Lymphatic growth (lymphangiogenesis) within lymph nodes functions to promote dendritic cell entry and effector lymphocyte egress in response to infection or inflammation. Here we demonstrate a crucial role for lymphotoxin-beta receptor (LT beta R) signaling to fibroblastic reticular cells (FRCs) by lymphotoxin-expressing B cells in driving mesenteric lymph node lymphangiogenesis following helminth infection. LT beta R ligation on fibroblastic reticular cells leads to the production of B-cell-activating factor (BAFF), which synergized with interleukin-4 (IL-4) to promote the production of the lymphangiogenic factors, vascular endothelial growth factors (VEGF)-A and VEGF-C, by B cells. In addition, the BAFF-IL-4 synergy augments expression of lymphotoxin by antigen-activated B cells, promoting further B cell-fibroblastic reticular cell interactions. These results underlie the importance of lymphotoxin-dependent B cell-FRC cross talk in driving the expansion of lymphatic networks that function to ...

Tumor-associated lymphangiogenesis is considered significant in number of solid malignancies. However, its impact on prognosis of intrahepatic cholangiocarcinoma (ICC) after resection remains further confirmation. Herein, we conducted this study to evaluate prognostic impact of tumor-associated lymphangiogenesis in patients with ICC. Extent of tumor-associated lymphangiogenesis of ICC was evaluated by quantifying microlymphatic vessel density (MLVD) from immunohistochemical staining of a lymphatic endothelial-specific antibody (podoplanin). Clinicopathological characteristics were comprehensively analyzed to identify MLVD-associated factors. The patients were stratified into high and low MLVD groups according to the distinctive correlation between the MLVD and overall survival using the Spearmans correlation test. Kaplan-Meier estimation was performed to confirm prognostic impact of MLVD in patients with ICC. Univariate and multivariate analyses were performed using the Cox proportional hazard model.

The formation of lymphatic vessels from pre-existing lymphatic vessels, in a method believed to be similar to blood vessel development or angiogenesis. See also: * Lymphedema * Pathophysiology of Lymphedema Lymphedema Genetics Genetics, Research, Lymphangiogenesis, Angiogenesis The Formation of Lymphatic Vessels and Its Importance in the Setting of Malignancy Lymphangiogenesis Breast Cancer the VEGF-C Lymphangiogenesis and Gastric Cancer Lymphangiogenesis in Head and Neck Cancer Lymphangiogenesis and Kaposis Sarcoma VEGF-C Lymphangiogenesis and Melanoma Lymphangiogenesis in Wound Healing A model for gene therapy of human hereditary lymphedema VEGFR-3 Ligands and Lymphangiogenesis (1) VEGFR-3 Ligands and Lymphangiogenesis (2) VEGFR-3 Ligands and Lymphangiogenesis (3) Vascular Endothelial Growth Factor; VEGF VEGF-D is the strongest angiogenic and lymphangiogenic effector Inhibition of Lymphatic Regeneration by VEGFR3 VEGFR3 and Metastasis in Prostate Cancer Radiogeneic Lymphangiogenesis in the ...

To study a possible role of sentinel LN angiogenesis and lymphangiogenesis in lymphatic dissemination in patients with breast cancer, we have investigated the association of these processes-quantified as ECP% and LECP%, respectively-with the presence of nonsentinel LN metastases in breast cancer patients with a positive sentinel node biopsy. Increased lymphangiogenesis, not angiogenesis, was associated with an increased frequency of involved nonsentinel LNs. In the multivariate model, LECP% was independently associated with the presence of nonsentinel LN metastases.. These findings support the hypothesis that sentinel LN lymphangiogenesis is involved in further lymphatic spread of human breast cancer. As previously mentioned, most animal studies on sentinel LN lymphangiogenesis focused on its role in the premetastatic remodeling of the sentinel LN (premetastatic niche). However, some data from these models indeed suggest that sentinel LN lymphangiogenesis is also involved in further metastatic ...

Metastasis of breast cancer occurs primarily through the lymphatic system, and the extent of lymph node involvement is a key prognostic factor for the disease. Whereas the significance of angiogenesis for tumor progression has been well documented, the ability of tumor cells to induce the growth of lymphatic vessels (lymphangiogenesis) and the presence of intratumoral lymphatic vessels have been controversial. Using a novel marker for lymphatic endothelium, LYVE-1, we demonstrate here the occurrence of intratumoral lymphangiogenesis within human breast cancers after orthotopic transplantation onto nude mice. Vascular endothelial growth factor (VEGF)-C overexpression in breast cancer cells potently increased intratumoral lymphangiogenesis, resulting in significantly enhanced metastasis to regional lymph nodes and to lungs. The degree of tumor lymphangiogenesis was highly correlated with the extent of lymph node and lung metastases. These results establish the occurrence and biological significance of

