Association between intratumoral free and total VEGF, soluble VEGFR-1, VEGFR-2 and prognosis in breast cancer

Vascular endothelial growth factor (VEGF) receptors consist of three cell-membrane type receptors (VEGFR-1, VEGFR-2 and VEGFR-3), and soluble form of VEGFR-1 (sVEGFR-1), an intrinsic negative counterpart of the VEGF. In this study, we measured intratumoral protein levels of free and total VEGF, VEGFR-2 and sVEGFR-1 from 202 primary breast cancer tissues and examined their prognostic values. A significant inverse correlation was found between free or total VEGF and oestrogen receptor (ER) status (P=0.042 and 0.032, respectively). A univariate analysis showed that low sVEGFR-1 and high total VEGF were significantly associated with poor prognosis in disease-free survival (DFS) and overall survival (OS). The ratio of sVEGFR-1 to total VEGF was a strong prognostic indicator (DFS: P=0.008; OS: P=0.0002). A multivariate analysis confirmed the independent prognostic values of total VEGF and the ratio of sVEGFR-1 to total VEGF. In subgroup analysis, total VEGF was a significant prognostic indicator for ER-positive tumours but not for ER-negative tumours, whereas sVEGFR-1 was significant for ER-negative tumours but not for ER-positive tumours. In conclusion, the intratumoral sVEGFR-1 level, VEGF level and the ratio of sVEGFR-1 to total VEGF are potent prognostic indicators of primary breast cancer, and might be relevant to ER status.     

Fibulin-7 is overexpressed in glioblastomas and modulates glioblastoma neovascularization through interaction with angiopoietin-1

Glioblastoma (GBM) is pathologically characterized by highly malignant neoplastic cells, focal necrosis and aberrant blood vessels composed of disorganized endothelial cells and pericytes. The recent cancer microarray database revealed upregulation of fibulin-7 (Fbln7), a member of the fibulin family, but provided no information on the tissue localization or biological function. In the present study, we demonstrated that Fbln7 is markedly overexpressed by the GBM tissue among astrocytic tumors, and immunolocalized mainly to endothelial cells and pericytes of the glomeruloid and hypertrophied microvessels. The production of Fbln7 by endothelial cells and pericytes was confirmed in cultured human umbilical vein endothelial cells (HUVEC) and human brain vascular pericytes (HBVP) and vascular endothelial growth factor (VEGF) stimulated the Fbln7 expression in HUVEC. Fbln7 bound to angiopoietin-1, but not angiopoietin-2 or Tie2 receptor, through interaction between the N-terminal portions of Fbln7 and angiopoietin-1, and it blocked phosphorylation of Tie2 receptor in HUVEC. In a coculture assay using HUVEC and HBVP, multilayered and irregular-shaped tube-like structures of HUVEC were induced by treatment with a high concentration of VEGF. This was accompanied by Fbln7 overproduction by HUVEC and angiopoietin-1 expression by HBVP. The production of aberrant VEGF-induced tube-like structures was attenuated by treatment with antibody or synthetic peptides specific to the Fbln7 N-terminal domain or knockdown of Fbln7. These data demonstrate that Fbln7 is overexpressed by endothelial cells and pericytes of the abnormal microvessels in GBM, and suggest that Fbln7 may contribute to the aberrant vessel formation by modulation of the angiopoietin-1/angiopoietin-2-Tie2 axis.     

Norepinephrine induces VEGF expression and angiogenesis by a hypoxia‐inducible factor‐1α protein‐dependent mechanism

