Elevated serum concentrations of activated hepatocyte growth factor activator in patients with multiple myeloma

Objectives: Hepatocyte growth factor (HGF) is a potential key factor in multiple myeloma. Conversion of pro‐HGF to its active form is a critical limiting step for its biological effects. We aimed to examine the levels of the most potent activator, the hepatocyte growth factor activator (HGFA), in serum and bone marrow plasma of patients with multiple myeloma. Methods: The activated form of HGFA was measured by an enzyme‐linked immunosorbent assay in serum (n = 49) and bone marrow plasma (n = 16) from multiple myeloma patients, and in serum from healthy controls (n = 24). Results: The median concentrations of activated HGFA in myeloma and control sera were 39.7 (range 6.2–450.0) and 17.6 ng/mL (range 4.8–280.6), respectively. The difference was statistically significant (P = 0.037). The median concentration of activated HGFA in bone marrow plasma was 6.1 ng/mL (range 3.5–30.0). Conclusion: We here show for the first time that the activated form of HGFA is present at high levels in serum and bone marrow of myeloma patients, thus providing a necessary prerequisite for the activation of HGF.     

Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma

Angiogenesis is a crucial process in growth and progression of cancer and there is growing evidence that neovascularisation is important in hematological malignancies. Since an increased angiogenic potential has been identified in multiple myeloma, we simultaneously measured circulating serum levels of the cytokines bFGF, VEGF, HGF and IL-6 by ELISA in 67 patients with multiple myeloma or monoclonal gammopathies of undetermined significance (MGUS) and in 20 controls. Median values of bFGF were 4.7 pg/ml in healthy volunteers, 6.2 in MGUS, 6.3 in myeloma stage I, 13.4 in stage II and 21.7 in stage III. Myeloma patients had significantly higher bFGF serum levels than controls (p<0.001). Pretreatment bFGF levels differed significantly in the Salmon and Durie stages I-III (p=0.02) and were significantly elevated in stage II-III compared to stage I myeloma (p=0.02). In patients responding to chemotherapy according to the CLMTF criteria, a significant decrease in serum bFGF, VEGF and HGF levels occurred (median pretreatment values for bFGF 23.9 pg/ml, post-treatment 6.5 pg/ml; p<0.001, for VEGF 223 pg/ml versus 105 pg/ml; p=0.02 and for HGF 1429 pg/ml versus 1077 pg/ml; p=0.02, respectively). In 11 patients who did not achieve a remission, there was no significant decrease in bFGF, VEGF and HGF levels. These data show that myeloma in stages II and III is associated with an increase in serum bFGF concentrations and give the first report that effective chemo-therapy is accompanied by a significant decrease in the angiogenic factors bFGF, VEGF and HGF, while no decrease of these factors could be found in nonresponders.     

Elevated serum concentration of hepatocyte growth factor in patients with multiple myeloma: correlation with markers of disease activity

Hepatocyte growth factor (HGF) has been shown to be involved in angiogenesis, epithelial cell proliferation, and osteoclast activation. HGF and its receptor are expressed on myeloma cell lines and could be involved in the pathogenesis of bone destruction in multiple myeloma (MM). The aim of this study was to examine serum levels of HGF in untreated MM patients and its correlation with bone turnover indices and markers of disease activity. Forty-seven newly diagnosed MM patients and 25 controls were included: 12 patients were of stage I, 13 of stage II, and 22 of stage III (Durie-Salmon classification). Bone lesions were scored from 0 to 3, according to X-ray findings. Serum osteocalcin (OC), interleukin-6 (IL-6), TNF-alpha, beta(2)-microglobulin (beta(2)M), CRP, calcium, and 24-hr urine N-telopeptide cross-links of collagen breakdown (NTx) were determined. HGF levels were significantly higher at stage III compared to stages II and I (medians: 1,990.4 vs. 1,743.8 and 1,432.4 pg/mL, respectively, P < 0.05). Similarly, NTx, IL-6, TNF-alpha, CRP, beta(2)M, and calcium increased significantly with advancing stage (P < 0.01). OC was higher at stage I in comparison to stages II and III (P < 0.01). All parameters were significantly higher in patients than controls. HGF showed a strong correlation with IL-6 and TNF-alpha and less with beta(2)M, CRP, NTx, and OC. We conclude that serum HGF levels are increased in advanced stages of MM disease and extended bone lesions. HGF correlates with IL-6 and TNF-alpha, which are cytokines involved in osteoclast stimulation in MM. However, an independent association of HGF with bone turnover markers was not shown in this study, thus its role in MM bone disease needs to be further clarified.     

