Cachexia is a metabolic syndrome consisting of massive loss of muscle mass and function that has a severe impact on the quality of life and survival of cancer patients. Up to 20% of lung cancer patients and up to 80% of pancreatic cancer patients are diagnosed with cachexia, leading to death in 20% of them. The main drivers of cachexia are cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), macrophage inhibitory cytokine 1 (MIC-1/GDF15) and transforming growth factor-beta (TGF-β). Besides its double-edged role as a tumor suppressor and activator, TGF-β causes muscle loss through myostatin-based signaling, involved in the reduction in protein synthesis and enhanced protein degradation. Additionally, TGF-β induces inhibin and activin, causing weight loss and muscle depletion, while MIC-1/GDF15, a member of the TGF-β superfamily, leads to anorexia and so, indirectly, to muscle wasting, acting on the hypothalamus center. Against this background, the blockade of TGF-β is tested as a potential mechanism to revert cachexia, and antibodies against TGF-β reduced weight and muscle loss in murine models of pancreatic cancer. This article reviews the role of the TGF-β pathway and to a minor extent of other molecules including microRNA in cancer onset and progression with a special focus on their involvement in cachexia, to enlighten whether TGF-β and such other players could be potential targets for therapy.

Cancer cachexia consists of dramatic body weight loss with rapid muscle depletion due to imbalanced protein homeostasis. We found that the mRNA levels of apelin decrease in muscles from cachectic hepatoma-bearing rats and three mouse models of cachexia. Furthermore, apelin expression inversely correlates with MuRF1 in muscle biopsies from cancer patients. To shed light on the possible role of apelin in cachexia in vivo, we generated apelin 13 carrying all the last 13 amino acids of apelin in D isomers, ultimately extending plasma stability. Notably, apelin D-peptides alter cAMP-based signaling in vitro as the L-peptides, supporting receptor binding. In vitro apelin 13 protects myotube diameter from dexamethasone-induced atrophy, restrains rates of degradation of long-lived proteins and MuRF1 expression, but fails to protect mice from atrophy. D-apelin 13 given intraperitoneally for 13 days in colon adenocarcinoma C26-bearing mice does not reduce catabolic pathways in muscles, as it does in vitro. Puzzlingly, the levels of circulating apelin seemingly deriving from cachexia-inducing tumors, increase in murine plasma during cachexia. Muscle electroporation of a plasmid expressing its receptor APJ, unlike apelin, preserves myofiber area from C26-induced atrophy, supporting apelin resistance in vivo. Altogether, we believe that during cachexia apelin resistance occurs, contributing to muscle wasting and nullifying any possible peptide-based treatment.

Cachexia is a lethal syndrome with massive muscle wasting that occurs in 60 % of colon cancer patients. Several studies in humans and mice show that males are more prone than females to muscle atrophy caused by colorectal cancer. Understanding whether muscle atrophy precedes or follows other organ alterations may unravel the sex-specific drivers of cachexia. In two mouse models of colon cancer, we explored when cachexia affects multiple organs in both sexes and their sex development, if/how sex hormone may affect in vitro the inflammatory state of colon adenocarcinoma C26, HCT116 and human primary colorectal cancer cells and in vivo the progression of cachexia in C26-carriers. We compared tumor growth and cachexia-related responses in C26 males and females and C57BL/6J-Apc^Min/+ mice of both sexes. C26, HCT116 and human primary colorectal cancer cells exposed to 17β-estradiol or the antagonist fulvestrant were analysed for Il-6 expression and secretion. β-estradiol 3-benzoate was given to C26 males. In both models, cancer-bearing males display more/earlier muscle wasting than females. Muscle proteasome activity is enhanced only in cachectic males and only when they are sexually mature. During cachexia hypogonadism appears earlier in males than females of both models. Tumor-bearing females as long as they are "cycling" are more preserved from cachexia than males. Circulating levels of IL-6 increased more in C26 males than C26 females and spleens were bigger in C26 males also displaying more atrophic and inflamed muscles. 17β-estradiol halved the expression of Il-6 and abrogated the secretion of IL-6 from C26 cells, while fulvestrant surprisingly highly enhanced Il-6 expression, supporting an anti-inflammatory effect of estrogens directly on C26 cells. Similar data were obtained from human (primary) colorectal cancer cells. In vivo β-estradiol 3-benzoate prevented some signs of cachexia in C26 carriers. Overall, we herein report a novel direct role of 17β-estradiol on colon cancer cells explaining why multiple tissues from males display more signs of cachexia than females.

Muscle atrophy occurs during physiological (i.e., fasting, aging) and pathological (i.e., amyotrophic lateral sclerosis, cancer) conditions and anticipates death. Since not all patients will undergo muscle wasting, it would be highly useful to identify them soon to intervene early. We have studied the promoters/enhancers of a subset of atrophy-related genes or atrogenes upregulated in muscles of rodents during various kinds of atrophy (i.e., disuse, diabetes, cancer, fasting, uremia) for their ability to induce early atrophy. Comparing their upstream non-coding regions, using as backbone MuRF1 promoter (one of the earliest muscle-specific genes induced by wasting), we cloned various promoters upstream of a doubled reporter system (FLuciferase/tdTomato). Through in vitro and in vivo studies in mice subjected to denervation or cancer injection, we selected a sequence (i.e., MyoRep) able to predict atrophy upon cut of the sciatic nerve or cancer. In vivo imaging of MyoRep mice emit a bioluminescent signal earlier than muscle loss. Importantly, MyoRep was unable to sense atrophy during fasting or physiological variations following the circadian rhythms. Since MyoRep can discriminate muscle loss due to pathological conditions from physiological ones anticipating wasting, it represents an unprecedented tool to predict it early in various diseases with local or systemic atrophy.