Expression of vascular endothelial growth factor-C and its receptor in osteosarcomas

Vascular endothelial growth factor-C (VEGF-C) and its receptor, vascular endothelial growth factor receptor-3 (VEGFR-3), have been implicated as important factors in the formation of lymphatic vessels, but its role in osteosarcomas has not yet been fully investigated. This study aims to define the expression of VEGF-C and VEGFR-3 in primary and metastatic osteosarcomas and their relationship to various clinicopathologic parameters. Thirty-three primary osteosarcomas and two pulmonary metastatic samples were immunostained for VEGF-C and VEGFR-3. In addition, VEGF-C and vascular endothelial growth factor-D (VEGF-D) mRNA expression levels in three different human osteosarcoma cell lines and control fibroblasts were evaluated by real-time quantitative polymerase chain reaction (PCR). Both VEGF-C and VEGFR-3 were expressed mainly in the cytoplasm of the tumor cells. Of the 35 patients with osteosarcoma, 16 patients (45.7%) showed strong positive reaction with VEGF-C. Four cases (11.4%) were negative, and 15 cases (42.9%) showed weak immunoreactivity. For VEGFR-3, 12 patients (34.3%) showed strong positive reaction. Fifteen cases (42.9%) were negative, and eight cases (22.8%) showed weak immunoreactivity. A significant, positive correlation (Rs=0.42, p=0.01) was found between the expression of VEGF-C and VEGFR-3 in osteosarcomas. The expression of VEGF-C was significantly associated with the osteoblastic subtype and high histologic grade in osteosarcomas. However, the expression of VEGF-C showed no significant correlation with the presence of metastasis. Expression of VEGFR-3 was not related to any clinicopathologic features analyzed. Two of the three osteosarcoma cell lines tested showed amplification of VEGF-C mRNA compared with control cells. No amplification of VEGF-D was noted in these cell lines. Our data suggest that VEGF-C and its receptor are expressed in osteosarcomas. Although the level of VEGF-C was high, it does not seem to have a direct influence on tumor metastasis in osteosarcomas.     

Loss of p27 nuclear expression in a prognostically favorable subset of well-differentiated pancreatic endocrine neoplasms

Decreased expression of p27 occurs in aggressive colon, breast, and prostate neoplasms; p27 loss often correlates with worsened prognosis. Paradoxical overexpression has been described in benign and malignant pancreatic endocrine neoplasms (PENs). To investigate prognostic usefulness of p27 expression in PENs, we immunolabeled 42 primary PENs, with or without metastases, for p27 and separated lesions using a nuclear labeling index (NLI) of 10%. Of the 42 lesions, 26 demonstrated a 10% or higher NLI and 16 an NLI less than 10%. Comparison of lymph node status revealed that 50% of primary PENs with a 10% or higher NLI (13/26) demonstrated lymph node metastases, whereas only 6% of lesions with an NLI of less than 10% (1/16) demonstrated lymph node metastases (P = .0067). We next examined 11 liver and 7 lymph node metastases for p27 immunolabeling to determine whether p27 also is paradoxically retained in lesions that have metastasized. All 18 lesions demonstrated an NLI of 10% or higher for p27. Expression of p27 protein therefore appears to be lost in a subset of well-differentiated PENs with indolent features but paradoxically retained in PENs associated with metastatic disease.     

炎性环境下内皮微粒介导单核细胞促内皮细胞增殖的作用

目的 探讨炎性环境中内皮微粒(EMPs)在单核细胞参与的促内皮细胞增殖中的作用,并探讨EMPs对单核细胞表达内皮细胞标志物的影响.方法 体外培养人脐静脉内皮细胞(HUVECs),炎性因子肿瘤坏死因子α(TNF-α)刺激内皮细胞,超速离心法获取EMPs;用透射电镜观察其形态和结构;运用酶联免疫吸附法(ELISA)检测经EMPs激活的单核细胞株THP-1对血管内皮生长因子(VEGF)中VEGF-A、VEGF-C的表达情况;将HUVECs和THP-1细胞或者经EMPs诱导的THP-1细胞共培养,检测HUVECs的增殖情况;运用RT-PCR和免疫荧光细胞化学技术,观察经EMPs激活的THP-1细胞对内皮细胞标志物vWF和血管内皮生长因子受体2(VEGFR-2)的表达情况.结果 内皮细胞经炎性因子刺激后释放EMPs,EMPs刺激的THP-1细胞上清中VEGF-A和VEGF-C蛋白水平明显升高;HUVECs细胞增殖实验中,与THP-1细胞或者经EMPs诱导的THP-1共培养的两种情况下,HUVECs均显著增多;与EMPs共培养3d后,THP-1中vWF和VEGFR-2蛋白表达为阳性,基因表达为阴性,共培养8d后,vWF和VEGFR-2的蛋白和基因表达均为阴性.结论 炎性环境中内皮细胞释放EMPs可以促使单核细胞分泌VEGF-A和VEGF-C,后两者可使HUVECs增殖,EMPs仅能使单核细胞一过性呈现内皮表型,而不能将其转分化为内皮细胞.     

