大肠癌EGFR、HER-2、VEGF表达特点及其对分子靶向治疗的指导意义

目的:探讨大肠癌中表皮生长因子受体(EGFR)、人类表皮生长因子受体-2(HER-2)和血管内皮生长因子(VEGF)的表达特点及其对大肠癌分子靶向治疗的指导意义.方法:随机选取2005-05/2009-03中国人民解放军空军总医院普通外科行根治性手术的大肠癌患者78例. 应用免疫组织化学法检测大肠癌肿瘤组织中EGFR、HER-2、VEGF的表达, 并结合其临床病理特点进行回顾性分析.结果:EGF R、HE R-2、VEGF在大肠癌中的阳性表达率依次为38 . 5%( 30 / 78 ) 、53.8%(42/78)、41.0%(32/78). 三者的表达与性别、年龄、肿瘤部位、分化类型无关, 而与肿瘤的大小、侵袭深度和转移密切相关.EGFR与HER-2及VEGF, HER-2与VEGF在大肠癌肿瘤组织中表达呈正相关(r = 0.421,0.484, 0.469, P = 0.019, 0.012, 0.016).结论:EGFR、HER-2、VEGF的表达参与大肠癌的生长、侵袭和转移过程. 三者的联合检测可作为判断大肠癌预后、筛选高危转移患者的有效指标, 同时, 也可用于指导大肠癌的靶向药物治疗.     

Metastasis-associated protein 1 induces VEGF-C and facilitates lymphangiogenesis in colorectal cancer

AIM:To study the correlation between high metastasisassociated protein 1(MTA1)expression and lymphangiogenesis in colorectal cancer(CRC)and its role in production of vascular endothelial growth factor-C(VEGF-C). METHODS:Impact of high MTA1 and VEGF-C expression levels on disease progression and lymphovasculardensity(LVD,D2-40-immunolabeled)in 81 cases of human CRC was evaluated by immunohistochemistry. VEGF-C mRNA and protein expressions in human LoVo and HCT116 cell lines were detected by real-time polymer...     

癌组织中VEGF-C及nm23基因蛋白表达与大肠癌浸润转移的关系

目的 探讨血管内皮生长因子c(VEGF-C)及nm23基因蛋白在大肠癌组织中的表达及其与癌局部浸润、淋巴结转移的关系。方法 采用免疫组化SP法,检测93例原发性大肠癌患者手术切除的癌组织中VEGF-C及nm23基因蛋白。结果 VEGF-C基因蛋白阳性表达率与大肠癌组织的分化程度无明显相关性(P>0.05),与癌的浸润深度、淋巴结转移呈正相关(P均<0.05)。nm23基因蛋白在大肠癌淋巴结无转移组中的阳性表达率显著高于有转移组(P<0.05)。结论 VEGF-C及nm23基因蛋白的异常表达在大肠癌的发生、发展和淋巴结转移中可能起重要作用。联合检测癌组织中VEGF-C及nm23基因蛋白,对判断大肠癌的临床分期、淋巴结转移及预后有一定的参考价值。     

Vascular endothelial growth factor-C (VEGF-C) is a more specific risk factor for lymph node metastasis than VEGF-D in submucosal colorectal cancer

BACKGROUND/AIMS: It is useful to decide whether lymphatic involvement or lymph node metastasis exists before polypectomy or operation in submucosal colorectal cancer. Whether vascular endothelial growth factor-C (VEGF-C) or VEGF-D could predict lymph node metastasis and lymphatic involvement is uncertain. METHODOLOGY: Expression of the VEGF-C and VEGF-D in human submucosal colorectal cancers was investigated in paraffin-embedded stepwise sections by means of immunohistochemistry, and the correlation between immunohistochemical expression pattern and clinicopathological features was also evaluated. RESULTS: The results showed that VEGF-C overexpression correlated with lymphatic involvement (P = 0.01) and lymph node metastasis (P = 0.02), but VEGF-D overexpression did not correlate significantly. In multivariate analysis lymphatic invasion was the predictive factor (P = 0.0129), but VEGF-C positivity was not predictive (P = 0.3437). CONCLUSIONS: These results may suggest that VEGF-C is a more specific risk factor for lymph node metastasis than VEGF-D in submucosal colorectal cancer.     