A growing number of studies have demonstrated that physiological factors can influence the progression of several cancers via cellular immune function, angiogenesis and metastasis. Recently, stress‐induced catecholamines have been shown to increase the expression of various cancer progressive factors, including vascular endothelial growth factor (VEGF), matrix metalloproteinases and interleukins. However, a detailed mechanism remains to be identified. In this study, we investigated the role of adrenergic receptors and hypoxia‐inducible factor (HIF)‐1α protein in catecholamine‐induced VEGF expression and angiogenesis. Treatment of the cells with norepinephrine (NE) or isoproterenol induced VEGF expression and HIF‐1α protein amount in a dose‐dependent manner. Induction of VEGF expression by NE was abrogated when the cells were transfected with HIF‐1α–specific siRNA. Similarly, adenylate cyclase activator forskolin and cyclic AMP‐dependent protein kinase A inhibitor H‐89 enhanced and decreased HIF‐1α protein amount, respectively. More importantly, conditioned medium of NE‐stimulated cancer cells induced angiogenesis in a HIF‐1α protein–dependent manner. In addition, pretreatment of cells with propranolol, a β‐adrenergic receptor (AR) blocker, completely abolished induction of VEGF expression and HIF‐1α protein amount by NE in all of the tested cancer cells. However, treatment with the α1‐AR blocker prazosin inhibited NE‐induced HIF‐1α protein amount and angiogenesis in SK‐Hep1 and PC‐3 but not MDA‐MB‐231 cells. Collectively, our results suggest that ARs and HIF‐1α protein have critical roles in NE‐induced VEGF expression in cancer cells, leading to stimulation of angiogenesis. These findings will help to understand the mechanism of cancer progression by stress‐induced catecholamines and design therapeutic strategies for cancer angiogenesis.     

High bone marrow angiopoietin-1 expression is an independent poor prognostic factor for survival in patients with myelodysplastic syndromes

Background:

Angiogenic factors have an essential role in normal and pathologic angiogenesis. However, the clinical implication of angiogenic factor expression in myelodysplastic syndromes (MDS) remains unclear.

Methods:

In this study, we sought to investigate the prognostic impact of the expression of genes encoding angiopoietin-1 (Ang-1), Ang-2, the receptor Tie2, vascular endothelial growth factor-A (VEGF-A) and VEGF-C in the bone marrow (BM) in 208 patients with newly diagnosed primary MDS.

Results:

BM Ang-1 expression was significantly higher in MDS patients, especially those with higher-risk subtypes, than in normal controls. With a median follow-up time of 32.9 months, the disease transformed to acute leukaemia more frequently in the patients bearing higher Ang-1 expression than in those with lower expression (31.5% vs 18.6%, P=0.023). The MDS patients with higher Ang-1 expression had shorter overall survival than those with lower expression (median 20.8±4.5 months vs 63.3±17.8 months, P<0.001). Multivariate analyses showed that higher Ang-1 expression was an independent unfavourable prognostic factor for overall survival. There was no impact of the expression of other angiogenic factors on survival.

Conclusion:

BM Ang-1 expression may serve as a new biomarker to predict clinical outcome in MDS patients.     

Cox-2抑制剂对人肺腺癌A549细胞VEGF和Angs基因表达的影响

目的 :探讨环氧化酶 -2 (Cox 2 )抑制剂Nimesulide(NIM )对人肺腺癌A 5 49细胞血管内皮生长因子 (VEGF)及血管生成素(Angs)基因表达的影响及意义。方法 :不同浓度 ( 2 5、5 0、10 0、2 0 0 μmol/L)NIM处理人肺腺癌A 5 49细胞 2 4、48、72h后 ,放射免疫法测定细胞培养上清液PGE2 水平 ,半定量RT PCR检测NIM处理人肺腺癌A 5 49细胞后48h其VEGF及Ang 1、Ang 2mRNA的表达水平。结果 :NIM处理A 5 49细胞后 ,细胞培养上清液PGE2 水平下降 ,呈浓度和时间依赖性 ;NIM处理A 5 49细胞后 48h ,VEGF、Ang 2mRNA水平下降 ,呈浓度依赖性 ;Ang 1mRNA水平则无显著改变。结论 :NIM可抑制Cox 2活性及下调VEGF、Ang 2基因表达 ,该作用可能是Cox 2抑制剂抑制肿瘤血管生成的机制之一     

Hypoxia-regulated protein expression, patient characteristics, and preoperative imaging as predictors of survival in adults with glioblastoma multiforme