The formation of new lymphatic vessels, or lymphangiogenesis, is a natural process involved in tissue repair and in the resolution of inflammatory reactions. In some cancers, this process is exploited by the tumor to promote its growth and its metastatic dissemination. Our group recently identified a role for the CD73-adenosine pathway in tumor angiogenesis. As angiogenesis and lymphangiogenesis are similar processes, often occurring in parallel, we suspect that the CD73-adenosine pathway could have a role in the regulation of lymphangiogenesis during inflammatory reactions and in the tumor microenvironment.. To confirm this hypothesis, we used in vivo models of inflammatory lymphangiogenesis induced by the administration of lipopolysaccharide (LPS) or Incomplete Freunds Adjuvant (IFA) in the peritoneal cavity of mice. These two models of peritonitis trigger the formation of new lymphatics in the diaphragm that can be analyzed by flow cytometry. To study tumor lymphangiogenesis, we used a ...

To determine the effect of celecoxib on lymphangiogenesis in Nasopharyngeal carcinoma Lymphangiogenesis and factors modulating lymphangiogenesis are associated with clinico-pathological outcome in Nasopharyngeal carcinoma and colorectal cancer. Celecoxib down-regulates lymphangiogenesis Archival colorectal cancer and Nasopharyngeal carcinoma tumor specimens will be obtained from the Department of Pathology. To determine the effect of celecoxib on lymphangiogenesis in Nasopharyngeal carcinoma, the investigators intend to analyze archived specimens collected in a previously conducted study. Colorectal tumor and nodal specimens and Nasopharyngeal carcinoma primary will be examined for MVD, LVD and growth factor expression using established haematoxylin and eosin and immunohistochemical techniques. Quantification of LVD and MVD shall be performed by two pathologists blinded to clinico-pathological variables using standardised methods ...

same day of injury or on day 7 after injury. Injured corneas were imaged using an Axiozoom V16 stereomicroscope and analyzed with Zeiss Zen imaging programs at day 1, 4, 7, 10 and 14. The areas of induced corneal blood and lymphatic vessels were calculated using Adobe Photoshop. Results : In the control group, without tamoxifen treatment, total corneal epithelial debridement resulted in enhanced corneal angiogenesis and lymphangiogenesis in all three mouse strains. In contrast, deletion of lymphatic endothelial VEGFR2 and/or VEGFR3 in the progression assay abolished the injury-induced corneal lymphangiogenesis in all three mouse strains. In the regression assay with tamoxifen treatment 7 days after corneal injury, no injury-induced corneal lymphangiogenesis was observed in mice with conditional deletion of VEGFR3 and those with conditional deletion of both receptors. However, injury-induced corneal lymphangiogenesis was observed in the mice with VEGFR2 deletion. Conclusions : Lymphatic ...

How tumors access and spread via the lymphatics is not understood. Although it is clear that dissemination via the blood system involves hemangiogenesis, it is uncertain whether tumors also induce lymphangiogenesis or simply invade existing peritumoral vessels. To address the issue we quantitated tumor lymph vessels in archival specimens of head and neck cancer by immunostaining for the recently described lymphatic endothelial marker LYVE-1, the vascular endothelial marker CD34, and the pKi67 proliferation marker, correlating lymph vessel density and proliferation index with clinical and pathological variables. Discrete hotspots of intratumoral small proliferating lymphatics were observed in all carcinomas, and a high intratumoral lymph vessel density was associated with neck node metastases (n = 23; P = 0.027) and an infiltrating margin of tumor invasion (P = 0.046) in the oropharyngeal subgroup. Quantitation of the lymphangiogenic growth factor vascular endothelial growth factor C by real-time PCR

Purpose.: To analyze whether insulin receptor substrate (IRS-1) is involved in lymphatic vessel development and whether IRS-1 blockade can inhibit lymphangiogenesis in vivo. Methods.: The impact of IRS-1 blockade by GS-101 (Aganirsen), an antisense oligonucleotide against IRS-1, on lymphatic endothelial cell (LEC) proliferation was assessed by ELISA. Furthermore, the effect of IRS-1 blockade on prolymphangiogenic growth factor expression by LECs and macrophages (peritoneal exudate cells) was tested by real-time PCR. The mouse model of inflammatory corneal neovascularization was used to analyze the effect of IRS-1 blockade in vivo: after corneal suture placement, mice were treated with GS-101 eye drops (twice daily afterwards for 1 week, 5 μL per drop; 50, 100, or 200 μM). Afterward, corneal wholemounts were prepared and stained for blood and lymphatic vessels. Results.: Blockade of IRS-1 by GS-101 inhibited LEC proliferation dose dependently. GS-101 led to decreased VEGF-A expression levels in ...