VEGFR-3信号途径相关蛋白在胃癌中的表达及意义

目的研究血管内皮生长因子受体（VEGFR）-3信号途径相关蛋白C、D（VEGF—C、VEGF—D）在胃癌中的表达并探讨其与淋巴结转移的关系。方法80例胃癌手术病例分为淋巴结阳性组（n=48）和淋巴结阴性组（n=32）,另设胃溃疡病例为对照组（n=10）。采用ELISA技术进行血清VEGF—C和VEGF-D水平检测,然后应用免疫组织化学EnVisionTM两步法检测胃溃疡组织和胃癌标本VEGF—C、VEGF-D表达。结果胃癌患者血清VEGF-C和VEGF—D水平明显高于对照组（P〈0．05）,胃癌患者血清VEGF-C水平与淋巴结转移有关（P〈0．05）;胃癌组织中VEGF—C、VEGF—D阳性表达率均高于对照组（P〈0．05）,伴淋巴结转移的胃癌组织VEGF-C阳性表达率较无淋巴结转移者更高（P〈0．01）。结论血清VEGF—C可作为胃癌的标记物,对术前判定淋巴结转移具有一定的临床价值。     

大肠癌血管内皮生长因子的表达及其意义

目的：探讨血管内皮生长因子（VEGF）mRNA在大肠癌和癌周组织中的表达及其与临床特征之间的关系,为在分子水平干预肿瘤血管形成,预防大肠癌复发和转移打下基础。方法：采用逆转录－聚合酶链反应（RT－PCR）检测方法,对68例大肠癌手术标本癌和癌周组织中VEGF mRNA的表达水平进行了相对定量研究。结果：肿瘤组织中VEGF mRNA的表达率为67．6％（46／68）,癌周组织表达率为32．4％（22／68）;肿瘤组织中VEGF mRNA表达水平在浆膜浸润组,淋巴结转移,远处转移和Dukes D期组分别显著高于未侵及浆膜组,无淋巴结转移组,无远处转移和Dukes A,B,C期组;肿瘤组织中VEGF mRNA表达水平在肿瘤直径大的大肠癌组（＞5cm)与大小肠癌组（≤5cm)以及不同组织学分组组之间相比差异无显著性。结论：VEGF在大肠癌浸润和转移过程中发挥重要作用,肿瘤血管形成与大肠癌浸润和转移关系密切。     

胃癌组织中VEGF-C、VEGF-D、MMP-9的表达变化及意义

目的观察血管内皮生长因子（VEGF）C、D和基质金属蛋白酶MMP-9在胃癌组织中的表达及其意义。方法采用免疫组织化学染色检测108例胃癌手术切除标本中VEGF-C、D及MMP-9的表达情况,并以正常胃黏膜组织作为对照。结果VEGF-C、VEGF-D及MMP-9在胃癌组织中的阳性表达率分别为55．7％、77．8％、75．0％,而在正常胃黏膜的阳性表达率分别为15．0％、20．0％、10．0％,三者的表达率在两组问均有明显差异（P均〈0．05）。伴淋巴结转移的胃癌病例其VEGF-D及MMP-9阳性表达率（87．0％,83．3％）高于无淋巴结转移者（31．5％,33．3％）,P均〈0．05;而VEGF-C在两组的阳性表达率相近,P〉0．05。结论VEGF-D及MMP-9的表达与胃癌分期、淋巴结转移关系密切,有望成为胃癌治疗的新靶点。     

Preoperative serum levels of serum VEGF-C is associated with distant metastasis in colorectal cancer patients

Purpose  Vascular endothelial growth factor-C (VEGF-C) is one of the most potent lymphangiogenic members of the VEGF family that has been associated with lymph node metastasis and poor prognosis in patients with colorectal cancer (CRC). In this study, we evaluated the relationship of preoperative serum VEGF-C (sVEGF-C) and survival in CRC patients. Materials and methods  sVEGF-C levels were determined, prior to resection, in a cohort of 120 newly presenting patients with CRC by quantitative ELISA. Results  Patients who had positive lymph node involvement and higher Dukes’ staging (C&D) were associated with shorter time to metastases as expected (p = 0.002 and 0.001, respectively). Patients with distant metastasis had significantly lower levels of sVEGF-C than those without histopathologically proven disease (p = 0.004). However, there was no significant difference in the median sVEGF-C level in patients with or without lymph node metastatic involvement (91 pg/ml vs. 124 pg/ml; p = 0.81). Patients with a sVEGF-C concentration less than the median value (103 pg/ml) showed a poorer overall survival than patients with sVEGF-C levels greater than the median; but this was not statistically significant. Conclusions  In this study, low sVEGF-C levels are associated with distant metastasis; hence, preoperative levels may aid in the selection of CRC patients who require further investigation.     

