肿瘤干细胞与肿瘤血管生成

肿瘤血管新生的过程是在一系列正反馈和负反馈因子作用下发生的复杂的链级反应.肿瘤干细胞是存在于肿瘤中一小部分具有自我更新和多向分化潜能的细胞群体.大量研究表明,肿瘤干细胞参与并促进肿瘤的血管新生,血管内皮生长因子能够调节内皮增殖和血管生成,从而促进肿瘤的生长和转移.     

抑制肿瘤血管的新生药物

血管新生在肿瘤的生长和侵袭过程中起着关键作用,随着肿瘤血管新生机制研究的深入及以肿瘤血管为靶点的药物在临床治疗肿瘤时取得较好的疗效,证实了通过抑制肿瘤血管新生来抑制肿瘤生长的理念.目前,抗血管新生药物基础和临床研究取得了新的进展,详细了解肿瘤血管新生的分子机制和抗血管新生药物的作用机制将有助于肿瘤的治疗,并为开发新型抗肿瘤药物提供科学依据.     

抗血管内皮生长因子药物治疗肿瘤的耐药机制

抗血管内皮生长因子(VEGF)药物治疗晚期肿瘤过程中所出现的耐药,可能与其他血管发生通路的激活、骨髓干细胞的动员、管周细胞及围管浸润的演变等相关.因此,探讨发生耐药的机制将有助于更深入了解正常组织、肿瘤及药物间的相互作用关系,并可能提示肿瘤治疗的新靶点.     

血管内皮生长因子与肿瘤放射治疗

实体肿瘤生长、浸润和转移必须有肿瘤血管形成，血管形成是在一系列血管生长因子的调控下实现的，血管内皮生长因子（VEGF）是最重要的血管形成因子。肿瘤放疗能影响肿瘤组织及血液中VEGF的表达水平，VEGF表达水平又能预示肿瘤放疗的疗效，因此肿瘤放疗与抗VEGF治疗的结合将是一个具有诱人前景的肿瘤治疗方案。     

缺氧诱导因子促进肿瘤血管生成的研究

缺氧诱导因子(HIF)是缺氧应答中起重要作用的转录因子,在实体瘤中普遍高表达,与肿瘤血管生成密切相关.其主要通过上调血管内皮生长因子(VEGF)基因的激活启动相关的血管生成,促进肿瘤的生长、侵袭及转移.随着HIF调控肿瘤血管生成机制的研究深入,HIF有望成为抗肿瘤血管生成治疗的重要靶点.     

VEGF反义核酸抑制肿瘤血管形成的研究

目的探讨ＶＥＧＦ反义核酸作为抗新生血管形成药物和抗肿瘤药物的可能性。方法在小鼠角膜肿瘤模型上,测定两种ＶＥＧＦ反义核酸序列的５种不同修饰之反义核酸,对肿瘤血管形成和肿瘤生长的抑制作用。结果线性片段疗效较差,部分硫代和发夹结构两种修饰的反义核酸疗效满意。两种序列反义核酸混合使用最好。结论ＶＥＧＦ反义核酸有望成为抗肿瘤和抗新生血管形成的药物。     

血管内皮生长因子C及其受体在血液肿瘤中的研究进展

血管/淋巴管新生是生物体重要的生理过程,在恶性肿瘤进展和浸润转移过程中也发挥着重要作用。血管内皮生长因子C（VEGF-C）可通过与其受体VEGFR-2,3信号途径诱导血管/淋巴管新生。许多血液肿瘤中均有VEGF-C及受体表达,它与临床分期、耐药、疗效和预后等有一定关系。随着对其研究的深入,针对VEGF-C及其受体靶点的治疗可能成为血液肿瘤治疗的新手段。     

血管内皮生长因子与肿瘤放射治疗

实体肿瘤生长、浸润和转移必须有肿瘤血管形成,血管形成是在一系列血管生长因子的调控下实现的,血管内皮生长因子(VEGF)是最重要的血管形成因子.肿瘤放疗能影响肿瘤组织及血液中VEGF的表达水平,VEGF表达水平又能预示肿瘤放疗的疗效,因此肿瘤放疗与抗VEGF治疗的结合将是一个具有诱人前景的肿瘤治疗方案.     