In melanoma, vascular endothelial growth factor-C (VEGF-C) expression and consequent lymphangiogenesis correlate with metastasis and poor prognosis. VEGF-C also promotes tumor immunosuppression, suggesting that lymphangiogenesis inhibitors may be clinically useful in combination with immunotherapy. We addressed this concept in mouse melanoma models with VEGF receptor-3 (VEGFR-3)-blocking antibodies and unexpectedly found that VEGF-C signaling enhanced rather than suppressed the response to immunotherapy. We further found that this effect was mediated by VEGF-C-induced CCL21 and tumor infiltration of naïve T cells before immunotherapy because CCR7 blockade reversed the potentiating effects of VEGF-C. In human metastatic melanoma, gene expression of VEGF-C strongly correlated with CCL21 and T cell inflammation, and serum VEGF-C concentrations associated with both T cell activation and expansion after peptide vaccination and clinical response to checkpoint blockade. We propose that VEGF-C ...

TY - JOUR. T1 - VEGFR-3 neutralization inhibits ovarian lymphangiogenesis, follicle maturation, and murine pregnancy. AU - Rutkowski, Joseph M.. AU - Ihm, Jong Eun. AU - Lee, Seung Tae. AU - Kilarski, Witold W.. AU - Greenwood, Veronique I.. AU - Pasquier, Miriella C.. AU - Quazzola, Alexandra. AU - Trono, Didier. AU - Hubbell, Jeffrey A.. AU - Swartz, Melody A.. PY - 2013/11/1. Y1 - 2013/11/1. N2 - Lymphatic vessels surround follicles within the ovary, but their roles in folliculogenesis and pregnancy, as well as the necessity of lymphangiogenesis in follicle maturation and health, are undefined. We used systemic delivery of mF4-31C1, a specific antagonist vascular endothelial growth factor receptor 3 (VEGFR-3) antibody to block lymphangiogenesis in mice. VEGFR-3 neutralization for 2 weeks before mating blocked ovarian lymphangiogenesis at all stages of follicle maturation, most notably around corpora lutea, without significantly affecting follicular blood angiogenesis. The numbers of oocytes ...

The physiological functions of LVs and their contributions to pathological mechanisms during chronic disease conditions have not been extensively investigated. We have addressed this gap in the context of CKD by comprehensively investigating the role of lymphangiogenesis in kidneys and RDLNs. We describe a previously unrecognized function of lymphangiogenesis as a key process in the kidney and RDLNs mediating intrarenal inflammation and progressive fibrosis. Although it has been previously reported that lymphangiogenesis is a common feature in the progression of renal fibrosis (19), the origin and function of intrarenal LVs in CKD remained undefined. Here, we observed extensive LEC proliferation in a cohort of 289 CKD patients that was not evident in healthy controls. CKD patients with higher density intrarenal LVs presented with more severe proteinuria and renal fibrosis and decreased eGFR. Our mouse model experiments revealed localized LEC proliferation as the cellular origin of ...

Previous studies identified a prominent role of S1PR1 in tumor progression linked to persistent STAT3 activation in tumor and myeloid cells (Lee et al., 2010; Deng et al., 2012; Degagné et al., 2014). We previously noticed STAT3 signaling downstream of S1PR1 in human macrophages, which contributed to establishing an anti-inflammatory phenotype (Weis et al., 2009). However, in the present study, S1PR1 signaling in CD11bhi CD206+ TAMs did not affect typical STAT3 target genes in macrophages. Rather, a so-far-unexplored S1PR1 signaling circuit in macrophages promoted lymphangiogenesis via NLRP3-dependent IL-1β secretion.. Our global mRNA expression data in TAMs failed to identify previously described macrophage-derived prolymphangiogenic factors such as VEGF-C or VEGF-D as targets of S1PR1 signaling (Kerjaschki, 2005). Rather, NLRP3 expression and the concomitant IL-1β release promoted lymphangiogenesis. Although an involvement of VEGFs in the prolymphangiogenic properties of TAMs in breast ...

