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The MET oncogene drives a genetic programme linking cancer to haemostasis


The close relationship between activation of blood coagulation and cancer is an old enigma. In 1865, migrans trombophlebitis (‘a condition of the blood that predisposes it to spontaneous coagulation’) was described as a forewarning of occult malignancy (Trousseau's sign1). This pioneering observation emphasized the existence of haemostasis disorders associated with cancer onset; this phenomenon has since been extensively reported in clinical and epidemiological studies2,3,4, but has so far resisted a mechanistic explanation. Here we report a mouse model of sporadic tumorigenesis based on genetic manipulation of somatic cells. Targeting the activated, human MET oncogene to adult liver caused slowly progressing hepatocarcinogenesis. This was preceded and accompanied by a syndrome manifesting first with blood hypercoagulation (venous thromboses), and then evolving towards fatal internal haemorrhages. The pathogenesis of this syndrome is driven by the transcriptional response to the oncogene, including prominent upregulation of plasminogen activator inhibitor type 1 (PAI-1) and cyclooxygenase-2 (COX-2) genes. In vivo analysis showed that both proteins support the thrombohaemorrhagic phenotype, thus providing direct genetic evidence for the long-sought-after link between oncogene activation and haemostasis.

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Figure 1: Pre-neoplastic and neoplastic lesions after liver transduction of the MET oncogene.
Figure 2: The thrombohaemorrhagic syndrome induced by transduction of the MET oncogene.
Figure 3: Upregulation of haemostasis genes in MLP29 hepatocytes after transduction of the MET oncogene.
Figure 4: Expression of PAI-1 and COX-2 in MET-transduced mice.

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  1. Trousseau, A. Phlegmasia alba dolens. Clinique Médicale de l'Hotel-Dieu de Paris Vol. 3, 654–712 (J. B. Ballière et Fils, Paris, 1865)

    Google Scholar 

  2. Baron, J. A., Gridley, G., Weiderpass, E., Nyrén, O. & Linet, M. Venous thromboembolism and cancer. Lancet 351, 1077–1080 (1998)

    Article  CAS  Google Scholar 

  3. Rickles, F. R. & Levine, M. N. Epidemiology of thrombosis in cancer. Acta Haematol. 106, 6–12 (2001)

    Article  CAS  Google Scholar 

  4. Lee, A. Y. Y. & Levine, M. N. Venous thromboembolism and cancer: risks and outcomes. Circulation 107 (suppl.), I17–I21 (2003)

    Google Scholar 

  5. Vigna, E. & Naldini, L. Lentiviral vectors: excellent tools for experimental gene transfer and promising candidates for gene therapy. J. Gene Med. 2, 308–316 (2000)

    Article  CAS  Google Scholar 

  6. Trusolino, L. & Comoglio, P. M. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nature Rev. Cancer 2, 289–300 (2002)

    Article  CAS  Google Scholar 

  7. Schmidt, L. et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nature Genet. 16, 68–73 (1997)

    Article  CAS  Google Scholar 

  8. Di Renzo, M. F. et al. Expression of the Met/HGF receptor in normal and neoplastic human tissues. Oncogene 6, 1997–2003 (1991)

    CAS  PubMed  Google Scholar 

  9. Pennacchietti, S. et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3, 347–361 (2003)

    Article  Google Scholar 

  10. Park, M. et al. Mechanism of met oncogene activation. Cell 45, 895–904 (1986)

    Article  CAS  Google Scholar 

  11. Dull, T. et al. A third-generation lentivirus vector with a conditional packaging system. J. Virol. 72, 8463–8471 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Follenzi, A., Sabatino, G., Lombardo, A., Boccaccio, C. & Naldini, L. Efficient gene delivery and targeted expression to hepatocytes in vivo by improved lentiviral vectors. Hum. Gene Ther. 13, 243–260 (2002)

    Article  CAS  Google Scholar 

  13. Ponder, K. P. et al. Mouse hepatocytes migrate to liver parenchyma and function indefinitely after intrasplenic transplantation. Proc. Natl Acad. Sci. USA 88, 1217–1221 (1991)

    Article  ADS  CAS  Google Scholar 

  14. Pfeifer, A. et al. Transduction of liver cells by lentiviral vectors: analysis in living animals by fluorescence imaging. Mol. Ther. 3, 319–322 (2001)

    Article  CAS  Google Scholar 

  15. Rickles, F. R., Levine, M. N. & Dvorak, H. B. in Hemostasis and Thrombosis (eds Colman, R. W., Hirsh, J., Marder, V. J., Clowes, A. & George, J. N.) 1132–1152 (Lippincott Williams & Wilkins, Philadelphia, 2000)

