Angiogenesis and cancer prevention: a vision.
Angiogenesis and cancer prevention: a vision.
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DOI：
10.1007/978-3-540-37696-5_19
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发表时间：
2007
期刊：
影响因子：
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通讯作者：
D. Noonan;R. Benelli;A. Albini
中科院分区：
文献类型：
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作者：
D. Noonan;R. Benelli;A. Albini
血管生成是实体瘤生长和扩散所必需的。除了血管生成之外，越来越清楚的是，炎症是可以促进肿瘤血管生成的癌症发病的关键组分。我们注意到，血管生成是大多数化学预防分子的共同和关键目标，它们最有可能抑制癌前肿瘤中的血管生成开关，我们称之为血管预防。我们已经表明，各种分子，如类黄酮，抗氧化剂和类维生素A，在肿瘤微环境中发挥作用，抑制募集和/或激活内皮细胞和吞噬细胞的先天免疫。N-乙酰半胱氨酸、绿色茶类黄酮表没食子儿茶素-3-没食子酸酯（EGCG）和啤酒/啤酒花衍生的查耳酮黄腐酚都能在体内Matrigel海绵血管生成测定中防止血管生成，并抑制裸鼠中高度血管生成的卡波西肉瘤肿瘤细胞（KS-Imm）的生长。合成类维生素A 4-羟基芬维A胺（4 HPR）也显示出抗血管生成作用。我们用功能基因组学分析了它们在培养的原代人脐静脉内皮细胞（HUVEC）中的基因表达调控。通过Affyscore基因芯片阵列获得的表达谱鉴定了由抗氧化剂调控的重叠基因组。相反，产生ROS的4 HPR诱导TGFβ-配体超家族的成员，这至少部分解释了其抗血管生成活性。NAC和黄酮类化合物均能抑制Ik B/NF-κB信号通路，即使在TNFα刺激NF-κB的情况下，也能降低许多NF-κB靶基因的表达。抗氧化剂对转化细胞而非内皮细胞的选择性凋亡作用可能与NF-κ B依赖性存活因子Bcl 2和Birc 5/surviving的表达减少有关，这些因子在转化细胞中选择性过表达。NF-κB途径的抑制表明抗氧化剂化合物的抗炎作用，其也可能代表血管生成抑制的间接作用。绿色茶类黄酮EGCG确实靶向炎症细胞，主要是中性粒细胞，并抑制炎症相关的血管生成。其他血管预防分子被证明是吞噬细胞募集和激活的有效调节剂，进一步将炎症和血管形成与肿瘤发生和进展联系起来，并为癌症预防提供了关键靶点。
Angiogenesis is necessary for solid tumor growth and dissemination. In addition to angiogenesis, it has become increasingly clear that inflammation is a key component in cancer insurgence that can promote tumor angiogenesis. We noted that angiogenesis is a common and key target of most chemopreventive molecules, where they most likely suppress the angiogenic switch in premalignant tumors, a concept we termed angioprevention. We have shown that various molecules, such as flavonoids, antioxidants, and retinoids, act in the tumor microenvironment, inhibiting the recruitment and/or activation of endothelial cells and phagocytes of the innate immunity. N-acetyl-cysteine, and the green tea flavonoid epigallocatechin-3-gallate (EGCG) and the beer/hops-derived chalcone Xanthohumol all prevent angiogenesis in the Matrigel sponge angiogenic assay in vivo and inhibit the growth of the highly angiogenic Kaposi’s sarcoma tumor cells (KS-Imm) in nude mice. The synthetic retinoid 4-hydroxyfenretinide (4HPR) also shows antiangiogenic effects. We analyzed the regulation of gene expression they exert in primary human umbilical endothelial cells (HUVEC) in culture with functional genomics. Expression profiles obtained through Affymetrix GeneChip arrays identified overlapping sets of genes regulated by anti-oxidants. In contrast, the ROS-producing 4HPR induced members of the TGFβ-ligand superfamily, which, at least in part, explains its anti-angiogenic activity. NAC and the flavonoids all suppressed the IkB/NF-κB signaling pathway even in the presence of NF-κB stimulation by TNFα, and showed reduced expression of many NF-κB target genes. A selective apoptotic effect on transformed cells, but not on endothelial cells, of the anti-oxidants may be related to the reduced expression of the NF-κB-dependent survival factors Bcl2 and Birc5/surviving, which are selectively overexpressed in transformed cells by these factors. The repression of the NF-κB pathway suggests anti-inflammatory effects for the antioxidant compounds that may also represent an indirect role in angiogenesis inhibition. The green tea flavonoid EGCG does target inflammatory cells, mostly neutrophils, and inhibits inflammation-associated angiogenesis. The other angiopreventive molecules are turning out to be effective modulators of phagocyte recruitment and activation, further linking inflammation and vascularization to tumor onset and progression and providing a key target for cancer prevention.