Le VEGF en physiologie et pathologie thyroïdienne

Angiogenesis is a physiological process involving the growth of new vessels from preexisting vasculature. The vascular endothelial growth factor (VEGF) is an important regulator of both benign and malignant disease process in the thyroid gland. The VEGF family includes seven members called respectively VEGF-A, also known as the VPF (vascular permeability factor), VEGF-B, VEGF-C, VEGF-D, all described in mammalians, VEGF-E (found in parapoxviridae), VEGF-F (also called svVEGF, for snake venom VEGF, found in the venom of viper) and PlGF (for placental growth factor). The thyrocytes are able to synthesize and to secrete the VEGF. VEGF-A is implicated in tumour growth and metastasis via blood vessels while VEGF-C and VEGF-D, implicated in lymphangiogenesis, favour metastasis to the cervical lymph nodes during papillary thyroid carcinomas. The importance of VEGF expression could correlate with a poorer outcome in papillary thyroid carcinomas. Because of its important role in malignant angiogenesis, the VEGF is the privileged target of a new variety of therapeutic agents called angiogenesis inhibitors.     

肿瘤抗淋巴管生成研究进展

肿瘤转移是癌症患者的主要死因之一,淋巴管转移是肿瘤转移的重要途径,研究发现VEGF-C/VEGF-D/VEGFR-3与肿瘤淋巴管生成、肿瘤转移、肿瘤预后密切相关.大量的研究证实VEGF-C/VEGF-D/VEGFR-3信号传导轴在调节肿瘤淋巴管生成中起主导作用,临床病理研究也显示VEGF-C/VEGF-D/VEGFR-...     

大肠癌组织中生长抑素和血管内皮生长因子-C的表达及其临床意义

目的探讨大肠癌组织中生长抑素（SS）和血管内皮生长因子-C（VEGF-C）的表达及其临床意义。方法采用免疫组化法检测60例大肠癌组织及20例正常大肠黏膜组织中SS蛋白和VEGF-C蛋白的表达，采用VEGF-C受体FLT-4阳性脉管标记淋巴管计数，分析SS与大肠癌淋巴管生成、转移的关系。结果SS蛋白表达阳性率在大肠癌组及正常大肠黏膜组分别为37．7％和65％，VEGF-C在癌及正常组阳性表达率分别为60％和30％，差别均有显著性；SS表达与肿瘤分化程度、淋巴结转移、淋巴管侵犯及远处转移密切相关，与浆面膜受累无关；VEGF-C表达与肿瘤淋巴结转移，淋巴管侵犯及远处转移密切相关，而与肿瘤分化和浆面膜受累无关；大肠癌组织中SS和VEGF-C蛋白表达呈显著负相关。结论SS可能通过对VEGF-C／FLT-4信号通路的阻滞而抑制大肠癌淋巴管生成及转移。     

OPN和VEGF-C在胃癌中的表达及其临床意义

目的:评价骨桥蛋白(osteopontin,OPN)和血管内皮生长因子C(vascular endothelial growth factor C,VEGF-C)在胃癌中表达及与临床病理参数之间相关性,进一步探讨二者的共表达在胃癌淋巴结转移中的机制.方法:收集复旦大学附属中山医院手术切除胃癌组织标本及患者相关临床资料,对纳入研究的93例胃癌原发灶标本采用免疫组织化学染色法(EnVision二步法),检测OPN与VEGF-C蛋白的表达.结果:93例胃癌组织中OPN与VEGF-C的阳性表达率分别为64.5%(60/93)和69.9%(65/93),在非肿瘤性胃黏膜中均未见其阳性表达;OPN和VEGF-C的表达与胃癌浆膜侵犯、TNM分期以及淋巴结转移呈明显相关(P<0.05).蛋白之间的相关性分析显示,OPN与VEGF-C之间存在正相关(r=0.493,P<0.01).结论:联合检测OPN与VEGF-C有助于阐述胃癌发生发展、浸润转移的机制,OPN可能通过上调VEGF-C的表达促进胃癌的淋巴结转移.     

