VEGF-C on Michael’s Domain

Delivery still limits VEGF therapy

Fri, 12 Sep 2025 00:00:00 +0000

Simply injecting a lab-made growth factor into the body isn’t enough to copy what the body does naturally. That’s because our own growth factors are released in the right place, at the right time, and in the right amount, and their levels are constantly adjusted using feedback loops.

Congratulations, Dr. Khushbu Rauniyar!

Sat, 10 Jun 2023 00:00:00 +0000

Defending a PhD thesis is a BIG thing in Finland, and you just did it. Unlike the rest of the world (perhaps except for Sweden), no other country requires as much demonstration of perseverance from PhD candidates as Finland does. On average, it takes four publications and 7 years. The long duration and the lack of well-defined requirements are two problems the Finnish Ministry of Education wants to address over the next few years to level the playing field for Finnish PhD graduates in the international job market. Completing a PhD in Finland takes a lot of Sisu. Sisu is a Finnish word which cannot be translated into any other language, but the recent movie with the same title can give you an idea. Wikipedia defines Sisu as extraordinary determination in the face of extreme adversity .In the “old times”, drugs were discovered based on their effects while not knowing their mechanism of action. This paradigm is more and more turned on its head. Researchers try to understand the mechanism that leads to disease before they start developing or finding a drug. Much of Khushbu’s thesis is about better understanding the mechanisms that govern the action of the primary lymphangiogenic growth factor VEGF-C: The evolutionary origin, activation, and potential as a drug target . Prof. Eckhard Lammert did a great job as the opponent, and Prof. Kari Keinänen did the same as the custos. Dear Khushbu , we wish you all the best for your next big project!

OMG: T. rex did not have VEGF-B!

Wed, 05 Apr 2023 00:00:00 +0000

Our work on the evolutionary origin of the PDGF and VEGF growth factors has just been published in Angiogenesis: https://doi.org/10.1007/s10456-023-09874-9 . We analyzed both PDGFs and VEGFs, but our focus was naturally on the VEGF side of things. It’s just a coincidence that the PDGFs happened to be a subgroup of the VEGFs and not vice versa, but that’s of course just our biased point of view :-)Since we do lymphatic research, we can proudly announce that the phylogenetic oldest VEGF likely resembled VEGF-C and featured the enigmatic silk homology domain. It makes intuitive sense (and had been proposed before by Jörg Wilting), because the most simple vascular systems that we know of are the so-called hemolymph systems (e.g., in insects), which share many features with the lymphatic system.With this publication, we did not do something exceptional that only a few can do. We did something everybody could do but nobody had done so far: looking systematically at which animals have which PDGFs and VEGFs. Actually, we did something new: we developed a crowdsourcing method for classifying PDGFs and VEGFs. Instead of asking people, we asked databases. There are many PDGF-like and VEGF-like sequences in databases, which are only recognizable as such by the homology of their amino acid sequence. In order to know whether we are dealing, e.g., with a VEGF-C or a VEGF-D, we are running many (PSI)BLAST searches, and then we tally up the majority opinion (as determined by the top hits).Many surprises waited for us after the bioinformatics script had finished its job after two weeks of finding and comparing PDGF- and VEGF-like sequences:

Bioactive VEGF-C from E. coli without in-vitro folding!

Fri, 28 Oct 2022 00:00:00 +0000

Our article Bioactive VEGF-C from E. coli has been published in Scientific Reports. Read here: https://doi.org/10.1038/s41598-022-22960-0.As a matter of fact, I did the first experiments expressing VEGF-C in E. coli in 1999, but never got active protein. In the following 15+ years, we exclusively used eukaryotic cells (yeast, S2/Sf9/Hi5 insect cells, CHO) to produce VEGF-C. We reactivated the “VEGF-C in E. coli” project a few years back and we finally reached our goal last year. However, it was much more work than we originally anticipated. In the beginning, all attempts went South, and to rescue the project, we developed an in-vitro folding protocol. It was perhaps more luck than ability that we stumbled upon a combination of solubility tag and redox-modified E. coli strain that can pull off the trick to produce directly bioactive VEGF-C without the need for an in-vitro folding step. We decided to include also our unsuccessful attempts (CyDisCo and periplasmic expression) in the results section to avoid the file drawer effect.

