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Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63 Page 17 of 31

Inflammation is the key trigger of muscle wasting inducing alterations in protein and amino acid
metabolism, together with activation of apoptosis and decreased regeneration [144] . Besides muscles wasting,
adipose tissue wasting is also present in the majority of cachexia patients. Indeed, cachectic patients
manifest high levels of circulating free fatty acids, glycerol and triacylglycerol [150] and the trigger of lipolysis
may be also systemic inflammation [151] . Another characteristic of cancer cachexia is the progressive switch
from white adipose tissue to brown adipose tissue-brown adipose tissue derives its name from the darker
color associated with the enrichment in mitochondria [152] . Pro-inflammatory factors either derived from
[152]
the host immune system or the tumor, contribute to this switch . Browning strongly contributes to the
increased energy expenditure common in cachectic patients and, interestingly, cachectic lipid wasting
occurs mostly in tumors actively secreting parathyroid hormone-related protein [152,153] . Pro-inflammatory
cytokines, such as IL-6, IL-1, TGF-β, and TNF‐α, are common denominators both for metastasis and
inflammation and for the metabolic reprogramming associated with cachexia [86,122,133] and their underlying
molecular pathways might overlap [154] . One of these molecular pathways might be exosome secretion by
tumour cells or adipose tissue. It has been shown recently that tumor related exosomes play a key role in
activating the inflammatory process in cancer; thus, they might be involved in both host-wasting processes,
as well as metastatic dissemination [155-158] . As a direct proof of this concept, a study [159] published in 2014,
showed that cancer-derived microvesicles containing miR-21 induce apoptosis of skeletal muscle and
lipolysis of the adipose tissue. Similarly, another study demonstrated that cancer associated microvesicles
induce muscle wasting in mice through releasing extracellular Hsp70 and Hsp90 [155] .

We will describe briefly below the contribution of different organs or body systems to cachexia. First, the
liver plays a major role in cachexia. In the KRAS/P53 mouse model it has been shown that lung tumors act
distally on the liver and reprograms hepatic metabolism through altered pro-inflammatory response via
the STAT3-Socs3 pathway resulting in inhibition of hepatic insulin signaling, increased glucose production
and a deregulated lipid synthesis [160] . The authors suggested that tumor-secreted ‘waste’ such as lactate is
converted to pyruvate and shunted through gluconeogenesis to produce glucose, which can further satisfy
the heightened energetic demand of cancer cells. A research team coordinated by Douglas Fearon also
demonstrated in two mouse models of cancer-induced cachexia that in pre-cachectic mice, even before the
onset of the weight-losing phase of the syndrome, tumor-induced IL-6 has altered the capacity of the liver
to respond to caloric deprivation [141] . Tumors induce a reprogramming of the hepatic metabolism blocking
the host’s capacity to make available endogenous sources of energy that compensate for decreased caloric
intake. Through supressing ketogenesis, the tumor hampers the host’s capacity to produce endogenous
sources of energy that compensate for decreased caloric intake. This energy deficit magnifies the host
stress response and leads to increased glucocorticoid levels that suppress the tumor immunity [140] . Using an
inducible lung cancer mouse model, a research group from WCMC, co-ordinated by Lewis Cantley, found
that cachexia was associated with low ketones and increased glucocorticoid levels that suppresses tumor
directed immunity [161] . The low ketones level associated with reduced expression of hepatic peroxisome
proliferator-activated receptor-α (PPARα) targets that regulate fatty acid oxidation and ketogenesis.
Treatment with fenofibrate, a PPARα agonist restored hepatic ketogenesis, prevented the reliance on
hepatic gluconeogenesis, and skeletal muscle wasting. This model was consistent with the hypothesis that
global inflammation induced by the tumor signals the brain that increases corticotropin-releasing hormone
(CRH) leading to glucocorticoid production that will induce type 2-skeletal muscle fibers breakdown [161] .

The pancreas also plays an important role in cachexia through secretion of insulin and glucagon. Insulin
resistance is both a risk factor for cancer and is associated with cancer progression. The increase in insulin
level driven by insulin resistance can drive cancer growth both directly through insulin receptors, and IGF-1
receptors present on the surface of cancer cells [162,163] and indirectly by promoting liver gluconeogenesis and
muscular wasting. Also, the increased production of glucagon in the alpha islet of pancreas during cancer
progression, may also increase liver gluconeogenesis [164] . Branched aminoacids released from the muscle