Acknowledgement
This study was supported by the National Natural Science Foundation of China (NSFC 81902995 and NSFC 81673498) and the Science and Technology Commission of Shanghai Municipality (STCSM 16431904600) and the Project funded by China Postdoctoral Science Foundation (2018M641936).
The authors would like to thank the Duoease Scientific Service Center for excellent language editing service and suggestions for figure revision.
Conflict of Interest Disclosures
None of the authors has a relevant conflict of interest.
Contributions
ZB, WM, and ZY performed all of the experiments; WT, YJ, MY, WQ, CD, LT and LY participated in the research; ZB and MW designed experiments, analyzed data, and wrote the paper; YM is the supervisor of ZB; HZ and WH collected the clinical samples. All authors read and approved the final manuscript.
References
Battinelli EM, Markens BA, Kulenthirarajan RA, Machlus KR, Flaumenhaft R, & Italiano JE (2014). Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response. Blood 123: 101-112.
Black PC, Mize GJ, Karlin P, Greenberg DL, Hawley SJ, True LD, et al. (2007). Overexpression of protease-activated receptors-1,-2, and-4 (PAR-1, -2, and -4) in prostate cancer. Prostate 67: 743-756.
Boire A, Covic L, Agarwal A, Jacques S, Sherifl S, & Kuliopulos A (2005). PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120:303-313.
Caine GJ, Stonelake PS, Lip GYH, & Kehoe ST (2002). The hypercoagulable state of malignancy: Pathogenesis and current debate. Neoplasia 4: 465-473.
Chen J, Ma Y, Wang Z, Wang H, Wang L, Xiao F, et al. (2014). Thrombin promotes fibronectin secretion by bone marrow mesenchymal stem cells via the protease-activated receptor mediated signalling pathways. Stem Cell Res Ther 5: 36.
Feistritzer C, & Riewald M (2005). Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 105: 3178-3184.
Grisaru-Granovsky S, Salah Z, Maoz M, Pruss D, Beller U, & Bar-Shavit R (2005). Differential expression of protease activated receptor 1 (Par1) and pY397FAK in benign and malignant human ovarian tissue samples. Int J Cancer 113: 372-378.
Horowitz NA, Blevins EA, Miller WM, Perry AR, Talmage KE, Mullins ES, et al. (2011). Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain. Blood 118: 2889-2895.
Huang QF, Zhang Z, Liao YD, Liu CY, Fan S, Wei X, et al. (2018). 17 beta-estradiol upregulates IL6 expression through the ER beta pathway to promote lung adenocarcinoma progression. J Exp Clin Canc Res 37.
Icli F, Akbulut H, Utkan G, Yalcin B, Dincol D, Isikdogan A, et al. (2007). Low molecular weight heparin (LMWH) increases the efficacy of cisplatinum plus gemcitabine combination in advanced pancreatic cancer. J Surg Oncol 95: 507-512.
Jeffers A, Owens S, Koenig K, Quaid B, Pendurthi UR, Rao VM, et al. (2015). Thrombin down-regulates tissue factor pathway inhibitor expression in a PI3K/nuclear factor-kappaB-dependent manner in human pleural mesothelial cells. Am J Respir Cell Mol Biol 52:674-682.
Joseph S. Palumbo KWK, Angela F. Drew, Timothy S. Grimes, John H. Kiser, Jay L. Degen, and Thomas H. Bugge (2000). Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood 96: 3302-3309.
Klepfish A, Greco MA, & Karpatkin S (1993). Thrombin stimulates melanoma tumor-cell binding to endothelial cells and subendothelial matrix. Int J Cancer 53: 978-982.
Kyu HH, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, et al.(2018). Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392: 1859-1922.
Lane DA, Philippou H, & Huntington JA (2005). Directing thrombin. Blood 106: 2605-2612.
Lyu YQ, Xiao QQ, Yin LF, Yang L, & He W (2019). Potent delivery of an MMP inhibitor to the tumor microenvironment with thermosensitive liposomes for the suppression of metastasis and angiogenesis. Signal Transduction and Targeted Therapy 4.
Mammadova-Bach E, Gil-Pulido J, Sarukhanyan E, Burkard P, Shityakov S, Schonhart C, et al. (2020). Platelet glycoprotein VI promotes metastasis through interaction with cancer cell-derived galectin-3. Blood 135: 1146-1160.
McLaughlin JN, Shen L, Holinstat M, Brooks JD, Dibenedetto E, & Hamm HE (2005). Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1. J Biol Chem 280: 25048-25059.
Mlak R, Krawczyk P, Ciesielka M, Koziol P, Homa I, Powrozek T, et al. (2016). The relationship between RRM1 gene polymorphisms and effectiveness of gemcitabine-based first-line chemotherapy in advanced NSCLC patient. Clin Transl Oncol 18: 915-924.
