The potential role of platelets in the consensus molecular subtypes of colorectal cancer

The consensus molecular subtypes (CMS) in colorectal cancer (CRC) represent distinct molecular subcategories of disease as reflected by comprehensive molecular profiling. The four CMS subtypes represent unique biology. CMS1 represents high immune infiltration. CMS2 demonstrates upregulation of canonical pathways such as WNT signaling. Widespread metabolic changes are seen in CMS3. CMS4 represents a mesenchymal phenotype with hallmark features including complement activation, matrix remodeling, angiogenesis, epithelial-mesechymal transition (EMT), integrin upregulation and stromal infiltration. In contrast to this new paradigm, a number of observations regarding CRC remain disconnected. Cancers are associated with thrombocytosis. Venous thromboembolic events are more likely in malignancy and may signify worse prognosis. Aspirin, an anti-platelet agent, has been linked in large observational studies to decrease incidence of adenocarcinoma and less advanced presentations of cancer, in particular CRC. Inflammatory bowel disease is a risk factor for CRC. Gross markers to recognize the immunothrombotic link such as the platelet to lymphocyte ratio are associated with poorer outcomes in many cancers. Platelets are increasingly recognized for their dual roles in coordinating the immune response in addition to hemostasis. Here, we explore how these different but related observations coalesce. Platelets, as first responders to pathogens and injury, form the link between hemostasis and immunity. We outline how platelets contribute to tumorigenesis and how some disconnected ideas may be linked through inflammation. CMS4 through its shared mechanisms has predicted platelet activation as a hallmark feature. We demonstrate a platelet gene expression signature that predicts platelet presence within CMS4 tumors.