Table 3.
Growth factors associated with tumor cell extravasation across the blood–brain barrier and the formation of brain metastases
| Growth factors | Findings | Primary tumor | Refs |
|---|---|---|---|
| CCL7 | Brain-metastasizing tumor cells secrete MMP1 and COX-2, inducing CCL7 expression by activated astrocytes. This promotes BBB permeability and the formation of brain metastasis in vivo | Breast cancer | [121] |
| CX3CL1 and CXCL13 | In vitro BBB permeability increases after applying sera from breast cancer patients with brain metastases, but was not increased with sera from patients with bone or visceral metastases. Significantly increased levels of the chemokines CX3CL1 and CXCL13 were only detected in the sera from the brain metastatic sera, which correlated with the tumor’s estrogen/progesterone receptor status | [150] | |
| CXCL12 and CXCL16 | Brain metastases-associated fibroblasts express significantly higher levels of CXCL12 and CXCL16 than fibroblasts from primary tumors or normal breast tissue, increasing tumor cell migration. Inhibition of CXCR4 or CXCL16 reduces tumor cell migration towards brain metastases-associated fibroblasts | [147] | |
| IL8, IL1β, CXCL1, and HGF | Secretion of IL8 and CXCL1 is induced by c-Met signaling resulting from tumor cell adhesion to the brain endothelium. Additional IL1β secretion causes the release of HGF by astrocytes creating a feed-forward loop c-Met/HGF. Inhibition of c-Met inhibits brain metastases in vivo. IL1β is able to disrupt BBB integrity and is able to enhance tumor cell migration. Astrocytes are activated by brain metastatic tumor cells expressing IL1β, upregulating the expression of Notch ligand, which increases cancer stem-like cell proliferation. A Notch inhibitor significantly reduced metastatic outgrowth in vivo | [142, 146, 153] | |
| IL6 and CCL2 | Tumor cell overexpression of astrocytic sphingosine-1 phosphate receptor 3 (S1P3) enhances IL6 and CCL2 production by astrocytes, increasing BBB permeability. Inhibition of S1P3 significantly reduces disruption of the BBB both in vitro and in vivo | [148] | |
| CCL5 | In this triple-negative breast cancer study, microglia adopt a M2 phenotype in response to estrogen, reducing anti-tumor immune functions. Metastasis outgrowth is stimulated by microglia-secreted CCL5 in response to estrogen. Tamoxifen treatment and ovariectomy reduces microglial polarization and brain metastatic outgrowth in vivo | [152] | |
| CXCL10 | Cxcl10 mediates recruitment of VISTAHi/PD-L1+ immune-suppressive CNS-native myeloid cells to brain metastatic tumors. Antibody blockage of VISTA and PD-L1 signaling reduces tumor outgrowth in vivo | [151] | |
| NT-3 | NT-3 mRNA levels significantly higher and NGF, BDNF and NT-4/5 mRNA levels significantly lower in brain metastatic tumor cells. In EMT-like tumor cells, ectopic NT-3 expression reduces migratory ability and increases HER2 and E-cadherin expression. The number of fully activated cytotoxic microglia is reduced by the endogenous and ectopic expression of NT-3 | [172] | |
| TGFβ2, TNF, and IL1β | Astrocytes produce TGF-β2 in response to tumor cell secreted IL-1β and TNF-α, upregulating Angiopoietin-like 4. Knockdown of Angiopoietin-like 4 reduces tumor cell outgrowth and improves survival in vivo | [169] | |
| Angiopoietin-2 | Angiopoietin-2 expression increased in tumor cells, associated with increased TJ disruption, and increased BBB permeability. Inhibiting angiopoietin-2 prevents BBB disruption and inhibits metastases formation in vivo | [143] | |
| CXCL1, IL6, IL8, CSF-2, and CCL5 | Tumor secretome upregulation in CXCL1, ICAM-1, IL6, IL8, CSF-2, and CCL5 compared to syndecan-1-silenced cells. Silencing of syndecan-1 significantly reduces brain metastases in vivo, while overexpressing increases metastases formation | [149] | |