Measurement of circulating levels of VEGF-A, -C, and -D and their receptors, VEGFR-1 and -2 in gastric adenocarcinoma

AIM： TO analyze the serum levels and prognostic significance of vascular endothelial growth factor （VEGF） -A, -C, and -D, and their receptors, VEGFR-1 and -2 in gastric adenocarcinomas. METHODS： The serum levels of VEGF family members were measured in 76 control subjects and 76 patients with gastric adenocarcinoma using an enzyme-linked immunosorbent assay （ELISA）. These measurements were correlated with clinco-pathological features and survival rates. RESULTS： The serum levels of VEGF-A and its receptor, VEGFR-1, were significantly higher in patients with gastric cancer than in healthy donors （t = 2.3, P = 0.02 and t = 4.2, P 〈 0.0001, respectively）. In contrast, the serum levels of VEGF-D were significantly higher in control subjects than in patients （t = 2.9, P = 0.004）. There was no significant difference in serum levels of VEGF-C and VEGFR-2 between patients and controls. VEGF-C was associated with advanced tumor stage and presence of metastasis. VEGFR-1 was associated with metastasis, advanced overall stage,tumor differentiation and survival. VEGFR-2 levels were associated with poor tumor differentiation. There was no significant prognostic value for any of the VEGF family members or their receptors except for VEGFR-1 where high levels were associated with a poor overall survival. CONCLUSION： Serum VEGF levels vary significantly in the same cohort of patients with variable clinicopathological features and prognostic values. The simultaneous measurement of VEGF receptors levels in sera may overcome the limitations of a single biomarker assay.     

Vascular endothelial growth factor C and D expression correlates with lymph node metastasis and poor prognosis in patients with resected esophageal cancer

Vascular endothelial growth factors C (VEGF-C) and D (VEGF-D) are important lymphangiogenic factors in human cancers. We studied the expression of VEGF-C and VEGF-D using immunohistochemistry in 73 resected esophageal cancer specimens, and correlated the results with patient clinicopathologic features and survival. High expression of VEGF-C was identified in 40 (54.7%) patients, and it correlated positively with histological grade (p=0.038), tumor stage (p=0.01), depth of tumor invasion (p=0.036) and lymph node metastasis (p=0.001). In 48 of 73 (65.7%) tumors, the VEGF-D protein was also expressed at high levels. VEGF-D immunoreactivity significantly correlated with tumor location (p=0.027), size of tumor (p=0.015), histological grade (p=0.02), depth of invasion (p=0.001) and lymph node metastasis (p=0.018). In logistic multivariate analysis, high expression of VEGF-C (OR 1.941, 95% CI 1.263-7.289, p=0.024) was associated with lymph node metastasis. Calculating the prognostic relevance revealed that both VEGF-C and VEGF-D correlated with decreased overall survival (p=0.01, p=0.003), disease free survival (p=0.02, p=0.006), and cancer-specific survival (p=0.03, p=0.005). In conclusion, our results suggest that high levels of both VEGF-C and VEGF-D proteins are associated with lymph node involvement, and that VEGF-C expression is an independent predictor of risk for lymph node metastasis in esophageal cancer. In locally advanced disease, overexpression of VEGF-C and VEGF-D may be useful in identifying patients who are more likely to have a poor prognosis even after curative resection.     

T cell-engaging BiTE antibodies specific for EGFR potently eliminate KRAS- and BRAF-mutated colorectal cancer cells

Epidermal growth factor receptor (EGFR)-specific monoclonal antibodies predominantly inhibit colorectal cancer (CRC) growth by interfering with receptor signaling. Recent analyses have shown that patients with CRC with mutated KRAS and BRAF oncogenes do not profit from treatment with such antibodies. Here we have used the binding domains of cetuximab and pantitumumab for constructing T cell-engaging BiTE antibodies. Both EGFR-specific BiTE antibodies mediated potent redirected lysis of KRAS- and BRAF-mutated CRC lines by human T cells at subpicomolar concentrations. The cetuximab-based BiTE antibody also prevented at very low doses growth of tumors from KRAS- and BRAF-mutated human CRC xenografts, whereas cetuximab was not effective. In nonhuman primates, no significant adverse events were observed during treatment for 3 wk at BiTE serum concentrations inducing, within 1 d, complete lysis of EGFR-overexpressing cancer cells. EGFR-specific BiTE antibodies may have potential to treat CRC that does not respond to conventional antibodies.     

