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n the News.. COVID-19 & T1D, Ozempic Pill Progress, Faster Insulin, “Beyond Misconceptions,” and More It's In the News.. a look at the top headlines and stories in the diabetes community. This week's top stories: A new study looks at the link between COVID-19 and very young children, Lilly moves ahead with their Ozempic oral pill, ultra-rapid insulin clears another hurdle, Beyond Type 1 launches a new campaign and more! Find out more about Moms' Night Out  Please visit our Sponsors & Partners - they help make the show possible! Learn more about Gvoke Glucagon Gvoke HypoPen® (glucagon injection): Glucagon Injection For Very Low Blood Sugar (gvokeglucagon.com) Omnipod - Simplify Life Learn about Dexcom   Check out VIVI Cap to protect your insulin from extreme temperatures The best way to keep up with Stacey and the show is by signing up for our weekly newsletter: Sign up for our newsletter here Here's where to find us: Facebook (Group) Facebook (Page) Instagram Twitter Check out Stacey's books! Learn more about everything at our home page www.diabetes-connections.com  Reach out with questions or comments: info@diabetes-connections.com Episode transcription with links: Hello and welcome to Diabetes Connections In the News! I'm Stacey Simms and every other Friday I bring you a short episode with the top diabetes stories and headlines happening now. XX https://www.scientificamerican.com/article/advances-in-type-1-diabetes-science-and-tech/ This article is part of “Innovations In: Type 1 Diabetes,” an editorially independent special report that was produced with financial support from Vertex. XX More evidence linking COVID 19 to type 1 diabetes.. but still exactly why is a mystery. During the COVID-19 pandemic, there was an unexpected increase in the number of cases of type 1 diabetes in Sweden, particularly among children under 5 and young adult men. The infection accelerated the onset of diabetes among children between the ages of 5 and 9. The researchers looked at data from a 17-year period on the incidence of type 1 diabetes among all people under the age of 30 in Sweden. In addition, they compared the risk of developing diabetes among 720,000 individuals with positive COVID-19 tests against a control group of 3.5 million people. The findings are published in the journal Diabetologia. The number of diabetes cases increased by 12% in 2021 and 9% in 2022 compared with previous years. In 2023, the number of cases was back to a normal level. Despite this, the researchers cannot distinguish a clear connection between COVID-19 infection and diabetes, except for children between 5 and 9 years old. They had an increased risk of type 1 diabetes about one month after a COVID-19 infection even though their total risk did not increase. "However, it's clear that the COVID-19 vaccine can be ruled out as a cause of the increase in diabetes cases. The recommendation for the age group where we saw the strongest increase was not to get vaccinated. In addition, other studies on adults have shown that vaccination reduces the risk of developing type 1 diabetes after a COVID infection." https://medicalxpress.com/news/2025-10-diabetes-young-people-pandemic.html XX A new gene therapy approach aimed at protecting people with type 1 diabetes from developing diabetic kidney disease—a serious and common complication of the condition, has shown promising results in a University of Bristol study. Findings from this new study, published in Molecular Therapy, demonstrated a 64% reduction in a damage indicator for kidney disease, paving the way for a potential new treatment. The study, explored the potential of delivering a protein called VEGF-C directly into kidney cells. Previous studies have shown VEGFC could protect against kidney disease as it helps keep blood vessels in the kidney filter healthy, repairing early signs of diabetes-related kidney damage. https://medicalxpress.com/news/2025-10-gene-therapy-kidney-disease-diabetes.html XX The FDA has agreed to consider Afrezza inhaled insulin for children and teens. The company said in August that it submitted a supplemental Biologics License Application (sBLA) for Afrezza in the pediatric population and it's been assigned a decision deadline date of the end of May, 2026. Afrezza first recieved FDA approval for adults (age 18 and up) in June 2014 https://www.drugdeliverybusiness.com/fda-accepts-application-mannkind-inhaled-insulin-kids/ Update on inhaled insulin for kids.. in the open-label, randomized, phase 