AbstractAngiogenesis is one of the pillars of neoplasia. Lymphangiogenesis in context of granulomas is not yet understood. This study aimed to evaluate the role of praziquantel (PZQ) and artemether (ART) as anti-angiogenic and anti-lymphangiogenic drugs in Schistosoma mansoni induced experimental hepatic model through immunohistochemical and serological studies, this can be used as a potential novel prophylactic approach in hepatic malignancy prevention and possible management. Forty female CD-1 Swiss albino mice were used divided into 4 groups (10 mice each); control healthy, control infected untreated, PZQ-treated and ART-treated. Angiogenic and lymphangiogenic effect of the drugs assessed pathologically through counting of the newly formed capillaries and lymphatics that immunohistochemically expressed by vascular Endothelial Growth Factor (VEGF), CD34 and D2-40 in liver sections using Cell Image Analyzer and serologically by evaluation of serum level of Tumor Necrosis Factor-Alpha (TNF-α). Our

Aged,Antigens, CD/*biosynthesis,Carcinoma, Small Cell/blood supply/*metabolism/*pathology,Female,Humans,Immunohistochemistry,Lung Neoplasms/blood supply/*metabolism/*pathology,Lymphangiogenesis,Lymphatic Metastasis,Male,Middle Aged,Neoplasm Staging,Prognosis,Receptors, Cell Surface/*biosynthesis,Retrospective ...

Studies of the last decades have revealed the importance of angiogenesis for normal growth and for the pathogenesis of numerous diseases. Much less studied is lymphangiogenesis, the growth of lymphatic vessels, which drain extravasated fluid, proteins, and cells and transport them back to the venous …

Cyclooxygenase-2 (COX-2) is associated with poor-prognosis breast cancer. We used a nude mouse xenograft model to determine the effects of COX-2 inhibition in breast cancer. Oestrogen receptor (ER)-positive MCF7/HER2-18 and ER-negative MDAMB231 breast cancer cell lines were injected into nude mice and allowed to form tumours. Mice then received either chow containing Celecoxib (a COX-2 inhibitor) or control and tumour growth measured. Tumour proliferation, apoptosis, COX-2, lymphangiogenesis and angiogenesis were assessed by immunohistochemistry (IHC), Western blotting or Q-PCR. Celecoxib inhibited median tumour growth in MCF7/HER2-18 (58.7%, P=0.029) and MDAMB231 (46.3%, P=0.0002) cell lines compared to control. Cyclooxygenase-2 expression decreased following Celecoxib treatment (MCF7/HER2-18 median control 65.3% vs treated 22.5%, P=0.0001). Celecoxib increased apoptosis in MCF7/HER2-18 tumours (TUNEL 0.52% control vs 0.73% treated, P=0.0004) via inactivation of AKT (median pAKT(ser473) 57.3% control

Many cancers, such as melanoma, are known to metastasize and spread by expanding nearby lymphatic vessels. This process, lymphangiogenesis, also helps the tumor evade the patients own immune system, and it would be expected that inhibiting lymphangiogenesis, could enhance the efficacy of cancer immunotherapies, which are only effective in a minority of patients. But in a surprising discovery, scientists from EPFL and the US found the opposite: lymphangiogenesis actually enhances the effectiveness of immunotherapy against melanoma. Published in Science Translational Medicine, the study has significant implications for new types of cancer therapies.. Cancer immunotherapy is one of the most promising treatments against tumors. The process involves overcoming the tumors suppression of immune attacks, thus allowing the patients own immune system to destroy it. But despite the highly encouraging results from clinics only a subset of patients is able to respond to immunotherapy. Until now, the ...

Background: Lymphangiogenesis, assessed as lymphovascular density (LVD), is the initial step of generalized tumor lymphovascular invasion (LVI). It also involves VEGF-C as the most important protein family. Lymphangiogenesis among breast cancer cases correlations with several clinicopathological factors are important to determine prognosis and treatment strategies, but results have been controversial and require clarification. Aim: To define correlations between VEGF-C expression, LVD and LVI with several clinicopathological parameters from Indonesian breast cancer patients. Materials and Methods: Using a cross-sectional study, a total of 48 paraffin-embedded tissues of breast cancer from Dr. Sardjito General Hospital Indonesia were assessed for VEGF-C expression, LVD and LVI by immunohistochemistry. Correlations of these markers with clinicopathological parameters like patient age, tumor size, lymph node status, grade, ER/PR and Her-2 status, cell proliferation and p-53 expression were ...

Scientists reveal new target for anti-lymphangiogenesis drugs Emerging field of study yields new hope for organ transplant rejection, cancer metastasis, and lymphedema BOSTON (April 12, 2016) - After an injury to tissues, such as in organ transplantation, the body grows new lymphatic vessels in a process known as lymphangiogenesis. A new study in Nature Communications… Read More ...

