RNA干扰对内皮祖细胞参与肿瘤血管和淋巴管新生的抑制作用

在趋化因子的作用下,内皮祖细胞(EPC)可定向迁移入肿瘤,经VEGF/VEGFR信号途径参与肿瘤血管和淋巴管新生.RNA干扰是由双链RNA引起的序列特异性基因沉默,主要通过小干扰RNA(siRNA)介导的靶mRNA降解,抑制基因表达.经siRNA干扰VEGF/VEGFR信号途径,抑制EPC向内皮细胞分化,有望达到抗肿瘤血管和淋巴管新生以及抗肿瘤生长和转移的目的.     

淋巴管生成与肿瘤转移

淋巴结转移是肿瘤分期的重要内容和预后指标。淋巴管生成不仅参与了正常胚胎淋巴管发育、组织修复，而且在肿瘤淋巴结转移等病理状况下也具有十分重要的作用。近年来多种淋巴管内皮标记物如LYVE1、Prox1、Podoplanin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VEGFC、VEGFD的表达和分子调控，以及其受体VEGFR3在促进肿瘤淋巴结转移过程中的地位。抗肿瘤淋巴管生成已经成为肿瘤生物治疗的新靶点，并证实阻断VEGFC/VEGFD/VEGFR3信号通路可以抑制肿瘤淋巴结     

胃肠道肿瘤淋巴管转移及其治疗

淋巴管转移是胃肠道肿瘤最基本的转移途径,也是患者死亡的主要原因。近年来随着淋巴内皮细胞特异性标记物的发现和对淋巴管生成的分子机制深入研究发现,淋巴管对胃肠道肿瘤淋巴管转移极其重要。血管内皮生长因子（VEGF）及其受体（VEGFR）信号转导通路与淋巴管生成的发生、发展及肿瘤细胞向区域淋巴结转移密切相关,其中VEGF家族的新成员VEGF—C和VEGF—D起着关键性作用。     

血管内皮生长因子-C与恶性肿瘤的淋巴管生成及淋巴结转移关系研究进展

血管内皮生长因子 -C (vascularendothelialgrowthfactor C ,VEGF C)是特异的血管、淋巴管内皮细胞调节因子 ,其结构与VEGF具有同源性 ,主要通过受体VEGFR 2及VEGFR 3发挥作用。近年来的研究发现 ,VEGF C通过其受体VEGFR 3介导肿瘤的淋巴管生成 ,与淋巴管浸润及淋巴结转移有关。     

以VEGF/VEGFR为靶点的抗肿瘤药物的研究进展

肿瘤的生长和迁移依赖于大量新生血管的生成，其中VEGF/VEGFR途径在肿瘤新生血管生成中起关键作用。近年来，以VEGF/VEGFR作为靶标的抗肿瘤药物的研发取得了很大的进展，已有数种药物进入临床试验或已上市。针对VEGF/VEGFR信号传导途径研发的抗肿瘤药物主要包括中和VEGF/VEGFR     

胃肠道肿瘤淋巴管转移及其治疗

淋巴管转移是胃肠道肿瘤最基本的转移途径,也是患者死亡的主要原因。近年来随着淋巴内皮细胞特异性标记物的发现和对淋巴管生成的分子机制深入研究发现,淋巴管对胃肠道肿瘤淋巴管转移极其重要。血管内皮生长因子(VEGF)及其受体(VEGFR)信号转导通路与淋巴管生成的发生、发展及肿瘤细胞向区域淋巴结转移密切相关,其中VEGF家族的新成员VEGF-C和 VEGF-D起着关键性作用。     

VEGF-C/D及其受体与胃癌淋巴转移关系的研究进展

淋巴管是肿瘤转移的一个重要途径,随着越来越多淋巴管生长因子和淋巴管标志物的发现,如血管内皮生长因子-C/ D（VEGF-C/D）及受体血管内皮生长因子受体（VEGFR）3在肿瘤淋巴管生成、肿瘤经淋巴结转移过程中的作用机制取得了较大进展。VEGF-C/D的表达与胃癌淋巴道转移、癌周淋巴管密度、生存率、预后等临床病理特征密切相关。此外,实验动物模型与体外实验研究显示,抑制VEGF-C/D表达在胃癌治疗上具有一定的应用前景。现就VEGF-C/D及其受体与胃癌淋巴转移的相关性予以综述。      

