRon-mediated cytoplasmic signaling is dispensable for viability but is required to limit inflammatory responses J Clin Invest 108 567–76 Occurrence Handle11518730 Occurrence Handle1:CAS:528:DC%2BD3MXmt1Sqtrk%3D

    PubMed  CAS  Google Scholar 

  11. A Iwama MH Wang N Yamaguchi et al. (1995) ArticleTitleTerminal differentiation of murine resident peritoneal macrophages is characterized by expression of the STK protein tyrosine kinase, a receptor for macrophage-stimulating protein Blood 86 3394–403 Occurrence Handle7579443 Occurrence Handle1:CAS:528:DyaK2MXovFahsLo%3D

    PubMed  CAS  Google Scholar 

  12. G Gaudino V Avantaggiato A Follenzi et al. (1995) ArticleTitleThe proto-oncogene RON is involved in development of epithelial, bone and neuro-endocrine tissues Oncogene 11 2627–37 Occurrence Handle8545120 Occurrence Handle1:CAS:528:DyaK28XlvF2gsg%3D%3D

    PubMed  CAS  Google Scholar 

  13. P Maggiora A Lorenzato S Fracchioli et al. (2003) ArticleTitleThe RON and MET oncogenes are co-expressed in human ovarian carcinomas and cooperate in activating invasiveness Exp Cell Res 288 382–9 Occurrence Handle12915129 Occurrence Handle1:CAS:528:DC%2BD3sXmt1ehu7w%3D

    PubMed  CAS  Google Scholar 

  14. Q Chen DW Seol B Carr R Zarnegar (1997) ArticleTitleCo-expression and regulation of Met and Ron proto-oncogenes in human hepatocellular carcinoma tissues and cell lines Hepatology 26 59–66 Occurrence Handle9214452 Occurrence Handle1:CAS:528:DyaK2sXkslagtL8%3D

    PubMed  CAS  Google Scholar 

  15. BE Peace KJ Hill SJ Degen SE Waltz (2003) ArticleTitleCross-talk between the receptor tyrosine kinases Ron and epidermal growth factor receptor Exp Cell Res 289 317–25 Occurrence Handle14499632 Occurrence Handle1:CAS:528:DC%2BD3sXnt1Ggtbs%3D

    PubMed  CAS  Google Scholar 

  16. C Bardella B Costa P Maggiora et al. (2004) ArticleTitleTruncated RON tyrosine kinase drives tumor cell progression and abrogates cell-cell adhesion through E-cadherin transcriptional repression Cancer Res 64 5154–61 Occurrence Handle15289319 Occurrence Handle1:CAS:528:DC%2BD2cXmtF2mtLs%3D

    PubMed  CAS  Google Scholar 

  17. K Rulli T Yugawa C Hanson et al. (2004) ArticleTitleEx vivo and in vivo biological effects of a truncated form of the receptor tyrosine kinase stk when activated by interaction with the friend spleen focus-forming virus envelope glycoprotein or by point mutation J Virol 78 4573–81 Occurrence Handle15078939 Occurrence Handle1:CAS:528:DC%2BD2cXjsVKisrk%3D

    PubMed  CAS  Google Scholar 

  18. EJ Leonard AH Skeel (1979) ArticleTitleEnhancement of spreading, phagocytosis, chemotaxis by macrophage stimulating protein (MSP) Adv Exp Med Biol 121B 181–94 Occurrence Handle317559 Occurrence Handle1:STN:280:Bi%2BC1Mrgs1w%3D

    PubMed  CAS  Google Scholar 

  19. EJ Leonard AH Skeel (1978) ArticleTitleIsolation of macrophage stimulating protein (MSP) from human serum Exp Cell Res 114 117–26 Occurrence Handle658151 Occurrence Handle1:CAS:528:DyaE1cXltVahsbo%3D

    PubMed  CAS  Google Scholar 

  20. T Yoshimura N Yuhki MH Wang et al. (1993) ArticleTitleCloning, sequencing, and expression of human macrophage stimulating protein (MSP, MST1) confirms MSP as a member of the family of kringle proteins and locates the MSP gene on chromosome 3 J Biol Chem 268 15461–8 Occurrence Handle8393443 Occurrence Handle1:CAS:528:DyaK3sXlvFOqtr0%3D

    PubMed  CAS  Google Scholar 

  21. EJ Leonard A Danilkovitch (2000) ArticleTitleMacrophage stimulating protein Adv Cancer Res 77 139–67 Occurrence Handle10549357 Occurrence Handle1:CAS:528:DC%2BD3cXltl2kuw%3D%3D Occurrence Handle10.1016/S0065-230X(08)60786-1