Making the cut: Why VEGF-C != VEGF-C

Wed, 28 Sep 2022 00:00:00 +0000

Yesterday, I talked about VEGF-C in the Zoom Lymphatic Seminar series, which is organized by Young Kwon Hong . Since there was not much time to ask questions, I am happy to answer them via email. If you have missed the link to the presentation slides, here it is: https://mjlab.fi/c . The take-home message: Many different mature forms of VEGF-C can be generated from pro-VEGF-C by proteolytic processing (and the same is true for VEGF-D). These forms behave VERY differently from each other. The extreme case is activation by Cathepsin D (CTSD): When activated by CTSD, VEGF-C becomes almost exclusively lymphangiogenic, while after activation by the same protease, VEGF-D becomes exclusively angiogenic. The detection of CTSD-activated VEGF-C is difficult because all well-functioning antibodies recognize epitopes N-terminal to the cleavage site (or they straddle the cleavage site). The second talk was by Barbara Garmy-Susini , and her topic was a nice fit since she talked about using VEGF-C in the therapy of lymphedema. But as we know already from VEGF-A, vascular growth factors alone might be not sufficient to generate a functional vasculature…

The evolution of PDGF/VEGF growth factors

Thu, 22 Sep 2022 00:00:00 +0000

We have uploaded a preprint of our most recent manuscript about the evolution of PDGF/VEGF growth factors to bioRxiv. We comprehensively analyzed the PDGF/VEGF part of the proteome in all animal species for which data is available. We have had some of this data already for a while, but now we enhance it with a detailed look at fishes. The vascular biology of fishes has become even more facinating after the publication of Das et al. earlier this year ( read more about this exceptional piece of work ).The remarkable heterogeneity of vascular systems in fishes seems to be supported by a similar extensive heterogeneity at the molecular level. Often, but not always can this genetic heterogeneity be traced back to whole genome duplications. Fishes tolerate full genome duplications better than mammals. At least there have been quite a few such duplications in various branches of the fish phylogenetic tree resulting in polyploid or even tetraploid species. That has resulted in some fish species featuring 4 times as many PDGF/VEGF genes compared to humans, and much more opportunities to diversify the functions of these molecules.The very first PDGF/VEGF-like molecule appeared likely more than 800 Million years ago during the Precambrian period when marine organisms started to show signs of tissue organization. If we set out to reconstruct this molecule, it would look remarkably similar to a modern VEGF-C. Specifically the C-terminal “silk homology domain” seems to have been invented early on in evolution. In fact, a large number of extant morphologically simple organisms feature such VEGF-C-like molecules still today (e.g. the nematode C. elegans). Beyond these insights into the evolution of PDGFs and VEGFs, there are some useful take-home messages for vascular biologists: For example, we did not find any functional VEGF-B genes in birds. Similarly, there seem to be no PlGFs in amphibians. Then, on the other hand, the VEGF-Fs - identified from snake venoms - appear to exist more broadly also in non-venomous lizards. This poses some limitations on some animal models (Xenopus, CAM assay), but it would be nice to know what VEGF-F is doing in geckos…Have a look at the manuscript and please comment or criticize, if you have any thoughts! The idea is to make this manuscript still a bit better before submitting it to a journal for the traditional peer-review.

"Bioactive VEGF-C from E. coli cytoplasm" preprint online

Fri, 01 Jul 2022 00:00:00 +0000

The preprint of our manuscript is online. We show how to produce bioactive mature VEGF-C in the cytoplasm of E. coli bacteria without the need for a folding step. It took us quite a while to get there, and we tried many things that did not work before we found a way how to do it. We describe also the methods that failed. It looks as if VEGF-C has simply too many cysteine residues that all have to pair up in the correct configuration. In the same manuscript, we also report a workable refolding method. Please have a look and give us some feedback: https://www.researchsquare.com/article/rs-1776636/v1 .

KLK3: tumorigenic or not?

Wed, 22 Dec 2021 00:00:00 +0000

We have just published our latest review about the role of KLK3 as an activator of VEGF-C and VEGF-D in prostate cancer . Prostate cancer is one of the most common cancers in males. It is not a question of whether you will get it but only when. Once you reach your 80s, the likelihood of you having prostate cancer is bigger than not having it. In a 2013 autopsy study of Japanese males , who died of other causes, 59% of those older than 80 had prostate cancer. It is likely that many of these cases were indolent and would never have caused any problems. Only a few of them might have become symptomatic had these men lived longer. So, there is a significant interest in distinguishing those cancers that are going to cause problems. Many prognostic markers have been proposed to do exactly that: to predict which cancers would become problematic.From the vascular biology point of view, angiogenesis and lymphangiogenesis are two hallmarks of cancers that have been previously proposed to have prognostic value. When we stumbled upon the fact that prostate-specific antigen (PSA, also known as KLK3) is able to activate VEGF-C and VEGF-D , we thought that this might have significance for prostate cancer. Meanwhile, further research has clarified some questions, and it really seems to be that both VEGF-C and VEGF-D are involved in cancer progression. it is not clear yet which proteases are responsible for the activation of VEGF-C and VEGF-D in real human cancers. KLK3- or Cathepsin D (CTSD)-activated VEGF-D might be a possible cause of the resistance of tumors to bevacizumab (Avastin) treatment. The consequences of VEGF-C activation, on the other hand, are more difficult to predict because activated VEGF-C does simultaneously both good and bad: On the one hand, it facilitates metastasis. On the other hand, it enables an enhanced immune response against the tumour. Interesting research lies ahead. Read more in our review: https://doi.org/10.3390/ijms222413545

