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This is a presentation and acorresponding abstract, loosely based on the talk "Medikamenteninduziere Lymphangiogenese", which was given by Michael Jeltsch at the 3. Swiss Lymphsymposium. The original presentation (in German) is available via the linkhttps://mjlab.fi/lymphangiogenese. The German language abstract of the talk is available from here:https://www.juzo.com/_Resources/Persistent/2/3/3/2/2332460dace3f338146016d46e11b52ac9a20205/abstract-michael-jeltsch-schweizer-lymphsymposium.pdf. The live version (which is subject to modification) can be accessed via this link: https://mjlab.fi/dil. &nbsp

In this focused review, we address the role of the kallikrein-related peptidase 3 (KLK3), also known as prostate-specific antigen (PSA), in the regulation of angiogenesis. Early studies suggest that KLK3 is able to inhibit angiogenic processes, which is most likely dependent on its proteolytic activity. However, more recent evidence suggests that KLK3 may also have an opposite role, mediated by the ability of KLK3 to activate the (lymph)angiogenic vascular endothelial growth factors VEGF-C and VEGF-D, further discussed in the review.

Simple Summary Vascular endothelial growth factors (VEGFs) regulate the growth of blood and lymphatic vessels. Some of them induce the growth of blood vessels, and others the growth of lymphatic vessels. Blocking VEGF-A is used today to treat several types of cancer (“antiangiogenic therapy”). However, in other diseases, we would like to increase the activity of VEGFs. For example, VEGF-A could generate new blood vessels to protect from heart disease, and VEGF-C could generate new lymphatics to counteract lymphedema. Clinical trials are testing the latter concept at the moment. Because VEGF-C and VEGF-D are produced as inactive precursors, we propose that novel drugs could also target the enzymatic activation of VEGF-C and VEGF-D. However, because of the delicate balance between too much and too little vascular growth, a detailed understanding of the activation of the VEGFs is needed before such concepts can be converted into safe and efficacious therapies. Abstract Specific proteolytic cleavages turn on, modify, or turn off the activity of vascular endothelial growth factors (VEGFs). Proteolysis is most prominent among the lymph­angiogenic VEGF-C and VEGF-D, which are synthesized as precursors that need to undergo enzymatic removal of their C- and N-terminal propeptides before they can activate their receptors. At least five different proteases mediate the activating cleavage of VEGF-C: plasmin, ADAMTS3, prostate-specific antigen, cathepsin D, and thrombin. All of these proteases except for ADAMTS3 can also activate VEGF-D. Processing by different proteases results in distinct forms of the “mature” growth factors, which differ in affinity and receptor activation potential. The “default” VEGF-C-activating enzyme ADAMTS3 does not activate VEGF-D, and therefore, VEGF-C and VEGF-D do function in different contexts. VEGF-C itself is also regulated in different contexts by distinct proteases. During embryonic development, ADAMTS3 activates VEGF-C. The other activating proteases are likely important for non-developmental lymphangiogenesis during, e.g., tissue regeneration, inflammation, immune response, and pathological tumor-associated lymphangiogenesis. The better we understand these events at the molecular level, the greater our chances of developing successful therapies targeting VEGF-C and VEGF-D for diseases involving the lymphatics such as lymphedema or cancer.

English version of the review "Imusuonet ja silmä".

The lymphatic system, fundamental for body fluid homeostasis and immune system functions, also participates in pathological processes including cancer, cardiovascular and neurodegenerative diseases. Many aspects of the lymphatic system are unclear, but great advancements have been made – e.g. the discovery of meningeal lymphatics and the lymphatic-like nature of Schlemm’s canal. Lymphatic-like structures were also recently discovered in proliferative diabetic retinopathy, a severe diabetic eye complication, where the treatment of pathological neovessel growth is not always effective. Novel findings in the field can help to develop new treatments for lymphatic disorders and for other diseases where lymphatic neovascular growth is involved.

