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Chronic platelet activation is related to worse outcome in cancer patients, and activated platelets have been proposed to enhance angiogenesis, to trigger proliferation, to inhibit apoptosis, to promote tumor cell arrest in the circulation, and to guard tumors from immune elimination. While results from prospective studies on the role of platelets and cancer risk are missing, both randomised trials and cohort studies have shown lower risk of cancer, particularly colorectal, but also breast and prostate cancer, in users of low-dose aspirin. Given that the main effect of low-dose aspirin is platelet inhibition, which may in turn prevent platelet-mediated COX-2 induction in stromal and epithelial cells, and thus lead to apoptosis and reduced proliferation, platelets may play an important role in early tumorigenesis as well.
We hypothesise that chronic platelet activation – a phenomenon driven by an “unhealthy” lifestyle, ie. a diet high in saturated fats and low in fibre, unsaturated fats and antioxidants, metabolic syndrome, inactivity, and smoking – not only increases the risk of cardiovascular disease, but also the risk of cancer. Our main objective is to evaluate the relationships between pre-diagnostic biomarkers of platelet activation (Thrombopoeitin, Thrombomodulin, Selectin P, and Fibrinogen) and cancer risk in the EPIC-Heidelberg study, a prospective cohort study, to clarify the role of platelets in cancer development. Moreover, we propose to assess the associations between platelet activation markers and dietary factors (on the levels of dietary patterns, food groups, and single constituents), metabolic syndrome, physical activity, smoking, and further background factors.
We will use a case-cohort study embedded in the EPIC-Heidelberg cohort including incident cases of colorectal (n=350), breast (n=500), and prostate cancer (n=550) as well as a random sub-cohort (n=2500). Biomarkers of thrombocytosis and platelet activation will be measured in pre-diagnostic blood samples. Cross-sectional associations between these biomarkers and dietary and lifestyle factors will be assessed and the relationships between biomarker levels and cancer risk will be evaluated. A wide range of potential confounders such as obesity, hypertension, hyperlipidemia, activity, medication use or markers of inflammation will be accounted for. Subgroup analyses by strata of potential confounders, e.g. BMI or smoking status will be conducted. The reproducibility of biomarker levels over time was tested using repeat blood samples, which were available for a subset of participants.
We propose the first comprehensive prospective study on chronic platelet activation as assessed in initially healthy subjects and subsequent cancer risk. Considering that platelets may not only be amenable to chemoprevention, but also to dietary and lifestyle interventions, we believe that the planned study is of special relevance in the context of the World Cancer Research Fund International's mission. The study may help to improve the understanding of the link between diet, lifestyle and cancer risk, and facilitate the identification of a promising target for primary prevention.
Platelets are blood cells with the function to prevent bleeding. They attach to each other and form an aggregate in order to plug damaged vessels. High blood pressure and/or blood lipids are conditions that lead to vessel damage and a constantly high activation of platelets. This overactivation can cause a blockage of vessels, which then leads to complications such as heart attack or strokes. The use of low-dose aspirin protects against such cardiovascular diseases, as aspirin inhibits platelet activation, thus preventing from blood clotting. Interestingly, it has recently been shown that aspirin also protects against cancer, especially colorectal cancer, probably because the aggregation of platelets that also seems to facilitate tumor growth is stopped by aspirin. This observation strongly points to platelet overactivation as a major shared risk factor for both cancer and cardiovascular diseases. Dietary and lifestyle factors, particularly a plant-based diet rich in antioxidants, regular physical activity, non-smoking, and weight maintenance, have been shown to reduce chronic platelet activation. Therefore, it occurs plausible that anti-platelet effects related to these lifestyle factors may decrease cancer risk, similarly as low-dose aspirin does.
The proposed study is set up to find out whether blood parameters of platelet activation, which were measured years before cancer occurrence, are associated with the risks of the most common cancer types – breast, prostate, and colorectal cancer – over time. Further, it will be investigated if dietary factors, physical activity, obesity, alcohol consumption, and smoking are related to platelet activation. The overall goal of the study is to answer the question whether platelet activation is an important link between diet, lifestyle and cancer development.
The research questions of the proposed project will be addressed by means of a prospective cohort study, the EPIC-Heidelberg study. For this study, 25 000 initially healthy adults from the general population in Heidelberg, Germany, were recruited between 1994 and 1998. At the baseline of the study, detailed information on habitual diet, lifestyle, health status, medication use, and socio-economic background was obtained by questionnaires and interviews, and a blood sample was taken. All participants attended the study follow-up during which the occurrence of new cancer diagnoses was monitored until the end of 2009. Within the planned project, blood parameters of platelet activation from baseline will be assessed in relation to diet and lifestyle as well as cancer risk throughout the course of the study.
The proposed study will be the first comprehensive prospective study on chronic platelet activation in initially healthy subjects and subsequent cancer risk. Moreover, the study provides the unique opportunity to evaluate the putative platelet cancer connection accounting for the role of a wide range of dietary and lifestyle factors. It is thus expected that the project will significantly contribute to the understanding of the link between diet, nutrition, and lifestyle and cancer risk. If associations between certain dietary and lifestyle factors and platelet activation on the one hand, and a relationship between platelet activation and cancer risk on the other hand could be demonstrated, the planned study would be an important starting point for future primary prevention measures against cancer.