    Article  PubMed  CAS  Google Scholar 

  22. A Skeel EJ Leonard (2001) ArticleTitlealpha 1-Antichymotrypsin is the human plasma inhibitor of macrophage ectoenzymes that cleave pro-macrophage stimulating protein J Biol Chem 276 21932–7 Occurrence Handle11274154 Occurrence Handle1:CAS:528:DC%2BD3MXksFGktr0%3D

    PubMed  CAS  Google Scholar 

  23. MH Wang YQ Zhou YQ Chen (2002) ArticleTitleMacrophage-stimulating protein and RON receptor tyrosine kinase: potential regulators of macrophage inflammatory activities Scand J Immunol 56 545–53 Occurrence Handle12472665 Occurrence Handle1:CAS:528:DC%2BD3sXjslGntA%3D%3D

    PubMed  CAS  Google Scholar 

  24. P Maggiora S Marchio MC Stella et al. (1998) ArticleTitleOverexpression of the RON gene in human breast carcinoma Oncogene 16 2927–33 Occurrence Handle9671413 Occurrence Handle1:CAS:528:DyaK1cXjvFSjuro%3D

    PubMed  CAS  Google Scholar 

  25. A Danilkovitch A Skeel EJ Leonard (1999) ArticleTitleMacrophage stimulating protein-induced epithelial cell adhesion is mediated by a PI3-K-dependent, but FAK-independent mechanism Exp Cell Res 248 575–82 Occurrence Handle10222149 Occurrence Handle1:CAS:528:DyaK1MXis1Kksrg%3D

    PubMed  CAS  Google Scholar 

  26. A Danilkovitch-Miagkova D Angeloni A Skeel et al. (2000) ArticleTitleIntegrin-mediated RON growth factor receptor phosphorylation requires tyrosine kinase activity of both the receptor and c-Src J Biol Chem 275 14783–6 Occurrence Handle10747844 Occurrence Handle1:CAS:528:DC%2BD3cXjsFansbk%3D

    PubMed  CAS  Google Scholar 

  27. D Liu J Aguirre Ghiso Y Estrada L Ossowski (2002) ArticleTitleEGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma Cancer Cell 1 445–57 Occurrence Handle12124174 Occurrence Handle1:CAS:528:DC%2BD38XltVKjsb8%3D

    PubMed  CAS  Google Scholar 

  28. JL Boerner A Danielsen NJ Maihle (2003) ArticleTitleLigand-independent oncogenic signaling by the epidermal growth factor receptor: v-ErbB as a paradigm Exp Cell Res 284 111–21 Occurrence Handle12648470 Occurrence Handle1:CAS:528:DC%2BD3sXitVylt7k%3D

    PubMed  CAS  Google Scholar 

  29. L Moro L Dolce S Cabodi et al. (2002) ArticleTitleIntegrin-induced epidermal growth factor (EGF) receptor activation requires c-Src and p130Cas and leads to phosphorylation of specific EGF receptor tyrosines J Biol Chem 277 9405–14 Occurrence Handle11756413 Occurrence Handle1:CAS:528:DC%2BD38Xitl2ktrg%3D

    PubMed  CAS  Google Scholar 

  30. J Gotzmann M Mikula A Eger et al. (2004) ArticleTitleMolecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis Mutat Res 566 9–20 Occurrence Handle14706509 Occurrence Handle1:CAS:528:DC%2BD2cXpt1Kg

    PubMed  CAS  Google Scholar 

  31. MY Hsu MJ Wheelock KR Johnson M Herlyn (1996) ArticleTitleShifts in cadherin profiles between human normal melanocytes and melanomas J Investig Dermatol Symp Proc 1 188–94 Occurrence Handle9627715 Occurrence Handle1:CAS:528:DyaK28Xktleqtr4%3D

    PubMed  CAS  Google Scholar 

  32. W Birchmeier J Behrens (1994) ArticleTitleCadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness Biochim Biophys Acta 1198 11–26 Occurrence Handle8199193 Occurrence Handle1:CAS:528:DyaK2cXktlaisrs%3D

    PubMed  CAS  Google Scholar 

  33. GF Scheumman C Hoang-Vu Y Cetin et al. (1995) ArticleTitleClinical significance of E-cadherin as a prognostic marker in thyroid carcinomas J Clin Endocrinol Metab 80 2168–72 Occurrence Handle7608273 Occurrence Handle1:CAS:528:DyaK2MXmvVyqtbY%3D

    PubMed  CAS  Google Scholar 

  34. D Wang Q Shen YQ Chen MH Wang (2004) ArticleTitleCollaborative activities of macrophage-stimulating protein and transforming growth factor-beta1 in induction of epithelial to mesenchymal transition: roles of the RON receptor tyrosine kinase Oncogene 23 1668–80 Occurrence Handle15001985 Occurrence Handle1:CAS:528:DC%2BD2cXhslGisLw%3D

