Background
Seed factors
EMT-MET and metastasis
CSCs and metastasis
Autophagy and metastasis
Metastatic dormancy
Tumor-secreted factors
Tumor-secreted extracellular vesicles (EVs)
Tumor-secreted cytokines and chemokines
Other molecular components
CTCs and metastasis
Soil factors (Fig. 2)
The primary soil factors
Stroma cell type | Molecules | Underlying mechanisms | Cancer type | Ref |
---|---|---|---|---|
TAMs | miR-223 | Regulates the invasiveness of cancer cells through exosome-mediated delivery of oncogenic miRNAs. | Breast cancer | [89] |
CCL18 | Promotes the invasiveness of cancer cells by triggering integrin clustering and enhancing their adherence to extracellular matrix. | Breast cancer | [90] | |
CCL20 | CCL20 secreted by TAMs enhances the invasive properties of cancer cells via its unique receptor CCR6. | Pancreatic cancer | [91] | |
Lcn2 | TAM-derived Lcn2 promotes cancer cell dissemination by inducing EMT and resulting in increased cancer cell motility and invasion. | Breast cancer | [92] | |
MSCs | CCL5/ CCR9 | MSC-derived chemokines act on cancer cells to enhance their motility, invasion and metastasis. | Breast cancer | |
DDR2 | MSC-derived DDR2 in the primary tumor endows cancer cells with growth and migratory advantage through alignment with collagen. | Breast cancer | [95] | |
ECs | PHD2 | Haplodeficiency of PHD2 normalizes the endothelial lining and vessel maturation, resulting in inhibited metastasis. | Melanoma Lung cancer Pancreatic cancer | [96] |
IL6 | EC-derived IL-6 triggers the increased invasion of cancer cell. | Prostate cancer | [97] | |
Undetermined | EC-bound tumor cells show a significantly higher anoikis resistance via the activation of Src-FAK pathway. | Squamous carcinoma | [98] | |
CAFs | SDF-1/CXCL12 | Promote tumor growth and angiogenesis through their ability to secrete stromal cell-derived factor 1 (SDF-1). | Breast cancer | [99] |
Cav1 | Stromal Cav1 remodels peri- and intratumoral microenvironments to facilitate tumor invasion, correlating with increased metastatic potency. | Breast cancer | [100] | |
Exosomes | Fibroblast-secreted exosomes promote breast cancer cell protrusive activity and motility via Wnt-planar cell polarity (PCP) signaling. | Breast cancer | [101] | |
Adipocytes | Undetermined | Adipocytes promote tumor cell invasion and EMT program. | Melanoma | [105] |
Undetermined | Pre-adipocytes increase prostate cancer metastasis via modulation of signaling pathways. | Prostate cancer | [106] | |
IGFBP-2 | Adipocytes stimulate invasion of cancer cells by secreting IGFBP-2. | Breast cancer | [107] |
Tumor-associated microphages (TAMs)
Mesenchymal stem cells (MSCs)
Endothelial cells
Carcinoma-associated fibroblasts (CAFs)
Adipocytes
Other cellular and molecular components
Hypoxia in primary soil
The secondary soil factors
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] |