BACKGROUND: Regions of hypoxia within glioblastoma multiforme (GBM) are common and may influence a tumor's aggressiveness, response to treatment, and the patient's overall survival. In this study, the authors examined 4 markers of hypoxia (hypoxia-inducible factor 1 [HIF-1alpha], glucose transporter 1 [GLUT-1], vascular endothelial growth factor [VEGF], and carbonic anhydrase 9 [CA IX]), cellular proliferation and microvascular density (MVD) indices, extent of surgical resection, and preoperative imaging characteristics and compared them with the overall survival rates of adults with GBM. METHODS: In this retrospective cohort study, patients who had lower grade astrocytomas were compared with patients who had GBM to verify that the methods used could establish differences between tumor grades. By using preoperative imaging, the amount of necrosis was established versus the overall tumor area. The authors also compared preoperative images with postoperative images to define the amount of tumor resected; and they compared molecular markers, proliferation, MVD, and imaging studies with survival among patients who had GBM. RESULTS: The hypoxia-regulated molecules (HRMs) and indices for MVD and cellular proliferation were associated significantly with tumor grade. Survival was improved when >or=95% of the tumor was resected. Although the total tumor area was associated with overall survival, no differences were observed when the amount of necrosis or a tumor necrosis index (area of necrosis/area of tumor) was compared with survival. The findings indicated that GLUT-1 and VEGF were correlated with survival after controlling for age. CONCLUSIONS: Tumor grade was differentiated with HRMs, MVD, and proliferation, but only GLUT-1 predicted survival in this group of patients with GBM. The results suggested that GLUT-1 may be an important independent prognostic indicator.     

大黄素抑制人肝癌HepG2细胞血管生成作用及其机制研究

目的 大黄素可促进人肝癌HepG2细胞的凋亡,然而其是否可抑制肝细胞癌(hepatocellular carcinoma,HCC)血管生成及其机制罕见报道.本研究探讨大黄素对人肝癌HepG2细胞血管生成以及缺氧诱导因子-1α (hypoxia inducible factor-1a,HIF-1d)和血管内皮生长因子(vascular endothelial growth factor,VEGF)的影响,以及大黄素体内抗肝癌机制.方法 采用体内鸡胚绒毛尿囊膜(chick chorioallantoic membrane,CAM)实验,实验随机分为阴性对照组(生理盐水)、大黄素低剂量组(10 μmol/L)、大黄素高剂量(20 μmol/L)和阳性对照组(0.15 mg/mL地塞米松),每组各10只,每24 h每组追加同样等量药物,共72 h,观察大黄素对CAM血管生成的抑制作用.体外培养HepG2细胞,以氯化钴(CoCl2)模拟化学缺氧,设立缺氧未处理组[阴性对照组(生理盐水)]、缺氧大黄素低剂量组(10 μmol/L)、缺氧大黄素高剂量组(20 μmol/L)和缺氧阳性对照组[10 μmol/L 5-氟尿嘧啶(5-fluorouracil,5-FU)],每组设6个复孔,处理24 h.采用小管形成实验,观察大黄素对HepG2细胞相对小管数目的影响,免疫细胞化学分析检测HIF-1α和VEGF阳性细胞的表达,Real-Time PCR分析检测HIF-1α mRNA和VEGF mRNA的表达.采用Graphpad 5.0软件进行描述性统计,组间比较采用one-way-ANOWA和Bonferroni检验.结果 CAM实验显示,实验组新生血管数目明显减少,与阴性照组比较,差异有统计学意义,F=13.374,P=0.002.阴性对照组新生血管数目为(31.47±1.81)个.给药后CAM血管生成减少,大黄素低剂量组、高剂量组和地塞米松组分别为(19.48±0.66)、(10.33±1.04)和(9.89±0.57)个,与阴性对照组比较,差异有统计学意义,P值分别为0.041、0.004和0.003;大黄素低剂量组和高剂量组与地塞米松组比较,差异无统计学意义,P值分别为0.539和1.000.小管形成实验显示,实验组相对小管数目明显减少,与阴性照组比较,差异有统计学意义,F=21.529,P＜0.001.阴性对照组相对小管数目为(100.00±0.00)％.给药后,相对小管数目明显减少,大黄素低剂量、高剂量组和阳性对照组分别为(65.85±12.67)％、(46.94±8.34)％和(41.77±7.53)％,与阴性对照组比较,差异有统计学意义,P值分别为0.049、0.001和＜0.001;大黄素低剂量组和高级剂量组与阳性对照组比较,差异无统计学意义,P值分别为0.104和0.069.免疫细胞化学分析显示,大黄素低剂量组、高剂量组和阳性对照组HIF-1α和VEGF阳性细胞显著减少.Real-Time PCR分析显示,实验组HIF-1α mRNA和VEGF mRNA表达降低,与阴性照组比较,差异有统计学意义(F=31.908,P＜0.001;F=25.146,P＜0.001).阴性对照组HepG2细胞HIF-1α mRNA和VEGF mRNA相对表达分别为0.92±0.15和0.95±0.15;大黄素低剂量组HIF-1α mRNA和VEGF mRNA相对表达分别为0.45±0.07和0.51±0.08,与阴性对照组比较,差异有统计学意义,P值分别为0.021和0.013;大黄素高剂量组HIF-1α mRNA和VEGF mRNA相对表达分别为0.32±0.05和0.40±0.07,与阴性对照组比较,差异有统计学意义,P值分别为＜0.001和0.001;阳性对照组HIF-1α mRNA和VEGF mRNA相对表达分别为0.30±0.04和0.34±0.05,与阴性对照组比较,差异有统计学意义,P值均＜0.001;大黄素低剂量组、高剂量组HIF-1α mRNA和VEGF mRNA相对表达与阳性对照组比较,差异无统计学意义,P值分别为0.663、0.362、0.443和1.000.结论 大黄素可能通过抑制HIF-1d mRNA的表达,从而降低VEGF mRNA的表达来抑制HepG2细胞新生血管的形成.     

