The MET oncogene drives a genetic programme linking cancer to haemostasis

Abstract

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.

The role of platelet activation in tumor metastasis

“…Finally, the positive effect of heparin treatment in Trousseau's syndrome patients may simply reflect the capacity of heparin to efficiently block P-and L-selectin mediated interactions. In the second model, targeting of activated human MET oncogene to the mouse liver resulted in slowly progressing hepatocarcinogenesis [6]. Prior to detection of dysplastic nodules all animals developed thrombohemorrhagic syndrome, similar to the symptoms observed in Trousseau's syndrome.…”

“…Since thrombosis occurs in the setting of occult carcinomas, it is reasonable to expect that a factor produced by tumor cells is being released into the bloodstream, which is responsible for thrombotic propensity [2]. There were two main studies investigating Trousseau's syndrome in animal models [6,68]. In the first model, purified carcinoma mucins, free of any TF, were shown to induce platelet-rich microthrombi formation in vivo [68].…”

“…5,6]. Experimentally induced thrombocytopenia (depletion of platelets) was shown to reduce the development of metastasis both in transplant and syngeneic mouse tumor models [7].…”

Silencing the MET oncogene leads to regression of experimental tumors and metastases

“…MET activation indeed remodulates the integrin repertoire, disrupts intercellular junctions and induces transcription and activation of matrix metalloproteinases (reviewed by Trusolino and Comoglio, 2002). Furthermore, it has recently been shown that MET activation induces a cell-autonomous pro-coagulant activity that leads to pericellular fibrin deposition, thus creating a micro-environment that supports the growth of the tumor, favors the incoming of new vessels and is fertile for tumor cell expansion and survival (Boccaccio et al, 2005). Experimental evidence in animal models demonstrates that ectopic overexpression of MET renders cells tumorigenic and metastatic in nude mice (Rong et al, 1994), while MET or HGF transgenic expression results in development of spontaneous tumors and metastasis (Takayama et al, 1997;Wang et al, 2001).…”

Senescence, Wound Healing, and Cancer: the PAI-1 Connection

“…50,51,[55][56][57][58] All these physiological and patho-physiological processes depend on uPA or plasmin activity and are governed by extensive cell-nonautonomous signaling. uPA is a secreted as well as cell surface-bound protease and PAI-1 is the major physiologic regulator of uPA activity; both modulate the extent and duration of extracellular matrix (ECM) remodeling.…”