    PubMed  CAS  Google Scholar 

  35. A Danilkovitch S Donley A Skeel EJ Leonard (2000) ArticleTitleTwo independent signaling pathways mediate the antiapoptotic action of macrophage-stimulating protein on epithelial cells Mol Cell Biol 20 2218–27 Occurrence Handle10688668 Occurrence Handle1:CAS:528:DC%2BD3cXhsVKmtrc%3D

    PubMed  CAS  Google Scholar 

  36. A Danilkovitch-Miagkova EJ Leonard (2001) ArticleTitleAnti-apoptotic action of macrophage stimulating protein (MSP) Apoptosis 6 183–90 Occurrence Handle11388667 Occurrence Handle1:CAS:528:DC%2BD3MXktF2qtbk%3D

    PubMed  CAS  Google Scholar 

  37. YQ Chen YQ Zhou JH Fisher MH Wang (2002) ArticleTitleTargeted expression of the receptor tyrosine kinase RON in distal lung epithelial cells results in multiple tumor formation: oncogenic potential of RON in vivo Oncogene 21 6382–6 Occurrence Handle12214279 Occurrence Handle1:CAS:528:DC%2BD38Xms1yrsrg%3D

    PubMed  CAS  Google Scholar 

  38. BE Peace MJ Hughes SJ Degen SE Waltz (2001) ArticleTitlePoint mutations and overexpression of Ron induce transformation, tumor formation, and metastasis Oncogene 20 6142–51 Occurrence Handle11593422 Occurrence Handle1:CAS:528:DC%2BD3MXnsFOitb0%3D

    PubMed  CAS  Google Scholar 

  39. HS Lin GJ Berry WE Fee SuffixJr et al. (2004) ArticleTitleIdentification of tyrosine kinases overexpressed in head and neck cancer Arch Otolaryngol Head Neck Surg 130 311–6 Occurrence Handle15023838

    PubMed  Google Scholar 

  40. CG Willett MH Wang RL Emanuel et al. (1998) ArticleTitleMacrophage-stimulating protein and its receptor in non-small-cell lung tumors: induction of receptor tyrosine phosphorylation and cell migration Am J Respir Cell Mol Biol 18 489–96 Occurrence Handle9533936 Occurrence Handle1:CAS:528:DyaK1cXis1Oisbw%3D

    PubMed  CAS  Google Scholar 

  41. MH Wang AL Kurtz Y Chen (2000) ArticleTitleIdentification of a novel splicing product of the RON receptor tyrosine kinase in human colorectal carcinoma cells Carcinogenesis 21 1507–12 Occurrence Handle10910951 Occurrence Handle1:CAS:528:DC%2BD3cXlvVeqsb8%3D

    PubMed  CAS  Google Scholar 

  42. YQ Zhou C He YQ Chen et al. (2003) ArticleTitleAltered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential Oncogene 22 186–97 Occurrence Handle12527888 Occurrence Handle1:CAS:528:DC%2BD3sXjtlGjsg%3D%3D

    PubMed  CAS  Google Scholar 

  43. T Okino H Egami H Ohmachi et al. (1999) ArticleTitlePresence of RON receptor tyrosine kinase and its splicing variant in malignant and non-malignant human colonic mucosa Int J Oncol 15 709–14 Occurrence Handle10493952 Occurrence Handle1:CAS:528:DyaK1MXntVSns7Y%3D

    PubMed  CAS  Google Scholar 

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Acknowledgments

Supported by National Institutes of Health (NIH) T32 Grant CA-09599 (E.R.C. and A.Y.), NIH 5 U54 CA90810 02 (L.M.E.), The Lockton Fund for Pancreatic Cancer Research (L.M.E.), and NIH Cancer Center Support Grant CA-16672. The authors thank Chrisine Wogan from Scientific Publishing and Rita Hernandez from Surgical Oncology, M. D. Anderson Cancer Center, for editorial assistance.

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Authors and Affiliations

  1. Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Unit 444, PO Box 301402, Houston, Texas, 77230-1402

    E. Ramsay Camp MD, Anthony Yang MD & Lee M. Ellis MD

  2. Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, 7777 Knight Road, Houston, Texas, 77054

    Wenbiao Liu MD, Fan Fan BS, Ray Somcio BA & Lee M. Ellis MD

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  1. E. Ramsay Camp MD
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  2. Wenbiao Liu MD
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  3. Fan Fan BS
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  4. Anthony Yang MD
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Correspondence to Lee M. Ellis MD.

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Published by Springer Science+Business Media, Inc. © 2005 The Society of Surgical Oncology, Inc.

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Camp, E.R., Liu, W., Fan, F. et al. RON, a Tyrosine Kinase Receptor Involved in Tumor Progression and Metastasis. Ann Surg Oncol 12, 273–281 (2005). https://doi.org/10.1245/ASO.2005.08.013

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  • DOI: https://doi.org/10.1245/ASO.2005.08.013

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