| IL6 | Brain metastatic tumor cells induce immunosuppression via IL6 influence on programmed death-ligand-1 expressing myeloid cells. Tumor-related IL6 is also induces M2 microglia via JAK2/STAT3 signaling, promoting brain colonization | Lung cancer | [157, 158] |
| IGF-1 and CCL20 | Nicotine enhances brain metastases by inducing M2 microglia phenotype, which increases the secretion of IGF-1 and CCL20, promoting metastatic outgrowth. Blocking M2 polarization reduces brain metastases in vivo | [159] | |
| CSF-3 | In brain metastatic tumor cells, pY696-EZH2-driven release of CSF-3 stimulated the recruitment of immunosuppressive neutrophils, which enhanced metastatic outgrowth. Anti-CSF-3 antibodies or immune checkpoint blockade therapies combined with Src inhibitors reduced tumor outgrowth in vivo | [162] | |
| VEGF-A and TNF-α | Tumor cell secreted factors, including VEGF-A and TNF-α, increase E-selectin expression and damage the glycocalyx on cerebral endothelial cells in vitro. Endothelial glycocalyx degradation correlates with increased tumor cell adhesion. Inhibition of E-selectin attenuates tumor cell adhesion | [155] | |
| MIF, IL8, IL6, TNF, and IL1β | Tumor cell factors, including MIF, IL-8 and plasminogen activator inhibitor-1 (PAI-1), activate astrocytes in vitro. Activated astrocytes secrete IL-6, TNF-α and IL-1β, promoting tumor cell proliferation | [154] | |
| TNF | Increased expression of TNF facilitates E-selectin adhesion of tumor cells to brain endothelium via CD15 | [156] | |
| TGF-β | PREP1 modulates tumor cell sensitivity to TGF-β and is involved in EMT, facilitating metastases. Accumulation of PREP1 detected in human brain metastatic lesions | [161] | |
| HGF | Co-overexpressing HGF and its receptor Met produces increased metastases, including to the brain | [144] | |
| CCL17, CCL2, CXCL10, IL6, and IL1β | Upregulation of CCL17, CCL2, CXCL10, IL6, and IL-1β are associated with astrogliosis in the early stages of the metastatic cascade. CCL17 is also upregulated in vemurafenib-resistant melanoma cells in vivo | Melanoma | [163, 164] |
| TNF | TNF and MMP2 expression is associated with tumor cell aggressiveness. TNF inhibition reduces proliferation rate in 3 out of 4 tumor cell lines with the highly aggressive A375 cell line showing lower sensitivity to inhibition | [124] | |
| TGF-β2 | TGF-β2 is a site-specific growth factor for the brain parenchyma but not for the leptomeninges and ventricles | [165] | |
| CXCL10 | CXCL10 is upregulated in tumor-associated astrocytes in vivo, enhancing tumor cell migration toward astrocytes. The receptor for CXCL10, CXCR3 is increased in neurotropic tumor cells. Inhibiting CXCR3 expression reduces the formation of brain metastases in vivo | [166] | |
| IL23 | IL23 is highly expressed by metastases-associated astrocytes in vivo, increasing tumor cell MMP2 secretion and invasiveness. Knocking down MMP2 or blocking IL23 halted this increase in tumor invasion | [167] | |
| CCL7 | CCR2 and CCL7 expression was significantly greater in brain metastatic tumor cells compared with primary tumor cells | Renal cell cancer | [168] |
| CCL23, CXCL5, CXCL8, CCL8, CCL13, CCL17, and CCL18 | In brain metastases, tumor-associated immune cells releases chemokines, including microglia (CXCL5 and CXCL8), monocyte-derived macrophages (CCL8, CCL13, CCL17, and CCL18) and tumor-associated macrophages (CCL23) | Multiple types | [247] |
| CCL2 | Astrocyte-expressed CCL2 promotes tumor cell chemotaxis and chemokinesis without disrupting the BBB in vitro and in vivo. CCR2-deficient tumor cells show significantly reduced arrest and extravasation in vivo | [170] | |
| MIF | PhosphoSTAT3 + reactive astrocytes associated with brain metastatic tumors reduce CD8 + T-cell activity and increase CD74 + microglia/macrophages population via a MIF–CD74–midkine axis, supporting tumor immune evasion | [171] | |
| VEGF | Tumor cell expression of the VEGF mRNA and protein positively correlates with angiogenesis and growth of brain metastases | [248] |