HIF-1的功能结构及其基因调控

HIF-1是氧平衡调控的转录因子，在肿瘤细胞缺氧适应过程中起着中枢调节作用，其对下游基因的表达调控广泛影响着肿瘤细胞的糖代谢、增殖、凋亡和肿瘤的血管形成．使缺氧的组织细胞能保持氧稳态以耐受缺氧状态。因此，探讨HIF-1的功能结构和活性表达及其对下游基因的表达调控，将HIF-1及其下游基因为靶点，有望成为抗肿瘤治疗的有效手段。     

Vascular endothelial growth factor expression is independent of hypoxia in human malignant glioma spheroids and tumours

We recently showed that severe hypoxia was not universally present adjacent to necrosis in human glioma xenografts and spheroids established from the M059K, M006, M006X, M006XLo and M010b cell lines. Using these glioma models, we wished to test whether oxygen serves as a regulator of cellular VEGF expression in situ. In situ hybridization (ISH) and immunohistochemistry (IHC) were used to detect vascular endothelial growth factor (VEGF) mRNA and protein expression in sections of glioma xenografts and spheroids in which hypoxic regions and regions with well-oxygenated necrosis were identified on contiguous sections by use of the hypoxia-specific marker, 3H-misonidazole. Independent validation of the presence of radiobiologically hypoxic cells in M006 xenografts was undertaken using the comet assay. Northern blotting analyses of monolayer cells demonstrated significant up-regulation of VEGF mRNA in the M006X line at oxygen concentrations of 6% and below. ISH analysis of VEGF mRNA showed unexpectedly strong staining for VEGF mRNA across the entire viable rim of M006X and M006XLo glioma spheroids. Similarly, in virtually all xenograft tumours of the M059K, M006 and M010b lines, VEGF ISH showed similar staining across all regions of healthy cells up to the border of necrosis. Only in one M006X tumour was there a suggestion of increased VEGF expression in cells adjacent to necrosis. IHC for VEGF showed good concordance with the ISH results. IHC analysis of the VEGF receptor flt-1 showed strong tumour cell staining in M006XLo glioma cells. In human glioma spheroids and xenograft tumours, regions of severe hypoxia do not correspond to areas of up-regulated VEGF expression; in fact, VEGF expression is quite uniform. Furthermore, this and our previous study demonstrate that levels of VEGF expression vary among sublines (M006, M006X and M006XLo) derived from a single human glioma specimen.     

Inhibition of HIF-1 alpha and VEGF expression by the chemopreventive bioflavonoid apigenin is accompanied by Akt inhibition in human prostate carcinoma PC3-M cells