榄香烯在抑制肿瘤血管生成中的作用

榄香烯是一种广谱的非细胞毒性抗肿瘤药物,能通过下调血管内皮生长因子(VEGF)表达、诱导血管内皮细胞凋亡、抑制肿瘤细胞生长等方面来抑制肿瘤血管生成.有望成为理想的抗肿瘤血管生成药物,但其具体机制尚需深入研究.     

Direct tumor growth suppressive effect of melanoidin extracted from immunomodulator-PSK

Melanoidin, which belongs to the melanin group of molecules, was extracted from the polysaccharide biological response modifier PSK. Melanoidin was cultured together with HCT-15 cells derived from human colon cancer and with AGS cells derived from human gastric carcinoma. After four days of culture, cell count was compared with that of the control cells. Significant suppression was observed, that is, 50% suppression was shown at concentrations of melanoidin between 200 and 100 micrograms/ml. A histogram generated by flow cytometry showed elevation of the tetraploid peak and of that between diploid and tetraploid peaks, suggesting blockage of S phase and G2 to M phase of the cell cycle. Thus, melanoidins contained in the immunomodulator PSK revealed to have a direct tumor cell growth inhibitory effect.     

大蒜素抑制肿瘤生长机制的实验研究

目的:研究大蒜素对肿瘤中血管内皮生长因子(VEGF)及其上游调节基因HIF-1α表达的影响,并探讨其抑制肿瘤生长的机制.方法:皮下荷瘤小鼠体内注射不同刺量的大蒜素,监测肿瘤生长情况;处死小鼠后以ELISA法检测小鼠血清VEGF的表达;realtime-PCR法检测肿瘤中VEGF和HIF-1α mRNA的表达;免疫组化法检测肿瘤中CD34的表达并量化微血管教;蛋白质印迹法检测HIF-1α蛋白的表达.结果:不同剂量大蒜素均对小鼠皮下肿瘤生长有抑制作用,且呈剂量依赖关系.低、高剂量大蒜素对肿瘤的抑制作用与对照组相比分别为71.4%和40.8%;小鼠体内以及肿瘤处的VEGF表达都显著降低,与对照组相比分别为64.5%和62.9%(血清)、34.6%和32.3%(瘤内);同时HIF-1α蛋白表达亦降低,分别是对照组的26.7%和25.1%;肿瘤组织中的CD34表达也明显减少,与对照组相比分别为16.8%和14.4%,P<0.01.结论:大蒜素可以通过抑制肿瘤VEGF的生成,进而抑制肿瘤血管的形成,可能是通过先阻断VEGF的上游调控基因HIF-1的表达来实现的,这为肿瘤临床药理学研究提供一定的理论基础.     

A novel polypeptide from shark cartilage with potent anti-angiogenic activity

Using guanidine-HCl extraction, acetone precipitation, ultra-filtration and chromatography, a novel polypeptide with potent anti-angiogenic activity was purified from cartilage of the shark, Prionace glauca. N-terminal amino acid sequence analysis and SDS-PAGE revealed that the substance is a novel polypeptide with MW 15500 (PG155). The anti-angiogenic effects of PG155 were evaluated using zebrafish embryos model in vivo. Treatment of the embryos with 20 microg/ml PG155 resulted in a significant reduction in the growth of subintestinal vessels (SIVs). A higher dose resulted in almost complete inhibition of SIV growth, as observed by endogenous alkaline phosphatase (EAP) staining assay. An in vitro transwell experiment revealed that the polypeptide inhibited vascular endothelial growth factor (VEGF) induced migration and tubulogenesis of human umbilical vein endothelial cells (HUVECs). Exposure of HUVECs in 20 microg/ml PG155 significantly decreased the density of migrated cells. Almost complete inhibition of cell migration was found when HUVECs were treated with 40-80 microg/ml PG155. PG155 (20 microg/ml) markedly inhibited the tube formation of HUVECs and a dose-dependent effect was also found when treatment of HUVECs with PG155 at the concentration from 20-160 microg/ml.     

