Table 3.

Factors that mediate extravasation during brain metastasis of melanoma.

Step of Extravasation	Factor	Effect	Regulation in BM	Reference
Adhesion	Pericytes	Secrete high amounts of extracellular matrix proteins and enhance adhesion.	Activation	[38]
	PI3K/AKT EndMT (TGF-β-dependent manner)	Enhance adhesion and transmigration.	Upregulation	[74] [75]
	VLA-4 (integrin α4β1)	Interacts with endothelial VCAM-1 to facilitate adhesion of melanoma cells to the BBB.	Upregulation	[119]
Alteration in the BBB permeability	EndMT (TGF-β-dependent manner)	Reduces expression of claudin-5 and VE-cadherin.	Upregulation	[75]
	STAT3	Upregulates MMP2 expression and subsequently enhances BM.	Upregulation	[102]
	MMP2 and MMP9	Disrupts BBB.	Upregulation	[103]
	S100A4	Interacts with RAGE to induce degradation of inter-endothelial junctions, occludin, and VE-cadherin.	Upregulation	[105]
	IL-23	Produced by astrocytes to induce TEM; upregulates MMP2 expression in melanoma cells.	Upregulation	[115]
Degradation of the basement membrane	Serine proteases	Degrades basement membrane components, mediating extravasation.	Upregulation	[106]
	Seprase and uPAR	Forms a membrane complex to degrade ECM.	Upregulation	[107]
	HPSE-1	Degrades ECM of BBB.	Upregulation	[108]
Trans-endothelial migration	PI3K/AKT	Induces adhesion and transmigration.	Upregulation	[74]
	EndMT (TGF-β dependent manner)	Enhances adhesion and transmigration.	Upregulation	[75]
	S100A4	Promotes transmigration of melanoma cells.	Upregulation	[105]
	PLEKHA5	Induces transmigration through mediating PI3K/AKT pathway.	Upregulation	[110]
	Plasminogen	Promotes TEM.	Upregulation	[111]
	MTf	Promotes TEM.	Upregulation	[114]
	IL-23	Produced by astrocytes to induce TEM. Upregulates MMP2 expression in melanoma cells.	Upregulation	[115]
	CXCL10	Produced by astrocytes to enhance migration of melanoma cells toward astrocytes via secretion of CXC3R.	Upregulation	[116]
	CCR4	Interaction of CCR4 with its ligand CCL17 promotes TEM of melanoma cells.	Upregulation	[117]