Inhibition of lymphangiogenesis,nodal and lung metastasis by dihydroartemisinin in mice bearing Lewis lung carcinoma

Objective：To investigate the activity of anti-malarial dihydroartemisinin （DHA） on tumor growth, lymphangiogenesis, nodal and lung metastasis and survival in mice bearing Lewis lung carcimoma （LLC）. Methods： The models of C57BL/6 mice transplantation tumors were established via subcutaneous injection of LLC cells and divided into 4 groups： control group, DHA group, DHA＋ferrous sulfate （FS） group and FS group, with 25 mice in each group. Tumor volumes and weights, nodal and lung metastasis, and survival were monitored. Tumor lymphatic microvessel density （LMVD） was determined by lymphatic vessel endothelial hyaluronan receptor-1 （LYVE-1） immnohistochemistry. After LLC cells were treated with DHA or DHA＋FS, protein and mRNA levels of vascular endothelial growth factor （VEGF） -C were evaluated by Western blotting and real time quantitative RT-PCR, respectively. Results： Oral administration of DHA or DHA＋FS inhibited lymph node and lung metastasis, and prolonged survival. However, no significant tumor growth retardation effect was observed when mice were treated with DHA alone. The inhibited tumor metastasis was related to the decreased LMVD in the peritumoral regions, but not in the intratumoral regions. DHA significantly down-regulated the expression of VEGF-C protein and mRNA in LLC cells. Conclusion： DHA effectively inhibits LLC transplantation tumor lymphangiogenesis, nodal and lung metastasis, and may be a promising chemotherapeutic agent for controlling lung cancer metastasis by decreasing VEGF-C expression.     

食管鳞癌组织中淋巴管生成2种检测方法比较

目的:探讨人食管鳞癌组织中淋巴管生成灵敏的检测方法.方法:分别采用免疫组化SP法(以血管内皮生长因子受体-3为淋巴管特异性标记物)和酶组织化学法检测49例食管鳞癌组织和癌旁组织中淋巴管密度(分别记为LVDi与LVDe).结果:癌组织中LVDe的表达和癌旁组织中LVDi、LVDe的表达在有、无淋巴结转移时差异均有统计学意义(P＜0.01).有淋巴结转移癌组织中LVDi与LVDe之间差异有统计学意义(P＜0.01).结论:酶组织化学法可较好地显示食管鳞癌组织中的淋巴管.     

胃癌淋巴管生成与淋巴管密度的相关性研究

胃癌的发病率日益增加,而淋巴转移是导致患者最终死亡的重要原因之一.血管内皮生长因子C(VEGF-C)、血管内皮生长因子D(VEGF-D)与其特异性的受体血管内皮生长因子受体3(VEGFR-3)结合能够促进淋巴管生成,并促进淋巴管转移,并且与肿瘤的淋巴管密度密切相关.近年来对于胃癌的淋巴管的研究正在开展,本文就胃癌淋巴管生成机制、淋巴管生成与淋巴管密度关系的最新研究进展以及此项研究的临床意义加以综述.     

Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis

Neural stem cells (NSCs) are slowly dividing astrocytes that are intimately associated with capillary endothelial cells in the subventricular zone (SVZ) of the brain. Functionally, members of the vascular endothelial growth factor (VEGF) family can stimulate neurogenesis as well as angiogenesis, but it has been unclear whether they act directly via VEGF receptors (VEGFRs) expressed by neural cells, or indirectly via the release of growth factors from angiogenic capillaries. Here, we show that VEGFR-3, a receptor required for lymphangiogenesis, is expressed by NSCs and is directly required for neurogenesis. Vegfr3:YFP reporter mice show VEGFR-3 expression in multipotent NSCs, which are capable of self-renewal and are activated by the VEGFR-3 ligand VEGF-C in vitro. Overexpression of VEGF-C stimulates VEGFR-3-expressing NSCs and neurogenesis in the SVZ without affecting angiogenesis. Conversely, conditional deletion of Vegfr3 in neural cells, inducible deletion in subventricular astrocytes, and blocking of VEGFR-3 signaling with antibodies reduce SVZ neurogenesis. Therefore, VEGF-C/VEGFR-3 signaling acts directly on NSCs and regulates adult neurogenesis, opening potential approaches for treatment of neurodegenerative diseases.     