Vascular endothelial growth factor-C, a potential paracrine regulator of glomerular permeability, increases glomerular endothelial cell monolayer integrity and intracellular calcium

We have previously reported expression of vascular endothelial growth factor (VEGF)-A and -C in glomerular podocytes and actions of VEGF-A on glomerular endothelial cells (GEnC) that express VEGF receptor-2 (VEGFR-2). Here we define VEGFR-3 expression in GEnC and investigate the effects of the ligand VEGF-C. Renal cortex and cultured GEnC were examined by microscopy, and both cell and glomerular lysates were assessed by Western blotting. VEGF-C effects on trans-endothelial electrical resistance and albumin flux across GEnC monolayers were measured. The effects of VEGF-C156S, a VEGFR-3-specific agonist, and VEGF-A were also studied. VEGF-C effects on intracellular calcium ([Ca²⁺]_i) were measured using a fluorescence technique, receptor phosphorylation was examined by immunoprecipitation assays, and phosphorylation of myosin light chain-2 and VE-cadherin was assessed by blotting with phospho-specific antibodies. GEnC expressed VEGFR-3 in tissue sections and culture, and VEGF-C increased trans-endothelial electrical resistance in a dose-dependent manner with a maximal effect at 120 minutes of 6.8 Ω whereas VEGF-C156S had no effect. VEGF-C reduced labeled albumin flux by 32.8%. VEGF-C and VEGF-A increased [Ca²⁺]_i by 15% and 39%, respectively. VEGF-C phosphorylated VEGFR-2 but not VEGFR-3, myosin light chain-2, or VE-cadherin. VEGF-C increased GEnC monolayer integrity and increased [Ca²⁺]_i, which may be related to VEGF-C-S particular receptor binding and phosphorylation induction characteristics. These observations suggest that podocytes direct GEnC behavior through both VEGF-C and VEGF-A.     

The significance of VEGF-C/VEGFR-2 interaction in the neovascularization and prognosis of nephroblastoma (Wilms' tumour)

AIM: To investigate the immunohistochemical expression of vascular endothelial growth factor (VEGF)-C and VEGFR-2 in nephroblastoma tissue and correlate their presence with the survival rate of children diagnosed with stage III Wilms' tumour. METHODS AND RESULTS: The material included nephroblastoma tissue obtained from 25 children hospitalized in the Department of Paediatric Oncology, Haematology and Transplantology between 1997 and 2003. VEGF-C and VEGFR-2 expression was evaluated by immunohistochemical assay. VEGF-C was expressed in all cells of the blastemal component and in 30% of tumour cells in the stromal part. It was absent from epithelial elements. VEGFR-2 expression was spread over the surface of numerous stromal cells as well as all the epithelial cells forming dysplastic tubules. The blastemal component of Wilms' tumour was VEGFR-2-negative. VEGF-C-immunopositive stromal cells were situated in the closest proximity to VEGF-C-immunonegative but VEGFR-2-immunoreactive tubules. VEGF-C expression was of prognostic value for both clinical progression (P = 0.0005) and tumour-related death (P = 0.0365). CONCLUSIONS: VEGF-C expression in Wilms' tumour constitutes a potent unfavourable risk factor and may direct future antiangiogenic treatment strategies. The proximity of VEGF-C and VEGFR-2 in the stromal and epithelial components of nephroblastoma could be the neoplastic equivalent of the binary VEGF-C function observed in epithelial and endothelial morphogenesis.     

Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome

Human placental development combines elements of tumorigenesis and vasculogenesis. The organ's specialized epithelial cells, termed cytotrophoblasts, invade the uterus where they reside in the interstitial compartment. They also line uterine arteries and veins. During invasion, ectodermally derived cytotrophoblasts undergo pseudovasculogenesis, switching their adhesion molecule repertoire to mimic that of vascular cells. Failures in this transformation accompany the pregnancy complication preeclampsia. Here, we used a combination of in situ and in vitro analyses to characterize the cell's expression of vascular endothelial growth factor (VEGF) family ligands and receptors, key regulators of conventional vasculogenesis and angiogenesis. Cytotrophoblast differentiation and invasion during the first and second trimesters of pregnancy were associated with down-regulation of VEGF receptor (VEGFR)-2. Invasive cytotrophoblasts in early gestation expressed VEGF-A, VEGF-C, placental growth factor (PlGF), VEGFR-1, and VEGFR-3 and, at term, VEGF-A, PlGF, and VEGFR-1. In vitro the cells incorporated VEGF-A into the surrounding extracellular matrix; PlGF was secreted. We also found that cytotrophoblasts responded to the VEGF ligands they produced. Blocking ligand binding significantly decreased their expression of integrin alpha1, an adhesion molecule highly expressed by endovascular cytotrophoblasts, and increased apoptosis. In severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome, immunolocalization on tissue sections showed that cytotrophoblast VEGF-A and VEGFR-1 staining decreased; staining for PlGF was unaffected. Cytotrophoblast secretion of the soluble form of VEGFR-1 in vitro also increased. Together, the results of this study showed that VEGF family members regulate cytotrophoblast survival and that expression of a subset of family members is dysregulated in severe forms of preeclampsia.     

血管内皮生长因子C、D和受体3在人胰腺癌组织中的表达

目的:通过观察不同临床指标的人胰腺癌组织VEGF-C、VEGF-D、VEGFR-3的表达,来探讨VEGF-C和VEGF-D对人胰腺癌转移的影响,为癌组织中淋巴管的生成机制以及癌的淋巴道转移机制提供理论依据。方法:取人胰腺癌标本33例及癌旁正常胰腺组织15例,用免疫组化的方法观察VEGF-C、VEGF-D及VEGFR-3在人胰腺癌和癌旁正常胰腺组织中的表达。结果:VEGF-C、VEGF-D和VEGFR-3在胰腺癌组织中的表达比例较在癌旁正常胰腺组织中的表达比例明显增高,并且VEGFR-3的表达与VEGF-D的表达具有显著相关性(P<0.01),与VEGF-C的表达不具有相关性(P>0.05)。胰腺癌组织中VEGF-C和VEGF-D的表达与患者的年龄、性别、远处转移无关(P>0.05)。结论:VEGF-C、VEGF-D在胰腺癌组织中的表达明显增高,并有可能通过与VEGFR-3的结合促进了癌组织中淋巴管的生成,从而对癌的淋巴道转移起促进作用。     

Fine-needle aspiration cytology of pancreatic somatostatinoma: the importance of immunohistochemistry for the cytologic diagnosis of pancreatic endocrine neoplasms

Pancreatic somatostatinoma is a rare pancreatic endocrine neoplasm representing as little as 1% of pancreatic endocrine neoplasms (PENs). The histologic features of this tumor are like those of other PENs, except that it commonly forms acinar structures and often has cells with abundant, granular cytoplasm. We have recently encountered two of these neoplasms sampled by endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA). We discuss the cytologic and immunohistochemical findings of these two cases and the cytologic similarities these neoplasms share with pancreatic acinar-cell carcinoma (PACC). We review the cytologic features of PEN and PACC and discuss the importance of cell block immunohistochemistry in the diagnosis of pancreatic neoplasia sampled by EUS-guided FNA.     

Localisation of members of the vascular endothelial growth factor (VEGF) family and their receptors in human atherosclerotic arteries

BACKGROUND: Vascular endothelial growth factor (VEGF) mediates endothelial cell mitogenesis and enhances vascular permeability. The existence of single or multiple VEGF isoforms and receptors suggests that these proteins may have overlapping but distinct functions, which may be reflected in their cell expression and distribution. METHODS: The localisation of VEGFs A-C and their receptors (VEGFRs 1-3, respectively) in 30 fresh human atherosclerotic arteries, 15 normal uterine arteries, and 15 saphenous veins using immunohistochemistry and western blotting. RESULTS: Saphenous veins showed no staining for VEGF-B or VEGFR-2. Smooth muscle cells (SMCs) showed the strongest staining for VEGF-A, VEGF-B, VEGFR-1, and VEGFR-2 in all specimens. Conversely, VEGFR-3 and VEGF-C were predominantly localised to the endothelial vasa vasorum in normal arteries, whereas medial SMCs showed the strongest staining in atherosclerotic arteries. Western blotting showed variations in VEGF protein localisation, with lower amounts of VEGF-B and VEGF-C in saphenous veins, compared with arterial tissue. Amounts of VEGF-C were lower than those of VEGF-A and VEGF-B in all specimens. CONCLUSION: This study provides direct evidence of the presence of VEGF proteins and receptors in human physiology and pathology, with variations in both the amounts of VEGF proteins expressed and their cellular distribution in normal arteries compared with atherosclerotic arteries. The presence of VEGFs A-C and their receptors in normal arterial tissue implies that VEGF functions may extend beyond endothelial cell proliferation. Reduced VEGFR-2 staining in atherosclerotic arteries may have implications for the atherosclerosis process and the development of vascular disease and its complications.     