Progression of cancer leads to hypoxic solid tumors that mount specific cell signaling responses to low oxygen conditions. An important objective of anti-cancer therapy is the development of new drugs that suppress hypoxic responses in solid tumors. Apigenin is a natural flavone that has been shown to have chemopreventive and/or anti-cancer properties against a number of tumor types. However, the mechanisms underlying apigenin's chemopreventive properties are not yet completely understood. In this study, we have investigated the effects of apigenin on expression of hypoxia-inducible factor-1 (HIF-1) in human metastatic prostate PC3-M cancer cells. We found that hypoxia induced a time-dependent increase in the level of HIF-1alpha subunit protein in PC3-M cells, and treatment with apigenin markedly decreased HIF-1alpha expression under both normoxic and hypoxic conditions. Further, apigenin prevented the activation of the HIF-1 downstream target gene vascular endothelial growth factor (VEGF). We then showed that apigenin inhibited expression of HIF-1alpha by reducing stability of the protein as well as by reducing the level of HIF-1alpha mRNA. We also found that apigenin inhibited Akt and GSK-3beta phosphorylation in PC3-M cells. Further experiments demonstrated that constitutively active Akt blunted the effect of apigenin on HIF-1alpha expression. Taken together, our results identify apigenin as a bioflavonoid that inhibits hypoxia-activated pathways linked to cancer progression in human prostate cancer, in particular the PI3K/Akt/GSK-3 pathway. Further studies on the mechanism of action of apigenin will likely provide new insight into its applicability for pharmacologic targeting of HIF-1alpha for cancer therapeutic or chemopreventive purposes.     

Flavopiridol inhibits vascular endothelial growth factor production induced by hypoxia or picolinic acid in human neuroblastoma

Human neuroblastoma (NB) tumors elaborate angiogenic peptides, and enhanced angiogenesis correlates with their aggressive behavior, metastatic spread and poor clinical outcome. Hence, inhibition of angiogenic factor production may represent a potential therapeutic target for NB treatment. There is currently little information regarding the stimuli that control NB production of angiogenic mediators. In this study, we analyzed the effects of hypoxia, a common feature of solid tumors and a major drive to tumor angiogenesis, and of PA, a tryptophan catabolite produced under inflammatory conditions and endowed with several biologic properties, on the production of the angiogenic activator VEGF by advanced-stage human NB cell lines. We demonstrate that both stimuli are potent inducers of VEGF expression and secretion. VEGF upregulation by PA involved iron chelation because iron sulfate prevented this effect whereas the iron-chelating agent DFX induced VEGF production. Conversely, the CDK inhibitor Flp completely blocked VEGF induction by hypoxia. This effect occurred as early as 3 hr after stimulation and did not require de novo protein synthesis. Moreover, Flp exerted similar inhibitory activity on VEGF induction by PA or DFX, suggesting that this compound targets an essential step in the signaling pathway that leads to VEGF expression. Our findings demonstrate that PA can modulate angiogenic factor production by tumor cells and establish the importance of Flp as an inhibitor of VEGF production by human NB.     

缺氧诱导因子及其应答基因BNIP3和血管内皮生长因子在胃腺癌中表达及临床意义

目的检测缺氧诱导因子（HIF）及其应答基因bcl-2／腺病毒E1B19000相互作用蛋白3（BNIP3）和血管内皮生长因子（VEGF）在胃腺癌中的表达，探讨它们之间的关系以及在胃腺癌中表达的临床意义。方法采用免疫组化S-P法，检测70例胃腺癌组织和12例癌旁正常组织中HIF-1α、HIF-2α、BNIP3和VEGF的表达。结果70例胃腺癌组织中，HIF—1α、HIF-2α、BNIP3和VEGF的阳性表达率分别为61．4％、37．1％、51．4％和62．9％；而在正常对照组中的阳性表达率分别为8．3％、0、0和0，4种基因在不同组织间的表达率差异均有统计学意义（P〈0．01）。HIF—1α和VEGF的表达与胃腺癌淋巴结转移密切相关，BNIP3的表达与淋巴结转移呈负相关；HIF-1α的表达与BNIP3和VEGF的表达呈正相关。结论HIF通过调节其下游基因的表达在胃癌的发生和发展中发挥着重要作用；VEGF的表达与胃腺癌的不良生物学行为相关，而BNIP3的表达则提示预后较好。     

Significance of vascular endothelial growth factor (VEGF)/soluble VEGF receptor-1 relationship in breast cancer