    Google Scholar 

  16. Muller-Berghaus, G., ten Cate, H. & Levi, M. Disseminated intravascular coagulation: clinical spectrum and established as well as new diagnostic approaches. Thromb. Haemost. 82, 706–712 (1999)

    Article  CAS  Google Scholar 

  17. Collen, D. The plasminogen (fibrinolytic) system. Thromb. Haemost. 82, 259–270 (1999)

    Article  CAS  Google Scholar 

  18. Smith, W. L., De Witt, D. L. & Garavito, R. M. Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem. 69, 145–182 (2000)

    Article  CAS  Google Scholar 

  19. Friederich, P. W. et al. Novel low-molecular-weight inhibitor of PAI-1 (XR5118) promotes endogenous fibrinolysis and reduces postthrombolysis thrombus growth in rabbits. Circulation 96, 916–921 (1997)

    CAS  PubMed  Google Scholar 

  20. Gupta, R. A. & DuBois, R. N. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nature Rev. Cancer 1, 13–20 (2001)

    Article  Google Scholar 

  21. Dvorak, H. F. Tumors: wounds that do not heal. N. Engl. J. Med. 315, 1650–1659 (1986)

    Article  CAS  Google Scholar 

  22. Zeng, Q., McCauley, L. K. & Wang, C. Y. Hepatocyte growth factor inhibits anoikis by induction of activator protein 1-dependent cyclooxygenase-2. Implication in head and neck squamous cell carcinoma progression. J. Biol. Chem. 277, 50137–50142 (2002)

    Article  CAS  Google Scholar 

  23. FitzGerald, G. A. COX-2 and beyond: Approaches to prostaglandin inhibition in human disease. Nature Rev. Drug Discov. 2, 879–890 (2003)

    Article  CAS  Google Scholar 

  24. Sidenius, N. & Blasi, F. The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy. Cancer Metastasis Rev. 22, 205–222 (2003)

    Article  CAS  Google Scholar 

  25. Nakamura, T. et al. Molecular cloning and expression of human hepatocyte growth factor. Nature 342, 440–443 (1989)

    Article  ADS  CAS  Google Scholar 

  26. Trusolino, L., Pugliese, L. & Comoglio, P. M. Interactions between scatter factors and their receptors: hints for therapeutic applications. FASEB J. 12, 1267–1280 (1998)

    Article  CAS  Google Scholar 

  27. Follenzi, A., Ailles, L. E., Bakovic, S., Geuna, M. & Naldini, L. Gene transfer by lentiviral vectors is limited by nuclear translocation and rescued by HIV-1 pol sequences. Nature Genet. 25, 217–222 (2000)

    Article  CAS  Google Scholar 

  28. Medico, E. et al. The tyrosine kinase receptors Ron and Sea control “scattering” and morphogenesis of liver progenitor cells in vitro . Mol. Biol. Cell 7, 495–504 (1996)

    Article  CAS  Google Scholar 

  29. Li, C. & Wong, W. H. Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc. Natl Acad. Sci. USA 98, 31–36 (2001)

    Article  ADS  CAS  MATH  Google Scholar 

  30. Oshima, M. et al. Chemoprevention of intestinal polyposis in the Apcdelta716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. Cancer Res. 61, 1733–1740 (2001)

    CAS  PubMed  Google Scholar 

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We thank M. Risio, E. David and their staffs for pathology, M. Cilli for mouse surgery, R. Albano, A. Ferraro and R. Lo Noce for technical assistance, and M. Belluardo for computational analysis. We thank A.Cignetto for secretarial assistance. G.S. is the recipient of an AIRC fellowship. This research was supported by AIRC, CNR-MIUR, FIRB-MIUR, MIUR-PRIN and the Foundations CRT and ‘Compagnia di San Paolo’.

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Correspondence to Carla Boccaccio.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Table 1

Transcriptional regulation 71 haemostasis-related transcripts in MLP29 cells transduced with MET under the albumin promoter (ALB-MET) or CMV promoter (CMV-MET). (DOC 91 kb)

Supplementary Figure 1

Time-course of the transcriptional response of PAI-1 and COX-2 to physiological activation of the endogenous, non-oncogenic MET receptor by its ligand HGF/SF in MLP29 cells. (DOC 20 kb)

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Boccaccio, C., Sabatino, G., Medico, E. et al. The MET oncogene drives a genetic programme linking cancer to haemostasis. Nature 434, 396–400 (2005).

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