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Page 14 of 31 Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63

The liver is a key player in the systemic inflammatory response. All the acute-phase proteins, including
C-reactive protein (CRP), amyloid A, α1 antitrypsin, and α1 acid glycoprotein, are synthesised in the
[94]
liver and secreted into the circulation . Classical studies have shown the deleterious role played by the
[95]
citokines secreted by the Kupfer cells in acute inflammation . For example, complete elimination of liver
macrophages, decreased the mortality of mice challenged with zimosan, a potent inflammatory agent, from
[96]
27% to 0% .
Another key component of the global inflammation network is the gut microbiota. The human body is in
symbiosis with the gut microbiota, which outnumbers human cells by a 10-fold factor. As shown by two
Science articles, gut microbiota modulates inflammation in both the tumor microenvironment and in the
[99]
systemic circulation [97,98] . Microbiota also regulates steady‐state myelopoiesis and neutrophil homeostasis .
Mouse models have shown that gut microbes promote the development of mammary carcinomas via a
neutrophil‐mediated mechanism [100] , and, microbiota‐driven mobilization of myeloid‐derived suppressor
cells, favors malignant progression through systemic tumor promoting inflammation [101] .

Increase of the systemic markers of inflammation as neutrophils, lymphocytes and platelet counts and acute
phase proteins, such as CRP and albumin or their combinations, computed in different scores, i.e., the
neutrophil lymphocyte ratio, the platelet lymphocyte ratio and the Glasgow Prognostic Score, are associated
with adverse prognosis in several malignancies [102] .

A systemic immune-inflammation index (SII), which is calculated as platelet (P) × neutrophil (N)/
lymphocyte (L) counts, has also been demonstrated to be closely associated with the prognosis of solid
tumors especially lung cancer [103] .

In most advanced cancers, systemic inflammation is caused by cancer itself and indicate the aggressiveness
of the tumor [104] . Unfortunately, despite pre-clinical efficacy demonstrated in several animal studies, until
present, agents used to manipulate systemic inflammation in the treatment of patients with advanced-
stage cancer have only shown modest results [105] . The clinical trials that used inhibitors of primary
inflammatory cytokines (e.g.,TNF‐α, IL-6, IL-8), in the treatment of various types of human cancers (i.e.,
pancreas, renal) showed only limited benefit. This is not surprising as the function of cytokine varies with
the clinical context and the same cytokine may promote or inhibit cancer progression. The same cytokine
can be beneficial in some clinical context and detrimental in others, and the term yin-yang has been used
for cytokine behavior [106] . Currently there are multiple clinical studies in progress using agents that target
cytokines (i.e., IL-1, CXCR4/CXCL12), transcription factors (i.e., JAK-STAT pathway inhibitors) or local
immune/inflammatory cells (i.e., macrophages M2) and the field of cancer inflammation is currently a very
active area of research [105,107] .

The immunity inhibition network
Tumor promoting inflammation and anti-tumor immunity are the two opposite factors that shape the
evolution of tumors [108] . As illustrated in the above section, tumors actively induce a global inflammatory
state. They also inhibit the immune system, both locally and systemically [Figure 7]. The local inhibition
of the immune system by the tumor checkpoint molecules has been well characterized and the use of
checkpoint inhibitors is currently approved in many types of cancers. Tumors may also have a global
inhibitory effect on the immune system as recently shown by a team from the University of Pennsylvania.
The researchers described the release of exosomes carrying programmed death-ligand 1 (PD-L1) on their
surface by metastatic melanoma cells. Stimulation with IFN-γ increased the amount of PD-L1 on these
vesicles, which suppressed the function of CD8 T cells and facilitated tumor growth [108] . Tumor cell-derived
exosomes can also impair immunity through different mechanisms: exosomes containing miR-203 secreted
by pancreatic cells may impair activation of the immune system through downregulation of toll-like