Page 340 - Read Online

Page 18 of 31 Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63

will be used in the liver for gluconeogenesis or protein synthesis in lung tumors [165] . Interestingly, the
increase of branched aminoacids blood levels may precede the clinical appearance of pancreatic cancer by
several years [166] .

The impact of gut on cachexia is mostly through the gut microbiota. Alteration of the gut flora due to
undernutrition and chemotherapy ultimately affects specific metabolite availability and absorption, which
in turn affects tumor growth and cachexia [167] . Host metabolism and energy balance are also influenced by
an interplay between the intestinal microbiota, bile acids and nutrients that may have an impact on global
inflammation, immune responses, gut hormone secretion and neuronal activity [168] .

Several hormones including insulin, cathecolamines and atrial natriuretic peptide are involved in
lipolysis [169] . Besides the endocrine system, the brain is also actively involved in the cachectic syndrome by
controlling food intake through appetite, satiation, taste and smell of food. Receptors of TNF-α and IL-1
are found in the hypothalamic areas of the brain, which regulate food intake. Anorexia induced by both
TNF-α and IL-6 can be blocked by inhibitors of cyclooxygenase, suggesting that a prostaglandin, such as
PGE2, may be the direct mediator of appetite suppression [169,170] . Autonomic nervous system dysfunction
has been also described in cancer patients with cachexia [171] . IL-6 was found to stimulate hypothalamic
release of CRH, and increase glucocorticoid production [172] .

Structural and functional heart changes similar to those found in cardiac failure are often associated with
the cachexia syndrome. In addition to a loss of skeletal muscle mass and function, many patients with
cancer cachexia also experience cardiac atrophy, remodeling, and dysfunction, which in the field of cancer
cachexia is described as cardiac cachexia [173,174] . It has been shown for more than two decades that cardiac
cachexia is linked to raised plasma levels of TNF‐α and other inflammatory cytokines and that the degree
of body wasting is strongly correlated with neurohormonal and immune abnormalities [175] .

Israel and Schwartz [176] postulated that cancer cells have hybrid metabolic features that take advantage of
the catabolic state that they also initially induce. The two French authors proposed a comprehensive model
of the systemic metabolic changes induced by cancer that I will describe briefly. Normally, in starvation,
when blood glucose level decreases, glucagon and epinephrine activate gluconeogenesis and ketogenesis to
form nutriments, mobilizing body stores. On the contrary, when glycemia is elevated, the pancreas releases
insulin, activating anabolism and oxidative glycolysis, energy being required to form new molecules
or refill stores. Usually, these two opposite physiological states exclude each other; when anabolism is
triggered by insulin, catabolism is blocked and the normal organism metabolic configuration is finely
regulated by the state of key enzymes. Depending on the needs, enzymes function like switches and direct
the metabolism towards different pathways that are open or closed depending on their phosphorylation
state. In cancer, some of their enzymes are phosphorylated as normally observed when catabolic hormones
stimulate Gs-coupled receptors, whereas other enzymes adopt a configuration normally found in anabolic
situations, mediated via tyrosine kinase receptors. Basically, despite the fact that the organism as a whole is
in a starvation-like state induced by cancer, tumor cells have their anabolic pathways turned ON through
tyrosine kinase receptors, sometimes constitutively activated through genetic mutations or amplifications.
The pyruvate kinase (PK) and pyruvate dehydrogenase (PDH) of cancer cells are OFF in a phosphorylated
form but the citrate synthase is ON pulling the glucose flux in the glycolytic direction. So, on one hand,
cancer cells, have their PKs and PDHs inhibited by phosphorylation, like in gluconeogenesis, on the other
hand they have an increased glycolysis that will be used for the synthesis of new molecular building blocks
for new mitotic daughter cells. As a result, cancer cells burn glucose and increase the tumor mass, at the
same time consuming the muscle proteins and the lipid stores of the organism. The outcome of this hybrid
rewired metabolism gives them a selective advantage over normal cells [176] . In subsequent publications,
Israël proposed that the reason for this hybrid metabolism is an alteration of the GABA selection switch