Metabolic Signatures Imaged in Cancer-Induced Cachexia

Abstract

Cancer-induced cachexia is a complex and poorly understood life-threatening syndrome that is characterized by progressive weight loss due to metabolic alterations, depletion of lipid stores and severe loss of skeletal muscle protein. Gaining the ability to non-invasively image the presence or onset of cachexia is important to better treat this condition, to improve the design and optimization of therapeutic strategies, and to detect the responses to such treatments. In this study, we used noninvasive magnetic resonance spectroscopic imaging (MRSI) and [18F] fluorodeoxyglucose (18FDG) positron emission tomography (PET) to identify metabolic signatures typical of cachectic tumors, using this information to determine the types and extents of metabolic changes induced by the onset of cachexia in normal tissues. Cachexia was confirmed by weight loss as well as analyses of muscle tissue and serum. In vivo, cachexia-inducing MAC16 tumors were characterized by higher total choline (tCho) and higher 18FDG uptake compared to histologically similar non-cachectic MAC13 tumors. A profound depletion of the lipid signal was observed in normal tissue of MAC16 tumor bearing mice but not within the tumor tissue itself. High-resolution 1H MR spectroscopy (MRS) confirmed the high tCho level observed in cachectic tumors that occurred due to an increase of free choline and phosphocholine (PC). Higher succinate and lower creatine levels were also detected in cachectic tumors. Taken together, these findings enhance our understanding of cancer’s effect on host organs and tissues as well as promote the development of noninvasive biomarkers for the presence of cachexia and identification of new therapeutic targets.

Histone Deacetylase 6 Is a FoxO Transcription Factor-dependent Effector in Skeletal Muscle Atrophy

“…Cancer cachexia is a major cause of muscle wasting, and negatively interferes with chemotherapies and is associated with 20% of cancer mortality (1).…”

“…Muscle atrophy can occur as a result of simple inactivity and aging or can be associated with various pathologies such as myopathies, hyperthyroidism, AIDS, or cancer (1).…”

Cancer Cachexia, Recent Advances, and Future Directions

“…In 1 H magnetic resonance spectroscopic imaging (MRSI) of a murine colon adenocarcinoma (MAC) model, cachectic MAC16 tumors were characterized by increased total choline (tCho) compared to non-cachectic MAC13 tumors [34]. Lactate+lipids maps showed that although the lactate+lipids content was not different between MAC13 and MAC16 tumors, the peripheral signal, most likely originating from subcutaneous lipids, was lower around the MAC16 tumor.…”

New Strategies for Metabolic Support in Cancer

“…A depletion of the lipid signal was observed in normal tissue of MAC16 tumor-bearing mice but not within the tumor tissue itself. Higher succinate and lower creatine levels were also detected in cachectic tumors [13]. Cachexia involves multiple pathways: procachectic and proinflammatory signals from tumour cells, systemic inflammation in the host, and metabolic changes (increased resting energy expenditure and alterations in metabolism of protein, fat, and carbohydrate) thus altering plasma fatty acid composition, proinflammatory cytokines and acute phase protein reactants [14].…”

“…Cachexia involves multiple pathways: procachectic and proinflammatory signals from tumour cells, systemic inflammation in the host, and metabolic changes (increased resting energy expenditure and alterations in metabolism of protein, fat, and carbohydrate) thus altering plasma fatty acid composition, proinflammatory cytokines and acute phase protein reactants [14]. These findings promote the development of noninvasive biomarkers for the presence of cachexia but understanding the complex interplay of tumour and host factors will also uncover new therapeutic targets [13,14].…”