乳脂肪球表皮生长因子8与乳腺癌相关性研究进展

乳脂肪球表皮生长因子Ⅷ(MFG-E8)是一种亲脂性糖蛋白,作为分泌型多效蛋白广泛存在于多种组织和细胞中,参与细胞间及细胞与基质间的相互作用.大量研究表明MFG-E8通过促进肿瘤细胞的增殖、抑制凋亡、促进肿瘤血管生成等在乳腺癌的发生、侵袭和转移过程及预后中起重要作用.     

血管内皮生长因子与肿瘤血管生成的研究进展

肿瘤的无限制侵袭性生长及转移依赖于血管的生成。肿瘤血管生成是一个复杂的多步骤过程,且有众多生长因子的参与,其中血管内皮生长因子(Vascular endothelial growth factor,VEGF)是最重要的促血管生长因子,与肿瘤的生长、转移及预后有关,也是抗肿瘤血管生成治疗的重要靶点之一。本文旨在对VEGF与肿瘤血管生成的研究进展作一综述。     

Vasohibin-1在常见肿瘤发生发展中作用的研究进展

肿瘤的形成、生长和侵袭转移依赖于肿瘤血管的生成。抑制肿瘤血管形成是阻止肿瘤进展的重要途径。肿瘤血管的生长受多种促进因子(如血管内皮生长因子、碱性成纤维细胞生长因子、胸苷磷酸化酶等)和抑制因子(如血管抑素、内皮抑素、血管生成抑制蛋白等)的共同调节。Vasohibin-1(VASH-1)作为一种新型血管抑制因子,受VEGF诱导表达于内皮细胞,发挥负性调控作用。近年来越来越多的研究发现VASH-1在多种肿瘤组织中异常表达并发挥作用。该文旨在对VASH-1在一些常见肿瘤发生、发展中的作用及机制作一综述。     

肿瘤相关巨噬细胞在血管生成和淋巴管生成中的研究进展

单核细胞进入肿瘤部位成为巨噬细胞。肿瘤相关巨噬细胞(TAM)通过促进血管生成因子的表达或释放而促进肿瘤血管生成。肿瘤血管生成供给肿瘤细胞营养和氧气,促进肿瘤细胞生长、增殖和侵袭,并使肿瘤细胞进入血管,通过血液循环至其他部位,形成转移灶。TAM同时也能诱导淋巴管生成,甚至促进肿瘤淋巴结转移。旁分泌方式和肿瘤细胞自治模式是TAM促进肿瘤淋巴管生成的主要途径。因此,TAM不仅能促进血管生成,同时也能诱导淋巴管生成,针对这两点的靶向治疗或许是未来肿瘤治疗的新途径。本文总结了TAM在血管生成和淋巴管生成中的研究进展。     

EGFL7在乳腺癌中的研究进展

表皮生长因子样结构域7是表皮生长因子样蛋白家族的成员,是一种极为关键的血管生成因子和血管发育调节因子,在不同类型细胞中均有表达。EGFL7在早期胚胎的血管中表达较高,主要调节发育过程中的血管生成,促进内皮细胞增殖,形成有功能的血管网,促进组织增长和再生。与其在胚胎期较强的表达相比,在成人体内的表达量微乎其微,异常高表达的EGFL7常在多种恶性肿瘤中出现。目前越来越多的证据表明,EGFL7可调节肿瘤血管生成、促进肿瘤转移和侵袭。肿瘤组织中EGFL7高表达常常提示肿瘤生长和转移较为活跃及不良的预后。近年来,一系列研究表明,EGFL7的表达与乳腺癌的发生发展、转移过程密不可分,且在提示预后方面发挥着关键作用。本文就EGFL7在乳腺癌中的研究进展作一综述,为临床诊断及治疗提供新思路。     

脂质介质在肿瘤血管生成中的作用

血管生成通过给予营养和氧气供应以及为远处转移提供通道,在恶性肿瘤的生长和扩散中发挥关键作用。血管生成涉及诸多生长因子及信号分子,其中一些脂质介质通过调节血管内皮生长因子(vascular endothelial growth factor, VEGF)、白细胞介素-8(interleukin-8, IL-8)、缺氧诱导因子(hypoxia inducible factor, HIF)、内皮型一氧化氮合酶(endothelial nitric oxide synthase, eNOS)以及高密度脂蛋白(high density lipoprptein, HDL)调节炎症及肿瘤的作用机制也已明确,由此针对这些脂质介质进行药物干预有望作为一种全新的靶向肿瘤治疗方法。该文总结了肿瘤血管生成过程中主要的促血管生成介质和抗血管生成介质,旨在为肿瘤的靶向治疗提供新思路。     

DLL4与血管生成的关系

血管生成是胚胎发育和肿瘤生长的重要因素.多项研究发现,参与Notch信号的Delta配体4(Delta-like ligand 4,DLL4)能抑制新生血管分支生成,促进新生血管的成熟.阻断DLL4可增加无功能性新生血管的数量,从而抑制肿瘤生长,这为肿瘤抗血管生成疗法提供了新的策略,使DLL4有可能成为肿瘤治疗的新靶点.     