3 INHALE-1 clinical trial Afrezza demonstrated safe and effective replacement for rapid-acting meal insulin in children with type 1 diabetes (T1D and demonstrates comparable glycemic control to injected rapid-acting insulin. The INHALE-1 clinical trial assessed the safety and efficacy of Afrezza among children and adolescents with T1D, including a total of 230 patients aged 4 to 17 years. Researchers used basal injected insulin and randomly assigned inhaled insulin or rapid-acting analogue for meals, evaluating the change in hemoglobin A1c levels at 26 weeks. After completing 26 weeks of randomly assigned treatment with either Afrezza or rapid-acting insulin injections combined with basal insulin, participants continued receiving the inhaled insulin until week 52 for an extension phase to evaluate the safety and effectiveness of Afrezza with continued use.1,2 https://www.pharmacytimes.com/view/inhaled-insulin-demonstrates-comparable-safety-lung-function-and-efficacy-to-injectable-insulin-in-type-1-diabetes XX Eli Lilly released the results of two new Phase 3 trials of an experimental GLP-1 pill that the company says could become a “foundational treatment” for type 2 diabetes. The Indianapolis-based drugmaker plans to submit global regulatory applications for orforglipron in the treatment of type 2 diabetes next year. The company said it will seek approval of the drug as an obesity medication by the end of 2025. Lilly is trying to build on the success of its Mounjaro/Zepbound franchise by offering patients a pill instead of an injection. But the company is trailing behind rival Novo Nordisk in developing an oral alternative, and data released so far has raised some skepticism among investors. A study released in August showed that orforglipron could help patients lose an average of about 12% of their body weight. Wall Street had been expecting more; Lilly's injectable drug Zepbound produced weight loss of as much as 21%, and Novo Nordisk has achieved 15% weight loss percentages for both oral and injectable versions of its Wegovy medication.   https://www.fiercebiotech.com/biotech/eli-lillys-orforglipron-bests-farxiga-padding-oral-glp-1-case-pair-phase-3-diabetes-wins   XX XX UF Health Cancer Center researchers have found a surprising culprit behind common health problems such as obesity, diabetes and fatty liver disease: silent genetic glitches in the blood system that occur naturally as people age. The findings, published in the Journal of Clinical Investigation, mean that in the future, simple blood tests could be developed to identify people most at risk early on, helping prevent chronic illnesses and cancer through strategies like diet or lifestyle changes. As people age, stem cells in the bone marrow that produce blood cells gradually accumulate mutations in their DNA. Most mutations don't cause any issues, but sometimes blood stem cells with a mutation can start crowding out their peers. Called clonal hematopoiesis, this condition affects about 10% of older people and is associated with an increased risk of blood cancers like leukemia. It's also linked to a higher risk of obesity and diabetes. But the prevailing thinking was that obesity and related conditions promoted blood cell changes, not the other way around. The new study reverses that. The implications could be far-reaching, particularly as obesity has now overtaken smoking as the most significant and preventable risk factor for cancer. The team is studying how the mutations drive disease. Next, they plan to test how drugs like those commonly used to treat diabetes and new popular weight loss drugs might help reverse or prevent diseases caused by blood cell changes. https://medicalxpress.com/news/2025-10-hidden-blood-mutations-obesity-diabetes.html XX A new ultra rapid insulin continues to move forward. A phase 3 clinical trial of BioChaperone Lispro (liss-pro) conducted in China found it safe and effective compared with Humalog along with a significant reduction of the rise of blood glucose after a test meal.     These results complete and confirm the positive outcomes previously obtained with THDB0206 injection in people with Type 2 Diabetes It combines Adocia's proprietary BioChaperone® technology with insulin lispro, the active ingredient in the standard of care, Humalog® (Eli Lilly).   