Cachexia is a multifactorial condition which accompanies the development of cancer and cannot be completely reversed with conventional therapies. It occurs in about 80% of cancer patients and is the leading cause of death in about 22% of this population. The hallmark of cancer cachexia is the loss of muscle mass and the loss of white adipose tissue (WAT). The loss of WAT has been reported to be associated with reduced quality of life, worse outcomes and shorter survival in cancer. Considering that cachexia is highly prevalent during gastrointestinal (GI) cancer, we aim to i) analyze the changes in the morphological structure and composition of subcutaneous WAT in GI cancer patients with and without cachexia compared to non-cancer patients undergoing elective surgery for a non-neoplastic disease (controls); ii) analyze adipose tissue-specific miRNAs and the expression of proteins involved in the browning of WAT and in the lipolytic mechanisms in patients and controls; iii) analyze the changes in serum levels of pro-inflammatory cytokines, myokines and adipokines; iiii) evaluate the correlation between WAT modifications, the occurrence of skeletal muscle atrophy and the short and long-term complications and survival after abdominal surgery for cancer. We will enroll GI cancer patients with and without cachexia undergoing surgery and controls. We will collect adipose tissue during surgery to perform immunohistochemistry and morphological analysis of WAT, the occurrence of WAT browning by rt-PCR analysis (Eva1, Pdk4, Tmem26, Tbx1) and the expression of the proteins involved in browning and lipolysis of WAT by western blotting analysis (Tbx1,Cgi58, UCP1, PGC1-alfa, perilipin-1). The results of this project will provide useful indications on the biological and molecular mechanisms underlying the browning phenomenon and the WAT wasting during cancer cachexia, as well as their short and long-term prognostic value in a population of GI cancer patients.
Cancer cachexia is a disabling clinical conditions, characterized by a progressive and generalized loss of skeletal muscle mass and AT and strongly correlated with a risk of negative outcomes such as physical disability, poor quality of life and death. It has been documented that cachexia is significantly associated with increased mortality in cancer patients compared to patients with the same non-cachectic diagnosis.
This project aims to evaluate the morphological and functional state of the subcutaneous AT in patients with gastric, pancreatic and colorectal cancer. Our interest in the development of this project is to clarify the role of the modifications in the structure and composition of fat depots, the expression of WAT browning-associated genes and proteins in the pathophysiology and progression/staging of cachexia. For this purpose, cancer cachectic and non-cachectic, and non-cancer patients (CON) will be compared.
Nowadays, there are not clear data available on the biochemical, molecular and histological patterns of the WAT among cachectic cancer patients. All the results deriving from these analyses can be considered preliminary.
The results of the project will provide useful indications on the biological and molecular mechanisms underlying the browning phenomenon and the TA wasting during cancer cachexia, as well as their short and long-term prognostic value in a population of patients with gastric, pancreatic or colorectal cancer undergoing surgery. The innovation of the project is based on the analysis of the molecular mechanisms underlying the browning of WAT in cancer patients, which is an almost unexplored field, although strongly supported by pre-clinical studies. The identification of changes in the structure and composition of TA and in the expression of AT-specific cytokines in cachectic patients undergoing surgery, might hopefully allow researchers and physicians to adequately identify in pre-operative phase an increased nutritional risk in cancer patients; to possibly develop personalized nutritional and metabolic interventions aimed at modulating inflammation and correcting adipose tissue loss, thus improving post-operative recovery and long-term survival.
In addition, this project aims to evaluate the role of miRs (epigenetic profiling) in the pathogenesis of adipose tissue wasting.
Therefore, the development of specific inhibitors targeting a wide spectrum of epigenetic enzymes offers a promising strategy for treating chronic inflammatory diseases, including cancer. The innovation of the project is based on targeting specific inflammatory pathways which are directly involved in the development of the clinical picture represented by adipose tissue and muscle wasting.
Research on environmental epigenetics represents a rapidly growing, promising field that is expected to lead to clinical and public health interventions. It relies on intense, and at times challenging, collaboration among basic scientists, and clinicians.
The identification of an epigenetic signature and miRs involvement in cancer cachexia and weight loss might allow researchers and physicians to better identify an increased nutritional risk in cancer patients to possibly develop tailored nutritional and metabolic interventions aimed at modulating systemic inflammation and lipolysis.