Table 1 Regulatory relationship between different types of cytokines and CAFs in the TME
Type of factor | Molecules | Secretory cell | Underlying mechanisms | Refs. |
|---|---|---|---|---|
Growth factor | TGF -β | CAFs | CAFs secretes a high level of TGFβ and CAFs activates HOTAIR transcription through TGF β-1 secretion, thus promoting the metastatic activity of breast cancer cells | [48] |
|  | TGF -β | CAFs | TGFβ and inflammatory cytokines secreted by breast cancer cells stimulated GREM1 expression in CAFs. Grem1 disrupts bone morphogenetic protein (BMP)/SMAD signaling in breast cancer cells, promoting their mesenchymal phenotype and invasiveness | [50] |
|  | TGF-β/SMAD | CAFs | CAFs promote an aggressive phenotype of breast cancer cells through paracrine TGFβ-induced EMT | [49] |
|  | TGF-β | CAFs | Knockdown FAP-α leads to EMT reversal and elimination of TGF-β1-activated CAF-induced tumor invasion and lung metastasis | [70] |
|  | TGF-β | CAFs | ECM hardness in TGF-β-related pathways can build bridges across the basement membrane, and CAFs are major contributors to ECM stiffness and degeneration, both of which contribute to cancer cell invasion | [71] |
|  | CTGF/TGF-β | CAFs | Nicotine-treated fibroblasts producing CTGF and TGF-β have proven essential for promoting EMT and cancer cell migration, as well as blocking CTGF and TGF-β in tumor motility by blockingNic-CM inhibition of tumor motility | [72] |
|  | TGF-β | CAFs | Loss of Tgfbr2 expression in breast fibroblasts is associated with tumorigenesis and metastasis | [73] |
|  | TGF-β | CAFs | CAFs promote aggressive phenotyping of breast cancer cells through paracrine TGF-β1-induced EMT | [49] |
| Â | HGF | CAFs | HGF secreted by fibroblasts has been shown to mediate proliferation and invasion of cancer cells | [51] |
| Â | FGF2 | CAFs | CAFs promote the growth, migration and invasion of MDA-MB-231 cells through paracrine FGF2-FGFR1 loop | [52] |
| Â | IGFs | BCs | The transformation of breast epithelial cells and stromal fibroblasts to CAFs is connected by IGFs/IGF-1R axis, which directly promotes TME remodeling and increases tumor invasion | [53] |
|  | TGF-β, PDGF | CAFs,Breast cancers (BCs) | TGF-β and platelet derived growth factor (PDGF) play a clear role in promoting tumor phenotype of fibroblasts | [54] |
Chemokines | CCL2/CCR2 | CAFs | The overexpression of CCR2 in ductal carcinoma enhances the invasive progress associated with fibroblast accumulation | [61] |
| Â | CXCL12 | CAFs | CAFs regulates the mdia2-directed cytoskeleton in breast tumor cells by secreting CXCL12, thus promoting the mechanism of tumor cell migration and invasion | [62] |
| Â | CXCL12 | CAFs | OPN produced by cancer cells and CXCL12 secreted by activated fibroblasts trigger EMT in breast cancer | [63] |
| Â | CXCL12 | CAFs | CXCL12 secreted by fibroblasts plays an important role in promoting angiogenesis and tumor cell infiltration | [26] |
| Â | CXCL1/CXCR12 | CAFs | phenotype of BCAHC-4 cells triggered by paracrine connections between insulin-activated tumor cells and CAFs on the CXCL1/CXCR12 axis | [64] |
| Â | CXCL8 | BCs | Tumor-stromal interactions provide the basis for activation of Notch1 leading to CXCL8 secretion and consequent pro-metastatic activity | [65] |
| Â | CCL2,CCL5,CXC-related chemokines | CAFs | These factors released by the inflammatory CAFs enhance the dispersal and migration of tumor cells | [17] |
Interleukin | IL-6 | CAFs | Elevated IL-6 in supernatants of isolated CAFs suppresses HIC1 expression in cancer cells and promotes breast cancer development in the TME through paracrine or autocrine signaling | [66] |
| Â | IL-6 | BCs | miR-216a regulates CAFs crosstalk in cancer cells by modulating the TLR4/IL6 pathway | [67] |
| Â | IL-11 | BCs | Interleukins secreted by BC promote migratory and invasive characteristics of mammary CAFs | [69] |
|  | IL32 | CAFs | CAFs-secreted IL32 promotes breast cancer cell invasion and metastasis through integrin β3-p38MAPK signaling | [68] |