PSA on Michael’s Domain

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

ISK 2019

Thu, 10 Oct 2019 00:00:00 +0000

The International Symposium on Kallikreins and Kallikrein-related Peptidases (ISK) took place on September 25.-27. in Prague. Being not from the kallikrein-field, I learned a lot. E.g. I was not aware that KLK4 can activate plasminogen (a fact that might explain some of our early, inconsistent results where KLK4 occasionally seemed to weakly activate VEGF-C in cell culture). Not surprisingly, many participants were interested in our findings that KLK3/PSA can activate the growth factors VEGF-C and VEGF-D, both of which are implicated in cancer progression, notably in metastasis. They confirmed that there is not very much research on the effect of KLK3/PSA mutations on human fertility, but I am sure that someone is going to look at that.Even though it is considered more prestigious to deliver a speech than to present a poster, I have to reconsider and perhaps will present next time a poster. What I would prefer most: talking AND presenting and poster. Why do so few conferences offer this possibility? What depth can you delve into if you have only 15 minutes on stage? Has the attention span of conference participants really decreased over the recent decades due to Facebook, Youtube and Instagram? Maybe: https://www.telegraph.co.uk/science/2016/03/12/humans-have-shorter-attention-span-than-goldfish-thanks-to-smart/The atmosphere at the conference was really friendly and cooperative, perhaps also owing to the relatively small number of participants. If we really should extend our excursion into the KLK-field, I have many experts to turn to for help. I also met some researchers from the Charles University of Prague, who are doing lymphatic research and it looks like we can help each other out with our specific experimental possibilities. All in all, a very successful trip. Excluding the Lufthansa flight back home, which arrived so late for transit in Frankfurt that I did not manage to do shopping there on my way back as I had originally planned (many shops in Germany do close at 5 pm).

Finnish abstract of our recent work about PSA (Prostate-specific antigen) in Duodecim

Sun, 25 Aug 2019 00:00:00 +0000

There is a nice Finnish language abstract about our recent finding that PSA (Prostate-specific antigen) activates VEGF-C and VEGF-D in the Finnish medical journal Duodecim: Eturauhassyövän merkkiaine PSA aktivoi syövän leviämiseen osallistuvia veri- ja imusuonikasvutekijöitä ( https://www.duodecimlehti.fi/lehti/2019/15/duo15024 ). Given the dominant position of the English language in medical science (and life science in general). Duodecim is arguably the only relevant, remaining Finnish language medical journal. Duodecim is the publication of the homonymous Association of Finnish Medical Doctors.

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.