Hemostatic proteins and cancer biology: news from the research groups

The expression of hemostatic proteins in cancer and their role in cancer biology is one of the themes that were discussed during ICTHIC 2018

One of the focuses was the extracellular vesicle-associated tissue factor (TF). Madkhali¹ analyzed the mechanisms of endothelial cell apoptosis induced by TF-rich microvesicles (MV) released by pancreas and kidney cancer cell lines. Inhibition of PAR-2 on endothelial cell or TF or factor VII (FVII) in MVs significantly reduced endothelial apoptosis, demonstrating a role of PAR2 in this process.

Another study² analysed the extracellular vesicle (EV)-associated TF activity in EV isolated from plasma of prostate cancer patients with disseminated intravascular coagulation (DIC), patients without DIC or matched healthy individuals. EVs from DIC patients reduced fibrin clot formation time of plasma in a TF dependent manner. Preliminary in vitro co-culture studies were presented that suggested the possible involvement of monocytes. Additional studies are needed to clarify the emerging complex interplay between tumor cells, EVs, TF and normal cells in this process.

How do neutrophil extracellular traps (NETs) interact with platelets? Elaskalani and colleagues³ contributed to further knowledge on the mechanism of such interaction. Thei data demonstrated that NETs ability to induce platelet aggregation was not affected by DNase nor by inhibitors of histones or histone receptors on platelets (GPVI, TLR2 and TLR4), thus indicating that DNA and histones are not directly involved in NET-induced platelet aggregation.

Also, new methodological approaches were described. Tikhomirova⁴ analyzed the association of blood rheological properties with hemostasis parameters, while Abubaker⁵ reported a novel flow cytometry assay for the detection of superoxide anion in human platelets.

With reference to the prognostic/predictive biomarkers in cancer patients, our editorial board fellow Kirwan⁶ reported a remarkable association between the tumor and stroma expression of extrinsic pathway markers with overall survival in a prospective study of 250 patients with early invasive breast cancers (with median follow up of five years). In this study, fibroblast TF expression was significantly associated with reduced overall survival, while tumor cell expression of thrombin was associated with reduced DFS. Interestingly, stromal TF emerged as an independent marker of overall survival on multivariate analysis. The author concluded that stromal, epithelial and systemic markers of the EC pathway may be associated with reduced survival in early breast cancer. There was discussion about whether or not patients with a procoagulant phenotype, which indicates worse prognosis, might benefit from therapies that target the clotting pathway, hence referring to a clinical trial presented on an earlier session⁷.

A broad investigative approach was presented by Ünlü et al.⁸: the group used Next Generation Sequencing to analyse RNA profile of tumor cells microdissected from CRC tumors in patients without VTE or with VTE events occurring before or after CRC diagnosis. Although based on a small number of patients, this original approach led to identify of a panel of differently expressed genes that might discriminate between cancer patients with low and high risk of VTE. The authors plan to analyze a larger cohort of patients to investigate whether these markers are indeed predictive of thrombosis,  and may be useful to select high-risk CRC patients for thromboprophylaxis.

 

References

1. Madkhali Y, Maraveyas A, Greenman J, Ettelaiea C. Cancer cell-derived microvesicles induce endothelial cell apoptosis mediated through tissue factor, factor VII and PAR2 activation. Thromb Res 2018, 164:S227. doi:10.1016/j.thromres.2018.02.102
2. Hell L, Ay C, Däullary Y, Mauracher LM, Grilza E, Hösel B, Schmid J ,Pabingera I, Thalera J. Extracellular vesicle-associated tissue factor activity is increased in prostate cancer patients with disseminated intravascular coagulation and induced by cellular interactions in vitro. Thromb Res 2018, 164:S230.
3. Elaskalani O, Razak NA, Metharom P. Extracellular DNA and histones are dispensable for neutrophil extracellular trap-induced aggregation of human washed platelets. Thromb Res 2018, 164:S229. doi:10.1016/j.thromres.2018.02.106.
4. Tikhomirova I, Malysheva Y, N. Kislovì N, Ryabov M, Muravyov A. Blood rheology and blood clotting in cancer. Thromb Res 2018, 164:S228. doi:10.1016/j.thromres.2018.02.104.
5. Abubaker AA, Vara D, Canobbio I, Pula G. A novel flow cytometry assay using ihydroethidium as redox-sensitive probe reveals NADPH oxidase-dependent generation of superoxide anion in human platelets.
6. Shaker H, Heah JYE, Castle J, Pritchard S, Albadry H,Nicholson S, Lumsdenb LJ, Kirwan CC. Extrinsic pathway markers predict survival in Early Breast Cancer. Thromb Res 2018, 164:S227-28. doi:10.1016/j.thromres.2018.02.103.
7. Castle J ,Harvey JR, Clarke R, Holcombe C, Volleamere A, Bramley M, Kokan J, Bundred NJ, Kirwan CC. Update for: Thrombin Inhibition Preoperatively (TIP) in Early Breast Cancer, the first clinical trial of DOACs as an anti-cancer agent. Thromb Res 2018, 164:S224-25.
8. Ünlüa B, van Es N, Arindrarto W, Kiełbasa SM, Mei H, J. Westerga J, Middeldorp S, Kuppen PJK, Otten JMMB, Cannegieter SG, Versteeg HH. Genes associated with venous thromboembolism in colorectal cancer patients. Thromb Res 2018, 164:S228-29.