Figure 1
Inflammation promotes tumor growth and survival. Tumor-infiltrating myeloid cells and lymphocytes produce inflammatory cytokines including TNFα, IL-6, IL-17, IL-21, IL-22 and IL-23. TNFα activates NF-κB in myeloid cells and stimulates tumor-associated inflammation. IL-23 signals to T lymphocytes and other immune cells to stimulate the production of IL-17, IL-21 and IL-22. TNFα, IL-6, IL-17, IL-21 and IL-22 activate STAT3 and NF-κB signaling in transformed epithelial cells. Activated STAT3 and NF-κB transcribe genes that support cell proliferation and survivial, thereby increases the rate of cancer growth, progression and metastatic spread.
Table 1
Cytokines in skin cancer development.
| Cytokine | Model | Effect | Mechanism of Action | References |
|---|---|---|---|---|
| TNFα | DMBA/TPA; UVR-induced skin cancer | pro-tumor | Activates NF-κB in tumor cells. Enhances tumor cell survival. Exacerbates tumor-associated inflammation. | [48, 49] |
| IL-1 | DMBA/TPA; K-Ras activation in skin cells. | pro-tumor | Activates NF-κB in tumor cells. Synergizes with K-Ras to drive cancer progression. Exacerbates tumor-associated inflammation. | [70] |
| IL-6 | Skin cancer cell culture | pro-tumor | Activates STAT3 transcription factor and upregulates Bcl-xL to promote cell survival. | [76] |
| IL-17 | DMBA/TPA | pro-tumor | Activates STAT3 in tumor cells and promotes skin tumor-associated inflammation | [94, 95, 96] |
| IL-23 | DMBA/TPA | pro-tumor | Activates Th17 cells and upregulates the production of IL-17. | [86] |
| IL-12 | DMBA/TPA | Anti-tumor | Activation of CTLs and NK cells in tumor. | [86] |
| IFN-γ | Carcinogen-induced sarcoma | Anti-tumor | Activation of CTLs and NK cells in tumor. | [100, 101 ] |
| IL-10 | UVR-induced skin cancer | Pro-tumor | Limits Th1 response in tumor. | [109] |
| TGF-β | DMBA/TPA, melanoma | Pro-tumor/anti-tumor | Inhibits keratinocyte proliferation; limits tumor-associated inflammation; limits cell-mediated immunity against cancer; promotes cancer metastasis. | [115, 116, 117, 118, 120] |
Figure 2
The roles of tumor infiltrating immune cells. Tumor infiltrating macrophages and neutrophils produce IL-6, IL-23, IL-1 and TNFα, and activate Th17 lymphocytes for the production of IL-17, IL-21 and IL-22. These cytokines act on cancer cells to drive their proliferation and survival. Dendritic cells (DC) facilitate T cell-mediated immunity against cancer by IL-12 production and antigen presentation. Th1 cells further activate natural killer (NK) cells and CTLs by secreting IFN-γ. NK cells and CTLs target cancer cells for destruction. Regulatory T cells (Treg) produce IL-10 and TGF-β and inhibit both pro- and anti-cancer immunity by contact dependent and independent mechanisms.