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| Lymphangiogenic factors | Receptors | Mechanism of action/association with cancer | References |
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| 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] |
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| 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] |
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| VEGF-A | VEGFR-2 | (i) VEGF-A induces tumor lymphangiogenesis and tumor metastasis to regional lymph node. | [105] |
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| 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] |
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| 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] |
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| 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] |
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| 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] |
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| 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] |
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| PDGF-BB | PDGFR-α and -β | Expression of PDGF-BB in murine fibrosarcoma cells induced intratumoral lymphangiogenesis and promote lymphatic metastasis | [118] |
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| 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] |
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| 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] |
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| 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] |
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| 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] |
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| Fibronectin | Integrin α4β1 | High expression of integrin α4β1 is detected on tumor lymphatic endothelium. | [127] |
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