宫颈腺癌主要肿瘤标志物研究进展

宫颈腺癌的标记物在其诊断治疗及预后方面有着重要的意义。其中bcl-2在早期宫颈腺癌中即可呈现高阳性表达，且表达阳性者预后好于阴性者；Fas-L在宫颈腺癌中起着免疫逃避的作用，可促进淋巴结转移；Ki-67及增殖细胞核抗原(proliferation cell nuclear antigen，PCNA)作为主要的增殖相关指标可反映其细胞增殖活性。C-erbB-2在宫颈腺癌呈阳性表达，且可上调血管内皮生长因子(vascular endothelial growth factor，VEGF)的表达；Survivin基因在宫颈腺癌的阳性表达高于宫颈鳞癌，它与宫颈腺癌的发生发展和预后密切相关；c-myc癌基因的表达与宫颈腺癌癌前趋病变有显著相关性，可作为早期宫颈腺癌的预测指标之一。p16．p53在宫颈腺癌中呈过度阳性表达，并与HPV感染相关；p53、p16高表达与p27低表达在宫颈腺癌患者中均为不良预后指标。PTEN基因突变与宫颈腺癌特别是HPV阴性的宫颈腺癌有关。在肿瘤相关性抗原中，CA125较CA19-9、SCC、CEA更具有敏感性，因此是筛选宫颈腺癌及宫颈鳞癌的首选方法。VEGF在宫颈腺癌中呈过表达，EGFR与宫颈腺癌早期病变有一定的相关性。这些标记物可成为在宫颈腺癌诊治过程中必不可少的监测手段。     

HSP70、p53和c—myc在宫颈鳞癌中的表达及与HPV16／18感染的关系

目的探讨热休克蛋白70(heat shock protein 70,HSP70)、抑癌基因p53、原癌基因c-myc在宫颈鳞癌中的表达及其与人乳头瘤病毒(HPV)感染的关系。方法采用免疫组化技术检测45例宫颈鳞癌、12例宫颈原位癌和20例正常宫颈组织中HSP70、p53、c-myc蛋白的表达,同时采用聚合酶链反应(PCR)技术检测HPV16/18的感染情况。结果①宫颈原位癌和宫颈癌中HSP70、p53、c-myc蛋白表达均显著高于正常宫颈组织。②HPV16/18阳性组HSP70表达明显高于HPV16/18阴性组,HPV16/18阴性组p53表达明显高于HPV16/18阳性组,但c-myc表达差异无显著性。结论在HPV感染的应激状态下,HSP70在宫颈鳞癌中过表达,p53则表达降低,c-myc蛋白的表达与HPV感染无相关性。     

宫颈鳞癌主要肿瘤标志物的研究进展

宫颈鳞癌的标记物在其诊断治疗及预后方面有着重要的意义。CRIPTO-1基因有助于正确评估患者的病情进展,HIF-2α基因可能与宫颈鳞癌的发生、发展及转移密切相关。Survivin基因作为目前发现的凋亡抑制作用最强的基因,具有抑制凋亡和调控周期的双重作用。EZH2和DEK可成为基因诊疗的新指标。PAX1基因在早期宫颈鳞癌中即可呈现阳性高表达,是早发现、早治疗的指标之一。FEZ1基因通过影响细胞周期、调节有丝分裂从而抑制细胞生长。FHIT基因表达降低是晚期宫颈癌患者预后不良的独立指标。PTEN、Maspin和p14ARF可作为早期筛查宫颈鳞癌的指标应用于临床。Ki-67作为主要的增殖相关指标可反映其细胞增殖活性。Livin可抑制细胞凋亡,加速细胞的恶性转化。HMGB1可抑制肿瘤细胞凋亡及促进细胞周期进程,导致肿瘤增殖及免疫逃逸,为宫颈鳞癌的预防提供新的免疫学策略。FoxM1基因是治疗宫颈鳞癌的理想靶点。VEGF、CTGF、EGFR及TGF-1R均与宫颈鳞癌的预后及淋巴结转移有密切关系。这些标记物可成为宫颈鳞癌诊治过程中必不可少的监测手段。     

