Accelerated endoplasmic reticulum and coagulation factor processing in platelets are linked with the hypercoagulable state of patients with lung cancer

Abstract Background The risk of venous thromboembolism in cancer is nine times higher than in the general population and the second leading cause of death in these patients. Platelets play a key role in tumour growth, metastasis, and cancer-associated thrombosis. Despite this widely observed functional role of platelets in the prothrombotic state of certain cancers, the underlying molecular mechanisms are largely unknown. Methods In order to comprehensively expose cancer-related biochemical changes, we compared the platelet proteome of two types of cancer with a high risk of thrombosis (22 patients with brain cancer, 19 with lung cancer) to 41 matched healthy controls using unbiased two-dimensional differential in-gel electrophoresis. Cancer-related platelet proteins were statistically characterised by adjusted one-way ANOVA and planned comparisons post hoc tests. Significantly changed platelet proteins were identified by mass spectrometry. Afterward, selected cancer-associated platelet proteins were validated by 1-D and 2-D Western blots and/or functional assessments were made by association analysis with central haemostatic plasma parameters. Results The examined platelet proteome was unchanged in patients with brain cancer, but considerably affected in lung cancer with 15 significantly altered proteins. Amongst these, the endoplasmic reticulum (ER) proteins CALR, HSPA5 and P4HB were significantly elevated. Accelerated conversion of the fibrin stabilising factor has been detected in platelets of patients with lung cancer by elevated levels of a F13A1 55 kDa fragment. A significant correlation of this F13A1 cleavage product with plasma D-dimer levels suggests an enhanced degradation in platelets by the fibrinolytic system. Functional protein association network analysis showed that lung cancer-related protein profiles were involved in platelet degranulation and upregulated ER protein processing. The latter is important in the glycosylation of coagulation factors. As a possible outcome, plasma FVIII, an immediate end product for ER-mediated glycosylation, correlated significantly with the ER-executing chaperones CALR and HSPA5. In addition, several lung cancer-related platelet proteins such as decreased levels of ITGA2B are significantly linked to the plasmatic haemostasis factors D-dimer and fibrinogen. Conclusions These new data on the differential behaviour of platelets in various cancers revealed F13A1 and ER chaperones as potential novel diagnostic and therapeutic targets in lung cancer patients.