Heparin and survival in cancer patients.
ABSTRACT The bi-directional association between cancer and the coagulation system has been known for almost 2 centuries. During the past 2 decades research has focused on the precise mechanisms through which cancer cells are able to induce a hypercoagulable state and how this leads to an environment favorable for cancer growth. Furthermore, the potential inhibitory effect of anticoagulant drugs on cancer progression has been explored. This article discusses these two aspects of the association.
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ABSTRACT: Protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor that functions as a cell-surface sensor for coagulation factors, and other proteases associated with the tumour microenvironment. Pancreatic cancer cells express high levels of PAR-2 and activation of PAR-2 may induce their proliferation and migration. Interestingly however, PAR-2 expression is increased in stromal rich pancreatic cancer regions suggesting a potential role of PAR-2 in the tumour microenvironment. Here, we assessed the importance of PAR-2 in the stromal compartment by utilizing an orthotopic pancreatic cancer model in which tumour cells are PAR-2 positive whereas stromal cells are PAR-2 negative. We assessed tumour weight/volume and we analyzed proliferation and (lymph)angiogenesis both in vivo and in vitro. We show that genetic ablation of PAR-2 from the stromal compartment inhibits primary tumour growth which is accompanied by reduced vascularization in primary tumours and reduced tube formation of vascular endothelial cells in vitro. In contrast to smaller primary tumours, the number of lymph node metastases was increased in PAR-2 deficient animals which was accompanied by an increased number of lymphatic vessels. In vitro tube formation assays show that PAR-2 does not inhibit the intrinsic tube forming capacity of lymphatic endothelial cells but that PAR-2 actually inhibits cancer cell induced tube formation. Overall, stromal PAR-2 thus plays a dual role in pancreatic cancer development by potentiating primary tumor growth but limiting lymphangiogenesis and subsequent lymph node metastasis. Our data identify a novel role of PAR-2 in the tumour microenvironment and pinpoint PAR-2 as a negative regulator of lymphangiogenesis.The Journal of Pathology 07/2014; · 7.33 Impact Factor
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ABSTRACT: Cancer is frequently associated with activation of blood coagulation, which in turn has been suggested to promote tumor growth and metastasis. Indeed, low molecular weight heparin treatment significantly prolongs the survival of a wide variety of patients with cancer. Based on this notion that anticoagulant treatment seems to benefit cancer patients, recent experiments aimed to elucidate the importance of the natural anticoagulant protein C pathways in cancer progression. Interestingly, these experiments showed that the repeated administration of exogenous activated protein C limits cancer cell extravasation in experimental animal models. In line, reducing endogenous activated protein C activity dramatically increased the number of experimental metastasis. These data thus strongly suggest that exogenous activated protein C administration may be a novel therapeutic avenue to limit cancer metastasis thereby prolonging overall survival of cancer patients. The current review provides an overview of recent data on the role of the protein C pathway in cancer metastasis. It discusses the potential of activated protein C as a novel target to reduce cancer progression, it points to several limitations of activated protein C administration in the setting of cancer cell metastasis and it suggest zymogen protein C as an attractive alternative.Thrombosis Research 04/2012; 129 Suppl 1:S80-4. · 2.43 Impact Factor