Searching for a lymphedema drug

Wed, 11 Aug 2021 00:00:00 +0000

More than 20 years ago, I cloned the VEGF-C cDNA into an adenovirus shuttle vector. Even though we had the vectors for the AdEasy system from Bert Vogelstein’s lab to make adenoviruses in-house, we preferred to team up with gene therapy expert Seppo Ylä-Herttuala to make the first adenovirus with VEGF-C cargo (AdVEGF-C). This and other VEGF-C-expressing adenoviruses have been used by Seppo and us in several preclinical studies to show that VEGF-C can be successfully used to treat the underlying cause of certain types of lymphedema.In 2018, Herantis Pharma started Phase 1 clinical trials with AdVEGF-C, which was branded under the name Lymfactin. After Eiger Biopharmaceuticals ’ Phase-2-trials with bestatin failed to show any effect on lymphedema, Lymfactin was the only drug in clinical trials that was aimed at lymphedema. This spring, Herantis announced that it is discontinuing the clinical trials with Lymfactin in order to focus on their neurodegenerative ( CDNF ) drug pipeline. On top of this bummer came the news that the assignment of patients for the phase-2 trial had been non-random and that the Phase-2 results are therefore inconclusive . This is bad news for lymphedema patients just when gene therapy, on the whole, is making a comeback after an almost two-decade-long hiatus.What is the way forward? Even though the small molecule drug bestatin was shown to increase VEGFR-3 expression and activation , it was never a pro-lymphangiogenic therapy. The mouse experiments had shown clearly that it merely supports the endogenous lymphatic repair that is naturally kicking in after acute lymphatic damage. It specifically counteracts too high leukotriene B4 levels, which inhibit lymphangiogenesis, but it does not carry any own lymphangiogenic signal.The strategy to inhibit an inhibitor was also used in mouse studies that were published today in Science Signaling by Kataru et al.: Kataru et al. Kataru et al. used genetic modification of lymphatic endothelial cells to block PTEN, an intracellular inhibitor of VEGFR-3 signalling. The results are convincing: Lymphangiogenesis without any of the drawbacks that are inevitably associated with growth factor therapy, such as having too high growth factor concentrations at the site of delivery, which can lead to vessel leakiness and other unwanted responses. Small molecule PTEN inhibitors do exist, but they are pretty toxic. If a reasonably non-toxic PTEN-inhibitory compound could be found, all that is left is to specifically target it to lymphatic endothelial cells. However, neither finding nor targeting are easy tasks, although there are enough ideas that could be followed if funding was available. Read more about this topic in our opinion piece about searching for a lymphedema drug in Science Signaling: doi-link , e-print link for those who have no access to the full text.

VEGF-C protects blood cell production

Fri, 28 Aug 2020 00:00:00 +0000

Vascular endothelial growth factor-C (VEGF-C) has been originally described as the primary growth factor for the lymphatic system. And not surprisingly, a constitutive inactivation of both VEGF-C gene alleles in mice is lethal.However, over the years, researchers have uncovered additional functions of VEGF-C. In 2016, it was shown that VEGF-C is necessary for the production of red blood cells (erythropoiesis) in the fetal liver. During embryonic development, the production site of red blood cells shifts twice: First from the yolk sac to the liver (in humans between the 3. and 4. month) and then, three months later, from the liver to the bone marrow, where it stays for the rest of the life. Vegfc appeared essential for the mobilization, maturation, and enucleation of primitive erythroblasts. When Vegfc was deleted on embryonic day 7.5 (E7.5), the liver colonization by erythro-myeloid progenitors and the macrophage/erythroid expansion was defective ( https://doi.org/10.1182/blood-2015-12-687970 ).Some, but not all of the effect was due to the VEGF-C that was produced by the hematopoietic cells themselves, which is not surprising since several blood cells are known to produce or contain VEGF-C (e.g. macrophages, platelets). In the 2016 paper, adult hematopoiesis appeared unaffected when VEGF-C was deleted in 8 week old mice. Also when erythropoiesis was upregulated by phenylhydrazine (PHZ)-stimulated anemia or when the bone marrow hematopoiesis was abrogated with fluorouracil (5-FU), no major changes had been seen. However, in the new paper, we show that VEGF-C does play an important role in the bone marrow recovery from radiation damage, and that it also is able to pro-actively protect the bone marrow when administered before the radiation damage occurs. The effect was partly due to bone marrow endothelial cells and LepR+ stromal cells, which, when stimulated with VEGF-C, produced factors favorable for the regeneration of hematopoietic stem cells ( https://doi.org/10.1182/blood.2020005699 ). However, the effect on LepR+ cells was likely indirect as they do not express receptors of VEGF-C. Considering that previous data show expression of VEGFR-2 on hematopoietic stem cells ( https://doi.org/10.1038/nature00821 ), and avian VEGFR-2 and-3 during in developmental endothelial/hematopoietic differentiation ( https://www.pnas.org/content/94/10/5141 and http://dev.biologists.org/content/125/4/743 ), also a direct effect of VEGF-C cannot imho be excluded although it was not analyzed.