宫颈腺癌HPV16／18感染与ki67、p53蛋白表达的关系

目的研究人宫颈腺癌组织中ki67、p53蛋白表达,分析HPV16／18感染与ki67、p53蛋白表达的关系。方法采用组织微阵列技术结合原位杂交和免疫组化（二步法）检测24例慢性宫颈炎和86例宫颈腺癌HPV16／18-E6DNA和ki67、p53蛋白表达情况。结果HPV16／18-E6DNA与ki67、p53蛋白表达在宫颈腺癌组织中的阳性率分别为65．1％、51．2％、45．3％,均显著高于慢性宫颈炎组织8．3％、0．0％、0．0％（P〈0．01）。HPV16／18感染与宫颈腺癌的病理分级和组织学类型无关,但与ki67表达呈正相关（P〈0．05）,与p53表达呈负相关（P〈0．05）。ki67、p53蛋白表达与宫颈腺癌的病理分级有关,G2、G3组阳性表达率均明显高于G1组（P〈0．05）。ki67、p53蛋白表达与宫颈腺癌组织学类型无相关性。结论宫颈腺癌的发生发展与HPV16／18感染及ki67、p53蛋白表达异常相关。     

宫颈癌p53和增殖细胞核抗原的关系研究

目的 探讨p53蛋白和增殖细胞核抗原（PCNA）在宫颈癌的表达及相关关性。方法 采用免疫组化ABC法检测52例浸润性宫颈鳞癌（ISCC）组织中p53蛋白标记指数(p53-LI)和PCNA标记指数（PCNA-LI）。结果 p53-LI和ISCC组织分化级别呈正相关，PCNA-LI与之无关，p53阴性和阳性两组间PCNA-LI无明显差异，p53阳性表达的宫颈鳞癌中，p53-LI和PCNA-LI呈直线正相关。结论 p53和PCNA的表达与宫颈鳞癌细胞的增殖状态有关。     

p53、PCNA及VEGF表达与食管鳞癌预后的相关性研究

目的 :探讨p53、PCNA、VEGF表达与食管鳞状细胞癌临床病理特性及预后之间的关系。方法 :用免疫组织化学SABC法 ,测定 10 0份食管癌组织的p53、PCNA及VEGF表达 ,分析其与临床病理因素及预后的关系 ,结果 :p53在食管鳞癌中的阳性表达与肿瘤浸润深度有关 ;PCNA阳性表达与肿瘤细胞分化程度、浸润深度、淋巴结转移状况有关 ;VEGF阳性表达与肿瘤细胞分化程度、肿瘤浸润深度相关 ;VEGF与生存期呈负相关。 3项基因表达阳性患者生存期明显短于单项表达阳性或 3项均阴性患者。结论 :食管鳞状细胞癌组织中p53、PCNA及VEGF表达阳性反映肿瘤的生物学行为。VEGF与食管鳞癌的恶性进程和不良预后有密切关系 ,是食管鳞癌一个独立预后因素。     