This innovative formulation acts significantly faster https://pharmatimes.com/news/ultra-rapid-insulin-shows-promise-in-phase-3-trial-for-type-1-diabetes/   Poor blood sugar control in adolescent patients with type 1 diabetes (T1D) may be associated with a higher risk of neuropathy in adulthood, according to recent research from the University of Michigan.1 The study included children diagnosed with T1D between 1990-1992 who were recruited into the Cognition and Longitudinal Assessment of Risk Factors over 30 Years cohort study in Australia. Investigators collected HbA1c from medical records, and microvascular complications were assessed through self-reports, clinical screenings, retinal photographs, and urinary albumin-creatinine testing.3   A total of 30 children were recruited from the original cohort with a mean diagnosis age of 2.9 years. After an average of 29.7 years (standard deviation [SD]: 3.9 years), 33% of participants (n = 13) developed neuropathy, 63% (n = 19) developed diabetes-related eye disease, and 10% (n = 3) developed neuropathy.3 Mean HbA1c estimates during adolescence (9% [74.9 mmol/mol]; 95% CI, 8.6-9.3 [70.5-78.1]) were substantially higher than childhood (8.2% [66.1 mmol/mol]; 95% CI, 7.8-8.5 [61.7-69.4]; P

I would like to share information about a paper authored by a team of researchers from Germany, Finland, and Switzerland, with Gunther Felmerer leading the group.The paper, titled "Increased levels of VEGF‑C and macrophage infiltration in lipedema patients without changes in lymphatic vascular morphology," was published in the peer-reviewed journal Scientific Reports in July 2020.The study aimed to investigate and characterize the tissue and lymphatic vascular aspects of lipedema. This research contributes another valuable piece to the understanding of lipedema.

We discuss the use of blockade of VEGF C and D in the treatment of neovascular AMD with Dr. Dante Pieramici, California Retina Research Foundation, California Retina Consultants.

[intro music]Host – Dan KellerHello, and welcome to Episode Fifty-Three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.This week’s podcast features Dr. Jonathan Kipnis, who discusses his recent discovery of lymphatic vessels in the meninges. But first, here are some new items in the MS Discovery Forum.According to our curated list of the latest scientific articles related to MS, 34 such articles were published between August 21st and 28th. To see these publications and the articles we selected as Editors Picks, go to msdiscovery.org and click on Papers. Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This week, we’ve added 6 pieces of information about alemtuzumab and fingolimod. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.The MSDF team is looking forward to attending next month’s ECTRIMS meeting in Barcelona, Spain. If you, too, will be at the conference and would like to meet with us – or if you’re interested in being interviewed about your research for a future podcast – please email us at editor@msdiscovery.org.[transition music]And now to Part 1 of our interview with Dr. Jonathan Kipnis, Professor of Neuroscience and Director of the Center for Brain Immunology and Glia at the University of Virginia in Charlottesville. His group recently published in Nature their discovery and characterization of lymphatic vessels in the meninges. Interviewer – Dan KellerYou've described in this paper about meningeal lymphatics, the novel but actually more conventional path for cerebrospinal fluid drainage from the CNS than I guess had been thought of before; it's sort of conventional as revolutionary. Can you tell me what you found and what led you to look?Interviewee – Jonathan KipnisYes, so we've been interested in the role of meningeal immune system for quite some time, and we've shown that changes in meningeal immunity could impact brain after a CNS injury, or also for normal brain function. So, for example, mice that have impaired meningeal immunity would show cognitive deficits and would show some little bit more prone to stress and other phenotypes. So we've been very interested in understanding how meningeal immunity is being regulated. So the assumption was at some point that there is no immune cells in the brain, which is true, except for microglial which reside in the brain and compose 10% of the brain cells, but there is no peripheral immune cells within the brain. But in very nearby areas, which is the surroundings of the brain – the choroid plexus, the meninges, and the CSF – that's where actually there are immune cells, and there are all types of immune cells. And so we have been very interested to understand how the cells are getting in and getting out. Through the use of parabiotic mice, we