Bcl-x(L) and Myeloid cell leukaemia-1 contribute to apoptosis resistance of colorectal cancer cells

AIM： TO explore the role of Bcl-XL and Myeloid cell leukaemia （Mcl）-I for the apoptosis resistance of colorectal carcinoma （CRC） cells towards current treatment modalities. METHODS： Bcl-XL and Mcl-1 mRNA and protein expression were analyzed in CRC cell lines as well as human CRC tissue by Western blot, quantitative PCRand immunohistochemistry. Bcl-XL and Mcl-1 protein expression was knocked down or increased in CRC cell lines by applying specific siRNAs or expression plasmids, respectively. After modulation of protein expression, CRC cells were treated with chemotherapeutic agents, an antagonistic epidermal growth factor receptor （EGFR1） antibody, an EGFR1 tyrosine kinase inhibitor, or with the death receptor ligand TRAIL. Apoptosis induction and cell viability were analyzed. RESULTS： Here we show that in human CRC tissue and various CRC cell lines both Bcl-xL and Mcl-1 are expressed. Bcl-xL expression was higher in CRC tissue than in surrounding non-malignant tissue, both on protein and mRNA level. Mcl-1 mRNA expression was significantly lower in malignant tissues. However, protein expression was slightly higher. Viability rates of CRC cells were significantly decreased after knock down of Bcl-xL expression, and, to a lower extent, after knock down of Mcl-1 expression. Furthermore, cells with reduced Bcl-xL or Mcl-1 expression was more sensitive towards oxaliplatinand irinotecan-induced apoptosis, and in the case of Bcl-xL also towards 5-FU-induced apoptosis. On the other hand, upregulation of Bcl-xL by transfection of an expression plasmid decreased chemotherapeutic drug-induced apoptosis. EGF treatment clearly induced Bcl-xL and Mcl-1 expression in CRC cells. Apoptosis induction upon EGFR1 blockage by cetuximab or PD168393 was increased by inhibiting Mcl-1 and Bcl-xL expression. More strikingly, CD95- and TRAIL-induced apoptosis was increased by Bcl-xL knock down. CONCLUSION： Our data suggest that Bcl-xL and, to a lower extent, Mcl-1, are important anti-apoptotic factors in CRC. Specific do     

血管内皮生长因子C及受体与胃癌淋巴转移关系的研究

目的探讨血管内皮生长因子-C(VEGF-C)及其受体-3(VEGFR-3)在胃癌中的表达及其与淋巴结转移的关系。方法检测延安大学附属医院2012年1月-2013年1月收治的78例原发性胃癌患者胃黏膜VEGF-C和VEGFR-3蛋白的表达,并与20例胃癌患者经病理证实为正常胃黏膜的远切端组织进行比较,分析胃癌淋巴结转移情况。结果 VEGF-C在正常胃黏膜组织中呈阴性表达,在胃癌组织中定位于癌细胞胞浆中,呈弥散性分布,78例胃癌组织中,60例表达阳性,阳性率为76.92%,胃癌组织与正常胃黏膜组织VEGF-C阳性率差异有统计学意义(P0.01);VEGF-C的表达与组织学分级、浸润深度、有无淋巴转移及TNM分期密切相关。VEGFR-3在正常胃黏膜细胞中着色均匀,主要分布于细胞胞浆内,阳性表达率为10.00%;在胃癌组织中的表达异质明显,呈灶状或弥散性分布,阳性率为66.67%,差异有统计学意义(P0.01);VEGFR-3表达与组织学分级、有无淋巴转移及TNM分期密切相关。VEGF-C与VEGFR-3表达呈正相关。结论 VEGF-C及其受体VEGFR-3在胃癌的发生、发展及淋巴转移中发挥着重要作用。     

肝细胞癌组织细胞因子信号转导抑制因子-1表达的研究

目的探讨细胞因子信号转导抑制因子(SOCS1)、血管内皮生长因子受体(VEGFR)-2和表皮生长因子受体(EGFR)在肝硬化、肝细胞癌组织中的表达变化。方法采用免疫组化法检测63例HCC组织、51例癌周肝组织、11例肝硬化组织及11例正常肝组织SOCS1蛋白的表达;另分别检测VEGFR2和EGFR在27例和41例HCC组织中的表达情况。结果癌周肝组织中SOCS1蛋白表达为阴性1例,弱阳性15例,阳性30例,强阳性5例,HCC组织中SOCS1蛋白表达为阴性11例,弱阳性38例,阳性14例,癌周肝组织中SOCS1蛋白表达强度显著高于HCC组织(P0.01);SOCS1蛋白在肝硬化组织和正常肝组织中无表达;SOCS1表达在瘤体大小间(瘤体5cm和≥5cm)有显著性差异(P0.001);SOCS1蛋白在HCC组织中的表达与VEGFR2和EGFR的表达无显著相关性(P0.05)。结论 SOCS1蛋白表达与HCC的发生发展密切相关。