Metastatin: a hyaluronan-binding complex from cartilage that inhibits tumor growth

In this study, a hyaluronan-binding complex, which we termed Metastatin, was isolated from bovine cartilage by affinity chromatography and found to have both antitumorigenic and antiangiogenic properties. Metastatin was able to block the formation of tumor nodules in the lungs of mice inoculated with B16BL6 melanoma or Lewis lung carcinoma cells. Single i.v. administration of Metastatin into chicken embryos inhibited the growth of both B16BL6 mouse melanoma and TSU human prostate cancer cells growing on the chorioallantoic membrane. The in vivo biological effect may be attributed to the antiangiogenic activity because Metastatin is able to inhibit the migration and proliferation of cultured endothelial cells as well as vascular endothelial growth factor-induced angiogenesis on the chorioallantoic membrane. In each case, the effect could be blocked by either heat denaturing the Metastatin or premixing it with hyaluronan, suggesting that its activity critically depends on its ability to bind hyaluronan on the target cells. Collectively, these results suggest that Metastatin is an effective antitumor agent that exhibits antiangiogenic activity.     

血根碱通过诱导细胞凋亡抑制卵巢癌肿瘤生长的机制研究

目的 探讨血根碱对卵巢癌细胞SKOV3生长抑制的作用机制。方法 采用CCK-8方法检测血根碱处理后卵巢癌细胞SKOV3的生长情况;采用流式细胞仪检测血根碱对细胞凋亡的影响;采用分光光度计法检测血根碱对活性氧产生的影响;采用小鼠卵巢癌肿瘤模型检测血根碱对小鼠肿瘤生长的抑制作用。结果 血根碱可以促进卵巢癌细胞SKOV3发生凋亡,并且呈剂量和时间依赖性。血根碱诱导的细胞凋亡与活性氧的产生相关,并激活了c-Jun-N-末端激酶(JNK)和核因子-κB(NF-κB)信号通路。在卵巢癌异种移植小鼠模型中,用血根碱静脉注射小鼠后,与对照组相比,血根碱处理组导致小鼠肿瘤生长明显迟缓。体外TUNEL染色表明血根碱显著诱导肿瘤组织凋亡。结论 血根碱可以显著抑制卵巢癌细胞SKOV3的生长,诱导细胞凋亡,增加活性氧的产生,抑制卵巢癌肿瘤生长。     

Loxoprofen sodium suppresses mouse tumor growth by inhibiting vascular endothelial growth factor

There is increasing evidence to suggest the anti-tumor effects of non-steroidal anti-inflammatory drugs (NSAIDs). In this study it was shown that the most popular NSAID in Japan, loxoprofen sodium (LOX), inhibited in vivo growth of implanted Lewis lung carcinoma (LLC), whereas LOX did not affect the proliferation and viability of LLC cells in vitro. Intratumoral vessel density in LOX-treated mice was significantly lower than that of mice without treatment. Intratumoral expressions of vascular endothelial growth factor (VEGF) mRNA were attenuated by the LOX treatment. LOX suppressed both intratumoral and systemic VEGF protein in LLC-implanted mice. LOX also inhibited tubular formation of primary cultured human umbilical vein endothelial cells, presumably due to the inhibition of VEGF. In patients with advanced non-small cell lung cancer, LOX medication (120 mg/day) for a week significantly decreased the plasma VEGF level. These results suggest that LOX may have potent anti-cancer effects in patients with advanced NSCLC.     

ZDHHC9 promotes colon tumor growth by inhibiting effector T cells

Zinc finger DHHC-type palmitoyltransferase 9 (ZDHHC9) has been reported to play an important role in the occurrence and development of several types of cancer. However, its effects on colon cancer growth remain unclear. Using Gene Expression Profiling Interactive Analysis and Tumor Immune Estimation Resource, data obtained from The Cancer Genome Atlas were analyzed, and the results showed that ZDHHC9 was highly expressed in colon cancer and that patients with higher ZDHHC9 expression levels had a worse prognosis. Inhibition of ZDHHC9 expression promoted the proliferation of colon cancer cells in vitro but decreased their growth in vivo. Additionally, inhibition of ZDHHC9 expression in cancer cells enhanced CD8⁺ T cell-mediated cytotoxicity in vitro and increased CD8⁺ T infiltration and activation in vivo. Furthermore, ZDHHC9 promoted IFN-γ-induced JAK/STAT1 activation and upregulated programmed death-ligand 1 (PD-L1) expression in colon cancer cells. In conclusion, the present findings showed that ZDHHC9 promoted colon cancer growth by upregulating the expression of PD-L1 and inhibiting the function of CD8⁺ T cells.     

