Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 26, Issue 23, Pages -Publisher
WILEY
DOI: 10.1111/jcmm.17571
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Funding
- Association of African Universities (AAU)
- National Research Foundation (NRF) of South Africa
- School of Medicine Research Committee
- Faculty of Health Sciences, small grants programme
- University of Pretoria, Pretoria, South Africa
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VEGF-C binds to VEGFR-3 and CXCR-4, activating signaling pathways that regulate cell migration and adhesion. Blocking VEGFR-3 and CXCR-4 could potentially inhibit tumor cell metastasis and adhesion.
Vascular endothelial growth factor-C (VEGF-C) binds to receptor vascular endothelial growth factor receptor-3 (VEGFR-3) expressed on lymphatic endothelial and melanoma cells. Binding of VEGF-C to VEGFR-3 enhances receptor phosphorylation that activates mitogen-activated protein kinase (MAP-K) and phosphatidylinositol-3-kinase (PI3K). These signalling pathways regulate cell migration and adhesion in response to internal or external changes.In addition, the overexpression of VEGF-C upregulates chemokine receptor CXCR-4 in tumours (melanoma). CXCR-4 is expressed on cells of the immune system (natural killer cells) and facilitates the migration of leukocytes in response to the CXCL12 ligand. The latter is expressed by lymphatic endothelial cells and by stromal cells in the tumour microenvironment (TME). The gradient established between CXCR-4 expressed on tumour cells and CXCL12 produced by stromal and lymphatic endothelial cells enhances tumour cell metastasis.3-(4-Dimethylamino-naphthalen-1-ylmethylene)-1, 3-dihydroindol-2-one, MAZ-51, is an indolinone-based synthetic molecule that inhibits the phosphorylation of the tyrosine kinase receptor VEGFR-3. CTCE-9908, a CXCR-4 antagonist derived from human CXCL12, hinders receptor phosphorylation and the subsequent signalling pathways that would be activated.VEGF-C is stimulated by transforming growth factor-beta 1 (TGF-beta 1), which facilitates cell-cell and cell-matrix adhesion by regulating cadherins through the activation of focal adhesion kinase (FAK) and mediates paxillin upregulation.Increased VEGF-C protein levels stimulated by TGF-beta bound to VEGFR-3 impact on intracellular pathways that promote tumour cell adhesion. In addition, increased VEGF-C protein levels lead to enhanced CXCR-4 protein expression. Therefore, effective blocking of VEGR-3 and CXCR-4 may inhibit tumour cell metastasis by hampering intracellular proteins promoting adhesion.
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