Platelets contribute to the initiation of colitis‐associated cancer by promoting immunosuppression

Abstract

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.

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases

“…TXA 2 synthesis is independent of COX-2 (90), which is consistent with our finding that the antitumor activity of preoperative ketorolac is mediated by COX-1/TXA 2 inhibition. In addition, 20% of mice treated preoperatively with the antiplatelet agent clopidogrel demonstrated long-term survival in our tumor-resection model, consistent with reports showing that clopidogrel prevents carcinogenesis by restoring antitumor immunity, including increasing the number of tissue CD8 + T cells (91). Clopidogrel also stimulates CD4 + and CD25 + T cells in an atherosclerosis model (92).…”

Platelets couple inflammation to tumorigenesis, a bridge too far

“…Servais et al . reveal that local thrombin generation in inflamed colonic mucosa not only supports key proinflammatory events that drive adenoma outgrowth, but also supports platelet‐mediated events that help to create the immunosuppressive microenvironment necessary for tumor growth . Together, these findings highlight the fundamental importance of the hemostatic system in early events that drive tumorigenesis.…”

“…In their article, Servais et al . push the field forward by illustrating that platelets represent a crucial link between inflammatory disease and tumorigenesis . This interesting article presents data showing that platelets promote intestinal tumorigenesis in the context of inflammatory colitis by supporting the recruitment and/or expansion of myeloid‐derived suppressor cells (MDSCs).…”

“…The finding that platelets support the recruitment/expansion of these cells indicates a previously unrecognized role of platelets as modulators of an immunosuppressive phenotype that is important for early tumor development. The authors show that local platelet activation in the colitis microenvironment shifts myeloid cells to an immunosuppressive phenotype by promoting the expression of key regulators of myeloid cell function, including arginase‐1, transforming growth factor (TGF)‐β, and C/EBPβ . The authors suggest that one potential mechanism coupling platelets to the regulation of MDSC functions is the release of serum amyloid A (SAA) proteins.…”

Do Aspirin and Clopidogrel Follow the Same Road Toward Prevention of Colorectal Cancer?

“…17,18 Collectively, the epidemiologic evidence is also supported by animal models that show that other non-aspirin antiaggregants, such as clopidogrel or ticagrelor, may inhibit colorectal carcinogenesis. 19,20 Implications and Future Perspectives Additional studies, ideally prospective cohort or even clinical trials, are needed to establish whether non-aspirin antiaggregants may also serve as chemopreventive agents for CRC and/or other cancers. If such studies show promise, it will be critical to determine whether their effect and safety profile are comparable or superior to that of low-dose aspirin and whether, like aspirin, specific patient subgroups could enjoy greater benefit and lower risk.…”