Dr. Sawan K. Jha: Mechanism of VEGF-C Activation […]

Mon, 01 Jun 2020 00:00:00 +0000

My first Ph.D. mentee successfully defended his thesis on the topic Mechanism of VEGF-C Activation and Effect on Lymphatic Growth and Regeneration . Due to the COVID-19 situation, we organized the event remotely and used the Zoom virtual meeting software. The opponent was Prof. Jonathan Sleeman from the University of Heidelberg. Both the defendant and the opponent did a fantastic job, and the discussion brought to light several new directions for future research, which I had not been thinking about before. VEGF-C is a tricky protein and I am sure it still holds some surprises for the diligent researcher. Unfortunately, there was no reception, no dinner, and no karonkka (after-dinner graduation party), but we are planning to have a party later this year when the COVID-19 situation permits!

Lymphatics and the eye

Wed, 12 Feb 2020 00:00:00 +0000

Our shared review about the eye lymphatics has been accepted for publication by Duodecim . In addition to review our current understanding about the eye lymphatics, it focuses on proliferative diabetic retinopathy (PDR). PDR is the advanced stage of diabetic retinopathy, which is one of the slowly developing complications of diabetes and which can result in blindness.It has been known for a long time that damage to the blood vessels in the retina is a central event in the disease development. Antiangiogenic therapy, targeting the major angiogenic growth factor VEGF-A, is a cornerstone of the therapy. However, the recent discovery of lymphatic-type vessels in the disease indicates, that it might be helpful to target also the lymphatic growth factors VEGF-C and VEGF-D. This is my first contribution to an article that is written in Finnish. While I even wrote some of the sentences in Finnish myself, big thanks go to Ani and Timo for weeding out the mistakes. However, my take-home message for similar future endeavors (i.e. writing with a team where key members are not very proficient in the target language) is that one should write everything first in English and then have it translated into the target language. If common languages are concerned, the best tool for the automated translation of scientific articles is DeepL . However, DeepL does not know Finnish, and adding Finnish is certainly not high on the developer’s priority list…

Re-purposing the growth factor VEGF-C

Sat, 22 Jun 2019 00:00:00 +0000

An eLIFE digest features our recent publication about VEGF-C ( https://elifesciences.org/digests/44478/re-purposing-the-growth-factor-vegf-c ). Even though our research did not deeply delve into the function of VEGF-C during reproduction, the reviewers comments and our answers (under the “Author response” heading) give more insight than the publication itself. We did not include the sperm motility data in the manuscript. Although sometimes stunning in its magnitude, we did not always measure increased sperm motility in response to active VEGF-C. As is common knowledge, sperm as a biological sample is of highly fluctuating consistency and quality. Interestingly, a paper in eLIFE published two years ago gives some additional insight in what we might be dealing with: Sperm competition risk drives rapid ejaculate adjustments mediated by seminal fluid . This paper shows that the swimming speed of sperm is rapidly regulated by males depending on the social situation (presence of a female or a male competitor). Imho, such factors seem to be almost impossible to control when dealing with human samples…However, the title ambiguously also refers to cancer. Based on our data, we speculate that VEGF-C can be repurposed from being lymphangiogenic to being angiogenic, and further, to be metastasis-promoting.

Lymphologische (Grundlagen-)Forschung: wie funktioniert das?

