Dr. Michael Jeltsch, adjunct professor, University of Helsinki & Wihuri Research Institute, Finland, firstname.lastname@example.org
Vascular endothelial growth factor C (VEGF-C) is essential for the development and growth of the lymphatic vasculature. Together with VEGF-D, it forms the lymphatic subgroup within the VEGF family of growth factors, whose other members (PlGF, VEGF/VEGF-A, VEGF-B) are primarily responsible for the growth and function of blood vessels.
VEGF-C was discovered as a ligand of the tyrosine kinase receptor VEGFR-3 (1) and its specific effect on lymph vessels was first described in 1997 (2,3). About one-third of hereditary lymphedema cases in humans result from mutations in genes involved in VEGF-C signaling (4). The complete absence of VEGF-C leads to death during embryogenesis (5). Likely for this reason, clinical cases of hereditary lymphedema are characterised by a partial inactivation of the signal transduction. VEGFR-3 (6) is affected in most cases, but mutations of the hereditary lymphedema are described or suspected for all components of the VEGF-C signal transduction described below. z.T. As part of a multifactorial inheritance.
Regulation of VEGF-C activity
The functional differences between the angiogenic and lymphangiogenic VEGFs are reflected in their structure. In contrast to the angiogenic VEGFs, which are active immediately after secretion, VEGF-C is produced as an inactive protein and is only activated by two enzymatic cleavages (7). The first enzymatic section is constitutive. The resulting pro-VEGF-C can bind the VEGFR-3, but not yet activate it. Only with the second cut VEGF-C becomes active. ADAMTS3 (A Disintegrin and Metalloproteinase with Thrombospondin motifs 3) was identified as responsible protease (8). To enable ADAMTS3 to activate VEGF-C, the CCBE1 (Collagen And Calcium binding EGF domains 1) protein is necessary. CCBE1 fulfills two functions: its C-terminal domain activates ADAMTS3 (9), while its N-terminal domain immobilizes VEGF-C on the lymphatic endothelial cell surface and thus assures efficient activation by the similarly cell surface-associated ADAMTS (10).
Unlike the VEGF-A production, which is triggered by hypoxia, the triggers for VEGF-C production are less well known. It has been hypothesized and appears plausible that larger caliber blood vessels are responsible for establishing tissue drainiage via VEGF-C secretion. Likley, interstitial pressure plays a role in both embryonic and adult lymphangiogenesis (11).
VEGF-C as a pharmacological target
The important role of the VEGF-C/VEGFR-3 in angiogenic signaling has established VEGF-C as a drug target in antiangiogenic tumor therapy (12). The active role of VEGF-C in lymphogenic metastasis and the therapeutic efficacy of a VEGF-C/VEGFR-3 blockade has been demonstrated in preclinical studies (13,14). However, due to significant differences between mice and men in the VEGF-C/VEGFR-3 axis (15/16), it remains unclear, how relevant these studies are for tumors in humans.
Newer studies show convincingly, that lymph node infiltration might rather be a proxy for metastasis potential than represent a stage of distant organ metastsis itself (17).
The design of the only completed clinical trial (Phase 1), in which VEGF-C signals have been blocked with antibodies, unfortunately does not allow conclusions as to whether a VEGFR-3 blockade inhibits lymphatic metastasis (monotherapy of colorectal carcinomas, n = 21, 18). Intermediate results from an ongoing study in which VEGF-A and VEGF-C signaling pathways are simultaneously blocked indicate that a combination therapy may be helpful (19). Compared with the anti-VEGF-A standard therapy (20), patients report increased edema symptoms (18).
Lymphangiogenesis stimulation as edema therapy?
Primary lymphoedema, whose molecular cause is a reduced VEGF-C signal, has been successfully treated by VEGF-C administration in preclinical studies in mice (21). In a clinical study, where the aim is to treat secondary lymphedema after a breast cancer surgery, VEGF-C is administered in conjunction with a lymph node transplant (brand name Lymfactin ™). This study by Herantis Pharma has treated almost a dozen patients since the end of 2014, but has not published any results yet (22,23).
The unforeseen effect of ketoprofen on lymphedema (24) is due to the inhibition of leukotriene A4 hydrolase. The drug Bestatin/Ubenimex does not inhibit prostaglandin synthesis to the same extent as ketoprofen and therefore, its side effects are less pronounced and it is used for the currently ongoing clinical studies (25). It has been proposed that its effect might be partly due to an indirect effect on VEGF-C production.
German abstract ("Was man in der Lymphologie über VEGF-C wissen sollte"): http://jeltsch.org/Abstrakt-BadSoden2017
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- Herantis Pharma. Lymfactin® for lymphedema. (2015). http://herantis.com/pipeline/lymfactin-for-lymphedema
- Nakamura, K., Radhakrishnan, K., Wong, Y. M. & Rockson, S. G. Anti-Inflammatory Pharmacotherapy with Ketoprofen Ameliorates Experimental Lymphatic Vascular Insufficiency in Mice. PLOS ONE 4, e8380 (2009). https://dx.doi.org/10.1371/journal.pone.0008380
- Tian, W. et al. Leukotriene B4 antagonism ameliorates experimental lymphedema. Science Translational Medicine 9, eaal3920 (2017). https://dx.doi.org/10.1126/scitranslmed.aal3920