L Servais1, O Wéra1, J Dibato Epoh1, C Delierneux1, N Bouznad1, S Rahmouni2, G Mazzucchelli3, D Baiwir3, P Delvenne4, P Lancellotti1,5, C Oury1. 1. Laboratory of Thrombosis and Hemostasis and Valvular Heart Disease, GIGA-Cardiovascular Sciences, Department of Cardiology, University of Liège, CHU Sart-Tilman, Liège, Belgium. 2. Immunology and Infectious Diseases Unit, GIGA-R, University of Liège, Liège, Belgium. 3. Laboratory of Mass Spectrometry, Chemistry Department, GIGA-R, CART, University of Liège, Liège, Belgium. 4. Department of Pathology, Laboratory of Experimental Pathology, University of Liège, Liège, Belgium. 5. Gruppo Villa Maria Care and Reseach, Anthea Hospital, Bari, Italy.
Abstract
Essentials Inflammation plays a key role in the development of colorectal cancer. Understanding mechanisms of cancer initiation might reveal new anticancer preventive strategy. Hyperactive platelets promote tumor formation by fostering immune evasion of cancer. Platelet inhibition by clopidogrel prevents carcinogenesis by restoring antitumor immunity. SUMMARY: Background Clinical and experimental evidence support a role for inflammation in the development of colorectal cancer, although the mechanisms are not fully understood. Beyond thrombosis and hemostasis, platelets are key actors in inflammation; they have also been shown to be involved in cancer. However, whether platelets participate in the link between inflammation and cancer is unknown. Objective To investigate the contribution of platelets and platelet-derived proteins to inflammation-elicited colorectal tumor development. Methods We used a clinically relevant mouse model of colitis-associated cancer. Platelet secretion and platelet reactivity to thrombin were assessed at each stage of carcinogenesis. We conducted an unbiased proteomic analysis of releasates of platelets isolated at the pretumoral stage to identify soluble factors that might act on tumor development. Plasma levels of the identified proteins were measured during the course of carcinogenesis. We then treated the mice with clopidogrel to efficiently inhibit platelet release reaction. Results At the pretumoral stage, hyperactive platelets constituted a major source of circulating protumoral serum amyloid A (SAA) proteins. Clopidogrel prevented the early elevation of the plasma SAA protein level, decreased colitis severity, and delayed the formation of dysplastic lesions and adenocarcinoma. Platelet inhibition hindered the expansion and function of immunosuppressive myeloid cells, as well as their infiltration into tumors, but increased the number of tissue CD8+ T cells. Platelets and releasates of platelets from mice with cancer were both able to polarize myeloid cells towards an immunosuppressive phenotype. Conclusions Thus, platelets promote the initiation of colitis-associated cancer by enhancing myeloid cell-dependent immunosuppression. Antiplatelet agents may help to prevent inflammation-elicited carcinogenesis by restoring antitumor immunity.
Essentials Inflammation plays a key role in the development of colorectal cancer. Understanding mechanisms of cancer initiation might reveal new anticancer preventive strategy. Hyperactive platelets promote tumor formation by fostering immune evasion of cancer. Platelet inhibition by clopidogrel prevents carcinogenesis by restoring antitumor immunity. SUMMARY: Background Clinical and experimental evidence support a role for inflammation in the development of colorectal cancer, although the mechanisms are not fully understood. Beyond thrombosis and hemostasis, platelets are key actors in inflammation; they have also been shown to be involved in cancer. However, whether platelets participate in the link between inflammation and cancer is unknown. Objective To investigate the contribution of platelets and platelet-derived proteins to inflammation-elicited colorectal tumor development. Methods We used a clinically relevant mouse model of colitis-associated cancer. Platelet secretion and platelet reactivity to thrombin were assessed at each stage of carcinogenesis. We conducted an unbiased proteomic analysis of releasates of platelets isolated at the pretumoral stage to identify soluble factors that might act on tumor development. Plasma levels of the identified proteins were measured during the course of carcinogenesis. We then treated the mice with clopidogrel to efficiently inhibit platelet release reaction. Results At the pretumoral stage, hyperactive platelets constituted a major source of circulating protumoral serum amyloid A (SAA) proteins. Clopidogrel prevented the early elevation of the plasma SAA protein level, decreased colitis severity, and delayed the formation of dysplastic lesions and adenocarcinoma. Platelet inhibition hindered the expansion and function of immunosuppressive myeloid cells, as well as their infiltration into tumors, but increased the number of tissue CD8+ T cells. Platelets and releasates of platelets from mice with cancer were both able to polarize myeloid cells towards an immunosuppressive phenotype. Conclusions Thus, platelets promote the initiation of colitis-associated cancer by enhancing myeloid cell-dependent immunosuppression. Antiplatelet agents may help to prevent inflammation-elicited carcinogenesis by restoring antitumor immunity.
Authors: Dipak Panigrahy; Allison Gartung; Jun Yang; Haixia Yang; Molly M Gilligan; Megan L Sulciner; Swati S Bhasin; Diane R Bielenberg; Jaimie Chang; Birgitta A Schmidt; Julia Piwowarski; Anna Fishbein; Dulce Soler-Ferran; Matthew A Sparks; Steven J Staffa; Vidula Sukhatme; Bruce D Hammock; Mark W Kieran; Sui Huang; Manoj Bhasin; Charles N Serhan; Vikas P Sukhatme Journal: J Clin Invest Date: 2019-06-17 Impact factor: 14.808
Authors: Wen-Yi Yang; Benedetta Izzi; Adam P Bress; Lutgarde Thijs; Lorena Citterio; Fang-Fei Wei; Erika Salvi; Simona Delli Carpini; Paolo Manunta; Daniele Cusi; Marc F Hoylaerts; Aernout Luttun; Peter Verhamme; Sheetal Hardikar; Tim S Nawrot; Jan A Staessen; Zhen-Yu Zhang Journal: PLoS One Date: 2022-04-07 Impact factor: 3.240