In nearly all human cancers, the presence of lymph node (LN) metastasis increases clinical staging and portends worse prognosis (compared to patients without LN metastasis). Herein, principally reviewing experimental and clinical data related to malignant melanoma, we discuss diverse factors that are mechanistically involved in LN metastasis. We highlight recent data that link tumor microenvironment, including inflammation (at the cellular and cytokine levels) and tumor-induced lymphangiogenesis, with nodal metastasis. Many of the newly identified genes that appear to influence LN metastasis facilitate general motility, chemotactic, or invasive properties that also increase the ability of cancer cells to disseminate and survive at distant organ sites. These new biomarkers will help predict clinical outcome and point to novel future therapies in metastatic melanoma as well as other cancers.

PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

All cells in our body need oxygen and they receive it via the circulating blood. Thats why the vascular system is the first organ system to function in a developing embryo. Before the heart starts pumping, the embryos 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 ...

Ebba Brakenhielm is an Editor at PeerJ. Bio: INSERM Tenured Researcher in the field of Cardiovascular Research, currently focusing on therapeutic angiogenesis with polymer-based targeted growth factor delivery. PhD in Tumor Biology (Pr Yihai Cao, Karolinska Institutet, Sweden), and expertise in Adipose tissue angiogenesis. Postdoc at UCLA (Pr Lily Wu) in molecular imaging and tumor lymphangiogenesis field. Member of European Vascular Biology Organisation, French society for Cardiovascular Research, French society for Angiogenesis Research.

Principal Investigator：MAJIMA Masataka, Project Period (FY)：2012-04-01 - 2015-03-31, Research Category：Grant-in-Aid for Challenging Exploratory Research, Research Field：General pharmacology

https://doi.org/10.18632/oncotarget.2032 Judit Berta, Mir Alireza Hoda, Viktoria Laszlo, Anita Rozsas, Tamas Garay, Szilvia Torok, Michael Grusch, Walter Berger, Sandor Paku, Ferenc Renyi-Vamos,...

Our mission is to build healthier lives, free of cardiovascular diseases and stroke. That single purpose drives all we do. The need for our work is beyond question. Find Out More about the American Heart Association. ...

Previous studies have shown that SphK1 is overexpressed in breast cancer, and its level of expression correlates with resistance to treatments and poor patient outcomes (16, 18, 20). However, several factors have hindered progress in determining the role of S1P, the product of SphK1, in tumorigenesis and tumor-induced hemangiogenesis and lymphangiogenesis in vivo. First, because S1P has such a profound role in immune function (35), studies of traditional in vivo metastatic breast cancer models with xenografts in immune-compromised mice that ignore the host immune response to cancer may be difficult to interpret. Second, it has not been possible to accurately quantify S1P in tumors until recently with the development of high sensitivity mass spectrometric assays (25). To this end, we utilized our newly established syngeneic breast cancer model, which not only retains the host immune responses but also more closely models progression of the human disease by forming lymph node and lung metastasis ...

Subject: Collagen And Calcium Binding EGF Domains 1 (CCBE1) is a coding protein which plays a significant role in extracellular matrix remodeling and migration and is involved in the development of Hennekam syndrome and lymphangiogenesis. Here, we investigate its prognostic value in prostate c...

Research into the molecular basis of lymphangiogenesis in embryonic development and pathological processes has led to a rapid increase of our knowledge (Krebs and Jeltsch 2013A, 2013B). The molecular biology era of lymphatic research began with the discovery of the VEGF growth factors and their receptors 25 years ago, and these molecules are the focus of this overview.. ...

Sentinel lymph node metastasis is a common and early event in the metastatic process of head and neck squamous cell carcinoma (HNSCC) and is the most powerful prognostic factor for survival of HNSCC patients. 3-O-acetyloleanolic acid (3AOA), a pentacyclic triterpenoid compound isolated from seeds of Vigna sinensis K., has been reported to have potent anti-angiogenesis and anti-tumor activities. However, its effects on tumor-related lymphangiogenesis and lymph node metastasis are not yet understood. The in vitro inhibitory effects of 3AOA on VEGF-A-induced lymphangiogenesis were investigated via in vitro experiments using mouse oral squamous cell carcinoma (SCCVII) cells and human lymphatic microvascular endothelial cells (HLMECs). The in vivo inhibitory effects of 3AOA on VEGF-A-induced lymphangiogenesis and sentinel lymph node metastasis were investigated in an oral cancer sentinel lymph node (OCSLN) animal model. 3AOA inhibited tumor-induced lymphangiogenesis and sentinel lymph node metastasis in an

Vascular endothelial growth factor (VEGF)-C and VEGF-D induce lymphangiogenesis through activation of VEGF receptor 3 (VEGFR-3) and have been implicated in tumor spread to the lymphatic system. Lymph node dissemination critically determines clinical outcome and therapeutic options of patients with non-small cell lung cancer (NSCLC). However, the relationship of VEGF-C, VEGF-D, and lymph node metastasis in cancers, including NSCLC, is still controversial. To evaluate the relationship between lymphangiogenesis and lymph node metastasis, the expression of VEGF-C and VEGF-D in NSCLC tumors were detected by immunohistochemistry and quantitative real-time polymerase chain reaction (QRT-PCR). QRT-PCR revealed that in marginal region VEGF-C and VEGF-D mRNA was significantly higher than in tumor center, and VEGF-D mRNA was also higher than that in peritumoral lung tissue. Immunohistochemically, we observed the same heterogeneous expression of VEGF-C and VEGF-D proteins. The group with high expression of ...