外泌体在肿瘤血管新生中的作用

肿瘤的生长与转移依赖于充足的血管生成以及血液供养,越来越多的研究证实肿瘤来源的外泌体参与促进肿瘤血管新生。本文通过综述外泌体如何驱动血管新生,为改进现有的抗血管生成疗法增加新的选择。     

神经菌毛蛋白1的研究进展

神经菌毛蛋白1(NRP1)是NRP家族的重要一员,其作为多种细胞外基质配体的共受体在神经发育、血管生成、肿瘤侵袭转移和免疫等方面发挥重要作用。NRP1可通过多种机制促进肿瘤的血管生成和肿瘤增殖转移,同时在免疫系统中可调节初级免疫反应并且是抗肿瘤免疫的关键因素。NRP1的进一步研究将为神经系统、血管系统及肿瘤的治疗提供新的方向和机遇。     

肿瘤血管生成和抗血管生成治疗的研究进展

肿瘤组织中的新生血管是保证肿瘤持续生长所必需的,也是肿瘤转移的重要途径之一.针对促进肿瘤血管生成和血管生成抑制物制定新策略,采用合适手段与方法,抑制肿瘤内血管新生,消除或减少肿瘤内原有血管,可达到治愈肿瘤的目的.     

Endothelial cells expressing Bcl-2 promotes tumor metastasis by enhancing tumor angiogenesis, blood vessel leakiness and tumor invasion

Metastatic spread of tumor cells to vital organs is the major cause of mortality in cancer patients. Bcl-2, a key antiapoptotic protein, is expressed at high levels in a number of human tumors. We have recently shown that Bcl-2 is also overexpressed in tumor-associated blood vessels in head-and-neck cancer patients. Interestingly, enhanced Bcl-2 expression in tumor blood vessels is directly correlated with metastatic status of these cancer patients. In addition, endothelial cells (ECs) expressing Bcl-2 showed increased production of interleukin-8 (IL-8) resulting in significantly enhanced tumor cell proliferation and tumor cell invasion. Therefore, we hypothesized that Bcl-2 expression in tumor-associated ECs may promote tumor metastasis by enhancing tumor cell invasiveness and release in the circulation. To test our hypothesis, we coimplanted tumor cells along with ECs expressing Bcl-2 (EC-Bcl-2) in the flanks of SCID mice. Our results demonstrate that incorporation of EC-Bcl-2 in primary tumors significantly enhanced tumor cell metastasis to lungs and this EC-Bcl-2-mediated tumor metastasis was independent of primary tumor size. In addition, Bcl-2-mediated tumor metastasis directly correlated with increased tumor angiogenesis. Bcl-2 expression in ECs also promoted transendothelial cell permeability, blood vessel leakiness and tumor cell invasion. EC-Bcl-2-mediated tumor cell proliferation and tumor cell invasion were significantly mediated by IL-8. These results suggest that Bcl-2, when expressed at higher levels in tumor-associated ECs, may promote tumor metastasis by enhancing tumor angiogenesis, blood vessel leakiness and tumor cell invasiveness.     

Lysophosphatidic acid induces lymphangiogenesis and IL-8 production in vitro in human lymphatic endothelial cells

The bioactive phospholipid lysophosphatidic acid (LPA) and its receptors LPA(1-3) are aberrantly expressed in many types of human cancer. LPA has been reported to induce tumor cell proliferation, migration, and cytokine production. However, whether LPA exerts an effect on lymphatic endothelial cells (LECs) or on lymphangiogenesis, a process of new lymphatic vessel formation that is associated with increased metastasis and poor prognosis in cancer patients, has been unknown. Here, we show that LPA induces cell proliferation, survival, migration, and tube formation, and promotes lymphangiogenesis in vitro in human dermal LECs. In addition, LPA induces IL-8 expression by enhancing IL-8 promoter activity via activation of the NF-κB pathway in LECs. Using IL-8 siRNA and IL-8 neutralizing antibody, we revealed that IL-8 plays an important role in LPA-induced lymphangiogenesis in vitro. Moreover, using siRNA inhibition, we discovered that LPA-induced lymphangiogenesis in vitro and IL-8 production are mediated via the LPA(2) receptor in LECs. Finally, using human sentinel afferent lymphatic vessel explants, we demonstrated that LPA up-regulates IL-8 production in the LECs of lymphatic endothelia. These studies provide the first evidence that LPA promotes lymphangiogenesis and induces IL-8 production in LECs; we also reveal a possible new role of LPA in the promotion of tumor progression, as well as metastasis, in different cancer types.     

