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Article

Alterations of the Platelet Proteome in Lung Cancer: Accelerated F13A1 and ER Processing as New Actors in Hypercoagulability

1
Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria
2
Centre for Physiology and Pharmacology, Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, 1090 Vienna, Austria
3
Department of Anaesthesiology and Intensive Care, Danube Hospital, 1220 Vienna, Austria
4
Centre for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, 1090 Vienna, Austria
5
I. M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
*
Authors to whom correspondence should be addressed.
Academic Editor: Florian Langer
Cancers 2021, 13(9), 2260; https://doi.org/10.3390/cancers13092260
Received: 26 April 2021 / Accepted: 5 May 2021 / Published: 8 May 2021
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. Tissue factor and downstream plasmatic coagulation cascade are largely responsible for the risk of thrombosis in cancer. In recent years, it has been increasingly recognised that platelets also play a central role in tumour growth and cancer-associated thrombosis. The underlying molecular mechanisms are largely unknown. In order to comprehensively investigate the biochemical changes in platelets from cancers with high risk of thrombosis, we examined the platelet proteome of brain and lung cancer patients in comparison to sex and age-matched healthy controls. However, we only found alterations in lung cancer, where some of these platelet proteins directly promote thrombosis. One example is the increased amount of the enzyme protein disulfide isomerase, which is clinically investigated as an antithrombotic drug target of the plant-based flavonol quercetin.
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. 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 calreticulin (CALR), endoplasmic reticulum chaperone BiP (HSPA5) and protein disulfide-isomerase (P4HB) were significantly elevated. Accelerated conversion of the fibrin stabilising factor XIII was detected in platelets of patients with lung cancer by elevated levels of a coagulation factor XIII (F13A1) 55 kDa fragment. A significant correlation of this F13A1 cleavage product with plasma levels of the plasmin–α-2-antiplasmin complex and D-dimer suggests its enhanced degradation by the fibrinolytic system. Protein association network analysis showed that lung cancer-related proteins were involved in platelet degranulation and upregulated ER protein processing. As a possible outcome, plasma FVIII, an immediate end product for ER-mediated glycosylation, correlated significantly with the ER-executing chaperones CALR and HSPA5. 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. View Full-Text
Keywords: cancer; lung cancer; thrombosis; platelets; proteomics; coagulation factor XIII; unfolded protein response; protein disulfide-isomerase; endoplasmic reticulum chaperones; therapeutic target cancer; lung cancer; thrombosis; platelets; proteomics; coagulation factor XIII; unfolded protein response; protein disulfide-isomerase; endoplasmic reticulum chaperones; therapeutic target
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MDPI and ACS Style

Ercan, H.; Mauracher, L.-M.; Grilz, E.; Hell, L.; Hellinger, R.; Schmid, J.A.; Moik, F.; Ay, C.; Pabinger, I.; Zellner, M. Alterations of the Platelet Proteome in Lung Cancer: Accelerated F13A1 and ER Processing as New Actors in Hypercoagulability. Cancers 2021, 13, 2260. https://doi.org/10.3390/cancers13092260

AMA Style

Ercan H, Mauracher L-M, Grilz E, Hell L, Hellinger R, Schmid JA, Moik F, Ay C, Pabinger I, Zellner M. Alterations of the Platelet Proteome in Lung Cancer: Accelerated F13A1 and ER Processing as New Actors in Hypercoagulability. Cancers. 2021; 13(9):2260. https://doi.org/10.3390/cancers13092260

Chicago/Turabian Style

Ercan, Huriye, Lisa-Marie Mauracher, Ella Grilz, Lena Hell, Roland Hellinger, Johannes A. Schmid, Florian Moik, Cihan Ay, Ingrid Pabinger, and Maria Zellner. 2021. "Alterations of the Platelet Proteome in Lung Cancer: Accelerated F13A1 and ER Processing as New Actors in Hypercoagulability" Cancers 13, no. 9: 2260. https://doi.org/10.3390/cancers13092260

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