The role of VEGF-C staining in predicting regional metastasis in melanoma

Sentinel lymph node status is the most important prognostic factor in primary melanoma. The number of melanoma-associated lymphatic vessels has been associated with sentinel lymph node status and survival. Vascular endothelial growth factor-C (VEGF-C) is found to promote tumour-associated lymphatic vessel growth. In many human neoplasms, VEGF-C expression in neoplastic cells or tumour-associated macrophages (TAMs) has been linked to lymphatic dissemination of tumour cells. Recent studies have suggested a correlation between VEGF-C expression in primary melanoma and the presence of lymph node metastasis. We performed VEGF-C immunohistochemical staining on melanoma tissues of 113 patients with known sentinel lymph node status. We showed that both high VEGF-C expression in melanoma cells and TAMs are positively associated with the presence of a positive sentinel lymph node. No correlation with Breslow thickness, Clark invasion level or ulceration could be detected. VEGF-C expression in melanoma cells was predictive of a shorter overall and disease-free survival, without being an independent predictor of survival. Our results confirm that VEGF-C expression in primary cutaneous melanoma plays a role in the lymphatic spread of the tumour.     

血管内皮生长因子C及其受体表达与肝细胞癌侵袭转移的关系

目的 研究人肝细胞癌(HCC)组织中血管内皮生长因子C(VEGF-C)、血管内皮生长因子受体2(VEGFR-2)及VEGFR-3表达与HCC临床病理特征之间的关系.方法 取HCC石蜡切片标本50例及正常肝组织标本15例,免疫组化法检测止常肝组织及HCC组织中VEGF-C、VEGFR-2及VEGFR-3表达,分析其与HCC临床病理特征之间的关系.结果 (1)HCC组织中VEGF-C、VEGFR-2及VEGFR-3表达阳性率高于正常肝组织(62%比26.7%,34%比6.7%,40%比0%,P均<0.05).(2)HCC组织中,VEGF-C表达与肝内转移、门静脉癌柃形成及肝门淋巴结转移有关(P<0.05);VEGFR-2表达与肝内转移及门静脉癌栓形成有关(P<0.05);VEGFR-3表达与肝门淋巴结转移有关(P<0.05).结论 HCC组织中VEGF-C、VEGFR-2及VEGFR-3表达与HCC的侵袭及转移有密切关系.     

血管内皮生长因子C及其受体在MNNG诱发的大鼠大肠癌细胞及淋巴管的表达

目的 观察大鼠大肠癌组织内血管内皮生长因子-C(VEGF-C)及其受体3(VEGFR-3)的表达情况,探讨VEGF-C及其受体VEGFR-3在肿瘤淋巴转移中的作用.方法 采用甲基硝基亚硝基胍(MNNG)诱发的大鼠大肠癌模型,应用免疫组织化学(SABC法)技术检测29例大鼠原发性大肠癌组织中VEGF-C及VEGFR-3蛋白,观察VEGF-C及VEGFR-3在大肠癌组织内的表达.结果 正常大肠组织内未见VEGF-C阳性表达,但可见淋巴管内皮细胞VEGFR-3阳性表达.在大肠癌组织内,VEGF-C蛋白表达于癌细胞,早期和中晚期癌的阳性表达率分别是75%和100%,(P＜0.05).VEGFR-3主要表达于淋巴管内皮细胞,早期和中晚期癌组织内淋巴管的阳性表达率分别是58.33%和94.12%(P＜0.05).结论 大鼠大肠癌VEGF-C的表达与肿瘤进展有关,推测VEGF-C通过受体VEGFR-3诱导淋巴管生成:VEGFR-3在淋巴管的阳性表达均随肿瘤进展增高,可能与大肠癌淋巴转移有关.     