Recombinant human prothrombin kringle-2 inhibits B16F10 melanoma metastasis through inhibition of neovascularization and reduction of matrix metalloproteinase expression

Angiogenesis, a multi-step process which involves endothelial cell proliferation, adhesion, migration, and basement membrane (BM) degradation, is essential for tumor metastasis. Here we show that recombinant human prothrombin kringle-2 (rk-2) inhibited bovine capillary endothelial cell migration with an IC₅₀ (concentration for half maximal inhibition) of 38 nM and inhibited adhesion to extracellular matrix (ECM) proteins. Because tumor metastasis requires angiogenesis, we examined whether rk-2 could inhibit metastases induced by injection of B16F10 melanoma cells into mice. The results revealed that the metastatic tumors in mouse lung were markedly decreased in a dose-dependent manner and acute lung injury induced by B16F10 melanoma metastasis was diminished by systemic rk-2 treatment. In immunohistochemical analysis, rk-2 reduced expression of vascular endothelial growth factor, which is a potent angiogenic activator and neovascularization in the mouse lung. Also, rk-2 diminished the expression of matrix metalloproteinase-2 and -9 in the mouse lung which induces tumor metastasis and angiogenesis. These data suggest that inhibition of B16F10 melanoma metastasis by rk-2 was caused by inhibition of neovascularization and reduction of matrix metalloproteinase expression.     

Amentoflavone Inhibits Experimental Tumor Metastasis Through a Regulatory Mechanism Involving MMP-2, MMP-9, Prolyl Hydroxylase,Lysyl Oxidase,VEGF, ERK-1, ERK-2, STAT-1, nm23 and Cytokines in Lung Tissues of C57BL/6 Mice

Amentoflavone has been shown to inhibit tumor metastasis in vivo, but its mechanism of action remains unclear. Here, C57BL/6 mice were injected once with B16F-10 melanoma cells via tail vein followed by amentoflavone treatment (50mg/kg BW) for 10 consecutive days. Twenty-one days after tumor injection, animals were euthanized, and tumor metastasis was found to confine in the lungs. As compared with the tumor controls, amentoflavone treatment significantly lowered the number of lung nodules (p<0.001). Amentoflavone treatment markedly decreased the mRNA expression of MMP-2, MMP-9, prolyl hydroxylase, lysyl oxidase, VEGF, ERK-1, ERK-2, TNF-α, IL-1β, IL-6, and GM-CSF in lung tissues. However, amentoflavone treatment increased the mRNA expression of STAT-1 and nm23 in lung tissues. Also in vitro studies indicate that amentoflavone treatment inhibits tumor cell invasion and migration. These results show that amentoflavone treatment reduces experimental tumor metastasis and suggest that such an action is associated with attenuation of tumor invasion, proliferation and angiogenesis.     

Amentoflavone inhibits experimental tumor metastasis through a regulatory mechanism involving MMP-2, MMP-9, prolyl hydroxylase, lysyl oxidase, VEGF, ERK-1, ERK-2, STAT-1, NM23 and cytokines in lung tissues of C57BL/6 mice

Amentoflavone has been shown to inhibit tumor metastasis in vivo, but its mechanism of action remains unclear. Here, C57BL/6 mice were injected once with B16F-10 melanoma cells via tail vein followed by amentoflavone treatment (50 mg/kg BW) for 10 consecutive days. Twenty-one days after tumor injection, animals were euthanized, and tumor metastasis was found to confine in the lungs. As compared with the tumor controls, amentoflavone treatment significantly lowered the number of lung nodules (p<0.001). Amentoflavone treatment markedly decreased the mRNA expression of MMP-2, MMP-9, prolyl hydroxylase, lysyl oxidase, VEGF, ERK-1, ERK-2, TNF-alpha, IL-1beta, IL-6, and GM-CSF in lung tissues. However, amentoflavone treatment increased the mRNA expression of STAT-1 and nm23 in lung tissues. Also in vitro studies indicate that amentoflavone treatment inhibits tumor cell invasion and migration. These results show that amentoflavone treatment reduces experimental tumor metastasis and suggest that such an action is associated with attenuation of tumor invasion, proliferation and angiogenesis.     

Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis

The incidence of brain metastasis is increasing, however, little is known about molecular mechanism responsible for lung cancer-derived brain metastasis and their development in the brain. In the present study, brain pathology was examined in an experimental model system of brain metastasis as well as in human brain with lung cancer metastasis. In an experimental model, after 3–6 weeks of intracardiac inoculation of human lung cancer-derived (HARA-B) cells in nude mice, wide range of brain metastases were observed. The brain sections showed significant increase in glial fibrillary acidic protein (GFAP)-positive astrocytes around metastatic lesions. To elucidate the role of astrocytes in lung cancer proliferation, the interaction between primary cultured mouse astrocytes and HARA-B cells was analyzed in vitro. Co-cultures and insert-cultures demonstrated that astrocytes were activated by tumor cell-oriented factors; macrophage migration inhibitory factor (MIF), interleukin-8 (IL-8) and plasminogen activator inhibitor-1 (PAI-1). Activated astrocytes produced interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β), which in turn promoted tumor cell proliferation. Semi-quantitative immunocytochemistry showed that increased expression of receptors for IL-6 and its subunits gp130 on HARA-B cells. Receptors for TNF-α and IL-1β were also detected on HARA-B cells but down-regulated after co-culture with astrocytes. Insert-culture with astrocytes also stimulated the proliferation of other lung cancer-derived cell lines (PC-9, QG56, and EBC-1). These results suggest that tumor cells and astrocytes stimulate each other and these mutual relationships may be important to understand how lung cancer cells metastasize and develop in the brain.     

Galectin-3 induces endothelial cell morphogenesis and angiogenesis

Increasing evidence suggests that carbohydrate-binding proteins play an essential role in tumor growth and metastasis. However, conflicting results on their function in the regulation of cell proliferation and differentiation during angiogenesis have been reported. We have examined the role of galectin-3 in the regulation of human umbilical vein endothelial cell proliferation, differentiation, migration, and neovascularization. Galectin-3, a carbohydrate-binding protein, with specificity for type 1 and 11 ABH blood group epitopes and polylactosamine glycan containing cell surface glycoproteins, is the major nonintegrin cellular laminin-binding protein. Because galectin-3 expression was shown to be associated in some tumor systems with metastasis, we questioned whether it induces endothelial cell morphogenesis. Here we show that galectin-3 affects chemotaxis and morphology and stimulates capillary tube formation of HUV-EC-C in vitro and angiogenesis in vivo. Endothelial cell morphogenesis is a carbohydrate-dependent process, as it is neutralized by specific sugars and antibodies. These findings demonstrate that endothelial cell surface carbohydrate recognition event(s) can induce a signaling cascade leading to the differentiation and angiogenesis of endothelial cells.     

The dual effects of interleukin-18 in tumor progression

Interleukin-18 （IL-18） was discovered as an interferon-y-inducing factor and had a critical role in inflammatory and immune respouse. It stimulates natural killer （NK） and T cells and enhances Thl immune response. These activated immune cells eliminate cancer cells and virus-infected cells effectively. However, IL-18 has also been found to promote tumor progression. Higher expression or secretion level of IL-18 is detected in various cancer cells in comparison with normal control, and IL-18 is able to induce angiogenesis, migration/metastasis, proliferation and immune escape. These dual effects and the mechanism of IL-18 need to be investigated further as it relates to cancer.     

Effects of lycopene and apigenin on human umbilical vein endothelial cells in vitro under angiogenic stimulation

Angiogenesis is the formation process of new blood vessels from preexisting vessels. Solid tumors need angiogenesis for growth and metastasis. The suppression of tumor growth by inhibition of neoangiogenic processes represents a potential approach to cancer treatment. Lycopene has powerful antioxidant capacities and anticarcinogenic properties. The aim of this study was to investigate the effects of lycopene on angiogenesis in vitro. For this reason, we measured in vitro angiogenesis in human umbilical vein endothelial cells including parameters of cell proliferation, tube formation, cell migration. Lycopene and apigenin were observed to block the endothelial cell proliferation in a dose-dependent manner. In addition, they significantly decreased the capillary-like tube lengths, tube formation and endothelial cell migration. This study provides indications that apigenin and lycopene, which are considered as chemopreventive agents, to be effective in vitro on endothelial cells and angiogenesis.