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Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63 Page 3 of 31

Figure 2. The cancer system and the body systems interact leading to novel cancer induced systemic pathologic networks

Cancer as a systemic disease
[4-8]
Over the last decade, several models of cancer as a systemic disease have been proposed . In 2010,
Mikala Egeblad and her collaborators introduced the model of the tumor as an organ that may influence
[4]
the immunity, the metabolism and the coagulation status of the host . In a paper published the same year,
Sandra Mc Allister and Robert Weinberg suggested that tumor-host interactions extend well beyond the
local tissue microenvironment and introduced the tumor “instigation” concept in which primary tumors
[5]
perturb normal host organs and support the growth of metastatic tumors at distant anatomic sites . They
listed several factors secreted by the tumors with systemic effects: vascular endothelial growth factor
(VEGF), interleukin (IL)-6, IL-8, stromal cell-derived factor-1 (SDF1), fibroblast growth factor, growth-
related oncogene-α (CXCL1), platelet-derived growth factor (PDGF), angiopoietins, transforming growth
factor β (TGF-β), hepatocyte growth factor (HGF), angiogenin, leptin, sonic hedgehog homolog, regulated
[5]
upon activation normal T-cell expressed (CCL5), and osteopontin . They also proposed a novel treatment
of metastases by blocking their access to supporting stromal cells derived from the bone marrow. In a
[7]
subsequent publication, the same authors , refined their original model bringing additional support to
the complementary idea that tumors can be also significantly influenced by systemic processes. In 2014, a
research team from Austria, introduced the concept of tumor macroenvironment and described mainly the
global metabolic changes that tumors exert on the whole organism .
[6]
This systemic perspective should not be limited solely to clinically stage IV cancers. Often, systemic effects
appear also when the tumors are localized and, in many instances, metastasis is present in a subclinical