demonstrated last year, we showed that immune population of the meninges is not static; the cells are being repopulated, and about 50% of T cells, for example, is being exchanged within about 10 days, and major exchange between the CSF or the meninges with the deep cervical lymph nodes. So nothing was really new, we just sort of established things maybe more solid way. Those cells can get in while still nobody understands very well how they get in; we'll assume they get in through the meningeal vasculature, which is probably true. But then how do they get out, or what happens with cells after they get to the CNS? Well, the assumptions were, well, they either die, magically disappear, or crawl under the nose through the cribriform plate and into the deep cervical lymph nodes through the nasal mucosa. They were okay explanations, but in our systems we did not find any of it to be sufficiently explaining what's going on in this really fast and pretty dramatic exchange of the immune system within the meningeal spaces. So when we just looking at it a bit closer, and it is very, very well established that there is lymphatic drainage from the CNS, so this needs to be remembered. So people in many labs have shown that if you put stuff in the brain – which stuff I mean proteins – if you put proteins or antigens in the brain, whether it's in the parenchyma or in the meninges or in the CSF, you will find those proteins, and you will find immune response to these proteins in the deep cervical lymph nodes.The question is, of course, how do they get there? And the path which was described just did not work in our hands, and so I was lucky to get a very, very talented postdoc, Antoine Louveau, at the lab. He realized that for us to understand how things get in and out, the only way to do it is to do live imaging and also to do a whole mount of the entire meninges. And I think that's when it was a breakthrough point. So Antoine laid out the entire meninges and was looking for location of the immune cells. And he said let's see where I see maximum accumulation of the immune cells, and then let's see how these places will change when we expose mouse to, for example, stress, learning, or EAE inflammation, viral infection, or whatever, let's see how these areas of dense immune population will change. And so he realized that there is a lot of immune activity around the major sinuses in the meninges, and then he saw that there are immune cells which are in the vascular structures which were not blood vessels. And I think that was the turning point. And I said, okay, if the cells are within the vasculature which is not blood vasculature, what would it be? Well, so I went to colleagues here and said what do you label lymphatic vessels with? And they didn't understand why would you want to label for lymphatic vessels, because they don't work with the brain. And so we labeled a lymphatic marker and we saw the vessels, which were lining the major sinuses and going all the way along them. So that's a very long answer to your very simple question.MSDFAnd Antoine Louveau's technique here that was the key to it was doing in situ fixation so he could get the meninges out intact?Dr. KipnisTo let's assume the meninges came out intact on the brain, and let's assume we had this beautiful staining. Let's say we did the coronal staining, and let's say we're labeling for lymphatic vessels. So you can imagine that what you'll see is at the border of the brain you will see a dot; you will see maybe three dots because there are three vessels going along the sinuses. And when you see a dot, you never take a dot seriously in immunohistochemistry. Now that we know that this dot represents the vessel, then we can actually go back and do those coronal sections and look at it. But back then only by seeing the whole meninges mounted as one on a slide, and by seeing those vessels there, I mean that's when we knew. And so to us it was obvious this is something that absolutely went under-noticed. And this technique of whole-mount meninges, I think, was absolutely crucial. MSDFDid he find these vessels in all layers of the meninges, or any specific ones?Dr. KipnisNo, no. Major lymphatic vessels are following the superior sagittal and the transverse sinuses, which is in the dura. So all the blood from the brain is being – at least in mice. In humans it goes a little bit different, but also through the sinuses, although sinuses are located so not all the blood in the human brain goes through the parasagittal sinus, but