不同宫颈组织中PIK3CA、PTEN和p16蛋白表达及其与HPV16/18感染的关系

 目的 探讨PIK3CA、PTEN和p16蛋白在人正常宫颈上皮、宫颈上皮内瘤变（cervical intraepithelial neoplasia,CIN） 和宫颈鳞癌组织中的表达,以及PIK3CA、PTEN和p16蛋白表达与人乳头瘤病毒（human papillomavirus,HPV）感染 之间的关系。方法采用免疫组织化学二步法在22例健康者宫颈组织、72例宫颈上皮内瘤变（cervical intraepithelial neoplasia,CIN）和30例宫颈鳞癌组织中检测PIK3CA、PTEN和p16蛋白的表达,显色原位杂交方 法检测高危型HPV16/18的感染。结果PIK3CA和p16蛋白表达阳性率和HPV16/18的感染率均随着宫颈上皮逐渐恶变而 上升,PTEN蛋白表达却 呈现相反的结果。PIK3CA、PTEN、p16蛋白和 HPV16/18的感染率在宫颈鳞癌和CIN Ⅱ～Ⅲ组中的表达分别与对照组和CIN Ⅰ组相比,差异均有统计学意义（P＜ 0.05）。在宫颈上皮内瘤变组织中,39例（76.47%）CIN Ⅱ～Ⅲ 中显示PIK3CA阳性,仅有9例 （42.86%）CIN Ⅰ中显示 PIK3CA阳性,两组间差异有统计学意义（P=0.006）,而PTEN和p16蛋白在宫颈上皮内瘤 变不同组别中相比差异均无统计学意义。在81例CIN Ⅱ～Ⅲ和鳞癌组织中,PIK3CA和p16蛋白呈显著正相关关系 （P=0.000,r=0.544）。PIK3CA、p16蛋白与PTEN蛋白表达之间,两者均呈显著负相关（P＜0.05）。 HPV16/18阳性的47例标本中,PIK3CA和p16蛋白几乎均呈阳性表达,呈显著正相关（P<0.01）,但PTEN蛋白却有37例呈阴性表达,无显著相关（P=0.116）。结论PIK3CA、PTEN、p16蛋白表达以及高危型HPV感染与宫颈癌的发生发展均密切相关。PIK3CA、PTEN、p16蛋白和高危型HPV感染联合检测,可作为宫颈癌早期癌变的分子标志物。高危型HPV感染可能有助于PIK3CA和p16蛋白的高表达。     

大肠癌组织中p53蛋白和增殖细胞核抗原表达的临床意义

目的探讨增殖细胞核抗原(PCNA)和p53蛋白在大肠癌中的表达及临床意义.方法应用免疫组化S-P方法检测60例大肠腺癌中的PCNA及p53蛋白的表达.结果大肠癌中p53蛋白阳性表达率为63.3%,PCNA增殖指数为(78.2±24.5)%,p53蛋白表达阳性者其细胞增殖活性为(83.1±18.6)%,明显高于p53蛋白阴性组(61.2±11.3)%(P＜0.01).p53蛋白阳性表达率与PCNA增殖指数随着大肠癌病理分级的上升而增加,且与预后呈负相关.结论同时检测p53蛋白、PCNA对大肠癌的诊断、病理分级及预后的评估有重要的指导意义.     

nm23-H1 c-erbB2 p53 蛋白在宫颈癌组织中的表达及临床意义

目的：探讨c-erbB2,nm23-H1,p53三种基因在宫颈癌中表达及其关系。方法：应用免疫组化法检测40例宫颈癌组织及10例宫颈不典型增生，20例宫颈炎组织标本中nm23-H1,c-erbB2，p53蛋白表达，采用统计学χ^2检验方法，分析这三种蛋白表达与临床病理及预后关系。结果：（1）宫颈癌nm23-H1蛋白表达率为41．14％，宫颈炎组织表达为5．00％，不典型增生组织未见阳性表达，差异有显著性P＜0．01，表达与病理分类有关，腺癌表达为83．33％，高于鳞癌32．35％，差异有显著性（P＜0．05），（2）c-erbB2表达率为37．50％，宫颈炎及不典型增生组织未见阳性表达，腺癌表达66．67％，高于鳞癌32．35％，但无显著差异（P＞0．05），鳞癌过表达与复发有关；（3）p52蛋白表达率为24．14％，宫颈炎组织未见阳性表达，1例重度不典型增生表达阳性，表达与宫颈癌病理分级相关。2．三种基因蛋白表达的比较，nm23-H1与c-erbB2,p53与mnm23-H1之间表达差异无显著性（P＞0．05），p53与c-erbB2之间表达差异有显著性，（P＜0．05），3，c-erbB2阳性／P53阳性患者复发与c-erbB2阴性＋P53阴性患者复发组对照，差异有显著性。结论：nm23-H1表达在宫颈腺癌早期呈高表达，可能为机体抑制肿瘤转移的防御性反应；c-erbB2表达是细胞恶性变标志，宫颈鳞癌中过表达与复发有关，P53表达与宫颈癌发生发展有关，检测c-erbB2/p53-一组基因对宫颈鳞癌预后更有价值。     

