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Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63 Page 13 of 31
[80]
release cytokines [i.e., SDF1] that once entered in the circulation may trigger the systemic release
from the bone marrow of stem cells and haematopoietic progenitors that will support the formation of
[81]
metastases . A research team from MD Anderson have shown that the origin of these cancer-associated
fibroblasts is primarily the bone marrow but their origin and function within the tumor stroma
[82]
[83]
varies . The existence of these networks of communication between geographically separated sites, brings
experimental evidence to the cancer system model, and, supports the idea that metastasis is a non-random,
finely regulated process.

The systemic inflammation network
The link between local stromal inflammation and cancer progression is well known and the molecular
[84]
pathways responsible for this link have been well characterized . As any pathologist would certify, local
inflammation is present in the stroma of many tumors and, inflammatory cells and molecules, may be
involved in almost every aspect of cancer progression, including the tumour cells’ ability to metastasize.
[85]
Colotta et al. proposed that cancer related inflammation represents a seventh hallmark of cancer.

As described by Grivennikov et al. , there are several types of inflammation that can promote cancer
[86]
development and progression, differing by cause, mechanism, outcome, and intensity. Briefly, there is
chronic inflammation associated with infections or autoimmune disease, there is inflammation due to
prolonged exposure to environmental irritants or obesity, there is another distinct type of inflammation
related to the tumor, and, finally, there is inflammation related to cancer therapies themselves.
Approximately 20% of human cancers may be related to chronic inflammation caused by infections, exposure
[87]
to irritants, or autoimmune disease . On the other hand, not only chronic inflammation may lead to
cancer, but cancer may also cause local and systemic inflammation. Oncogene activation in cancer cells
lead to expression of pro-inflammatory transcription factors within tumor cells [such as nuclear factor-
kappaB (NF-κB), signal transducer and activator of transcription (STAT)3 or HIF-1α]. These activated
transcription factors mediate the expression of key cytokines and chemokines as well as inflammatory
enzymes within the tumor microenvironment. At the tissular level, different cytokines can either promote
or inhibit tumor development and progression. Some of them may lead to tumor progression (IL-6, IL-17,
IL-23), and also have direct effects on cancer cell growth and survival [TNF-related apoptosis-inducing
ligand, Fas ligand, TNF-α, epidermal growth factor receptor (EGFR) ligands, TGF-β]. Others [IL-12,
[86]
interferon (IFN)γ] may have an anti-tumor effect .

Cancer inflammation is not only a local phenomenon [Figure 6]. High serum concentrations of inflammatory
cytokines, (i.e., IL-1, IL-6) are found in many advanced malignancies . Circulating cytokines and small
[88]
inflammatory molecules, such as chemokines and matrix-degrading proteins, are also involved in the systemic
inflammation, and play a crucial role in the metastatic process . IL-1, for example, is involved in invasion
[88]
and angiogenesis. IL-1 may enhance the invasiveness of already existing tumor cells by the induction of
inflammatory molecules, such as MMPs, VEGF, heparanase, chemokines, and integrins on the malignant cells
[89]
and endothelial cells, or by switching on the angiogenesis leading to tumor dissemination and metastasis .
Systemic inhibition of IL-1 with anakinra (a recombinant derivative of IL-1RN) inhibits the growth and
density of new vessels in IL-1-producing human tumor cell lines xenografted into immunodeficient mice,
[90]
but not in their counterparts that do not produce IL-1 . A recent review , provided a comprehensive list of
[91]
factors associated with colorectal systemic inflammation including cytokines, chemokines and growth factors
(IL-6, C-C Motif Chemokine Ligand (CCL)2, CXCL (C-X-C Motif Chemokine Ligand)8, CSF1 [macrophage
colony-stimulating factor (M-CSF)], and CSF2 [granulocyte-macrophage colony stimulating factor (GM-
CSF)]. The authors noted that immune cells and fibroblasts are capable of producing many of these factors at
much higher level than tumor cells and pointed out to the role of the stroma in systemic inflammation. Some
of these immunomodulatory effects are modulated by exosomes that contain in their cargo a large variety of
[93]
molecules [92,93] . Exosomes secreted by tumors contain IL-8, CCL2, CCL3, CCL4, CCL5, CCL20 and TGF-β .