in the mouse brain all the blood goes through the sinuses in the dura. So major sinuses through which all the blood is being collected from the brain, and then goes out there. And so along those sinuses we find the lymphatic vessels, so they are sitting in the dura. MSDFAnd this system also has been found in humans?Dr. KipnisWell, that's a good question. You know, it's very hard to obtain high-quality human samples from the dura, because nobody really cares about this area. So we were lucky in the triple operation of Bea Lopes, who's a really great neuropathologist here at UV; she was able to give us, I think, nine samples from patients of dura of the sinus; these were all fixed in formalin. So we looked at those, and as you can imagine, the sinus in the human is huge, so obviously compared to a mouse. So in two out of nine, we were able to identify vessels that looked like meningeal vessels, but I think it warrants much deeper and much farther investigation to be able to say, yes, here they are. But if you ask me personally, why wouldn't they be? Why would mice have them and humans won't have them. So I think it's a matter of identifying their location and the best markers to use for them, but I think they should be there again. In two out of the nine samples, we were able to demonstrate that this is something that looks very, very good. MSDFAnd you did immunohistochemistry on these to show the lymphatic properties and not general blood circulatory vasculature properties, either in the mice or human?Dr. KipnisOh, yes. So in the mice we identified the characteristics of those vessels really, really well. You know, nothing is perfect, that every marker on mouse markers are expressed by different cells, so you need here to provide a series of markers and to demonstrate that this is also indeed the real lymphatic cells. So we stained for LYVE1 and we showed beautiful staining with LYVE1, also with macrophages. And those are vascular structures and they came out to be macrophages. But one of the major transcription factors that will define lymphatic and endothelial cells is a Prox1. So we demonstrated two ways of Prox1; one is transgenic mouse and the other is staining for Prox1. And we also did two other molecules. One is a Podoplanin which is expressed in tissue lymphatics, and these vessels are expressive. And the other molecule, she is very interesting. It's a receptor for VEGF3, VEGF-C. And this receptor is first on the lymphatic and endothelial cells. In the periphery, lymphatic and endothelial cells will respond to recombinant VEGF-C and will expand. So what we did here, we also injected a recombinant VEGF-C and we showed these vessels expanding. So we know now that the receptor is actually functional in the vessels, but also we now can expand the vessels. Whether it will impact any neurological disease, we don't know, but at least we have the capability to do so. And then we also identified them by flow cytometry. We took samples from skin and from diaphragm where lymphatics are very, very well defined, and using the exact same antibodies we did also flow cytometry on our meningeal samples. And we show that the cells look exactly like they look from the skin and from the diaphragm; of course, the numbers are much smaller. So I think in terms of their calculation in a mouse, we are very convinced.Now for humans it's more difficult. Like I said, the sample was in formalin and it's very hard to work with those samples, and, again, the area is huge to go through. So we were able in humans to get two markers to work; one was LYVE1 and the other was Podoplanin. We could not make Prox1 to work, I think it's a problem with the antibody and not with the vessel or potentially with the tissue as well. And these vessels would not label for some other markers, which would be characteristic of, for example, macrophages. So we were able to attack on them two out of four markers that would potentially allow for him to see. But we are now trying to identify those vessels by other means in humans as well, and I think flow cytometry may be the way to go. MSDFNow you've shown that these lymphatic vessels drain into the deep cervical lymph nodes, and it looks like you've also been able to rule out drainage through the cribriform plate back into the cervical lymph nodes. Is that true? Dr. KipnisI'm glad you bring this up, this is very important. So if you think of CSF, CSF is composed of several things. So we have the liquid itself, we have the macromolecules within the CSF, and then we have the immune cells within the CSF. So I don't think there is anybody would argue against liquid being drained through the cribriform plate and through the granulation; this is funny to argue. And obviously we are not claiming anything until we're absolutely sure; there is beautiful works from many, many labs showing that. But for the macromolecules and for the immune cells, the path which was proposed through the cribriform plate most probably if it's not a wrong one, it's probably not the major one. [transition music]Thank you for listening to Episode Fifty-Three of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.[outro music]

