Table 1.

Mediators of microenvironment as enhancers of mCRC progression.

Molecule	Role	References
VEGF	Stimulate migration of myeloid cells to metastatic niche	[9]
	Angiogenesis	[3] [10] [8]
	Chemoattractant for macrophages (VEGFA)	[3]
	Stimulate lymphangiogenesis (VEGFA, C, D)	[3] [8] [18]
TNF-α	Stimulate migration of myeloid cells to metastatic nice	[9] [10]
	Pro-inflammatory	[9] [10]
	Extravasation	[6]
	Immunosuppression	[5]
TGF-β	Stimulate migration of myeloid cells to metastatic nice	[9]
	TME remodeling	[11]
	Pro-inflammatory	[9] [10]
	Macrophage polarization to M2 phenotype	[5]
	Fibroblast activation	[10,19]
CXCL5	Liver metastasis	[11]
CCR6	Liver metastasis	[11]
	Tumor cell recruitment	[16]
EGF	TME remodeling	[11]
IGF	TME remodeling	[11]
Glutamate	Liver metastasis	[12]
ICAM and VCAM	Cell adhesion	[6]
	Extravasation	[6]
MMP	TME remodeling (MMP-2, -9, -13)	[11]
HIF-1	Formation of pre-metastatic nice	[9]
	Extravasation	[8]
CXCR4	Local tumor expansion	[3]
	Extravasation	[3]
CXCL2 CXCL3 CXCL8	Hepatic metastasis (CXCL2)	[3]
	Promote tumor vascularization	[3] [11]
CTLA-4	Immunosuppression	[5]
	Macrophage polarization to M2 phenotype	[5]
PD-1	Immunosuppression	[5]
PDL-1	CD8+ T cell suppression	[9]
CXCL1 CXCL2	MDSC recruitment	[5]
	T-cell inhibition	[5]
CCL5	Liver metastasis	[3]
	T-cell inhibition	[5]
ROS	T-cell inhibition	[5]
ARGINASE	T-cell inhibition	[5]
IL2	Immunosuppression	[5]
	Macrophage polarization to M2 phenotype	[5]
IL10	Immunosuppression and macrophage polarization to M2 phenotype	[5]
IL6	Promote extravasation from lymphatic vessels	[8,20]
	Inflammation	[8]
CCL20	Liver metastasis (attraction of CCR6+ tumor cells)	[16]
CEA	Liver metastasis	[17]
INTEGRINS	Cell adhesion	[6]
	Liver metastasis (α6β1, α6β4, α2β1, αvβ6, αvβ5)	[15] [10] [21]
OSTEOPONTIN	Liver metastasis	[15]