Table 2.
Tumor lymphangiogenic growth factors and their receptors.
| Lymphangiogenic factors | Receptors | Mechanism of action/association with cancer | References |
|---|---|---|---|
| VEGF-C | VEGFR-2, VEGFR-3 | (i) Overexpression of VEGF-C by tumor induces tumor lymphangiogenesis, dilated lymphatics and increases metastasis to lymph node. (ii) Proteolytic VEGF-C also binds to VEGFR-2 and therefore can also induce tumor angiogenesis |
[77–80, 94] |
|
| |||
| VEGF-D | VEGFR-2, VEGFR-3 | (i) VEGF-D plays a role in stimulation of tumor lymphangiogenesis and lymph node metastasis. (ii) Proteolytic VEGF-D also binds to VEGFR-2 and can induce tumor angiogenesis. |
[98–100, 108] |
|
| |||
| VEGF-A | VEGFR-2 | (i) VEGF-A induces tumor lymphangiogenesis and tumor metastasis to regional lymph node. | [105] |
|
| |||
| FGF-2 | FGFR-3 [109] | (i) Induces both angiogenesis and lymphangiogenesis through the control of VEGF-C and VEGF-D expression. (ii) Increased expression of FGF-2 is associated with lymphatic metastasis. |
[110, 111] |
|
| |||
| Hepatocyte growth factor (HGF) | c-met | (i) Overexpression of HGF in mice/intradermal delivered HGF induces lymphatic vessel hyperplasia. (ii) HGF stimulate the outgrowth of peritumoral lymphatics, via activation of VEGFR-3. (iii) HGF contribute to lymphatic metastasis when overexpressed in tumor. |
[112, 113] |
|
| |||
| Insulin-like growth factor-1, 2 | Insulin-like growth factor receptor | (i) IGF-1, -2 induce lymphangiogenesis in a mouse cornea assay. (ii) IGF-IR is involved in angiogenesis and lymphangiogenesis through modulation of VEGF ligand expression in gastric cancer cell line MKN45. |
[106, 114] |
|
| |||
| Ephrin-B2 | Eph. receptor tyrosine kinase | (i) PDZ interaction site in Ephrin-B2 is required for the remodelling of lymphatic vasculature. (ii) Tumor angiogenesis was inhibited in Ephrin-B-mutant mice in an orthotopic glioma tumor model. |
[30, 115] |
|
| |||
| Angiopoietin-1, -2 (Ang-1, -2) | Tie-2 | (i) Overexpression of Ang-1 in adult mouse tissues leads to lymphatic sprouting and hyperplasia. (ii) Ang-1 is moderately expressed by tumor cells; Ang-2 is expressed by activated endothelial cells and upregulated during tumorigenesis. (iii) Ang-2 levels are associated with disease progression in melanoma patients. |
[55, 116, 117] |
|
| |||
| PDGF-BB | PDGFR-α and -β | Expression of PDGF-BB in murine fibrosarcoma cells induced intratumoral lymphangiogenesis and promote lymphatic metastasis | [118] |
|
| |||
| Growth hormone (GH) | Growth hormone receptor | (i) GH promotes lymphangiogenesis in the granulation tissue of full-thickness skin wounds. (ii) Ectopic GH expression has been found in breast cancer and pancreatic cancer tissue. |
[119–121] |
|
| |||
| Adrenomedulin (AM) | Calcrl associated with RAMP2 (*) | AM is a multifunctional regulatory peptide that is overexpressed in cancer cells and help them to develop to malignant growth. | [122] |
|
| |||
| Endothelin-1 (ET-1) | Endotheline B receptor (ETBR) | (i) ET-1/ETBR expression is correlated with lymphatic invasion in human breast cancers. (ii) ET-1/ETBR enhances VEGF-A/C and VEGFR-3 expression and induces formation of lymphatic vessels. (iii) ET-1 is one of significantly upregulated genes in LEC isolated from metastatic LN. |
[123–125] |
|
| |||
| Neutrin-4 | (i) Netrin-4 is expressed in human breast tumor lymphatic and blood vessels. (ii) In mouse model of netrin-4 overexpressing breast cancer, lymph node metastasis and lung metastasis were significantly increased. (iii) Netrin-4 stimulates lymphatic permeability via activation of small GTPase and Src family kinase/FAK and downregulating tight junction protein. |
[126] | |
|
| |||
| Fibronectin | Integrin α4β1 | High expression of integrin α4β1 is detected on tumor lymphatic endothelium. | [127] |
*Calcrl: calcitonin receptor-like receptor; RAMP2: receptor activity-modifying protein.