Das Glioblastoma multiforme (GBM, WHO-Grad IV) ist ein äußerst aggressiver und stark vaskularisierter Tumor. Trotz multimodaler Therapiekonzepte mit chirurgischer Resektion, Bestrahlung und Chemotherapie haben die betroffenen Patienten eine schlechte Prognose von lediglich 9 bis 15 Monaten Überlebenszeit nach Diagnosestellung. Innovative Therapiekonzepte sind daher dringend erforderlich. Im Fokus dieser Arbeit stand das abnorme Gefäßsystem maligner Hirntumoren. Aufbauend auf einem besseren Verständnis der Gefäßbiologie dieser Tumoren wurden potenzielle Strategien für Diagnostik und Therapie entwickelt und evaluiert. Progenitorzellen aus dem Knochenmark sind in vielfacher Weise an der Neoangiogenese von Tumorgefäßen beteiligt. Immundefizienten Ratten wurden in dieser Arbeit primäre humane MSC systemisch appliziert, nachdem den Tieren zuvor ein humanes Gliom implantiert worden war. Die Rekrutierung der MSC in den Tumor wurde immunhistochemisch nachgewiesen. Die endotheliale Differenzierung der MSC konnte mit gentechnisch modifizierten MSC-Linien bestätigt werden. Diese Zellen enthielten einen Vektor mit dem Reportergen RFP (red fluorescent protein), dessen Expression unter der Kontrolle des endothelspezifischen Tie2-Promotor/Enhancer-Konstruktes steht. Darauf aufbauend wurde eine MSC-Linie etabliert, bei der statt des Reportergens RFP das Selbstmordgen HSV-TK unter der Kontrolle des Tie2-Promoters steht. Die Hypothese hierzu ist, dass nach systemischer Verabreichung dieser MSC durch Zugabe von Ganciclovir eine selektive Toxizität auf den Tumor bewirkt wird. Zur genaueren Charakterisierung der Gefäßstrukturen in Hirntumoren wurde die Expression Lymphgefäß-assoziierter Moleküle in Gewebe unterschiedlicher Gliome untersucht. Die lymphangiogenen Wachstumsfaktoren VEGF-C,-D und ihr Rezeptor VEGFR-3 zeigten im GBM hohe Expressionswerte. Die Expression von VEGFR-3 unterschied sich signifikant von der in niedriggradigen Astrozytomen (WHO-Grad II). Podoplanin war in allen Gewebeproben des GBM sehr hoch exprimiert, in einigen Zellen zeigte sich eine Co-Lokalisation mit Prox-1. Die Expression war allerdings nicht gefäßassoziiert, sondern ausschließlich auf den Tumorzellen zu finden. Eine streng endotheliale Lokalisation zeigte sich dagegen im anaplastischen Oligodendrogliom (WHO-Grad III), in dem Podoplanin mit VEGFR-3 co-exprimiert ist. Durchgehend negativ für Podoplanin waren alle untersuchten Astrozytome (WHO-Grad II). Für weiterführende Untersuchungen zur Funktion von Podoplanin wurden zwei GBM-Zelllinien etabliert, die einen Podoplanin-Überexpressionsvektor stabil exprimieren. Die Ergebnisse dieser Arbeit unterstreichen die zentrale Bedeutung des Gefäßsystems für das GBM. Es wurde gezeigt, dass MSC effektiv aus der Peripherie in den Hirntumor rekrutiert werden und dort aktiv an der Angiogenese beteiligt sind. MSC eignen sich somit, nach genetischer Modifikation, als Vehikel für therapeutisch wirksame Gene, mit denen das neu entstehende Gefäßsystem des GBM gezielt angegriffen werden kann. Für die entsprechenden in vivo-Versuche wurde bereits eine gentechnisch modifizierte MSC-Linie entwickelt und ein Therapieschema entworfen. Obwohl das Gehirn unter normalen Bedingungen kein Lymphgefäßsystem besitzt, wurden im Gewebe der malignen Hirntumoren in dieser Arbeit auch Lymphgefäß-assoziierte Moleküle nachgewiesen. Die Expression des Rezeptor-Liganden-Systems VEGFR-3/ VEGF-C,-D korreliert dabei mit dem Malignitätsgrad der Hirntumoren. Das gegensätzliche Expressionsmuster von Podoplanin könnte ein diagnostisches Kriterium darstellen, um Hirntumore mit unterschiedlichem Malignitätsgrad histopathologisch voneinander zu unterscheiden oder es könnte eine potenzielle Zielstruktur für neue Therapieansätze darstellen. Mit den etablierten GBM-Zelllinien steht ein Zellmodell zur weiteren Analyse der noch ungeklärten Funktion des Podoplanins im GBM zur Verfügung.