甲状腺癌淋巴管生成与转移的研究进展

淋巴道转移是甲状腺乳头状癌最常见的转移途径,是决定甲状腺乳头状癌分期、选择治疗方案和影响预后的重要因素。淋巴管生成在淋巴道转移过程中起着决定作用,而肿瘤淋巴管生成的分子机制尚未完全明确。研究较多且可以肯定的是VEGF家族在肿瘤淋巴管生成中起重要作用,最近研究发现类肝素酶（heparanase,HPSE）可以诱导VEGF—C的产生进而促发淋巴管生成,进一步深化了淋巴管生成的研究。一些特异性强的淋巴管内皮标记物相继发现,如：VEGFR-3、LYVE-1、Pwxl、D2—40等,也为研究淋巴管在肿瘤生物学中的作用提供了必要前提条件。研究甲状腺癌淋巴管生成和转移的分子发生机制,阐明淋巴管生成在甲状腺癌淋巴转移中的作用,将为甲状腺癌的分子靶向治疗和判断预后提供新的理论依据。     

VEGF／VEGFR信号通路抑制剂疗效预测的研究进展

血管生成是肿瘤转移的基础,新生血管形成是肿瘤复发转移不可或缺的条件。血管内皮生长因子（VEGF）及其受体（VEGFR）是肿瘤血管形成过程中的重要调节因子。VEGF／VEGFR信号通路抑制剂已经成功进入临床应用阶段,但只有一部分患者能够从中获益。探索能够可靠预测VEGF／VEGFR信号通路抑制剂疗效的评价指标,将会给肿瘤患者带来更大的临床获益。本文将对VEGF/VEGFR信号通路抑制剂疗效预测指标的研究进展作一综述。     

VEGF/VEGFR2信号通路调控机制的研究进展

血管生成贯穿恶性实体肿瘤发生发展的全过程,与肿瘤的发生发展、浸润转移以及预后不良密切相关。在促进恶性肿瘤血管生成的诸多因素中,血管内皮细胞生长因子(VEGF)与血管内皮细胞生长因子受体2(VEGFR2)构成的信号通路发挥着不可替代的作用,阻断该信号通路已成为肿瘤抗血管治疗的主要方法之一,然而有关该信号通路上游的分子调控机制尚不明确。本文对VEGF/VEGFR2信号通路分子调控机制的最新研究进展作一简要综述,以期为肿瘤抗血管靶向治疗提供新思路。     

VEGF—C、VEGFR-3在肿瘤淋巴管生成中作用的研究进展

血管内皮生长因子C是调节淋巴管生成的主要因子,在许多肿瘤组织中高表达,与其受体血管内皮生长因子受体3结合后,可特异性作用于淋巴管内皮,刺激淋巴上皮增殖,诱导瘤内或瘤周围淋巴管生成和／或扩张,促进肿瘤微淋巴管生成。肿瘤淋巴管生成是肿瘤转移过程中的重要条件,肿瘤细胞可通过表达淋巴管生成的调控因子VEGF—C和VEGFR-3促使淋巴管生成,促进肿瘤细胞的淋巴转移。肿瘤淋巴管生成及其对抗研究是当前肿瘤研究的热点,并有可能成为治疗肿瘤淋巴转移的靶点。二者间关系密切,且相互作用,相互影响。     

Thromboxane A₂ receptor signaling facilitates tumor colonization through P-selectin-mediated interaction of tumor cells with platelets and endothelial cells

Thromboxane A(2) (TXA(2) ) is a prostanoid formed by thromboxane synthase using the cyclooxygenase product, prostaglandin H(2), as the substrate. TXA(2) was shown to enhance tumor metastasis, but the underlying mechanism remains unclear. B16F1 melanoma cells were intravenously injected into TXA(2) receptor (TP) knockout mice (TP(-/-) ) and wild-type littermates (WT). TP(-/-) showed a reduction in B16F1 lung colonization and mortality rate, which were associated with a decreased number of platelets. Platelet activation as assessed by P-selectin expression was suppressed in TP(-/-) . A selective P-selectin neutralizing antibody decreased the lung colonization in WT mice, but not in TP(-/-) . The expression of P-selectin glycoprotein ligand-1 in B16F1 and HUVEC were enhanced by treatment with U46619, a thromboxane analog. The plasma levels of vascular endothelial growth factor (VEGF) and stromal-derived factor (SDF)-1 were lower in TP(-/-) . In TP(-/-) , the mobilization of progenitor cells expressing CXCR4(+) VEGFR1(+) from bone marrow and the recruitment of those cells to lung tissues were suppressed. These results suggest that TP signaling plays a critical role in tumor colonization through P-selectin-mediated interactions between platelets-tumor cells and tumor cells-endothelial cells through the TP signaling-dependent production of VEGF and SDF-1, which might be involved in the mobilization of VEGFR1(+) CXCR4(+) cells. Blockade of TP signaling might be useful in the treatment of tumor metastasis.     

