Table 2.
Molecules and factors relating to intranodal LECs and LN metastasis.
| Division | Molecules and Factors | Function and Property | References |
|---|---|---|---|
| LEC-Tumor Cell Interface and Prometastatic Factors | TGF-β | Tumor lymphangiogenesis and extracellular matrix formation; Lymphatic invasion and metastasis via EMT activation |
[120,125] |
| SIX-1 | Promoting tumor lymphangiogenesis and LN metastasis via upregulation of TGF-β and VEGF-C expression, and EMT activation | [121,122,123] | |
| CCL19/CCL21/CCR7 | LN metastatic dissemination of malignant cells; Lymphatic spread by recruiting tumor cells to T cell zone |
[130,131] | |
| CCL1-CCR8 | Mediating entry of tumor cells into LNs; TNF, IL-1β and lipopolysaccharide increase CCL1 production by LECs |
[133] | |
| CXCL12 (SDF-1)/CXCR4 | Controlling tumor metastasis by a lymphatic premetastatic niche | [135] | |
| IL-1 | Promotion of lymphangiogenesis and LN metastasis through M2-type macrophages | [140] | |
| Integrin, ICAM-1, VCAM-1 | Regulation of vascular stability, permeability, leukocyte migration and valve formation; Promotion of LN metastasis by adhesion of tumor cells to LN-LECs, and by establishment of a metastatic niche in LNs |
[40,124,141,142] | |
| TLRs | Heterogeneous expression in LECs derived from different tissues; TLR deficiency is involved in decreased lymphangiogenesis and macrophage infiltration, and abnormal lymphatic architecture; Tumor progression and immune responses; Induction of prometastatic inflammatory response |
[145,146,147,148,149] | |
| PPP2R1A-PPP2R1A homodimers | Expression on tumor cells and LECs; Regulation of cell-cell interactions at the lymphatic-tumor interface |
[150] | |
| LN Lymphangiogenesis and Metastasis | VEGF-C | Abnormal, nonfunctioning or immature lymphatic formation; Promotion of tumor cell survival inside LNs and entry into afferent lymphatics; Increased lymph flow |
[21,153,154] |
| EMILIN-1 | Regulation of tumor phenotype and dormancy; Promotion of premetastatic niche formation and LN Invasion |
[155] | |
| Apelin | Accelerated tumor growth; Increased intratumoral lymphangiogenesis |
[156] | |
| Erythropoietin | Increase of VEGF-C expression in LN macrophages; Increase of LN lymphangiogenesis and nodal metastasis |
[157] | |
| Prostaglandin | LN lymphangiogenesis; Induction of premetastatic niche formation |
[158] | |
| Inhibitors of Lymphatic Metastasis | SphK1 inhibitor | Suppressing lymphangiogenesis in tumor tissues and draining LNs; Suppressing S1P levels and tumor metastases to LNs |
[50] |
| LyP-1 | Inhibiting tumor growth; Reduction of tumor lymphatic numbers |
[159] | |
| BMP-9 | Inhibition of lymphatic formation during tumorigenesis; Induction of dedifferentiation of LECs to BECs by reduction of Prox-1 expression |
[160] | |
| mTOR inhibitors | Reduction of tumor lymphangiogenesis; Prevention of cancer cell dissemination to LNs |
[161,162] | |
| IL-7 | Induction of lymphangiogenesis; Improvement of T-cell survival, numbers and repertoire diversity; Promotion of lymph drainage and antigen transport |
[55,163] | |
| AdVEGF-C, AdVEGF-D | Improvement of survival and functionality of transferred LNs; Increase of lymphatic numbers; Promotion of lymph drainage |
[164] | |
| Blockade of VEGF receptors | Anti-lymphangiogenic therapies; Inhibiting tumor metastasis |
[165] | |
| COX-2 inhibitors | Inhibiting tumor lymphangiogenesis and metastasis | [166,167] | |
| TGF-β inhibitors | Reduction of tumor lymphangiogenesis and LN invasion | [117,168] | |
| Neuropilin-2 inhibitors, Recombinant semaphorin-3C/-3F | Promoting LEC collapse and inhibiting lymphangiogenesis | [169,170,171] |
TGF-β, transforming growth factor-β; SIX-1, sine oculis homeobox homolog 1; CCL19, chemokine (C–C motif) ligand 19; CCL21, chemokine (C–C motif) ligand 21; CCR7, chemokine (C–C motif) receptor 7; CCL1, chemokine (C–C motif) ligand 1; CCR8, chemokine (C–C motif) receptor 8; CXCL12, chemokine (C–X–C motif) ligand 12; CXCR4, chemokine (C–X–C motif) receptor 4; SDF-1, stromal cell-derived factor 1; IL-1, interleukin-1; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1; TLRs, Toll-like receptors; PPP2R1A, protein phosphatase 2 regulatory subunit A, α-isoform; EMILIN-1, elastin microfibril interface-located protein 1; SphK1, sphingosine kinase 1; LyP-1, lymphatic peptide 1; BMP-9, bone morphogenetic protein 9; mTOR, mammalian target of rapamycin; IL7, interleukin 7; AdVEGF-C/-D, adenoviral VEGF-C/-D; COX-2, cyclooxygenase-2; LN, lymph node; LECs, lymphatic endothelial cells; EMT, epithelial-mesenchymal transition; BECs, blood vascular endothelial cells; Prox-1, prospero-related homeobox 1; TNF, tumor necrosis factor.