The role of members of the Vascular Endothelial Growth Factor (VEGF) family and their receptors in angiogenesis, progression and pathophysiology of pituitary tumours is still poorly understood. In the present work, the expression and localization of the angiogenic factor VEGF-A and the lymphangiogenic factor VEGF-C, as well as VEGF receptors (VEGFR-1, VEGFR-2, VEGFR-3 and neuropilin-1), have been studied in normal and tumoural pituitary tissue and in transformed pituitary tumour cell lines. In addition, the role and mechanism of action of VEGFR-1 ligands have been investigated in normal and transformed rat pituitary cells. Immunohistochemical investigations in 3 normal human adenohypophyses showed that VEGFR-2 and neuropilin-1 were localized in blood vessel endothelial cells, while VEGFR-1 was found in endocrine cells. VEGF-A significantly induced ACTH and prolactin secretion in normal rat pituitary cell cultures, indicating a role of VEGF-A and VEGFR-1 in the regulation of the secretion of these pituitary hormones. In contrast, VEGFR-2 and its co-receptor neuropilin-1 may be needed to maintain optimal intrapituitary vascularization and blood vessel permeability. Although no lymphatic vessels were identified in normal adenohypophysis, the lymphangiogenic factor VEGF-C and its receptor VEGFR-3 were detected by immunohistochemistry, suggesting the involvement of the VEGF-C/VEGFR-3 system, usually implicated in lymphangiogenesis, in the maintenance of blood vessel permeability. The expression of VEGFR-1, VEGFR-2 and neuropilin-1 in a series of 39 pituitary adenomas reflected the same immunohistochemical localization pattern as observed in the normal adenohypophysis tissue. It was highly heterogeneous and mostly no significant correlation with different parameters, such as: tumour type, tumour grade, proliferation index (PI) and blood vessel number, was noticed. Only the absence of VEGFR-2 and neuropilin-1 correlated with a low PI, suggesting a role of these two receptors in increasing vessel permeability and consequently the availability of nutrients and oxygen for tumour cells. Functional studies, with the VEGFR-1-positive somatotrophinoma rat pituitary cell line MtT-S, showed that VEGF-A and the VEGFR-1 specific ligand PlGF, significantly stimulated the cell proliferation, through the activation of PI3K pathway and the induction of the anti-apoptotic factor Bcl-2 and the cell cycle promoter cyclin D1. VEGF-C immunostaining was detected in endocrine tumour cells of 10 adenomas and VEGFR-3 immunopositive vessels were found in 22 tumours, even if only 9 of them were positive for both VEGFR-3 and LYVE-1 (specific lymphatic vessel marker), suggesting that the VEGF-C/VEGFR-3 system may have a role in the regulation of tumour angiogenesis of pituitary adenomas, rather than in lymphangiogenesis, as already shown in other tumour types. In conclusion, the results of the present study provide strong evidence that VEGF may not only have a role in regulating pituitary adenoma neovascularization but also, through VEGFR-1, may affect pituitary adenoma pathophysiology by modulating growth, cell cycle progression and survival of the adenoma cells.

Vascular endothelial growth factors ( VEGF)- A, - C and - D are members of the proangiogenic VEGF family of glycoproteins. VEGF-A is known to be the most important angiogenic factor under physiological and pathological conditions, while VEGF-C and VEGF-D are implicated in the development and sprouting of lymphatic vessels, so called lymphangiogenesis. Local tumor progression, lymph node metastases and hematogenous tumor spread are important prognostic factors for esophageal carcinoma ( EC), one of the most lethal malignancies throughout the world. We found solid evidence in the literature that VEGF expression contributes to tumor angiogenesis, tumor progression and lymph node metastasis in esophageal squamous cell carcinoma ( SCC), and many authors could show a prognostic value for VEGF-assessment. In adenocarcinoma (AC) of the esophagus angiogenic properties are acquired in early stages, particularly in precancerous lesions like Barrett's dysplasia. However, VEGF expression fails to give prognostic information in AC of the esophagus. VEGF-C and VEGF-D were detected in SCC and dysplastic lesions, but not in normal mucosa of the esophagus. VEGF-C expression might be associated with lymphatic tumor invasion, lymph node metastases and advanced disease in esophageal SCC and AC. Therapeutic interference with VEGF signaling may prove to be a promising way of anti-angiogenic co-treatment in esophageal carcinoma. However, concrete clinical data are still pending.