Wed, 29 May 2019 00:00:00 +0000

Vortrag für den 43. Jahreskongress der Deutschen Desellschaft für Lymphologie

PD Dr. Michael Jeltsch Universität Helsinki & Wihuri-Forschungsinstitut Haartmaninkatu 8 FIN-00290 Helsinki, Finnland michael@jeltsch.org

KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D

Sat, 18 May 2019 00:00:00 +0000

Prostate-specific antigen (PSA) is well known - at least among older males - as a prostate cancer marker, but few people know its physiological function: Sperm cells are trapped in fresh ejaculate, which has a jelly-like consistence. In order to release the sperm cells, the ejaculate needs to be liquefied and precisely this liquefaction is the task of PSA.Also surprising for many people is the fact, that scientists still do not know why high PSA levels are associated with prostate cancer. In our latest research published yesterday in eLIFE , we have made a big step ahead in understanding the role of PSA in both reproductive and cancer biology.It appears that PSA (aka as kallikrein-related peptidase 3 - KLK3) and another enzyme called cathepsin D can activate two growth factors which have been implicated in cancer progression: VEGF-C and VEGF-D . These growth factors do likely contribute to tumor angiogenesis and tumor lymphangiogenesis. By inducing angiogenesis - the growth of blood vessels - the tumor ensures its own supply with nutrients and oxygen. Such blood supply is necessary for a tumor to grow beyond the size of a few millimeters. Likewise, tumor lymphangiogenesis happens when the tumor induces the growth of lymphatic vessels and it is tightly linked to the lymphatic spread (metastasis) of the tumor.Both VEGF-C and VEGF-D are produced as inactive precursors (pro-VEGF-C, pro-VEGF-D) and need to be activated in order to induce the growth of blood or lymphatic vessels. With ADAMTS3 , we have identified the enzyme that activates VEGF-C during embryonic development - which also requires vessel growth - in 2014 ( Jeltsch et al. ). However, it remained unclear whether the same enzyme is responsible also for pathological vessel growth. Now it seems likely that patholigical vessel growth uses different enzymes and PSA and cathepsin D have become prime suspects. Our next experiments will test whether we can slow down or halt cancer growth by blocking these enzymes.

1000+ citations

Wed, 15 May 2019 00:00:00 +0000

The first among my publications to brake the 1000 citations-barrier was Gerhardt et al. 2003 . With the “tip cell concept”, it set a paradigm for vascular biology research: Not all endothelial cells are equal and the tip cell is a specialized cell that marks the forefront of the angiogenic sprout. However, my contribution was limited (number 7 out of 11 authors): I produced most of the proteins that were needed for the study. This spring, Jeltsch et al. 1997 crossed the first time the 1000-citation mark. The paper describes a mouse, that overexpresses VEGF-C in the skin. It is the first ever in-vivo demonstration of a lymphangiogenic growth factor. Although not setting any paradigm, it marks the start of the molecular era in lymphatic research . What percentage of papers achieve 1000+ citations? That differs between disciplines, but e.g. according to https://en.wikipedia.org/wiki/Citation_impact on average it is less than 1 in 4000. Compare this to the average paper, which receives 7.8 citations. And even this average is heavily influenced by a few highly-cited papers ( similar to the Impact Factor ). The median number of citations is 4, meaning that about half of all papers have less than 4 citations (see here ).

VEGF-C Review in Frontiers in Bioengineering and Biotechnology

Mon, 12 Feb 2018 00:00:00 +0000

The editors of Frontiers in Bioengineering and Biotechnology, section Tissue Engineering and Regenerative Medicine (Andrea Banfi, Wolfgang Holnthoner, Mikaël M. Martino and Seppo Ylä-Herttuala) asked us to contribute to the research topic Vascularization for Regenerative Medicine. We wrote a small review about VEGF-C, which specifically addresses the molecular biology of VEGF-C in relationship to regenerative medicine, i.e., (re)growing lymphatic vessels in vitro or in vivo.You can get it from the publisher directly https://www.frontiersin.org/articles/10.3389/fbioe.2018.00007/full or from here . **UPDATE (April 1, 2023):**The question of whether Frontiers Media is a predatory publisher did not even cross our minds when we were asked to contribute with a review. I know the guest editors of this Research Topic and can vouch for their scientific integrity. However, the journal has recently ended up on the list of predatory journals ( https://predatoryreports.org/news/f/list-of-all-frontiers-media-predatory-journals ), and the issues are discussed here in detail. Our review has meanwhile gathered:

Lymphologica 2017

Wed, 01 Nov 2017 00:00:00 +0000

On the Lymphologica 2017 (Lymphologie 2017) congress in Bad Soden (Oct. 5-7, Frankfurt, Germany), I presented an introduction to the molecular biology of VEGF-C and how mutations in the genes of the VEGF-C/VEGFR-3 signaling axis can cause or contribute to hereditary lymphedema. The talk was targeted at healthcare practitioners who work in the lymphology field. A mini-review based on this talk was published in Vasomed and was available online , but has meanwhile disappeared. You can download the presentation slides and the English translation of the mini-review via the download link below.

Essentials facts about VEGF-C in lymphology

Fri, 05 May 2017 00:00:00 +0000

Essentials facts about VEGF-C in lymphology

Dr. Michael Jeltsch, Adjunct Professor, University of Helsinki & Wihuri Research Institute, Finland, michael@jeltsch.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, partly within a multifactorial inheritance.