Liposomal honokiol inhibits VEGF‐D‐induced lymphangiogenesis and metastasis in xenograft tumor model

Lymph nodes metastasis of tumor could be a crucial early step in the metastatic process. Induction of tumor lymphangiogenesis by vascular endothelial growth factor‐D may play an important role in promoting tumor metastasis to regional lymph nodes and these processes can be inhibited by inactivation of the VEGFR‐3 signaling pathway. Honokiol has been reported to possess potent antiangiogenesis and antitumor properties in several cell lines and xenograft tumor models. However, its role in tumor‐associated lymphangiogenesis and lymphatic metastasis remains unclear. Here, we established lymph node metastasis models by injecting overexpressing VEGF‐D Lewis lung carcinoma cells into C57BL/6 mice to explore the effect of honokiol on tumor‐associated lymphangiogenesis and related lymph node metastasis. The underlying mechanisms were systematically investigated in vitro and in vivo. In in vivo study, liposomal honokiol significantly inhibited the tumor‐associated lymphangiogenesis and metastasis in Lewis lung carcinoma model. A remarkable delay of tumor growth and prolonged life span were also observed. In in vitro study, honokiol inhibited VEGF‐D‐induced survival, proliferation and tube‐formation of both human umbilical vein endothelial cells (HUVECs) and lymphatic vascular endothelial cells (HLECs). Western blotting analysis showed that liposomal honokiol‐inhibited Akt and MAPK phosphorylation in 2 endothelial cells, and downregulated expressions of VEGFR‐2 of human vascular endothelial cells and VEGFR‐3 of lymphatic endothelial cells. Thus, we identified for the first time that honokiol provided therapeutic benefit not only by direct effects on tumor cells and antiangiogenesis but also by inhibiting lymphangiogenesis and metastasis via the VEGFR‐3 pathway. The present findings may be of importance to investigate the molecular mechanisms underlying the spread of cancer via the lymphatics and explore the therapeutical strategy of honokiol on antilymphangiogenesis and antimetastasis. © 2008 Wiley‐Liss, Inc.     

VEGF-C及VEGFR-3在食管鳞癌组织中的表达及与淋巴结转移的关系

目的：研究食管癌组织中VEGF-C和VEGFR-3的表达及其与食管癌淋巴结转移的关系,探讨VEGF-C和VEGFR-3在食管癌淋巴转移中的作用.方法：总结48例食管癌患者的临床资料,采用Westernblot法检测VEGF-C和VEGFR-3在4例食管癌患者癌组织、癌旁组织、正常组织中的表达,分析其表达强弱及与淋巴结转移的相关性,探讨VEGF-C和VEGFR-3与食管癌淋巴结转移及食管癌预后的关系.结果：食管癌组织中VEGF-C的表达强度高于癌旁组织及正常食管组织,VEGFR-3的表达强度与癌旁组织及正常食管组织没有明显差异.伴有淋巴结转移患者的食管癌组织中,VEGF-C和VEGFR-3的表达均高于无淋巴结转移者.结论：食管癌组织中VEGF-C的表达高低与组织恶性程度有关,VEGF-C和VEGFR-3的表达高低与食管癌患者是否伴有淋巴结的转移有关,VEGF-C和VEGFR-3的高表达提示食管癌患者伴有淋巴结转移且预后不良.VEGF-C和VEGFR-3联合检测可作为判断食管癌患者是否伴有淋巴转移及评价预后的指标之一.     

Chemokine expression in tumor-to-tumor metastasis

Chemokines play an important role in cancer metastasis by modulating the directional cell movement and migration of tumor cells. The most commonly overexpressed chemokine receptor in human cancer is CXCR4. Once activated by its ligand CXCL12 (stromal cell-derived factor-1 ligand/SDF1), CXCR4 stimulates several key migratory, proliferative and survival signaling cellular pathways. CXCR4 is expressed in small-cell lung carcinoma (SCLC) cells and other tumors. To further characterize the role of chemokines in tumor-to-tumor metastasis, we analyzed the tissue expression of CXCR4 and CXCL12 in the surgical specimen of a patient with this phenomenon. We performed immunohistochemical analysis for the expression of CXCR4 and CXCL12 in metastatic tumor tissue of a 69-year-old Caucasian male with extensive SCLC metastatic to a renal oncocytoma. The oncocytoma tissue harboring SCLC showed CXCL12 expression, but not CXCR4. A high expression of the two molecules was found in a normal renal parenchymal control. Our results suggest that CXCR4 and CXCL12 plays a role in this condition, but their expression may be affected by the microenvironment of the harboring malignancy. Further characterization of these phenomena is needed to shed light on the biological mechanisms of tumor metastasis.     

