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 sign). This pioneering observation emphasized the existence of haemostasis disorders associated with cancer onset; this phenomenon has since been extensively reported in clinical and epidemiological studies, 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.
Boccaccio
Carla
C
Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Turin Medical School, Str. Prov. 142, I-10060 Candiolo, Torino, Italy. carla.boccaccio@ircc.it
Sabatino
Gabriella
G
Medico
Enzo
E
Girolami
Flavia
F
Follenzi
Antonia
A
Reato
Gigliola
G
Sottile
Antonino
A
Naldini
Luigi
L
Comoglio
Paolo M
PM
D000818:Animals; D001777:Blood Coagulation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D051546:Cyclooxygenase 2; D019281:Dimerization; D006402:Hematologic Diseases / Q000235:genetics / Q000473:pathology; D006487:Hemostasis / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D009857:Oncogenes / Q000235:genetics*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D008565:Membrane Proteins; D017395:Plasminogen Activator Inhibitor 1; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met