Background: Vascular endothelial growth factor-C (VEGF-C), a homologue of VEGF family, plays a key role in lymphangiogenesis. Recently, we demonstrated that VEGF-C is closely associated with dyslipidemia and atherosclerosis. However, the relationship between serum VEGF-C levels and cardiovascular events in patients with atherosclerotic disease is unknown.. Methods and Results: We performed a prospective cohort study involving a total of 209 patients with arteriosclerotic obliterans (ASO) (age, 73±8 y [SD]; male, 75%; hypertension, 88%; diabetes, 69%; dyslipidemia, 72%; history of smoking, 76%; Fontaine class, 2.1±0.8). Serum levels of VEGF-C, VEGF-A and high-sensitivity C-reactive protein (hsCRP) were determined employing specific enzyme-linked immunosorbent assays. The primary outcome was major adverse cardiac events (MACEs) defined as all-cause mortality, hospitalization due to acute coronary syndrome, stroke, congestive heart failure, aortic disease, and coronary/peripheral ...

Edema occurs in asthma and other inflammatory diseases when the rate of plasma leakage from blood vessels exceeds the drainage through lymphatic vessels and other routes. It is unclear to what extent lymphatic vessels grow to compensate for increased leakage during inflammation and what drives the lymphangiogenesis that does occur. We addressed these issues in mouse models of (a) chronic respiratory tract infection with Mycoplasma pulmonis and (b) adenoviral transduction of airway epithelium with VEGF family growth factors. Blood vessel remodeling and lymphangiogenesis were both robust in infected airways. Inhibition of VEGFR-3 signaling completely prevented the growth of lymphatic vessels but not blood vessels. Lack of lymphatic growth exaggerated mucosal edema and reduced the hypertrophy of draining lymph nodes. Airway dendritic cells, macrophages, neutrophils, and epithelial cells expressed the VEGFR-3 ligands VEGF-C or VEGF-D. Adenoviral delivery of either VEGF-C or VEGF-D evoked lymphangiogenesis

PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Background: Metastasis to regional lymph nodes (LNs) through lymphatic vessels is common in cancer progression and is an important prognostic factor in many cancers. Recent evidence suggests that tumour lymphangiogenesis promotes lymphatic metastasis.. Aims: To study the role of lymph vessel density (LVD) in gastric cancer and investigate whether LVD is associated with LN metastasis/prognosis.. Methods: Lymphatics of 117 primary human gastric cancer cases were investigated by quantitative immunohistochemical staining for podoplanin. The relation between LVD and LN metastasis and other established clinicopathological parameters was analysed. The relation between LVD and prognosis was also studied.. Results: Mean LVD of hot spots was 11.6/case. LVD significantly correlated with LN and podoplanin positive lymphatic invasion. High LVD was associated with worse overall survival. In multivariate analysis, positive LVD was a significant independent predictor of overall survival, depth of invasion, ...

Dry eye disease (DED) is one of the most common ocular surface diseases, affecting millions of individuals. Over the last years it became a public health disorder, concerning especially the elderly. Patients who suffer from dry eye, report symptoms like dryness, irritation and decreased visual acuity leading to a loss of lifes quality. Even if the underlying immunopathogenesis has been verified in recent years more and more accurately, no causal treatment is available due to the various factors triggering dry eye disease and its self-intensifying viscious circle. Artificial tears and anti-inflammatory eye drops are nowadays the conventional therapy. Thus the identification of new treatment strategies is essential. Recent data suggest that the anti-angiogenic privilege, which maintains the transparency of the cornea and preserves high visual acuity, is disturbed in DED leading to a selective and spontaneous outgrowth of lymphatic vessels. These vessels are known as risk factor for corneal graft ...

https://doi.org/10.18632/oncotarget.12978 Olaia Martínez-Iglesias, David Olmeda, Elvira Alonso-Merino, Sara Gómez-Rey, Ana M. González-López, Enrique Luengo, María S. Soengas, José Palacios, Javier...

