Lymphangiogenesis on Michael’s Domain

Inauguration of the new professors

Thu, 28 May 2026 00:00:00 +0000

We - the new professors in the Faculty of Pharmacy at the University of Helsinki - gave our inaugural lectures yesterday!

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.

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.

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 ).

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.

Angiogenesis landmark publications

Thu, 09 Mar 2017 00:00:00 +0000

According to Nature, our Science paper from 1997 is a landmark paper for the angiogenesis field: *“A paper establishing the role of VEGF-C and VEGF-R3 signaling in lymphangiogenesis. A new field is born."*The collection of landmark papers for the angiogenesis field from the last 80 years ( http://www.nature.com/focus/angiogenesis/classics/vegf.html ) was published first in 2003 and unfortunately has not been updated to include later seminal studies. However, until today, most of these 86 papers are still must-reads for every PhD student in the angogenesis field.

Centrifugal and centripetal embryonic lymphatic development

Tue, 19 Jan 2016 00:00:00 +0000

Since the beginning of last century, researchers have been arguing about the embryonic origin of the lymphatic system. Some claimed that it is in its entirety an outgrowth from blood vessels (so-called centrifugal hypothesis with Florence Sabin and Louis-Antoine Ranvier as early proponents, this mechanism of growth is called “lymphangiogenesis”). Others maintained the view that the lymph vessels do form newly from precursor cells in the mesenchyme (so-called centripetal hypothesis with George Huntington and Charles McClure as early proponents, this mechanism is called “lymphvasculogenesis”). This controversy has been going on for more than a century and several published studies within the last years show, that the truth lies somewhere in between both views. Such synthesis had been proposed already in 1932 by van der Jagt. Kenny Mattonet and myself wrote a short update on the topic and you can read the English version or the German original .

Lymphangiogenesis in health and disease

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

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Best paper award

Fri, 01 May 2015 00:00:00 +0000

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![](/sites/]( http://www.med.helsinki.fi/english/news/2015/20150505_Jeltsch.html)We have won Circulation’s 2014 Best Paper Award in the category of Basic Science. Circulation is the leading cardiology journal and the organ of the American Heart Association . Already when we published the paper (titled [/files/files/Jeltsch%20et%20al.%20-%202014%20-%20CCBE1%20Enhances%20Lymphangiogenesis%20via%20A%20Disintegrin.pdf">“CCBE1 Enhances Lymphangiogenesis via A Disintegrin and Metalloprotease With Thrombospondin Motifs-3–Mediated Vascular Endothelial Growth Factor-C Activation”](/sites/<?php print $_SERVER[)), it was clear that it provided a major overhaul of our understanding of the VEGF-C growth factor and it got featured by Open Heart . The article manages to provide multiple new insights:

38. Annual Congress of the German Society for Lymphology

Sun, 05 Oct 2014 00:00:00 +0000

I participated in the 38th Congress of the German Lymphological Society ( http://www.dglymph.de/ ) in Halle (Saale). The conference was very refreshing and interesting: It was very different from the meetings I typically attend because it was focussed on the practical aspects of clinical and ambulant management of diseases that involve the lymphatics. Because my talk was an introductory lecture about lymphangiogenesis research, it did not contain any unpublished data and hence I make it available for download. However, the slides are in German and - depending on the target audience - might require some commentary. The talk is a chronological account of the important publications in the field of lymphangiogenesis research starting from about 20 years ago; heavily biased towards my own work and work in which I have been participating.

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.

We got featured by Circulation!

Mon, 12 May 2014 00:00:00 +0000

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!

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.

FEBS 2004

Fri, 10 Sep 2004 00:00:00 +0000

My poster for the FEBS 2004 conference in Warsaw.

Dissecting Lymphangiogenesis and Angiogenesis

Fri, 07 Sep 2001 00:00:00 +0000

The presentation slides below are for some reason extremely slow to load (about 2 minutes). You need to be very patient! Flash support has been ended by all current browsers, and this page uses Ruffle , a Flash Player emulator written in Rust, to resurrect these dead files.

Kloster Seeon Conference (October 1-4, 2000): Exploring the VEGF protein space

Wed, 01 Nov 2000 00:00:00 +0000

I participated in the first International Kloster Seeon “Angiogenesis” Meeting" https://www.vwfb.de/seeon-meetings in Germany, with a poster about VEGF growth factors. The venue was excellent: a former Benedictine monastery in Upper Bavaria .