Top Highlights

• The tumor cells are known to secrete cytokines that can both in autocrine fashion generate a forward-feedback loop to stimulate self-proliferation, expansion, and drug resistance, and in paracrine fashion induce recruitment, activation, and differentiation of other cells in the TME, such as IL-6, IL-8 and even VEGF
• Signaling by the inflammatory cytokines induced by NF-kB including IL-1, IL-6, TNF, IL-8, IL-17, IFN-γ, and CCL-5 among others (23) promotes tumor growth by induction of cell proliferation
• The local senescence cells secrete the senescence-associated secretary phenotype (SASP), which includes a vast array of pro-inflammatory cytokines including IL-1α, IL-1β, IL-6, IL-8, CXCL-1, and CXCL-2, that is capable of inducing tumorigenesis in a paracrine fashion (26).
• The process of metastasis is started by epithelial-to-mesenchymal transition (EMT), whereby the tumor cells lose their cell-to-cell adhesion mediated by E-cadherin
• Angiogenesis is induced by several factors including VEGF and FGF (68), IL-8 (49) and TGF-β (69), mainly secreted by cancer cells, but also TAMs, endothelial cells, and fibroblasts in the TME.

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