多发性骨髓瘤血管内皮生长因子和白细胞介素-6相互作用的研究

目的　研究人类多发性骨髓瘤(MM)细胞系和MM患者骨髓基质细胞(BMSCs)之间相互作用对血管内皮生长因子(VEGF)和IL6分泌的调控作用,分析VEGF和IL6的相互作用在MM发病机制中的意义。方法　建立MMBMSCs和正常人BMSCs(NBMSCs)的培养体系,用IL6、抗IL6抗体、VEGF、抗VEGF抗体作用于BMSCs和(或)MM细胞系U266后,ELISA方法检测其VEGF和IL6的分泌量。结果　U266分泌VEGF,但不分泌IL6,而MMBMSCs和NBMSCs既分泌VEGF又分泌IL6。重组人VEGF刺激BMSCs后,以时间和剂量依赖性的方式诱导IL6的分泌,此效应可被抗VEGF抗体抑制。外源性IL6促进BMSCs分泌VEGF。当U266与BMSCs黏附后,VEGF分泌增加25~50倍,IL6增加55~90倍,两者差异有统计学意义(P<005);分别加入抗VEGF或抗IL6抗体,IL6或VEGF的分泌受抑。重组人IL6作用于U266,可诱导剂量依赖性的VEGF分泌的增加,此反应可被抗IL6抗体抑制。结论　在MM中,MM细胞和BMSCs之间的相互作用调节VEGF和IL6的分泌,促进MM细胞的生长和血管新生,在MM的发病机制中发挥重要作用,为针对骨髓微环境的靶位治疗提供了理论依据。     

非霍奇金淋巴瘤患者sVEGF和sbFGF水平的变化及临床意义

目的:研究非霍奇金淋巴瘤(NHL)患者血清血管内皮生长因子(sVEGF)及血清碱性成纤维细胞生长因子(sbFGF)水平与临床特征的关系,探索其临床意义.方法:ELISA法检测36例不同病期NHL患者sVEGF、sbFGF水平,并收集临床资料,进行统计分析.结果:NHL患者sVEGF、sbFGF水平明显高于对照组(均P＜...     

去甲斑蝥素对多发性骨髓瘤细胞周期和血管内皮细胞生长因子的影响

目的 探讨去甲斑蝥素(NCTD)抗骨髓瘤效应的机制.方法 利用流式细胞术检测不同浓度NCTD作用24h后细胞周期的改变,Western blot检测CDK1、cyclin A和cyclin B1的改变,免疫组化和RT-PCR测定血管内皮细胞生长因子(VEGF)的表达.结果 经NCTD处理24h后,随着NCTD浓度增加,G2/M期细胞明显增加,S期细胞明显减少,呈剂量依赖性;NCTD以剂量依赖的方式抑制cyclin B1、CDK1和cyclin A的表达;NCTD以剂量依赖的方式抑制VEGF mRNA和蛋白的表达.结论 NCTD对U266细胞有抗增殖和促凋亡作用,其作用机制可能与调节细胞周期和抑制VEGF的表达有关.     

VEGF与VEGF-C蛋白在胆管癌中的表达及意义

目的探讨VEGF与VEGF-C蛋白在胆管癌的表达及其与临床病理特征的关系。方法采用免疫组化SP法检测49例胆管癌组织中vEGF与VEGF-C叠白的表达。结果胆管癌VEGF和VEGF—C蛋白的表达率分别为65．3％和69．4％。VEGF和VEGF-C蛋白的高表达与胆管癌淋巴结转移及分化程度有关。VEGF与VEGF—C的表达有显著相关性（P＜0．01）。结论VEGF和VEGF—C蛋白的表达与胆管癌侵袭转移有关。     

Targeting the vascular endothelial growth factor in hematologic malignancies

There exists increasing evidence that apart from solid tumors, angiogenic growth factors also play important roles in the development and/or maintenance of hematolymphoid malignancies. Thus, in these cancers, angiogenesis and bone marrow microvessel density often correlate with prognosis and disease burden. Several reports speculated on the role of angiogenesis and the resulting possible therapeutic options in hematologic malignancies. The most prominent angiogenic factor, vascular endothelial growth factor (VEGF), is expressed in a number of established leukemic cell lines as well as in freshly isolated human leukemias and lymphomas, and several human leukemias express VEGF receptor 1 and/or VEGF receptor 2. VEGF/VEGF‐receptor interactions are also involved in proliferation, migration, and survival of leukemic cells by autocrine and paracrine mechanisms. As a consequence, a possible drugable effect by inhibiting VEGF signaling in different hematologic malignancies has been discussed. This review focuses on angiogenesis‐independent effects of VEGF on survival and proliferation of leukemic or lymphoma cells and on possible therapeutic approaches using anti‐VEGF/VEGF‐receptor therapies to inhibit proliferation or induce apoptosis of malignant cells in hematologic diseases.     