蚯蚓组织中抑制肿瘤细胞生长物质的分离提取及其作用机制初探

目的 探索一条从蚯蚓中分离有效抑癌成分的途径，并对其作用机制进行初探。方法 选取赤子爱胜蚓(Eisenia Foe—tida)，采用硫酸铵分段盐析、DEAE纤维素-DE52离子交换柱层析、SephadexG100凝胶过滤柱层析等方法分离纯化。MTT方法测定各分离步骤所得样品对于肿瘤细胞的抑制作用。流式细胞术、共聚焦激光扫描显微镜检测细胞凋亡。结果 蚯蚓组织抽提液经分离纯化后，得一蛋白组分。它可有效抑制BEL-7402细胞(人原发性肝癌细胞系)、HeLa细胞(人宫颈癌细胞系)的生长。凝胶过滤测其分子量为42．2kD，SDS-PAGE显示两条带(分别为33和10kD)。细胞凋亡检测结果证实此组分有促肿瘤细胞凋亡的作用。结论 对蚯蚓组织进行分离提取，可得到抑制实体瘤细胞生长的活性组分。它可引起肿瘤细胞的凋亡，凋亡机制有待进一步探索。     

A novel angiogenic inhibitor derived from Japanese shark cartilage (I). Extraction and estimation of inhibitory activities toward tumor and embryonic angiogenesis.

Guanidine extraction and crude fractionation of Japanese shark cartilage by ultrafiltration on a molecular weight basis were conducted and the antiangiogenic activities were assayed as to the inhibitions of tumor and embryonic angiogenesis. Significant inhibition of angiogenesis was found, and there was a linear relationship between the results of the two assays. The inhibitory activities were concentrated in the fraction in the molecular weight range of 103 to 104, and were resistant to heat treatment.     

Silibinin inhibits colorectal cancer growth by inhibiting tumor cell proliferation and angiogenesis

Herein, for the first time, we investigated in vivo efficacy and associated molecular biomarkers and mechanisms of a chemopreventive agent, silibinin, against human colorectal carcinoma (CRC) HT29 xenograft growth. Nude mice were implanted with HT29 cells and fed with vehicle (carboxymethyl cellulose or phosphatidylcholine) or 200 mg/kg/d dose of silibinin or 100 and 200 mg/kg/d doses of silybin-phytosome (5 days per week) for 32 days. Silibinin inhibited tumor growth that accounted for 48% (P = 0.002) decrease in tumor volume and 42% (P = 0.012) decrease in tumor weight at the end of the experiment without any adverse health effect. A stronger antitumor efficacy was observed with silybin-phytosome preparation. Silibinin decreased proliferation index by 40% (P < 0.001), increased apoptotic index by approximately 2-fold (P = 0.001), and reduced microvessel density by 36% (P = 0.001) in tumors. Antiproliferative and proapoptotic effects of silibinin were associated with down-regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation as well as cyclin D1 expression. Antiangiogenic effect of silibinin was coupled with a strong decrease in inducible nitric oxide synthase (NOS) and NOS3, cyclooxygenase-1 (COX-1) and COX-2, and hypoxia-inducing factor-1 alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF). These findings suggest in vivo antitumor efficacy of silibinin against CRC involving its antiproliferative, proapoptotic, and antiangiogenic activities. The inhibition of ERK1/2 and Akt signaling may account for antiproliferative and proapoptotic effects, whereas down-regulation of NOS, COX, HIF-1 alpha, and VEGF expression could lead to antiangiogenic effect of silibinin against CRC. Overall, potential use of silibinin against human CRC could be suggested.