Interleukin-6 signalling regulates vascular endothelial growth factor-C synthesis and lymphangiogenesis in human oral squamous cell carcinoma

Lymph node metastasis is associated with resistance to conventional therapy and poor survival of patients with oral squamous cell carcinoma (OSCC). Although lymphangiogenesis is well known to be associated with the occurrence of lymph node metastasis in various cancers, the precise mechanisms of lymphangiogenesis in OSCC are largely unknown. IL-6, a potent pro-inflammatory cytokine, has been shown to play active roles in various cancers, including OSCC. This study aimed to investigate the involvement of IL-6 signalling in lymphatic metastasis and to evaluate the efficacy of tocilizumab, a humanized anti-human IL-6 receptor antibody, as an anti-lymphangiogenic agent for OSCC. This investigation confirmed that levels of expression of IL-6 protein and VEGF-C mRNA in OSCC tissues were significantly correlated with lymph node metastasis in patients with OSCC, as assessed by immunohistochemical analysis and real-time quantitative RT-PCR. In vitro studies showed that IL-6 regulated VEGF-C mRNA expression in a human OSCC cell line, SAS cells, through the phosphoinositide 3-kinase-Akt pathway. In addition, treatment with tocilizumab led to markedly reduced VEGF-C mRNA expression and OSCC-related lymphangiogenesis in SAS xenografts. Together, these data suggest that tocilizumab acted as expected: it inhibited lymph node metastasis in OSCC by reducing tumour lymphangiogenesis.     

淋巴管生成因子在肿瘤淋巴管生成中的研究进展

淋巴结转移是肿瘤分期的重要内容和预后指标,而淋巴管生成对肿瘤淋巴结转移等具有十分重要的作用.随着多种淋巴管内皮标记物的发现和淋巴管生成模型的建立,使得人们逐渐认识到淋巴管生成因子的表达和分子调控,以及其受体在促进肿瘤淋巴管生成过程中的地位.淋巴管生成因子正逐渐成为肿瘤淋巴道转移机制和抗肿瘤研究的新热点.     

Angiogenic/lymphangiogenic factors and adaptation to extreme altitudes during an expedition to Mount Everest

Aim: To analyse the correlation between production of angiogenic [vascular endothelial growth factor A (VEGF‐A) and interleukin 8 (IL‐8)] and lymphangiogenic factors (VEGF‐C and D) and adaptation to high altitude (>8000 m). Erythropoietin (EPO) served as a positive control. Methods: We analysed the percentage of oxygen saturation and the plasmatic contents of VEGF‐A, C, D, IL‐8 and EPO in seven mountaineers and four Sherpas during an expedition to Mount Everest. Acute mountain sickness was also evaluated using the Lake Louise score. Results: Whereas VEGF‐A, IL‐8, VEGF‐C and EPO were transiently up‐regulated at 5000 m and decreased at the highest altitudes, VEGF‐D remained elevated throughout the ascent. Sherpas had increased basal levels of VEGF‐A, C, IL‐8 and EPO and up‐regulation of all the tested factors when they passed the altitude at which they lived. Conclusion: Our data suggest that expression of angiogenic and lymphangiogenic factors is up‐regulated directly or indirectly by altitude‐dependent hypoxia. Both factors could be involved in a mechanism of adaptation to high altitudes.     

内皮特异性分子-1在乳腺浸润性导管癌中的表达与淋巴管增生的关系

目地：探讨内皮特异性分子（ESM）-1在乳腺浸润性癌淋巴管生成和淋巴道转移中的作用及其与临床病理指标的关系。方法：免疫组化检测108例乳腺浸润性导管癌者的ESM-1表达,D2-40标记淋巴管内皮,并计数微淋巴管密度（LMVD）,分析上述指标与临床病理特征的关系。结果：ESM-1主要表达于肿瘤细胞中。ESM-1表达与肿瘤大小,淋巴结转移,LMVD相关（P〈0.001）。结论：ESM-1能促进乳腺癌淋巴管增生,并与肿瘤大小和淋巴道转移相关。     

Dermatological aspects of angiogenesis

Neovascularization is vital for the growth of tumours, providing a lifeline for sustenance and waste disposal. Tumour vessels can grow by sprouting, intussusception or by incorporating bone marrow-derived endothelial precursor cells into growing vessels. Recent advances in vascular biology have identified some key factors that control vascular growth, and have led to the hypothesis that in normal tissues vascular quiescence is maintained by the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli. In contrast, increased secretion of angiogenic factors and the down-regulation of endogenous angiogenesis inhibitors induce tumour angiogenesis. Vascular quiescence in the skin seems to be primarily maintained by a balance between the endogenous angiogenesis inhibitors thrombospondin 1 and thrombospondin 2 and the potent proangiogenic factor vascular endothelial growth factor A. Inhibiting tumour growth by controlling angiogenesis is an intriguing approach with great potential for the treatment of vascular tumours such as haemangioma, Kaposi's sarcoma and solid cutaneous tumours such as squamous cell carcinoma, melanoma and basal cell carcinoma. In this review, the role of angiogenesis and more recent topics such as lymphangiogenesis in cutaneous tumour growth, invasion and metastasis will be discussed.