Table 1 A summary of the determinative molecules and related mechanisms that guide induction towards various target organs

Lung

Exosomal RNA

Recognition of exosomal RNA by TLR3 induces the expression of HAO1 in alveolar epithelial cells, leading to excessive oxalate production. Accumulation of oxalate in the lungs initiates the formation of neuroendocrine tumours, thereby triggering premetastatic niche genesis.

[83]

Lin28B

Lin28B sourced from tumour-derived exosomes also instigates the production of IL-6 and IL-10 within the premetastatic niche, sufficiently prompting N2 conversion to upregulate PD-L2 and induce a dysregulated cytokine milieu, resulting in peritumoral immune suppression and fostering premetastatic niche formation.

[84]

ANGPTL2

The tumour-secreted ANGPTL2 activates the integrin α5β1 receptor on nonepithelial cells, inducing the production of chemotactic factors that drive the recruitment of neutrophils, thereby playing a role in the establishment of the premetastatic niche.

[85]

Oxysterols

The oxysterol 27-HC recruits immunosuppressive neutrophils within the metastatic niche and reprograms the tumour microenvironment through sulfotransferase 2B1b-mediated oxysterol depletion, favouring control over the formation of breast tumours and metastasis.

[86]

Breast

Morgana

Morgana is indispensable for bridging the IKK (IκB kinase) complex to its substrate IκBα (NF-κB inhibitor α), initiating subsequent NF-κB activation within primary tumours and inducing the production of diverse cytokines. These cytokines have the capability to modulate NK cell inactivation and neutrophil recruitment, thereby fostering metastatic progression.

[87]

Lymph nodes

EV

Primary tumours continuously secrete extracellular vesicles (EVs), which are actively taken up by lymphatic endothelial cells. Subsequently, lymphatic endothelial cells secrete CXCL8 or CXCL2 upon receiving EVs. Both CXCL8 and CXCL2 serve as potent neutrophil chemoattractants and effective inducers of neutrophil extracellular trap (NET) formation.

[88]

FGF19

FGF19 induces the phosphorylation of the cancer cell transcription factor ETV4, increasing the recruitment of tumour-associated neutrophils (TANs) by cell-derived chemokines C-X-C motif ligands (CXCL) 1/8 and resulting in increased levels of vascular endothelial growth factor A (VEGFA) and matrix metalloproteinase-9 (MMP9) to promote lymphatic vessel formation and the LN metastasis of primary carcinomas.

[89] [90]

Liver

FGF19

FGF19 activates the autocrine effect of IL-1α via the FGFR4-JAK2-STAT3 pathway, mediating the polarization of hepatic stellate cells towards inflammatory cancer-associated fibroblasts (iCAFs). FGF19-induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation by generating complement C5a and IL-1β, thereby facilitating metastasis.

[91]

CEMIP

CEMIP has the potential to increase the hepatic infiltration of immunosuppressive neutrophils through the TGFβ-chemokine (C-X-C motif) ligand (CXCL)3/1-CXCR2 axis, thereby promoting the formation of the premetastatic niche.

[92]

CXCL-8

A positive feedback loop exists between tumoral IL-8 and NETs, culminating in the substantial generation of NETs at metastatic sites within the liver and thereby facilitating the successful metastasis of the tumour.

[93]

Mesothelin

Mesothelin secreted by pancreatic cancer cells initially stimulates macrophages to produce a large amount of S100A9. This protein can guide neutrophil infiltration of the lungs and the formation of neutrophil extracellular traps to facilitate successful metastasis.

[94]

Brain

C-Met

The overexpression of c-Met in premetastatic sites promotes the secretion of various inflammatory cytokines, including CXCL1/2 and G/GM-CSF, thereby increasing the infiltration and survival of neutrophils. This process leads to the substantial production of LCN2 by neutrophils, facilitating the settlement and progression of tumour cells.

[95]

CXCL1

The substantial amount of CXCL1 produced within brain metastatic foci is recognized and bound by CXCR2 on the surface of neutrophils, leading to the recruitment of a significant number of neutrophils into the metastatic site. This process results in the generation of a large quantity of NETs, thereby promoting the success of metastasis.

[96]

Pancreas

collagen

In the cancer microenvironment, activation of DDR1 in cancer cells under the influence of collagen becomes the primary stimulus for CXCL5 production. This activation leads to the recruitment of neutrophils into premetastatic organs, the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell metastasis.

[97]

CXCL2

Neutrophil-secreted CXCL1 and 2 from tumours can be carried into premetastatic sites by exosomes, thereby inducing the entry of neutrophils. These neutrophils express growth arrest-specific 6 (Gas6), leading to the activation of the AXL receptor on tumour cells and enabling their successful colonization and progression.

[98]