The Role of the VEGF-C/VEGFRs Axis in Tumor Progression and Therapy

Abstract

Vascular endothelial growth factor C (VEGF-C) has been identified as a multifaceted factor participating in the regulation of tumor angiogenesis and lymphangiogenesis. VEGF-C is not only expressed in endothelial cells, but also in tumor cells. VEGF-C signaling is important for progression of various cancer types through both VEGF receptor-2 (VEGFR-2) and VEGF receptor-3 (VEGFR-3). Likewise, both receptors are expressed mainly on endothelial cells, but also expressed in tumor cells. The dimeric VEGF-C undergoes a series of proteolytic cleavage steps that increase the protein binding affinity to VEGFR-3; however, only complete processing, removing both the N- and C-terminal propeptides, yields mature VEGF-C that can bind to VEGFR-2. The processed VEGF-C can bind and activate VEGFR-3 homodimers and VEGFR-2/VEGFR-3 heterodimers to elicit biological responses. High levels of VEGF-C expression and VEGF-C/VEGFRs signaling correlate significantly with poorer prognosis in a variety of malignancies. Therefore, the development of new drugs that selectively target the VEGF-C/VEGFRs axis seems to be an effective means to potentiate anti-tumor therapies in the future.

Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis

“…It has been verified that lymphangiogenesis, which is correlated with LN metastasis and metastasis-free survival in bladder cancer, is a necessary step for LN metastasis of human cancer (9)(10)(11). Accumulating evidence has shown that upregulated VEGF-C, a lymphangiogenic growth factor, positively correlates with regional LN metastasis and poor survival in multiple human malignancies, including bladder cancer (9,(11)(12)(13)(14)(15). Several groups have reported that when VEGF-C signaling is blocked via either small interfering RNAs or a neutralizing antibody to VEGF-C or VEGF-R3, the lymphatic-based metastatic spread of human malignancies can be inhibited (9,(16)(17)(18).…”

Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization

“…It is noteworthy that L1 promotes the expression of various genes causally linked to tumor vascularization, such as VEGF-A, VEGF-C, Dll4, and HOXB9 (34)(35)(36). On the other hand, the endothelial expression of L1 itself is induced by classical angiogenic factors, including VEGF-A, ANGPTL4, TNF-α, and IFN-γ (10, 11).…”

Expression of D2-40 in Benign and Malignant Breast Lesions and Study the Correlation between Lymphovascular Density and other Prognostic Factors of Breast Cancer

“…Lymphovascular invasion as the main route of LN metastasis is defined by the presence of cancer cells in the lymphatic vessel. The presence of carcinoma cells in lymphatic vessels is a significant prognostic factor in invasive breast cancer and associated with poor survival [5,6,22,44]. So, LVI is a critical step in the process of tumor metastasis and it is an important criterion for further patient's management.…”

“…VEGF-C is synthesized as propeptide then activated by proteolysis to form a high-affinity ligand that binds to the extracellular domain of vascular endothelial growth factor receptor-3 (VEGFR-3), which is expressed on lymphatic endothelium (LECs), and induces tyrosine phosphorylation of VEGFR-3. Thus, VEGF-C promotes lymphangiogenesis and lymphatic metastasis in tumors [21][22][23]. Several studies [24][25] have shown that D2-40 IHC labels glandular MECs, while using it as the marker for lymphatic endothelial cells, which triggered this study to further, explore the possibility of using D2-40 as an additional MECs marker in breast pathology and in the same time using it as a prognostic marker as it is now one of the most specific and sensitive lymphatics markers.…”