TY - JOUR. T1 - Radiation-induced VEGF-C expression and endothelial cell proliferation in lung cancer. AU - Chen, Yu Hsuan. AU - Pan, Shiow Lin. AU - Wang, Jing Chi. AU - Kuo, Sung Hsin. AU - Cheng, Jason Chia Hsien. AU - Teng, Che Ming. PY - 2014/11/22. Y1 - 2014/11/22. N2 - Background: The present study was undertaken to investigate whether radiation induces the expression of vascular endothelial growth factor C (VEGF-C) through activation of the PI3K/Akt/mTOR pathway,subsequently affecting endothelial cells.Materials and methods: Radiotherapy-induced tumor micro-lymphatic vessel density (MLVD) was determined in a lung cancer xenograft model established in SCID mice. The protein expression and phosphorylation of members of the PI3K/Akt/mTOR pathway and VEGF-C secretion and mRNA expression in irradiated lung cancer cells were assessed by Western blot analysis, enzyme-linked immunosorbent assays (ELISAs), and reverse transcriptase-polymerase chain reaction (RT-PCR). Moreover, specific chemical ...

Lymphatic remodeling in tumor microenvironments correlates with progression and metastasis, and local lymphatic vessels play complex and poorly understood roles in tumor immunity. Tumor lymphangiogenesis is associated with increased immune suppression, yet lymphatic vessels are required for fluid drainage and immune cell trafficking to lymph nodes, where adaptive immune responses are mounted. Here, we examined the contribution of lymphatic drainage to tumor inflammation and immunity using a mouse model that lacks dermal lymphatic vessels (K14-VEGFR3-Ig mice). Melanomas implanted in these mice grew robustly, but exhibited drastically reduced cytokine expression and leukocyte infiltration compared with those implanted in control animals. In the absence of local immune suppression, transferred cytotoxic T cells more effectively controlled tumors in K14-VEGFR3-Ig mice than in control mice. Furthermore, gene expression analysis of human melanoma samples revealed that patient immune parameters are ...

Abstract. Lymphatic dilatation, dysfunction, and lymphangiogenesis are hallmarks of patent lymphatic filariasis, observed even in those with subclinical microfilaremia, through processes associated, in part, by vascular endothelial growth factors (VEGFs). A panel of pro-angiogenic factors was measured in the plasma of subjects from filaria-endemic regions using multiplexed immunological assays. Compared with endemic normal control subjects, those with both subclinical microfilaremia, and those with longstanding lymphedema had significantly elevated levels of VEGF-A, VEGF-C, VEGF-D, and angiopoeitins (Ang-1/Ang-2), with only levels of basic fibroblast growth factor (bFGF) and placental growth factor (PlGF) being elevated only if lymphedema was evident. Furthermore, levels of these factors 1-year post-treatment with doxycycline were similar to pretreatment levels suggesting a minimal role, if any, for Wolbachia. Our data support the concept that filarial infection per se is associated with elevated levels

The lymphatic system is intimately linked to tissue fluid homeostasis and immune cell trafficking. These functions are paramount in the establishment and development of an inflammatory response. In th

The small intestine is a dynamic and complex organ that is characterized by constant epithelium turnover and crosstalk among various cell types and the microbiota. Lymphatic capillaries of the small intestine, called lacteals, play key roles in dietary fat absorption and the gut immune response; however, little is known about the molecular regulation of lacteal function. Here, we performed a high-resolution analysis of the small intestinal stroma and determined that lacteals reside in a permanent regenerative, proliferative state that is distinct from embryonic lymphangiogenesis or quiescent lymphatic vessels observed in other tissues. We further demonstrated that this continuous regeneration process is mediated by Notch signaling and that the expression of the Notch ligand delta-like 4 (DLL4) in lacteals requires activation of VEGFR3 and VEGFR2. Moreover, genetic inactivation of ...

Migration of LECs has previously been shown to be dependent on VEGF-C/Vegfr-3 signaling.12 We analyzed LECs for Vegfr-3 tyrosine phosphorylation (pTYR/Vegfr-3) in situ, using a proximity ligation assay.13 We quantified both the number of Lyve-1+ cells and the number of pTYR/Vegfr-3 sites per Lyve-1+ cell at E10.5 and E12.5 and confirmed a reduction in the number of Lyve-1+ cells in Ccbe1−/− embryos (Online Figure II). However, at critical stages of LEC migration, levels of phosphorylated Vegfr-3 per Lyve-1+ cell were unaltered, indicating that Vegfr-3 activation is not affected by the absence of CCBE1 and suggesting that CCBE1 may function independently of Vegfr-3 phosphorylation (Online Figure II).. Because Vegfr-3 phosphorylation appeared normal in Ccbe1−/− LECs and as suggested by the CCBE1 domain structure, we considered whether CCBE1 might be part of the extracellular matrix (ECM). Because we were unable to produce full-length CCBE1, and because previous6,7,14 and new genetic ...

