[en] Background: Clinical and experimental evidence support a role for inflammation in the development of colorectal cancer, though the mechanisms are not fully understood. Beyond thrombosis and hemostasis, platelets are key actors of inflammation; they also have been 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 their reactivity to thrombin were assessed at each stage of carcinogenesis. We conducted an unbiased proteomic analysis of releasates of platelets isolated at pre-tumoral 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 pre-tumoral stage, hyperactive platelets were a major source of circulating pro-tumoral serum amyloid A (SAA) proteins. Clopidogrel prevented the early elevation of plasma SAA, 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 in tumors, while tissue CD8 T cells were augmented. Platelets or releasates of platelets from cancer mice both were able to polarize myeloid cells toward an immunosuppressive phenotype.
Conclusions: Thus, platelets promote initiation of colitis-associated cancer by enhancing myeloid cell dependent immunosuppression. Antiplatelet agents may help prevent inflammation-elicited carcinogenesis by restoring antitumor immunity.
Disciplines :
Oncology
Author, co-author :
Servais, Laurence ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : GIGA - Cardiovascular Sciences
Wéra, Odile ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : GIGA - Cardiovascular Sciences
Dibato Epoh, John; Université de Liège - ULiège > Département Sciences Biomédicales et Précliniques > GIGA-Sciences Cardiovasculaires
Delierneux, Céline; Pennsylvania State University College of Medicine > Department of Cellular and Molecular Physiology
Bouznad, Nassim; Ludwig-Maximilians-University Munich > Institute of Pathology
Rahmouni, Souad ; Université de Liège - ULiège > Département des sciences cliniques > GIGA-R:Immunopath. - Maladies infect. et médec. inter. gén.
Mazzucchelli, Gabriel ; Université de Liège - ULiège > Département de chimie (sciences) > Laboratoire de spectrométrie de masse (L.S.M.)
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