Mo W, Zhang YL, Chen HS, Wang LS, & Song HY (2009). A novel hirudin derivative characterized with anti-platelet aggregations and thrombin inhibition. J Thromb Thrombolysis 28: 230-237.
Morabito A, Carillio G, Daniele G, Piccirillo MC, Montanino A, Costanzo R, et al. (2014). Treatment of small cell lung cancer. Crit Rev Oncol Hematol 91: 257-270.
Nierodzik ML, Chen K, Takeshita K, Li JJ, Huang YQ, Feng XS, et al. (1998). Protease-activated receptor 1 (PAR-1) is required and rate-limiting for thrombin-enhanced experimental pulmonary metastasis. Blood 92: 3694-3700.
Nierodzik ML, Kajumo F, & Karpatkin S (1992). Effect of thrombin treatment of tumor cells on adhesion of tumor cells to platelets in vitro and tumor metastasis in vivo. Cancer Res 52: 3267-3272.
Pelayo Alvarez M, Westeel V, Cortes-Jofre M, & Bonfill Cosp X (2013). Chemotherapy versus best supportive care for extensive small cell lung cancer. Cochrane Database Syst Rev: CD001990.
Plantureux L, Crescence L, Dignat-George F, Panicot-Dubois L, & Dubois C (2018). Effects of platelets on cancer progression. Thrombosis Research 164: S40-S47.
Queiroz KCS, Shi K, Duitman J, Aberson HL, Wilmink JW, van Noesel CJM, et al. (2014). Protease-activated receptor-1 drives pancreatic cancer progression and chemoresistance. International Journal of Cancer 135: 2294-2304.
Reddel CJ, Allen JD, Ehteda A, Taylor R, Chen VM, Curnow JL, et al. (2017). Increased thrombin generation in a mouse model of cancer cachexia is partially interleukin-6 dependent. J Thromb Haemost 15: 477-486.
Rickles FR, Edwards RL, Barb C, & Cronlund M (1983). Abnormalities of blood coagulation in patients with cancer. Fibrinopeptide A generation and tumor growth. Cancer 51: 301-307.
Sjoberg E, Meyrath M, Milde L, Herrera M, Lovrot J, Hagerstrand D, et al. (2019). A Novel ACKR2-Dependent Role of Fibroblast-Derived CXCL14 in Epithelial-to-Mesenchymal Transition and Metastasis of Breast Cancer. Clinical Cancer Research 25: 3702-3717.
Soff G (2019). Thrombosis and Hemostasis in Cancer. Scope of the Problem and Overview. Cancer Treat Res 179: 1-9.
Tan LY, Sun Y, Zhu LL, Lei X, Liang DY, Rao NY, et al. (2019). Risk factors of catheter-related thrombosis in early-stage breast cancer patients: a single-center retrospective study. Cancer Manag Res 11: 8379-8389.
Vu TK, Hung DT, Wheaton VI, & Coughlin SR (1991). Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64: 1057-1068.
Vuong L, Kouverianou E, Rooney CM, McHugh BJ, Howie SEM, Gregory CD, et al. (2019). An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade. Cancer Research 79: 1480-1492.
Vyse S, & Huang PH (2019). Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Signal Transduct Target Ther 4:5.
Wang Z, Cai XJ, Chen LY, Cheng B, Shi L, Lei L, et al. (2018). Factors potentially associated with gemcitabine-based chemotherapy-induced thrombocytopenia in Chinese patients with nonsmall cell lung cancer. J Cancer Res Ther 14: S656-S660.
Xue YH, Zhang XF, Dong QZ, Sun JA, Dai C, Zhou HJ, et al. (2010). Thrombin is a Therapeutic Target for Metastatic Osteopontin-Positive Hepatocellular Carcinoma. Hepatology 52: 2012-2022.
Yokota N, Zarpellon A, Chakrabarty S, Bogdanov VY, Gruber A, Castellino FJ, et al. (2014). Contributions of thrombin targets to tissue factor-dependent metastasis in hyperthrombotic mice. J Thromb Haemost 12: 71-81.
Yokoyama Y, Mori S, & Matsuura N (2008). Effect of Platelet Derived Growth Factor on Development and Progression of Breast Cancer. Tumor Biol 29: 77-77.
Yuan M, Huang L-L, Chen J-H, Wu J, & Xu Q (2019). The emerging treatment landscape of targeted therapy in non-small-cell lung cancer. Signal Transduction and Targeted Therapy 4.
Zaborowska-Szmit M, Krzakowski M, Kowalski DM, & Szmit S (2020). Cardiovascular Complications of Systemic Therapy in Non-Small-Cell Lung Cancer. J Clin Med 9.
Zhao B, Zhang Y, Huang Y, Yu J, Li Y, Wang Q, et al. (2017). A novel hirudin derivative inhibiting thrombin without bleeding for subcutaneous injection. Thromb Haemost 117: 44-56.