Scientific abstract
Background
Obesity, known to be associated with a pro-inflammatory, pro-thrombotic humoral milieu, confers a worse prognosis in prostate cancer (PrCa). Circulating tumour cells (CTCs) are identified in the blood in advanced cancer. Their quantitation provides prognostic information. “Cloaking” of CTCs by adherent platelets impedes NK-cell clearance of CTCs from the circulation, enhancing metastatic spread. NK-cell function in blood and in solid organs is quantitatively and qualitatively reduced in obesity. Platelet cloaking may be enhanced in obesity due to the pro-inflammatory, pro-thrombotic state, and may be a mechanism for worse cancer-specific outcomes in this group.
Obesity and its biochemical effects may be influenced by lifestyle changes such as exercise. Physical activity reduces levels of systemic inflammatory mediators and so a walking exercise intervention may represent an accessible and cost-effective means of ameliorating the pro-inflammatory effects of obesity.
Objectives
To determine whether:
- Platelet cloaking of PrCa CTCs is more prominent in men with obesity than without.
- Regular exercise can improve quality of life (QoL) and ameliorate platelet cloaking.
- The degree of platelet cloaking varies with levels of systemic and primary tumour inflammation and coagulability.
- Expression of an obesity-associated lethality gene signature leads to variation in platelet cloaking.
Setting and methods
This international multicentre prospective study will recruit 200 men with metastatic PrCa, dividing them into exposed and non-exposed groups based on BMI >25. Participants will be recruited from centres in Dublin (Ireland), Orebro (Sweden) and London (UK), and will be randomized to intervention and comparison groups. Blood samples will be taken at recruitment (T0) and at three (T3) and six months (T6).
Project 1: CTCs will be enumerated in the T0 samples. Adherent platelets will be quantified and compared between the exposed and non-exposed groups, and correlated with clinicopathological parameters.
Project 2: The intervention group will undertake a regular supervised group walking programme, whereas the comparison group will not. T3 and T6 blood samples will be assessed for CTC numbers and platelet cloaking. Changes will be compared with the T0 sample and between exposed and non-exposed and intervention and comparison groups. Participants will complete a detailed questionnaire to assess QoL at each visit.
Project 3: All blood samples will be assessed for NK-cell number and activation, markers of systemic inflammation, adipokines and serum factors related to platelet activation. The prostate needle core biopsies will be examined microscopically for atrophy and inflammation, by morphology and immunohistochemistry, with particular reference to NK-cells. All variables will be correlated with platelet cloaking.
Project 4: NCBs will be assessed for expression of an obesity-associated lethality gene signature (whose genes are known to play a role in obesity or platelet aggregation and coagulation), and correlated with platelet cloaking.
Impact
This study aims to elucidate a potential mechanism by which obesity confers a worse prognosis in PrCa, two increasingly prevalent diseases in the western world. We hope to show that a low-cost, accessible intervention can improve QoL and potentially ameliorate the effects of obesity through alterations in the systemic adipokine and inflammatory mediator profile.
Plain language abstract
Background
Obesity is an increasing public health problem. It is known that men who have prostate cancer are more likely to die of their disease if they are overweight or obese than if they are of a healthy weight. In men with advanced cancer, individual cancer cells spread beyond the prostate gland and can be found floating in the blood (“circulating tumour cells”, CTCs). Tiny blood particles (platelets) become stuck to these CTCs (“platelet cloaking”) and may prevent the body’s immune system from hunting down and killing the cancer cells before they can spread around the body. There is a greater tendency for blood to clot (due to stickier platelets) in obesity. This suggests that there may be more platelet cloaking of CTCs in overweight men with prostate cancer, which in turn makes the cancer more aggressive. Exercise can reduce the stickiness of platelets and may therefore be useful in making prostate cancer less aggressive in overweight men.
Aims and goals
To determine whether, in prostate cancer:
- There is more platelet cloaking of CTCs in men who are overweight compared to men who are not.
- Regular exercise can improve quality of life and reduce platelet cloaking of CTCs.
- Platelet cloaking varies relative to measurements of how easily the blood clots.
- There are specific genes which make platelet cloaking worse.
How it will be done
We will recruit 200 men with advanced prostate cancer from three European cities and measure their weight and height to determine whether they are overweight or not. Blood samples will be taken at recruitment (T0) and three (T3) and six (T6) months later. At each visit, men will complete a questionnaire asking them about their physical and emotional health, and how their disease is affecting them. In addition, men will be randomly assigned to take part (or not to take part) in an organised exercise programme for six months.
We will count the CTCs and measure platelet cloaking in all blood samples. This will enable us to compare CTC numbers and platelet cloaking between men who are overweight and those who are not; between men who took part in the exercise programme and men who did not; and to determine whether the exercise programme leads to changes in CTC numbers and platelet cloaking.
We will also measure a number of substances in the blood samples which will tell us about the reasons why obesity affects platelet cloaking, and we will test the participants’ tissue biopsies for several genes which we think may explain the link.
Potential impact
This study aims to investigate why obesity makes prostate cancer more aggressive. This is important because both obesity and prostate cancer are becoming a lot more common, and the relationship between the two in an individual patient is becoming more important. We hope to show that a simple exercise programme can improve quality of life for advanced prostate cancer patients, and hopefully reduce the bad effects of being overweight on cancer outlook for these men.