Clinical significance of vascular endothelial growth factor in patients with primary lung cancer

OBJECTIVE: Vascular endothelial growth factor (VEGF) is an angiogenesis factor closely associated with the growth and metastasis of malignant tumours. METHODOLOGY: In the present study, we measured plasma VEGF levels in 20 normal subjects (N), 35 patients with benign lung diseases (B), 28 patients with untreated advanced lung cancer (NT) and 10 patients with treated lung cancer (T). In addition, we measured the VEGF levels in pleural effusions from five patients with primary lung cancer and two patients with active infectious diseases. Vascular endothelial growth factor was measured by ELISA. RESULTS: The mean (+/-SD) plasma VEGF level in NT patients (160.8 +/- 177.4 pg/mL) was fivefold higher than that in other patient groups (T, 17.7 +/- 4.9 pg/mL; B, 28.3 +/- 17.6 pg/mL) and the N group (14.9 +/- 7.0 pg/mL; P < 0.01). Vascular endothelial growth factor from lung cancer pleural effusions (17 526.0 +/- 22 498.2 pg/mL) was 25-fold higher than that from patients with active infectious diseases (665.5 +/- 259.0 pg/mL). CONCLUSIONS: Plasma VEGF may be a good clinical indicator for the assessment of primary lung cancer and pleural effusion VEGF in primary lung cancer is higher than pleural effusion VEGF in patients with inflammatory diseases.     

High levels of serum angiogenic growth factors in patients with AL amyloidosis: comparisons with normal individuals and multiple myeloma patients

Serum levels of five angiogenic cytokines were evaluated in 82 patients with primary systemic amyloidosis (AL). Angiopoietin‐1, vascular endothelial growth factor, basic fibroblast growth factor and angiogenin were higher in AL patients than in controls (n = 35) and newly‐diagnosed, symptomatic, myeloma patients (n = 35). Angiopoetin‐1/Angiopoetin‐2 ratio was lower in AL compared to controls but higher than in myeloma patients. Angiopoetin‐2 correlated with cardiac dysfunction indices; however, none of the angiogenic growth factors was prognostically significant. The increased angiogenic cytokine levels observed in AL seem to represent either a toxic effect of amyloid fibrils or light chains, or a compensatory response to organ dysfunction.     

LKB1和血管内皮生长因子在胃癌组织中的表达及其临床意义

目的探讨LKB1和血管内皮生长因子(VEGF)在胃癌中的表达及临床意义。方法采用免疫组织化学(SP)法检测115例胃癌组织和20例胃正常组织中LKB1和VEGF的表达,并探讨其与胃癌分期、淋巴结转移、Lauren's分型及预后的关系。结果 LKB1在胃癌组织中的阳性率为20.9%,低于正常胃组织中的95.0%(P0.01);VEGF在胃癌组织中的阳性率为64.3%,高于正常胃组织中的5.0%(P0.01)。LKB1在胃癌组织中的低表达与胃癌的TNM分期、淋巴结转移、Lauren's分型及预后有关(P0.05);VEGF在胃癌中的表达与淋巴结转移、远处转移、TNM分期及预后相关(P0.05)。结论 LKB1的低表达与胃癌的发生、发展有关,对胃癌恶性生物学行为的评估及预后判断具有重要的指导意义。     

IgD myeloma with multiple cutaneous plasmacytomas

Extramedullary cutaneous plasmacytoma is an uncommon observation in clinical practice. In most of the cases it is usually an extension of underlying medullary plasmacytoma. This case report describes a patient with IgD myeloma who went into plateau phase following standard intravenous chemotherapy. After more than a year in plateau phase, he developed multiple fleshy nodular lesions in the skin. Biopsy of one of the lesions revealed relapse of myeloma in the skin. His IgD paraprotein remained in plateau phase and the bone marrow showed only 1% plasma cells. The patient has been treated with systemic intravenous chemotherapy followed by local radiotherapy.     

人脑胶质瘤中血管内皮细胞生长因子表达及其与细胞增殖的关系

为探讨人脑胶质瘤组织中血管内皮细胞生长因子 (VEGF)表达及其与细胞增殖的关系 ,应用链霉菌抗生物素蛋白 -过氧化物酶连接法 (SABC)免疫组织化学技术检测了 6 7例人脑胶质瘤、8例正常脑组织中 VEGF表达及增殖细胞核抗原 (PCNA)标记指数 (PCNA L I)。结果 VEGF在人脑胶质瘤组织中的阳性表达率为 83.6 %,正常脑组织中无表达 (P<0 .0 0 5 ) ;肿瘤组织中 VEGF表达与 PCNA L I呈显著正相关 (P<0 .0 0 5 )。认为胶质瘤细胞能分泌 VEGF,VEGF表达在肿瘤细胞增殖中起重要作用。     

