Table 2.

Factors of secondary soil-to-seed signals involved in promoting metastasis

Metastatic sites	Molecules	Cell type	Underlying mechanisms	Cancer type	Ref
Lung	POSTN	Stromal cells	POSTN expressed in stroma recruits Wnt ligands and thereby increases Wnt signaling in cancer stem cells.	Breast cancer	[27]
	MMP9/ VEGFR-1TK	Macrophages Endothelial cells	MMP9 is specifically induced in pre-metastatic lung endothelial cells and macrophages, thus promoting metastasis.	Lung cancer Melanoma	[119]
	α4-integrins	Macrophages	Macrophage binding to receptor VCAM-1 in cancer cells transmits survival signals.	Breast cancer	[120]
	CCL5	Endothelial cells	CCL5 expression enhances lung colonization by recruiting innate immune cells to the metastatic microenvironment.	Colorectal cancer	[121]
	S100A8/ S100A9	Undetermined	Upregulation of chemoattractants and recruitment of myeloid cells facilitate the pre-metastatic niche formation.	Lung cancer Melanoma	[122]
	IFN-γ/ MMP9	Myeloid cells	Remodel the pre-metastatic lung into an inflammatory and proliferative environment, thus diminishes immune protection.	Breast cancer	[123]
	Versican	Myeloid Progenitor Cells	Versican induces mesenchymal to epithelial transition of metastatic cancer cells by attenuating phospho-Smad2 levels.	Breast cancer	[124]
	Leukotrienes	Neutrophils	Neutrophil-derived leukotrienes aid lung colonization by selectively expanding cancer cells with tumorigenic potential.	Mammary tumor	[125]
	PHD proteins	T cells	PHD proteins function in T cells promoting lung colonization by establishing an immunologically tolerant metastatic niche.	Melanoma	[126]
Liver	Undetermined	Hepatic stellate cells (HSCs)	HSCs play a critical role in mediating pro-metastatic niche.	Colorectal cancer	[127]
	Granulin	Metastasis-associated macrophages (MAMs)	MAMs activate resident hepatic stellate cells (hStCs) to transition into myofibroblasts, thus promoting metastasis.	PDAC	[128]
	MIF	Hepatic sinusoidal endothelial cells (HHSECs)	MIF enhances migration and EMT and facilitates proliferation and apoptotic resistance in cancer cells.	Colorectal cancer	[129]
	Angiopoietin-like 6	Undetermined	Angiopoietin-like 6 accumulates in normal vessels and interacts with the cancer cell, thus promoting colonization.	Colorectal cancer	[130]
	LSECtin	Undetermined	LSECtin expressed in liver promotes colon carcinoma cell adhesion and migration.	Colorectal cancer	[131]
Bone	Fibronectin	BMDCs	BMDCs upregulate fibronectin in resident fibroblasts, facilitating the pre-metastatic niche formation.	Lung cancer Melanoma	[132]
	N-cadherin	Osteogenic cell	Osteogenic niche activates the mTOR pathway in cancer cells, promoting bone colonization.	Breast cancer	[133]
	CCL5/MMP	Osteocytes	Upregulation of CCL5 and MMP in osteocytes promotes cancer invasion and growth.	Prostate cancer	[134]
	Extracellular ATP adenosine	Osteocytes	ATP and adenosine released by osteocytes promotes cancer cell migration, growth and metastasis.	Breast cancer	[135]
Brain	Extracellular matrix	Astrocytes	Extracellular matrix secreted by astrocyte stimulates cancer cell proliferation and EMT process.	Prostate cancer	[136]
	IL-23	Astrocytes	Astrocyte-derived molecules facilitate metastasis by enhancing invasion of cancer cell.	Melanoma	[137]
	Exosomal miRNAs	Astrocytes	Astrocyte-derived factors induce PTEN loss in cancer cells, promoting brain metastasis outgrowth.	Breast cancer	[138]