Table 1:

Genes and proteins that mediate migration of metastatic cancer cells through the blood-brain barrier

Gene/Protein	Expression in metastasis	Mechanism of action	Primary tumor	Refs
ADAM8	Overexpression	Upregulated MMP9	Breast cancer	[41]
Adenosine A2A receptor	Downregulation	Inhibition of the A2A receptor downregulates expression of CLDN5, occludin and ZO-1	NSCLC	[98]
AKR1B10	Overexpression	Affects the expression of MMP-2 and MMP-9 via MEK/ERK signaling	NSCLC	[43]
ALCAM	Overexpression	Increases cancer cell adhesion to endothelial cells	NSCLC	[70]
Angiopoietin-2	Overexpression	Changes ZO-1 and claudin-5 tight junction protein structures	Breast cancer	[22]
Annexin A1	Overexpression	Cancer cell expresses high levels of annexin A1 and releases it outside, facilitating entry into brain	SCLC	[83]
Cathepsin S	Overexpression	Induces the proteolysis of the junctional adhesion molecule, JAM-B	Breast cancer	[23]
CEMIP	Overexpression	Uptake of CEMIP+ exosomes by brain endothelial and microglial cells induce endothelial cell branching and inflammation leading to vascular remodeling and metastasis	Breast cancer	[58]
CLDN5	Downregulation	Untightens endothelial cellular adhesion and destabilize the tight junctions	Lung cancer	[95]
COX2	Overexpression	Facilitates the angiogenic formation of new blood vessels that help tumor cells connect to the circulation	Breast cancer	[71, 72]
CXCR4	Overexpression	Activates the PI3K/AKT signaling	Breast cancer	[80]
Desmin+	Overexpression	-	Breast cancer	[16]
FUT4	Overexpression	Codes for CD15 expression that increases adhesion of metastatic cancer cells to the BBB	Lung cancer	[86]
FUT7	Overexpression	Codes for CD15s expression that increases adhesion of metastatic cancer cells to the BBB	Lung cancer	[86]
GBP1	Overexpression	Induced by the T cells upon interaction with breast cancer cells vamps the metastatic potential	Breast cancer	[82]
HBEGF	Overexpression	Activated EGF receptors and their downstream signaling.	Breast cancer	[71, 73]
Heparanase	Overexpression	Degrading and compromising ECM structural integrity leading to the release of growth factors, chemokines, and angiogenic factors that are important for the passage of metastatic cancer cells. Promotes Akt signaling and stimulates PI3K- and p38-dependent endothelial cell migration and invasion	Melanoma	[50–52]
Laminin α2	Downregulation	-	Breast cancer	[16]
MFSD2a	Downregulation	Increased the propensity of brain metastasis by reducing DHA transport and altering lipid metabolism	Breast cancer Lung cancer Prostate cancer	[88]
miR-105	Overexpression	Targets the tight junctional protein ZO-1	Breast cancer	[55]
miR-143–3p	Overexpression	Inhibits VASH1 expression and triggers proteasomal mediated degradation of endothelial junctions	Lung cancer	[57]
miR-181c	Overexpression	Delocalize actin by downregulating phosphoinositide-dependent kinase-1 (PDPK1)	Breast cancer	[56]
miR-509	Downregulation	Increases RhoC and TNF-α that control the invasion of cancer cells and the trans-endothelial cell migration through MMP9.	Breast cancer	[94]
MLCK	Overexpression	Activated at the adhesion site, leading to regional myosin contraction and, eventually, intravasation of the tumor cell	Breast cancer	[81]
MMP1	Overexpression	ECM degrading capacity and facilitate the angiogenic formation of new blood vessels	Breast cancer	[38]
MMP2	Overexpression	Deregulation of the MAPK pathway	Breast cancer	[40]
PLEKHA5	Overexpression	Adaptor protein that mediates Phosphoinositide 3-kinases (PI3K) signaling	Melanoma	[78]
PLGF	Overexpression	Activation of Rho/ROCK followed by activation of ERK1/2 and Ser/Thr phosphorylation of occludin	SCLC Breast cancer Colorectal cancer Gastric cancer	[44–48]
Rab7	Downregulation	Increases endothelial recycling endocytic transcytosis	Breast cancer	[99]
Rho GTPase	Overexpression	Increasing actomyosin contractility	SCLC	[64]
S1P3	Overexpression	Release of IL-6 and CCL2, which causes relaxation of the tight junctions between endothelial cells	Breast cancer	[54]
Sdc1	Overexpression	Increased adhesion to the perivascular regions of the brain and led to eventual trans-endothelial migration	Breast cancer	[85]
SEMA4D	Overexpression	Binds to Plexin-B1 receptors in pericytes to promote pro-inflammatory responses that disrupts BBB endothelial tight junctions	Breast cancer	[61]
Seprase	Overexpression	Formation of proteinase-rich membrane domains by these enzymes is believed to contribute to the ECM degradation	Melanoma	[24]
Serine Protease	Overexpression	Apoptotic induction of the endothelial cells and disruption of tight junctions	Melanoma	[20]
Slug	Overexpression	Binds to the promoter region of MMP1 in breast cancer cells, leading to its overexpression	Breast cancer	[39]
ST6GALNAC5	Overexpression	Enhances adhesion of cancer cells to brain endothelial cells	Breast cancer	[71]
TNF	Overexpression	TNF receptor-1 pathway	Breast cancer	[21, 22]
uPA	Overexpression	Formation of proteinase-rich membrane domains by these enzymes is believed to contribute to the ECM degradation	Melanoma	[24]
VASH1	Downregulation	Triggers proteasomal mediated degradation of endothelial junctions	Lung cancer	[57]
Visfatin	Overexpression	Upregulation of the cytokine CCL2, which opens the tight junctions	SCLC	[53]
VLA-4	Overexpression	Induces cells to intercalate into the tight monolayer of endothelial cells causing its destabilization	Melanoma	[69]
αB-crystallin	Overexpression	Adhesion occurs via α3β1 integrin-dependent mechanism	Breast cancer	[84]
αv-integrin	Overexpression	Influence cancer cell attachment and angiogenesis	Breast cancer Lung cancer Renal cancer Melanoma	[67]