大肠癌血管内皮生长因子和新生血管的临床意义研究

目的　探讨血管内皮生长因子 (VEGF)和微血管密度 (MVD)在大肠癌组织中的表达 ,及其与肿瘤血管生成和预后的关系。方法　采用免疫组织化学方法 ,分别用 VEGF抗体和 CD34 因子抗体检测 97例大肠癌组织标本中 VEGF的表达水平和 MVD。结果　 97例大肠癌组织中 6 8例 VEGF阳性表达 ,主要表达于肿瘤细胞浆内 ,在低分化腺癌中的表达量最高 ;VEGF表达与性别、年龄和临床分期无相关性 ;VEGF阳性者和 VEGF阴性者的 MVD值比较有极显著性差异 (P<0 .0 1)。结论　大肠癌组织中 VEGF阳性表达不能作为判断患者预后的独立指标。 VEGF在大肠癌的肿瘤血管生成过程中发挥重要作用 ;MVD可以作为大肠癌患者独立的预后指标     

Prognostic significance of vascular endothelial growth factor immunoexpression in the context of adverse standard prognostic factors in multiple myeloma

OBJECTIVES: Vascular endothelial growth factor (VEGF) acts in several steps of multiple myeloma (MM) pathogenesis and it is an important mediator of tumor angiogenesis. The aim of this study was to examine the prognostic significance of VEGF immunoexpression in the context of standard prognostic factors present in a cohort of advanced MM patients. METHODS: Fifty untreated MM patients were enrolled from May 2000 to December 2002. Bone marrow sections were subjected to morphologic assessment and immunohistochemical studies with antibodies against CD34 and VEGF. Angiogenesis was measured by microvessel density (MVD) and stratified into high (MVD > or = 20) and low angiogenesis status (MVD < 20). VEGF immunoreactivity was examined on the basis of intensity and percentage of positive plasma cells (PC). RESULTS: Ninety-four percent of patients presented advanced disease at diagnosis. Median PC marrow infiltration was 80%. Twelve percent of patients presented plasmablastic morphology. Low angiogenesis was present in 27% of patients, while high angiogenesis was present in 73%. Twenty-nine percent of patients had VEGF < 10% and 71% had VEGF > or = 10%. Weak-intensity VEGF was observed in 34% of cases, while 37% had moderate/strong VEGF intensity. Although VEGF had prognostic impact on overall survival (OS) and event-free survival (EFS) in univariate analysis, multivariate analysis identified only plasmablastic morphology and elevated serum lactate dehydrogenase (LDH) level as independent prognostic factors to predict OS (P = 0.04 and P = 0.02, respectively). With regard to EFS, although VEGF showed statistical trend to influence survival (P = 0.08), the parameters of independent prognostic value were also plasmablastic morphology (P = 0.01) and elevated LDH level (P = 0.01). CONCLUSION: Our findings underline the frequent expression of VEGF in advanced-stage MM and the greater prognostic information of simple and readily available factors, namely plasmablastic morphology and elevated LDH. Moreover, despite the absence of prognostic importance in multivariate analysis, VEGF and its receptors remain promising therapeutic targets in MM.     

多发性骨髓瘤并发髓外浸润的临床分析

目的:了解多发性骨髓瘤(MM)髓外浸润的发生率及临床特点.方法:回顾分析357例MM患者中并发髓外浸润患者的临床表现、实验室检查、疗效及预后.结果:共有43例患者在初诊或治疗过程中出现髓外浸润,发生率为12.04%.Logistic回归分析,发现仅M蛋白类型与是否浸润相关(P<0.05).最常见的发病部位为软组织(19...     

急性白血病患者血清血管内皮细胞生长因子测定及临床意义

目的探讨血管内皮细胞生长因子(VEGF)在急性白血病(AL)患者中的表达和临床意义.方法采用双抗体夹心ELISA法检测了41例AL初发患者(ANLL32例,其中是M14例、M24例、M38例、M44例、M512例和ALL9例)血清VEGF含量,并且检测了其中10例获得完全缓解后的AL患者血清VEGF水平;同时留取41例AL初发患者和10例获得完全缓解后AL患者骨髓涂片,进行瑞特染色后检测骨髓原始和幼稚细胞百分率.结果血清VEGF在ANLL和ALL中分别是(807.76±347.04)ng/L、(998.18±387.80)ng/L,均高于正常对照组(461.43±127.05)ng/L,均P＜0.01;ANLL和ALL之间血清VEGF水平差异无统计学意义(P＞0.05);10例完全缓解的AL患者,其血清VEGF含量为(495.28±102.79)ng/L明显低于初发时(1263.44±490.39)ng/L,P＜0.01;AL缓解组血清VEGF含量与其骨髓中原始幼稚白细胞百分率具有一定相关性,r=0.57,P＜0.01.结论血清VEGF在AL患者中明显升高,且血清VEGF水平与病情和预后密切相关.