VEGF R1 (Flt-1), VEGF R2 (KDR/Flk-1), and VEGF R3 (Flt-4) belong to the class III subfamily of receptor tyrosine kinases (RTKs). All three receptors contain seven immunoglobulin-like repeats in their extracellular domain and kinase insert domains in their intracellular region. They are best known for regulating VEGF family-mediated vasculogenesis, angiogenesis, and lymphangiogenesis. They are also mediators of neurotrophic activity and regulators of hematopoietic development. Human VEGF R2 is thought to be the primary inducer of VEGF-mediated blood vessel growth, while VEGF R3 plays a significant role in VEGF-C and VEGF-D-mediated lymphangiogenesis ...

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June 2020. Our paper Endothelial YAP1 in Regenerative Lung Growth through the Angiopoietin-Tie2 Pathway has been selected for one of the best Junior Investigators papers of American Journal of Respiratory Cell and Molecular Biology (Red Journal). March 2020. Katharine has gotten EB travel award! Congraturations!. Tada presented the poster Age-related changes in lymphangiogenesis in the lung at Gordon Research Conference at Ventura, CA.. Akiko presented the poster Role of lymphangiogenesis in lung regeneration at Gordon Research Conference at Ventura, CA.. Feb 2020. Tendai Hunyenyiwa has joined to our lab as a graduate student.. Akiko and Tada presented the poster Twist1 in hypoxia-induced vascular remodeling at PVRI.. Dec 2019. Maria Leiva has joined to Mammoto Lab.. Nov 2019. Tada presented Biologically Inspired Organ Engineering for Children at CRI Research Conference at MCW.. Akiko and Tada presented Mechanosensitive Mechanism of Angiogenesis in Lung Gerenration at Dev and Stem ...

Author Summary Herpes simplex virus-type 1 is the leading cause of infectious corneal blindness in the industrialized world. Most of the morbidity associated with the virus is due to the host response to episodic reactivation of latent virus. Corneal immunologic privilege is associated with a number of factors including the absence of blood and lymphatic vessels. Conversely, corneal hem (blood)- and lymph-angiogenesis driven by inflammation correlate with the loss of privilege. Neovascularization is a common phenomenon in HSV-1 keratitis that correlates with poor prognosis. We have previously discovered HSV-1 elicits corneal lymphangiogenesis through a unique mechanism involving vascular endothelial growth factor (VEGF)-A independent of that described for other insults including transplantation or bacterial infection. However, the viral-encoded product(s) that elicit host production of VEGF-A is(are) unknown. In this paper, we have identified infected cell protein-4 (ICP4) as the primary virus-encoded

RESULTS: The receptors for LXA4, ALX/Fpr-rs-2 and for RvE1, ChemR23 were each expressed by epithelium, stromal keratocytes, and infiltrated CD11b(+) cells in corneas. Compared to the vehicle-treated eye, ATLa-, RvD1-, and RvE1-treated eyes had reduced numbers of infiltrating neutrophils and macrophages and reduced mRNA expression levels of TNF-alpha, IL-1 alpha, IL-1 beta, VEGF-A, VEGF-C, and VEGFR2. Animals treated with these mediators had significantly suppressed suture-induced or IL-1 beta-induced hemangiogenesis (HA) but not lymphangiogenesis. Interestingly, only the application of ATLa significantly suppressed VEGF-A-induced HA ...

TY - CHAP. T1 - Mast cells, angiogenesis and cancer. AU - Ribatti, Domenico. AU - Crivellato, Enrico. PY - 2011. Y1 - 2011. N2 - Mast cells (MCs) were first described by Paul Ehrlich 1 in his doctoral thesis. MCs have long been implicated in the pathogenesis of allergic reactions and certain protective responses to parasites. As most tumors contain inflammatory cell infiltrates, which often include plentiful MCs, the question as to the possible contribution of MCs to tumor development has progressively been emerging. In this chapter, the specific involvement of MCs in tumor biology and tumor fate will be considered, with particular emphasis on the capacity of these cells to stimulate tumor growth by promoting angiogenesis and lymphangiogenesis. Data from experimental carcinogenesis and from different tumor settings in human pathology will be summarized. Information to be presented will suggest that MCs may serve as a novel therapeutic target for cancer treatment.. AB - Mast cells (MCs) were ...

In squamous cell carcinoma of the pores and skin, Hirakawa et al. showed that VEGF-C overexpressing tumors managed their lymphangiogenic profile right after

so recently, have so far not been subject to any request. In April 2014, for the first time, the Deontology committee had a discussion as to whether the CCBE should issue interpretations of the CCBE Code... ...