Systemic inflammation in cachectic cancer patients: mechanisms and therapeutical strategies, a translational medicine approach

Abstract

Cachexia is a devastating wasting syndrome associated with poor prognosis and survival of cancer patients. Its aetiology has not been fully unveiled and the syndrome is frequently under diagnosed, despite afflicting around 40% of all cancer patients, and 80% of hospitalized patients. Chronic systemic inflammation is a main feature of cachexia, to which the white adipose tissue (WAT) plays a major contribution, as we have previously shown in animal models. It is our aim to address the role of WAT in the onset and maintenance of systemic inflammation in HUMAN cachexia, within a translational medicine approach. Preliminary results obtained over the last 24 months demonstrate that the adipose depots of cachectic cancer patients are infiltrated with immune cells, and actively secrete pro-inflammatory factors, similarly to what we described in animals. Bearing in mind that cachexia is systemic we have previously addressed (in models) the effect of an anti-inflammatory strategy encompassing the whole organism-regular sub-maximal intensity exercise, with very encouraging results. Therefore, a second goal of the project is to test the hypothesis that chronic exercise counteracts cachexia-associated WAT inflammation. We hypothesise (based on our animal studies) that, by decreasing WAT inflammatory factor secretion, the strategy will also reduce systemic inflammation, with reflexes in the liver, muscle, and in the tumour, which we also intend to examine. After informed consent, patients of the University Hospital shall be enrolled into 4 groups-cachectic cancer patients, non-cachectic cancer patients, cachectic patients, and Controls. The groups shall be further divided into sedentary (lst Phase) and trained (2nd Phase). The latter will be submitted to 6 wk endurance exercise (the protocol has been already tested and standardised for HU patients, after approval by the Ethics Committee). Plasma and tissue samples of both Sedentary and Trained patients will be collected during surgical procedure for tumour excision. We intend to investigate the effects of 1) cachexia and 2) the anti-inflammatory strategy on parameters regarding quality of life, and WAT, liver, skeletal muscle and tumour biology. Extensive biochemical, morphological and molecular analysis will be performed in collaboration with 6 different International (NIH; Boston University; University of Barcelona; University of Potsdam; University la Sapienza, CSIC) and 9 Brazilian (UNICAMP, UNIFESP, UMC, RDO-Diagnósticos, ICB-USP, FMUSP, IME-USP, EEFE-USP) institutions. The RESULTS will provide further insight on the mechanisms and molecular bases of cachexia, contributing for early and PRECISE DIAGNOSIS of the syndrome. The comprehensive screening of inflammation in cachexia intended shall warrant subsidy for the proposition of reliable markers, allowing not only the diagnosis of the syndrome, but also grading, and thus for the development of a diagnostic kit, for which we may require patent. Furthermore, the study aims at examining possible REGULATORS OF THE INFLAMMATORY SYNDROME, putting forward the hypothesis that the infiltrating immune cells in WAT, in the tumour and/or gut micro-biota may determinate the patient's disposition to develop cachexia, when compared with subjects matched for tumour type and staging who do not present the syndrome. Results of Phase 2 experiments shall very likely offer the possibility of TREATMENT FOR CACHEXIA, with strong impact in public health management, as exercise training is a low cost strategy, devoid of collateral effects, having been proven not to interfere with chemotherapy, but actually decreasing its deleterious side effects. Finally, the statistical analysis of the results and the establishment of all possible correlations will require the setting of a specific bioinformatics data platform. For that purpose two collaborating groups (University of Potsdam and IME-USP) will develop software's for which we intend to obtain patent. (AU)