Science good, coffee bad

Thu, 26 Jan 2017 00:00:00 +0000

Last week I took part the Vascular Cell Biology Gordon Research Conference in Ventura (California). My two previous Gordon Conferences (2001 Rhode Island, 2014 Lucca/Italy) were outstanding and also this one did not disappoint.Even though there were many European researchers (19%), the US made up for 69% of the participants (Asia 6%, rest of the Amerikas 5%). This is probably a good representation of where the cutting edge research in vascular biology happens. Makes me wonder why the coffee in the US is as bad as it is (my bias got confirmed again). It cannot be explained by the lack of scientific expertise.Gordon conferences are designed to promote the exchange of unpublished data and hence I am not writing anything about the science. One exception: There are clinical trials to treat lymphedema with leukotriene B4 inhibitors ), but this is already public knowledge and the mouse studies are mostly published ( http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008380) . So no secrets leaked here… I myself presented a poster about the continued CCBE1 story that is currently under review and some preliminary data about additional VEGF-C activating enzymes.Obviously, the outcome of the presidential elections was a popular topic during lunch and dinner conversations especially as it relates to science funding and science policy. Opinions ranged from “We have no clue what to expect” to “Be afraid. Be very afraid.” I personally enjoyed about 8 hours of Trump presidency since my return flight from Los Angeles to Munich left last Friday at a quarter past five in the afternoon.In the free afternoons, I tried to catch the America-exclusive Taurus Pokémon for my daughter Milena. Sadly, the conference location was almost entirely devoid of poke stops and therfore I was chronically short of poke balls. Insiders told me that Santa Monica beach is the place to go to in order to catch Pokémons. I actually planned to go there Friday morning, but it was raining cats and dogs and so I tried my luck at the airport and about an hour before departure I finally managed to catch a Taurus and another one just before boarding the plane. So all in all a very successful conference journey!

Lymphangiogenesis in health and disease

Thu, 11 Jun 2015 00:00:00 +0000

Available Downloads

Get the presentation in PDF format.

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New Mechanisms of Lymphangiogenesis and Lymphedema

Fri, 26 Sep 2014 00:00:00 +0000

Here is the presentation that I could not give, because my schedule was too tight to allow for a 1 hour 20 minute delay. If you have questions concerning the talk, please ask via e-mail: michael@jeltsch.org.My Lufthansa flight LH855 from Helsinki to Frankfurt got delayed by 1 hour 20 minutes. Because I had only 1 hour 15 minutes to change my plane in Frankfurt on my way to the 40th Congress of the European Society of Lymphology in Genova/Italy, I did not even board the plane and rather canceled my talk. Because I have another appointment on Saturday in Germany, I had planned the return flight for Friday early morning and hence could not move my talk either. Next time I’ll be smarter.

From the molecular biological foundations to causal treatment options for diseases of the lymphatic system

Tue, 22 Jul 2014 00:00:00 +0000

PD Dr Michael Jeltsch, University of Helsinki, Finland

Research into the molecular basis of lymphangiogenesis in embryonic development and pathological processes has led to a rapid expansion of our knowledge (Krebs and Jeltsch 2013a, 2013b). The molecular biology era of lymphatic research began with the discovery of VEGF growth factors and their receptors 25 years ago. This review therefore focuses on these molecules.

The molecular basis of Hennekam syndrome

Thu, 20 Feb 2014 00:00:00 +0000

Finally our CCBE1 manuscript is out! You can access it from the Circulation’s homepage . If your library does not have a subscription, just drop me an e-mail . It nicely complements the article by Le Guen et al. from Ben Hogan’s group in Development. While Le Guen and colleagues analyzed the interaction of CCBE1 with the VEGF-C/VEGFR-3 pathway mainly at the genetic level in zebrafish, we tried to describe the molecular details of the interaction using in vitro assays which we complement with in vivo mouse data. We describe that the primary lymphangiogenic factor VEGF-C is produced as an inactive precursor (pro-VEGF-C). Pro-VEGF-C (that is the 29/31-kDa-form) does bind to VEGFR-3 on endothelial cells, but is unable to activate it. Until now, the common wisdom was that pro-VEGF-C is only a less potent activator of VEGFR-3 than mature VEGF-C. In fact, it actually acts as a competitive inhibitor of mature VEGF-C. The task of CCBE1 is to assist the ADAMTS3 protease in cleaving cell-surface bound pro-VEGF-C and thus to localize the concentration of active VEGF-C. In hereditary diseases that are caused by mutations in CCBE1 ( Hennekam syndrome ), this activation of VEGF-C is impaired and causes lymphedema. Because of the importance of lymphatic vessels in many diseases, CCBE1 and ADAMTS3 are interesting drug targets. In cancer, for example, it would be a tremendous benefit if one could prevent the activation of VEGF-C and thus prevent VEGF-C-mediated metastasis.

