Characterisation of circulating tumour cells in men with advanced prostate cancer and correlation with numbers of circulating and tissue-based inflammatory cells
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HAYES, BRIAN DERMOT, Characterisation of circulating tumour cells in men with advanced prostate cancer and correlation with numbers of circulating and tissue-based inflammatory cells, Trinity College Dublin.School of Medicine, 2019Download Item:
Abstract:
Many men with prostate cancer present with advanced stage disease, and in these men treatment is directed towards improved survival and quality-of-life rather than cure. Exercise therapies are recognised to have benefits in quality-of-life, all-cause and cancer-specific mortality in cancer patients, and prostate cancer is no exception. Obesity and metabolic syndrome are encountered with increasing frequency in prostate cancer patients, either as pre-existing comorbidities or as a side-effect of androgen deprivation therapy. The systemic inflammatory milieu which underpins the obese state has profoundly negative effects on cancer survivorship, but new data show that control of obesity, including through managed exercise interventions, can improve outcomes.
Circulating tumour cells (CTCs) derived from the primary tumour are considered an intermediate step in the metastatic cascade and therefore a potentially useful target for therapy. Interventions (including exercise) targeted at improving the deleterious pro-oncogenic systemic consequences of obesity may in part exert their effects by interfering in interactions between platelets, CTCs and cells of the immune system. Adhesion of platelets to CTCs may impair the ability of NK-cells to destroy them. It has been hypothesised that enhanced platelet cloaking of CTCs in obese men with prostate cancer, due to increased systemic inflammation, is a mechanism underlying the worse prognosis of cancer in these patients.
The ExPeCT clinical trial recruited men with advanced prostate cancer and randomised them either to participation in a formal six-month supervised exercise programme (exercise group), or to usual care (control group). Blood samples were taken, quality-of-life questionnaires were completed and clinical data were gathered at the time of recruitment (T0) and after three (T3) and six (T6) months. Participants were divided into ?exposed? and ?non-exposed? groups based on baseline body mass index ≥ 25 kg/m2 or < 25kg/m2 respectively. Blood samples were passed through microporous ScreenCell Cyto filters, allowing isolation of CTCs on the basis of size, and examined by light microscopy using standard cytological techniques. CTCs were enumerated on each filter and the presence or absence of platelet cloaking was recorded. The participants? original diagnostic biopsy tissue blocks were stained with H&E and immunohistochemical antibodies for T-cells, NK-cells and macrophages, and examined histologically. In addition flow cytometry for numbers and subsets of circulating lymphocytes was undertaken in a subset of Dublin-based participants.
61 men were recruited over the course of the trial and had at least a T0 blood sample drawn, of whom 30 were randomized to the exercise group and 31 to the control group. There were 11 participants in the non-exposed group and 50 in the exposed group. CTCs were identified on the vast majority of ScreenCell filters, and there was a significant reduction in their numbers between T0 and T3, with the change driven by differences in the control group and the exposed group. Platelet cloaking was significantly more frequently seen in blood draws from the control group than the exercise group participants, which might suggest that the exercise intervention played a role in altering platelet adhesion to those men who participated in the exercise prgramme. However morphological assessment of platelet cloaking was found to be difficult, as the majority of CTCs present on the filters lacked cytoplasm, perhaps consequent upon the shear forces exerted on the cells during the filtration process.
A higher circulating fraction of CD3-positive T-cells and a lower circulating fraction of B-cells and NK-cells were found in the exercise group compared with the control group. Linear correlations were identified between CTCs numbers on the one hand and platelet count, total lymphocyte count, CD4-positive T-cell count and NK-cell count on the other hand, relationships which were found to be independent of one another by multiple regression analysis. The demonstration of a relationship with platelet count is the first such report in men with prostate cancer. No correlation was seen between CTC numbers and the density of inflammatory cell subsets in core biopsy tissue.
Overall this study provides useful support for the hypothesis that metastasis, platelet function, systemic inflammation and hypercoagulability are closely linked in advanced cancer, and elucidates several potentially valuable directions for future research.
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World Cancer Research Fund
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APPROVED
Author: HAYES, BRIAN DERMOT
Advisor:
Finn, StephenQualification name:
Doctor of Medicine (M.D.)Publisher:
Trinity College Dublin. School of Medicine. Discipline of Clinical MedicineType of material:
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