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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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’.
The authors declare that they have no competing financial interests.
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)
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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