A Nobel Prize for angiogenesis research?

Sun, 27 Oct 2013 00:00:00 +0000

In 2008, during a dinner in Stockholm (when I participated in the Novo Nordisk Foundation 8th Annual Conference on Vascular Biology in Diabetes Complications) I proposed to Christer Betsholtz to award the Nobel Prize to the world-wide community of postdocs, which are the unsung heroes of today’s research. But the Statutes of the Nobel Foundation forbid to award the price to more than three people. However, statutes can be changed and the Nobel Foundation did exactly that 40 years ago when they stopped awarding the price to dead people. And in this changing world, less and less discoveries and inventions are made by individuals. But here’s my newest proposal, which adheres to the rule of maximally three: Kari Alitalo is probably the only Nobel Prize worthy researcher in the country where I work (Finland). Seriously: after Judah Folkman has passed away, there are not many options to award the prize to somebody from the angiogenesis field. Judah Folkman was the father of the hypothesis, that all tumors should be treatable by anti-angiogenesis ( Folkman J. Tumor Angiogenesis: Therapeutic Implications. New England Journal of Medicine. 1971;285(21):1182–6 ). The Nobel Prize committee missed that chance. And because the field has already significantly contributed to the treatment of cancer (and arguably will still contribute much), it is not so far off to think of a shared prize for the discoverers of the VEGFs. VEGF was discovered more or less independently by several research groups around 25 years ago, among them Napoleone Ferrara ’s and Harold Dvorak ’s. Most notably, Ferrara’s group at Genentech continued the research most successfully until today resulting in the first antiangiogenic cancer drug in 2004. While the discovery of VEGF and the resulting angiogenesis research was not dependent on any single lab, the lymphangiogenesis field was essentially single-handedly re-invented and brought into the molecular era by Kari Alitalo in the years following 1995 - after it had become senile and was lingering without any significant progress since the 1960s. A shared prize to Ferrara, Dvorak and Alitalo? There is an anti-VEGF-A cancer drug on the market and the only thing lacking is a successful anti- or pro-VEGF-C drug. Both are in clinical trials as of this writing ( anti-VEGF-C , pro-VEGF-C ).

Self Archiving and Open Access

Sun, 07 Jul 2013 00:00:00 +0000

I recently wrote a review article for the journal Lymphologie in Forschung ind Praxis . Its title was “Die lymphangiogenen Wachstumsfaktoren VEGF-C und VEGF-D” and it was the first paper I wrote in my mother tongue, German. This journal’s impact factor has been consistently below 1, which is not uncommon for non-English journals. However, in the big European countries like Germany, France and Italy, there are still many doctors who are not comfortable reading English. I though I’d help them out catching up on the latest in lymphatic research. Opening up access to science and visibility of science is all good, so I thought.Because my boss argued that it was a waste of time (I hope to prove him wrong - help me out here DLG !), I minimized the effort by engaging another knowledgeable German researcher at the University of Helsinki. Luckily I had already a draft when I was asked to write the review, even though I started to write it about two years ago and it was targeted for my website. When the article was published I received two physical reprints. When I tried linking to the online version of the article, I had to realize that it was behind a paywall . Because most publishers nowadays support self archiving , I asked the publisher about their policy. I presume that the publisher did not have any policy in place concerning self archiving, because they said they would agree to it, but I would have to get the green light from the board of directors of the DLG .I really hope to get this permission because this is the only way I can fulfill reprint request without hassle (yes I could copy the pages and send them by post (but aren’t we living in the 21st century?). If I won’t get the permission, one legal and easy way to distribute this article would be to put a pre-print version (i.e. the manuscript that I wrote) online. Luckily the copyrights of the publisher cover only the published version and not the pre-print versions. Others have done it this way (and they attached a list of the changes, that were made to make the pre-print version identical to the published version). This is a suboptimal solution, but maximizing accessibility and visibility. My University has a loose requirement to publish only in Open Access journals. However, exceptions to this policy of the University of Helsinki concerning Open Access are made on a regular basis, but they will get more and more difficult as the EU tightens their funding policy including the requirements for Open Access to research results . According to the EU’s interpretation, a journal could be considered Open Access if it allows for self archiving of the published article, self archiving being the second, “green” route to Open Access. The Academy of Finland (my main funding source) has a similar interpretation: “We further recommend that Academy-funded researchers publish their articles in open-access scientific journals, if there are online journals in the field in question that are at least of the same high quality as traditional subscription journals. The articles can also be saved in open-access electronic archives.” For employees of Helsinki University, self archiving is mandatory since 2010 .That makes sense to me: As a scientist I work with tax payers’ money; therefore all tax payers should have access to the results of my work. Even though I worked for this review only in my spare time, technically the requirements still apply as I used a computer, that was paid with tax payers’ money… Stay tuned and if you need the article now (and don’t want to wait for the DLG to decide), please e-mail me!

