Table 2.
The roles of different cells in the microenvironment of breast cancer liver metastasis.
| Cell type | Molecules or cytokines | Interaction with other cells |
|---|---|---|
| Cancer stem cells (CSCs) | TGF-β1 pathway promote liver metastasis of breast cancer by inducing the CD44high/CD24- breast cancer stem cell population (68, 69) | Interaction between CSCs and liver microenvironment cells promote metastasis (70, 71) |
| Liver sinusoidal endothelial cells (LSECs) | TNF-α or IL-1 stimulate the attachment of tumor cells to LSECs and lead extravasation (49–51); LSECs secret fibronectin induce EMT and promote metastasis (72); CXCL12, ICAM-1, STAT3, PD-L1 and microRNA-20a expressed by LSECs interact with cancer cells and involve in liver metastasis (64) | Obstruction of the sinusoids by tumor cells can lead ischemia, trigger inflammatory response and damage disseminated tumor cells (73–78) |
| Hepatocytes | Claudin-2 (52, 79–81), E-cadherin (82) promote the adhesion between tumor cells and hepatocytes; hepatocytes release IGF-1 and HGF to promote metastasis (53); HGF-like protein secreted by hepatocytes activate RON to promote metastasis (53) | Tumor-hepatocyte interactions promote liver metastasis (52, 79–83) |
| Liver macrophages | M1 to M2 repolarization induced by IL-4, IL-13 and STAT6 pathway contribute to metastasis (57, 58, 84, 85); PLD-2 promote TAMs infiltration in breast tumor and liver metastasis (86) | M2 macrophage phenotype regulate EMT of breast cancer cells, and promote liver metastasis (39) |
| Kupffer cells (KCs) | KCs relase oxygen metabolites, cytotoxic cytokines, proteases, TNF-α and IL-1β to damage disseminated tumor cells (53, 85, 87, 88); KCs decrease cancer cells by promoting secreting GM-CSF and IFN-γ (53); KCs release growth factors (HGF, VEGF), cytokines (TNF-α, Il-1, IL-1β, IL-6 and IL-10), MMP9 and MMP14 to promote extravasation (49–51, 53) and outgrowth of metastases (53, 59–61) | KCs fused with exosomes secreted from cancer cells and contributed to the premetastatic niche formation (44); KCs damage disseminated tumor cells through recruitment of NK cells (85, 87, 88) |
| Cancer-associated Fibroblasts (CAFs) | CAFs promote metastasis through exhibiting antitumor immune suppression depends on CXCL12 or NOX4 signaling (89, 90) | CAFs modify ECM which may facilitate cancer cell migration or act as barrier (91) |
| Hepatic stellate cells (HSCs) | Activated HSCs promote metastasis through exhibiting antitumor immune suppression response by releasing potent immune suppressor TGF-β (46); HIF-1 activates TWIST and promotes the binding of VEGF to VEGFR to contribute liver metastasis (92); RLN target activated HSCs inhibit metastasis (92) | Activated HSCs promote metastasis by organization of ECs into neo-vessel network (62) and inducing LSECs and ECs to form vascular tube (63); activated HSCs promote metastasis by inducing T cell apoptosis and NK cells quiescence (93, 94); HSCs modify ECM which may facilitate cancer cell migration or act as barrier (91, 95) |
| Neutrophils | Neutrophils inhibit tumor growth by releasing cytolytic factors (40); aged neutrophil promote metastsis by releasing promoting factors (96); neutrophil-derived transferrin promote metastasis (97); loss of p53 in cancer cells triggers WNT-dependent systemic inflammation promote metastasis (98) | Neutrophils inhibit tumor growth through recruiting CD8+ cytotoxic T cells or macrophages (54, 99); physical interaction of neutrophils with tumor cells enhance migration of tumor cells into the extravascular space (55) |
| Myeloid-derived suppressor cells (MDSCs) | MDSCs can be recruited to the metastases by chemokines (CXCL1 and CXCL2) (100); S100A8/Gr1-positive MDSCs (101) can promote growth and aggressiveness of cancer cells by producing arginase and IL-6 (102–104) | Tumor cells recruiting MDSCs can induce immune tolerance state to contribute tumor growth (47, 48) |
| Regulatory T cells (Tregs) | – | Tregs contribute metastasis by inhibiting antitumorigenic T-cell (65) |
TAM, Tumor-associated macrophage; EMT, Epithelial-to-mesenchymal transition; NK cells, Natural killer cells; ECM, Extracellular matrix; EC, Endothelial cell; TGF-β, Transforming growth factor-β; TNF, Tumor necrosis factor; CXCL, Chemokine (C-X-C Motif) ligand; NOX4, Nicotinamide adenine dinucleotide phosphate oxidase 4; IL, Interleukin; STAT, Signal transducer and activator of transcription; PLD, Phospholipase D; HGF, Hepatocyte growth factor; ICAM-1, Intercellular adhesion molecule 1; PD-L1, Programmed cell death-ligand 1; IGF-1, Insulin-like growth factor 1; HIF, Hypoxia induced factor; GM-CSF, Granulocyte macrophage colony stimulating factor; IFN-γ, Interferon γ; MMP, Matrix metalloproteinase; VEGF, Vascular endothlial growth factor; VEGFR, Vascular endothelial growth factor recepter; RLN, Relaxin.