Advances in the research on lymphangiogenesis in carcinoma tissues (Review)

Metastatic spread of tumors is an important prognostic factor for cancer patients. The effect of angiogenesis on cancer cell proliferation and metastatic spread has been confirmed. However, less attention has been focused on research involving tumor lymphangiogenesis as opposed to research on tumor angiogenesis, due to the lack of specific markers for lymphatic vessel endothelial cells (LVECs). Recently, the improvement of isolation techniques for LVECs and the discovery of specific LVEC markers such as vascular endothelial growth factor receptor-3 (VEGFR-3), podoplanin, lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and Prox1 have led to advances in research involving lymphangiogenesis in carcinoma tissues. New lymphatic vessels in tumor tissues may originate from bone marrow endothelial progenitor cells, directly from the preexisting lymphatic vessels, and even by cell transformation. Peritumoral lymphatic vessels play a more important role in the process of tumor metastasis by providing more channels for lymphatic invasion and metastatic spread. The molecular mechanism of tumor lymphangiogenesis is complicated, and numerous factors such as VEGF-A, platelet-derived growth factors (PDGFs), hepatocyte growth factor (HGF), fibroblast growth factor-2 (FGF-2), and angiopoietins (Ang) are directly or indirectly involved in the process. However, it has been demonstrated that the VEGF-C/VEGF-D/VEGFR-3 signaling pathways are the most important mechanism underlying tumor lymphangiogenesis.     

VEGF121 promotes lymphangiogenesis in the sentinel lymph nodes of non-small cell lung carcinoma patients

BACKGROUND: The sentinel lymph node (SLN) concept is that lymphatic flux from a primary tumor initially flows into a SLN. The mechanism mediating tumor metastasis within SLNs remains largely unknown; however, primary tumors overexpressing vascular endothelial growth factor (VEGF)-A appear to induce SLN lymphangiogenesis prior to metastasis in animal model. Our aim was to further investigate the capacity of VEGFs to induce lymphangiogenesis within SLNs and to assess their role in SLN metastasis in non-small cell lung carcinoma (NSCLC). METHODS: Real-time quantitative RT-PCR was used to assess expression of mRNAs encoding several VEGFs (VEGF121, VEGF165, VEGFR1, VEGFR2, VEGFR3, VEGF-C and VEGF-D) in resected lymph node specimens from 35 NSCLC patients, after which we compared their expression SLNs and non-SLNs. In addition, expression of the lymphatic endothelium-specific hyaluronan receptor (LYVE)-1 was used to assess lymphangiogenesis in SLNs and non-SLNs. RESULTS: Immunohistochemical staining revealed substantial expression of LYVE-1 in SLNs. Moreover, levels LYVE-1 mRNA were significantly higher in SLNs than non-SLNs (P<0.05), as were levels of VEGF121 and VEGFR2 mRNA (P<0.01 and P=0.02, respectively). In addition metastasis-positive SLNs showed significantly higher levels of VEGF121, VEGF-C and VEGF-D mRNA than metastasis-negative SLNs (P<0.001, P=0.01 and P=0.01, respectively), and VEGF121 induced the proliferation of lymphatic endothelial cells (P<0.01). CONCLUSIONS: Our findings suggest that active lymphangiogenesis is ongoing within SLNs from NSCLC patients, even before metastasis. This lymphangiogenesis may be promoted by upregulation of VEGF121, which may in turn act in part via induction of VEGF-C.     

甲状腺肿瘤VEGF—C、CXCR4的表达及意义

目的：探讨甲状腺肿瘤中VEGF—C、CXCR4的表达及其意义。方法：采用免疫组化法检测100例甲状腺癌以及20例甲状腺腺瘤中VEGF—C、CXCR4的表达。结果：甲状腺癌组VEGF—C和CXCR4的表达显著高于甲状腺腺瘤组;甲状腺癌淋巴结转移组VEGF—C和CXCR4的表达显著高于无淋巴结转移组;不同病理类型、不同分期的甲状腺癌中VEGF—C和CXCR4的阳性表达率显著不同。结论：VEGF—C、CXCR4在甲状腺良恶性肿瘤的鉴别诊断、甲状腺癌淋巴结转移及预后判断中有重要价值。