Angiogenesis, the formation of new blood vessels, is controlled by a balance between positive and negative endothelial regulatory factors. Soluble vascular endothelial growth factor receptor-1 (sVEGFR1), a naturally occurring soluble form of VEGFR1, is a negative counterpart of the vascular endothelial growth factor (VEGF) signaling pathway, which has been characterized as one of the most important endothelial regulators in human tumor angiogenesis. In our study, we examined the expression of sVEGFR1 in 110 primary breast carcinomas, and assessed its clinical significance. Ninety-four of 110 tumors showed > or = 0.1 ng/mg protein of sVEGFR1 (range:0. 1-6.9 ng/mg protein; median: 1.03 ng/mg protein) as determined by a specific enzyme-linked immunosorbent assay (ELISA). Immunoblot analysis confirmed the presence of sVEGFR1 in breast tumor tissues. The levels of sVEGFR1 were correlated significantly with the levels of VEGF. There was no significant correlation between the levels of sVEGFR1 and any clinico-pathological factors including age, menopause, nodal involvement and hormone receptor status. A univariate prognosis analysis showed that the intratumoral VEGF status, as determined by ELISA, was a significant prognostic indicator, but sVEGFR1 status was not. In the combined analysis, however, the ratio of sVEGFR1 and VEGF levels provided more statistically significant prognostic value than VEGF status alone. Tumors in which the sVEGFR1 levels exceeded VEGF levels 10-fold had a markedly favorable prognosis. Multivariate analysis also demonstrated that the ratio of sVEGFR1 and VEGF was an independent prognostic indicator after nodal status. In conclusion, sVEGFR1, an intrinsic inhibitor of VEGF, frequently co-expressed with VEGF in primary breast cancer tissues. The intratumoral balance between sVEGFR1 and VEGF levels might be crucial for the progression of breast cancer.     

甲状腺癌组织中VEGF与TGF-β1的表达及其意义

目的探讨血管内皮生长因子（VEGF）及转化生长因子（TGF-β1）在甲状腺癌组织中的表达及其与临床病理特征的关系.方法对48例甲状腺乳头状腺癌,10例滤泡状腺癌组织标本,采用SP免疫组化染色法检测VEGF与TGF-β1的表达.结果 VEGF与TGF-β1在甲状腺癌组织中表达率分别为51.7%和56.9%,且随着肿瘤体积,病灶数量,病理分期的增加和淋巴结的转移而表达增多;两者在甲状腺癌中的表达阳性率呈正相关关系.结论 VEGF可促进肿瘤的增生和转移;在甲状腺癌的生长过程中,随着表达量由低到高,TGF-β1可能先起到抑制,而后促进肿瘤细胞生长的作用.     

VEGF与Notch1在乳腺癌浸润和转移中的作用及其相关性

目的探讨血管内皮生长因子(VEGF)和Notch1在乳腺癌组织中的表达及与肿瘤浸润和转移之间的关系。方法采用免疫组化S-P法检测VEGF和Notch1蛋白在60例乳腺癌组织及20例癌旁正常乳腺组织中的表达情况,并分析两者与乳腺癌患者临床病理学特征的关系。结果 VEGF和Notch1蛋白在乳腺癌组织中的表达高于癌旁正常组织(P均<0.05)。VEGF的表达与乳腺癌的淋巴结转移、组织学分级、临床分期有关(P均<0.05),Notch1蛋白的表达与乳腺癌的淋巴结转移、组织学分级有关(P均<0.05),两者在乳腺癌组织中的表达呈正相关关系(r=0.414,P=0.001)。结论 VEGF和Notch1可能在乳腺癌的发生、发展中起重要作用,两者的高表达有可能作为预测乳腺癌浸润、转移的指标。     

沙利度胺对人鼻咽癌细胞株血管内皮生长因子表达影响的观察

目的:探讨沙利度胺对人鼻咽癌细胞株体外生长及对血管内皮生长因子表达的影响。方法:采用MTT法检测沙利度胺对人鼻咽癌细胞增殖的抑制率;RT-PCR和免疫细胞化学方法分别检测沙利度胺作用前后血管内皮生长因子基因和蛋白表达水平的变化。结果:沙利度胺能抑制CNE-2细胞增殖,呈浓度依赖性,当60mg/L沙利度胺作用72h,其抑制率为45.6%;不同浓度沙利度胺作用后VEGFmRNA和VEGF-CmRNA表达均降低,VEGFmRNA下降最明显,P<0.05;蛋白表达与其相应mRNA呈正相关,r值分别为0.959和0.974,P值分别为0.035和0.021。结论:沙利度胺能够抑制CNE-2细胞增殖,其作用机制可能与其下调血管内皮生长因子的表达有关。