The enzymatic cleavage of the protein backbone (proteolysis) is integral to many biological processes, such as for the breakdown of proteins in the digestive system. Specific proteolytic cleavages are also used to turn on or off the activity of proteins. For example, lymph­angiogenic vascular endothelial growth factor C (VEGF-C) is synthesized as a precursor molecule that must be converted to a mature form by the enzymatic removal of C- and N-terminal propeptides before it can bind and activate its receptors. The constitutive C-terminal cleavage is mediated by proprotein convertases such as furin. The subsequent activating cleavage can be mediated by at least 4 different proteinases: by plasmin, ADAMTS3, prostate-specific antigen (PSA) and cathepsin D. Processing by different proteinases results in distinct forms of "mature" VEGF-C that differ in their affinity and their receptor activation potential. The CCBE1 protein regulates the activating cleavage of VEGF-C by ADAMTS3 and PSA, but not by plasmin. During embryonic development of the lymphatic system, VEGF-C is activated primarily by the ADAMTS3 proteinase. In contrast, it is believed that plasmin is responsible for wound-healing lymphangiogenesis and PSA for tumor-associated pathological lymphangio­genesis. Cathepsin D has also been implicated in tumor lymphangiogenesis. In addition, cathepsin D contained in saliva might activate latent VEGF-C upon wound licking, thereby accelerating wound healing. The molecular details of proteolytic activation of VEGF-C have only recently been extensively explored, and it is likely that not all activating proteinases are known as yet. It appears that the activity of VEGF-C is regulated for different specific functions by different proteinases. Although VEGF-C clearly plays a pivotal role for tumor progression and metastasis in experimental animal studies, the relevance of most correlative studies on the role of VEGF-C in human cancers has been quite limited until now, also due to the lack of methods for differentiating between inactive and active forms of VEGF-C

English version of the review "Die proteolytische Aktivierung des Vaskulären Endothelzellwachstumsfaktors-C."

The present invention relates to the utilization of ADAMTS3 metalloprotease. More specifically, the present invention relates to a method of producing fully processed mature VEGF-C polypeptide by a cell and a method of cleaving VEGF-C polypeptides. Furthermore, the present invention relates to different uses of ADAMTS3, ADAMTS3 inhibitors or compositions comprising ADAMTS3 or ADAMTS3 inhibitors, and a method of treating a lymphatic disorder. In addition, the invention relates to a method of producing VEGF-Cbinding molecules.

The present invention relates to therapeutic methods, us- es and compositions comprising CCBE1 and VEGF-C for treating disorders and conditions involving impaired lymphatic system, particularly lymphedema.

Vascular endothelial growth factor C (VEGF-C) and VEGF-D are the two central signaling molecules that govern the development and growth of the lymphovascular system. The presence or absence of lymphangiogenesis plays a central and sometimes causative role in a variety of diseases. Therefore, molecules that govern lymphangiogenesis, especially VEGF-C and VEGFR-3, offer the possibility for therapeutic interventions. Although the blockade of lymphangiogenesis does not yet exist as an independent therapeutic concept, a number of anti-lymphangiogenic drugs are now being tested in clinical trials. The rationale is that targeting VEGF-C and VEGF-D can improve the current anti-angiogenic treatment, since tumors may deploy the angiogenic forms of VEGF-C and VEGF-D when VEGF-A-mediated angiogenesis is blocked therapeutically. Despite numerous attempts, no breakthroughs have occurred in pro-angiogenic thera- pies to date. Furthermore, pro-lymphangiogenic, VEGF-C- or VEGF-D-based, therapies have not yet even entered the clinical trial phase. However, one clinical study with VEGF- C is now in preparation, namely in combination with lymph node transplantation for the treatment of postmastectomy edema. Here, we review the roles that VEGF-C, VEGF-D and their receptors play in diseases involving the lymphatic vascular system, and we present possibilities for utilizing these molecules to stimulate lymphatic vessel growth to treat lymphedema, or to block their functions in order to inhibit tumor angiogenesis and tumor lymphangiogenesis.