Inhibition of VEGFR-3 activation in tumor-draining lymph nodes suppresses the outgrowth of lymph node metastases in the MT-450 syngeneic rat breast cancer model

For many types of human cancer, the expression of vascular endothelial growth factor-C (VEGF-C) correlates with enhanced tumor-associated lymphatic vessel density, metastasis formation and poor prognosis. In experimental animals, VEGF-C produced by primary tumors can induce lymphangiogenesis within and/or at the periphery of the tumor, and promotes metastasis formation. Tumor-induced lymphangiogenesis is therefore thought to expedite entry of tumor cells into the lymphatic vasculature and their trafficking to regional lymph nodes, thereby fostering metastatic dissemination. Tumour-produced VEGF-C can also drain to the regional lymph nodes and induce lymphangiogenesis there. Whether this activity promotes metastasis formation remains unclear. To address this issue we manipulated VEGF-C activity and VEGFR-3 activation in the lymph nodes draining syngeneic rat breast cancers using intra-dermal delivery of either recombinant VEGF-C or VEGFR-3 blocking antibodies to induce or suppress lymph node lymphangiogenesis, respectively. Recombinant VEGF-C induced lymph node lymphangiogenesis, but was not sufficient to promote metastasis formation by poorly metastatic NM-081 breast tumours. Conversely, inhibition of lymph node lymphangiogeneis induced by highly metastatic MT-450 breast tumours suppressed the outgrowth of lymph node metastases, but not the initial colonization of the lymph nodes. Lung metastasis was also not affected. We conclude that tumor-derived VEGF-C draining to regional lymph nodes promotes the outgrowth of lymph node metastases. VEGF-C may induce lung metastasis independently of its effects on lymph node metastasis.     

血管内皮生长因子C及其受体3在人恶性黑色素瘤组织内的表达及意义

目的 观察人恶性黑色素瘤组织内血管内皮生长因子C(VEGF-C)及其受体3(VEGFR-3)的表达,探讨VEGF-C和VEGFR-3在恶性黑色素瘤淋巴管生成及淋巴道转移中的作用.方法 取人恶性黑色素瘤组织48例(石蜡标本30例,术后新鲜组织18例),应用免疫组织化学和RT-PCR技术,观察VEGF-C和VEGFR-3蛋白及mRNA在恶性黑色素瘤组织内的表达情况.以淋巴管内皮透明质酸受体(LYVE-1)标记淋巴管,计数恶性黑色素瘤组织淋巴管数密度.结果 VEGF-C和VEGFR-3蛋白主要表达于恶性黑色素瘤细胞胞浆内,在肿瘤周围的血管和淋巴管内皮上也可见VEGFR-3蛋白表达,VEGF-C和VEGFR-3蛋白在淋巴结转移组恶性黑色素瘤组织内的表达水平明显高于无淋巴结转移组(P<0.05).在18例新鲜恶性黑色素瘤中,淋巴结转移组VEGF-C和VEGFR-3mRNA的表达明显高于无淋巴结转移组(P<0.01).LYVE-1表达于肿瘤间质内的淋巴管内皮细胞,淋巴结转移组恶性黑色素瘤组织中的淋巴管数密度(LMVD)为9.845±2.454,无淋巴结转移组恶性黑色素瘤组织中的淋巴管数密度为6.534±2.193,淋巴结转移组恶性黑色素瘤组织内的淋巴管数密度明显高于无淋巴结转移组(P<0.01).结论恶性黑色素瘤组织内VEGF-C表达明显增高,并通过上调其受体VEGFR-3的表达促进恶性黑色素瘤组织内淋巴管的生成,从而促进恶性黑色素瘤的淋巴道转移.     

Immunohistochemical localization of endothelial cell markers in solitary fibrous tumor

Solitary fibrous tumor (SFT) is an uncommon tumor first reported in the pleura, but recently described in other tissues. CD34, which is expressed in hematopoietic stem cells, endothelial progenitor cells and vascular endothelial cells, is observed in most SFT and some investigators believe that its expression is a definitive marker of this tumor. In the present study, the expression of vascular endothelial cell markers, such as vascular endothelial growth factor receptor (VEGFR)-1 (flt-1), VEGFR-2 (flk-1/KDR), Tie-2 and c-Met, was examined in SFT to clarify the relationship between SFT and endothelial cells. By immunohistochemical staining of tumor cells from 26 patients, VEGFR-1 was detected in 24 (92%), VEGFR-2 in five (19%), Tie-2 in 14 (54%), and c-Met, a specific receptor of hepatocyte growth factor (HGF) in 23 patients (88%). Furthermore, VEGFR-3 (flt-4) immunoreactivity was detected in eight of 26 patients (31%). In contrast, VEGF, VEGF-C and HGF, which are ligands for the receptors, were not localized in the SFT cells. These findings indicate that most SFT may closely relate to vascular or lymphatic endothelial cells and the endothelial growth factors may contribute to the growth of SFT in a paracrine manner.     

