ABSTRACT
Cancer cachexia is a disorder of energy balance characterized by the wasting of adipose tissue and skeletal muscle resulting in severe weight loss with profound influence on morbidity and mortality. Treatment options for cancer cachexia are still limited. This multifactorial syndrome is associated with changes in several metabolic pathways in adipose tissue which is affected early in the course of cachexia. Adipose depots are involved in energy storage and consumption as well as endocrine functions. In this mini review, we discuss the metabolic reprogramming in all three types of adipose tissues - white, brown, and beige - under the influence of the tumor macro-environment. Alterations in adipose tissue lipolysis, lipogenesis, inflammation and adaptive thermogenesis of beige/brown adipocytes are highlighted. Energy-wasting circuits in adipose tissue impacts whole-body metabolism and particularly skeletal muscle. Targeting of key molecular players involved in the metabolic reprogramming may aid in the development of new treatment strategies for cancer cachexia.
ABSTRACT
BACKGROUND: Lung cancer is the primary cause of cancer deaths worldwide. Activation of epidermal growth factor receptor (EGFR) leads to lung cancer progression and poor prognosis while involuntary weight loss remains a major problem. Tumour-derived parathyroid hormone-related protein (PTHrP) emerged as a potential mediator of cachexia. Here, we investigated the modulatory role of EGFR signalling in PTHrP (encoded by Pthlh) gene expression and the impact of this relationship on cancer cachexia. METHODS: Global gene expression profiles of Lewis lung carcinoma (LLC) cells were analysed. Pthlh mRNA levels were measured by qRT-PCR in LLC cells treated with EGFR ligands and tyrosine kinase inhibitors (TKIs). LLC tumour-bearing mice received EGFR TKI erlotinib for 7 days via intraperitoneal injection or oral gavage. Tumour Pthlh mRNA, weight of fat/muscle tissue, and grip strength were assessed. RNA-seq data from The Cancer Genome Atlas and gene expression analysis tools were used to characterize expression profiles of PTHLH and EGFR along with correlation analysis of PTHLH with EGFR and transforming growth factor alpha (TGFA) in human lung cancer and head and neck squamous carcinoma (HNSC). Survival of lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) patients with EGFR gene alterations was analysed in regard to PTHLH expression. RESULTS: Expression of EGFR ligands, EGFR itself, and PTHrP co-clusters in LLC cells. Activation of EGFR signalling with its ligands significantly increases (3.8-fold, P < 0.0005) while EGFR TKIs significantly decrease (90%, P < 0.0005) Pthlh mRNA levels in LLC cells. Pthlh mRNA drops 65-75% (P < 0.0005) in tumours upon treatment of LLC tumour-bearing mice with erlotinib while their muscle mass and grip strength increase (9.2% P < 0.05, 23% P < 0.005, respectively) compared with tumour-bearing control mice. PTHLH is overexpressed in tumours of LUSC (45.8-fold, P < 0.05) and HNSC (17.5-fold, P < 0.05) compared with normal tissue. PTHLH expression correlates with EGFR and its ligand TGFA in both cancers (LUSC: n = 745, R = 0.32, P < 0.0001 and R = 0.51, P < 0.0001; HNSC: n = 545, R = 0.34, P < 0.001 and R = 0.50, P < 0.001, respectively). High PTHLH mRNA associates with poor overall survival in LUAD patients with activating EGFR mutations (n = 40, log-rank test, P = 0.0451). CONCLUSIONS: Epidermal growth factor receptor signalling regulates expression of cachexia mediator PTHrP. EGFR inhibition reduces PTHrP expression in LLC tumours and ameliorates cachexia in LLC tumour-bearing mice.
Subject(s)
Carcinoma, Lewis Lung , Carcinoma, Non-Small-Cell Lung , Head and Neck Neoplasms , Lung Neoplasms , Animals , Cachexia/etiology , Cachexia/genetics , Carcinoma, Lewis Lung/complications , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Lewis Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , ErbB Receptors/genetics , ErbB Receptors/metabolism , Erlotinib Hydrochloride/pharmacology , Erlotinib Hydrochloride/therapeutic use , Genes, erbB-1 , Humans , Ligands , Lung Neoplasms/complications , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mice , Parathyroid Hormone-Related Protein/genetics , Parathyroid Hormone-Related Protein/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Squamous Cell Carcinoma of Head and NeckABSTRACT
CD40 is an important tumor necrosis factor receptor (TNFR) family protein for the development of antitumor response against cancer cells, apart from its role in the regulation of the immune system as a costimulatory molecule. It is broadly expressed on the surface of immune cells and in diverse cancer types, including breast cancer. Here, we analyzed both CD40/CD40 ligand expression in breast cancer cells and tissues using public data sets and overall survival analysis in ungrouped breast cancer patients, as well as in the triple-negative breast cancer subtype. We detected CD40 gene expression along with its 3 different splice variants (variants 1-3), predominantly in the triple-negative subgroup of breast cancer cell lines. The results of the overall survival analysis showed that high CD40 gene expression, particularly in the triple-negative subgroup of breast cancer patients, is associated with better survival. In addition to the transcriptional levels of CD40 splice variants, investigation of protein levels of these variants will allow the categorization of breast cancer cells and reveal their potential as an immunotherapeutic target.