Lymphangiogenese-Regulation durch Wachstumsfaktoren

Thu, 19 Jan 2012 00:00:00 +0000

Alle Zellen unseres Körpers benötigen Sauerstoff und sie werden über das Blut damit versorgt. Deshalb ist das Gefässsystem das erste funktionsfähige Organ im wachsenden Embryo. Bevor das Herz seine Pumpfunktion aufnimmt, deckt der Embryo seinen Sauerstoffbedarf einzig durch Diffusion. Dies ist ihm allerdings nur bis zu einer Grösse von einigen Millimetern möglich.Tumoren haben das gleiche Problem, wenn sie eine ähnliche Grösse erreichen. Beide - der wachsende Embryo und die Krebsgeschwulst - können ihr Wachstum nur fortsetzen, wenn es ihnen gelingt, ein Gefässsystem zu bilden, das ihnen den benötigten Sauerstoff und die Nährstoffe bereitstellt.Das Krebswachstum ist also abhängig vom Wachstum und von der Neubildung von Blutgefässen. Andererseits gibt es aber auch Krankheiten, die von unzureichendem Blutgefäss-Wachstum charakterisiert werden. Bei der koronaren Herzkrankheit z. B. können die Blutgefässe dem Herzmuskel nicht genügend Sauerstoff liefern.Neben dem Herz-Kreislaufsystem gibt es noch ein anderes Gefässsystem: das Lymphgefässsystem. Es leitet überschüssige Gewebsflüssigkeit zuruck ins Blut und spielt eine wichtige Rolle in der körpereigenen Abwehr gegen Bakterien und Viren. Ähnlich dem Blutgefässsystem spielt das Lymphsystem eine wichtige Rolle in vielen Krankheiten. Lymphödem-Patienten z. B. leiden unter Schwellungen der Gliedmassen, weil entweder nicht aysreichend Lymphgefässe vorhanden sind oder die vorhandenen in ihrer Funktion eingeschränkt sind. Auch die Verbreitung von Krebs (Metastasierung) hängt eng mit dem Lymphsystem zusammen, weil Krebszellen die Lymphgefässe als Transportwege innerhalb des Körpers benutzten.

VEGF-C/VEGFR-2 complex structure took 13 years to solve

Wed, 03 Feb 2010 00:00:00 +0000

Finally our paper was accepted for publication in PNAS (downloadable also from here ). I started the project by making the first construct 13 years ago, but it went nowhere for the first 9 years due to insufficient concentration of efforts and a few unlucky choices in the experimental design. I opted for bacterial protein first, but although the refolding worked, it was very inefficient (Ala mutation and a smart trimming of N- and C-terminus. More…

Growth factor regulation of lymphangiogenesis

Sun, 06 Aug 2006 00:00:00 +0000

All cells in our body need oxygen and they receive it via the circulating blood. That’s why the vascular system is the first organ system to function in a developing embryo. Before the heart starts pumping, the embryo’s need for oxygen has to be met by diffusion alone. But diffusion is sufficient only until the embryo reaches a size of several millimetres. Tumours face the same problem, when reaching a similar size. Both the developing embryo and the solid tumor can only continue growing if they manage to establish a circulatory system that supplies them with oxygen and nutrients. While cancer depends on the pathological growth of blood vessels, other diseases are caused by insufficient vascular function. E.g. in cardiovascular disease the blood vessels cannot deliver enough oxygen to the heart muscle. Apart from the cardiovascular system there is another vascular system: the lymphatic system. It functions mainly in tissue drainage and immune defense against pathogens. Similar to the cardiovascular function, the lymphatic system plays an important role in several diseases. E.g. in lymphedema patients suffer from swollen limbs because lymphatic vessels are absent or not functioning properly. And the spread of cancer (“metastasis”) seems to be intimately related to the lymphatic system as the cancer cells use the lymphatic vessels as pathways to travel within the body.

Unlocking the drains

Mon, 01 Aug 2005 00:00:00 +0000

Nice article by Phyllida Brown in Nature describing the discovery of the VEGF-C/VEGFR-3 signalling axis, and how research on the lymphatic system turned into a hot topic: https://www.nature.com/articles/436456a .

What you should know about VEGF-C

Wed, 03 Sep 2003 00:00:00 +0000