VEGF-D in association with VEGFR-3 promotes nodal metastasis in human invasive lobular breast cancer

We assessed the expression of vascular endothelial growth factors (VEGF-C and VEGF-D) in breast cancer cells and the density of lymph vessels and VEGF receptor-3 (VEGFR-3)-positive vessels in and around the tumor in invasive lobular breast cancer. We found significant correlation between peritumoral lymph vessel density and presence of lymph node metastases (P=.001) and the number of metastatic lymph nodes (P<.001). A significant correlation was detected between tumor cell VEGF-D expression and lymph node status (P=.001) and density of lymphatic vessel endothelial receptor (LYVE)-1-positive vessels (P=.035). VEGFR-3+/VEGF-D+ and VEGFR-3+/VEGF-C+ tumors had a significantly higher number of metastatic lymph nodes than tumors with other staining patterns (P<.001). Tumors positive for neither VEGF-D nor VEGFR-3 had a lower density of LYVE-1+ vessels than tumors with other staining patterns (P=.033). Our results indicate that peritumoral lymph vessel density is associated with lymph node metastases in invasive lobular breast cancer and that invasive lobular cancer producing VEGF-D, surrounded by VEGFR-3+ vessels, has a significantly higher peritumoral lymph vessel density and a higher number of metastatic lymph nodes.     

Expression and localization of placenta growth factor and PlGF receptors in human meningiomas

It has previously been suggested that in human brain tumours, endothelial cell proliferation during angiogenesis is regulated by a paracrine mechanism involving vascular endothelial growth factor (VEGF) and its receptors (VEGF receptor 1 and VEGF receptor 2). The mechanism of growth factor up-regulation is based on hypoxic activation of mRNA expression and mRNA stabilization and genetic events, leading to an increase of growth factor gene expression. The role of the other newly discovered VEGF family members with a high specificity for endothelial cells in the pathogenesis of glial neoplasms is unknown. To investigate which other members of the VEGF family are overexpressed in human brain tumours, the mRNA levels of placenta growth factor (PlGF), VEGF-A, and VEGF-B genes were determined by northern blot analysis in surgically obtained human meningiomas. In the 16 meningiomas examined, the mRNA for PlGF was highly expressed in four tumours and VEGF-A mRNA was highly abundant in three tumour samples. There was no close correlation between PlGF mRNA levels and VEGF-A expression levels. VEGF-B mRNA was abundantly expressed in all tumour samples at uniform levels. In a PlGF-positive tumour sample, immunoreactive VEGFR-1 and VEGFR-2 were detected in endothelial cells of the blood vessels. PlGF protein was detectable in most but not all capillaries of the tumour. PlGF is thus highly up-regulated in a subset of human meningiomas and may therefore have functions, in some tumour vessels, connected to endothelial cell maturation and tube formation. These findings suggest that PlGF, in addition to VEGF-A, may be another positive factor in tumour angiogenesis in human meningiomas. Copyright © 1999 John Wiley & Sons, Ltd.     

VEGF-C is a trophic factor for neural progenitors in the vertebrate embryonic brain

Vascular endothelial growth factor C (VEGF-C) was first identified as a regulator of the vascular system, where it is required for the development of lymphatic vessels. Here we report actions of VEGF-C in the central nervous system. We detected the expression of the VEGF-C receptor VEGFR-3 in neural progenitor cells in Xenopus laevis and mouse embryos. In Xenopus tadpole VEGF-C knockdowns and in mice lacking Vegfc, the proliferation of neural progenitors expressing VEGFR-3 was severely reduced, in the absence of intracerebral blood vessel defects. In addition, Vegfc-deficient mouse embryos showed a selective loss of oligodendrocyte precursor cells (OPCs) in the embryonic optic nerve. In vitro, VEGF-C stimulated the proliferation of OPCs expressing VEGFR-3 and nestin-positive ventricular neural cells. VEGF-C thus has a new, evolutionary conserved function as a growth factor selectively required by neural progenitor cells expressing its receptor VEGFR-3.