p73和p63蛋白在胰腺癌组织中过表达的意义

目的:探讨p53家族新成员p73和p63蛋白在胰腺癌组织中过表达的意义。方法:应用免疫组化LSAB法检测75例人胰腺癌组织中p73和p63蛋白的过表达。结果:p73和p63蛋白在人胰腺癌中的过表达率分别为46·7%(35/75)和42·7%(32/75),p73蛋白在胰腺囊腺癌中的过表达率88·9%(8/9)明显高于导管腺癌41·8%(23/55),P=0·009,且p73蛋白过表达与胰腺癌淋巴结转移、肿瘤大小、神经侵犯和p53表达呈显著负相关性,P<0·05;在腺鳞癌或腺癌伴鳞状上皮化生中p63蛋白的过表达率(100%,13/13)明显高于导管腺癌(40·0%,22/55),P=0·007,但p63蛋白过表达与胰腺癌临床病理学指标及p53和增殖细胞核抗原(pro-liferatingcellnuclearantigen,PCNA)表达间无明显相关性。结论:p73蛋白低表达可能在胰腺癌发生中起重要作用;p63蛋白过表达与腺鳞癌或腺癌鳞化有关。     

Squamous Cell Carcinoma Antigen and Cancer Antigen 125 in Southern Indian Cervical Cancer Patients

Our objective was to evaluate the diagnostic value of squamous cell carcinoma antigen (SCC-ag) and cancerantigen (CA) 125 serum tumor markers for the detection of cervical cancer. Abnormal SCC-ag(>1.5 ng/mL) andCA125 (>35 U/mL) levels were found in 64.2% and 18.9% of a series of SCC patients and in 25.0% and 42.6%of adenocarcinoma (AC) patients. The SCC-ag and CA 125 markers appeared rather specific for cervical SCCsand ACs, respectively, also correlating with clinical stage and lymph node metastasis, but not tumor size orpatient age. In conclusion, SCC-ag and CA 125 are useful and reproducible markers for advanced stage diseaseand thus prognosis of cervical cancer.     

Immunohistochemical study of β-catenin and functionally related molecular markers in tongue squamous cell carcinoma and its correlation with cellular proliferation

β-catenin plays an important role in the maintenance of cell adhesion and is a key component of the Wnt signaling pathway. However, little is known about its prognostic significance or its role in tumor progression in tongue squamous cell carcinoma (SCC). This study conducted an immunohistochemical analysis of the expression of β-catenin. Moreover, its possible correlation with clinical parameters and with the expression of the functionally related molecular markers cyclin D1 and p53 was evaluated in 50 cases of tongue SCC and 10 cases of normal tongue epithelium. The ki-67 labeling index (LI) was also examined to evaluate cellular proliferation. Our results showed a higher frequency of abnormal β-catenin expression, positive cyclin D1 and p53 expression, and a significantly higher ki-67 LI in the tongue SCC samples compared with normal tongue epithelium (P<0.05). Abnormal β-catenin and a higher ki-67 expression was significantly associated with moderately or poorly differentiated carcinoma (P<0.05). Cyclin D1-positive immunostaining showed a statistically significant association with lymph node metastasis (P<0.05). Furthermore, the abnormal expression of β-catenin significantly correlated with a higher ki-67 LI and p53 expression (P<0.05); however, there was no correlation with cyclin D1 expression (P>0.05). Taken together, our results suggest that abnormal β-catenin expression is related to the impaired cellular differentiation and proliferation involved in tumor progression in tongue SCC.     

VEGF and bFGF expression and microvessel density of maxillary sinus squamous cell carcinoma in relation to p53 status, spontaneous apoptosis and prognosis

We have previously reported that p53 mutations, loss of bax expression or decreased spontaneous tumor apoptosis were associated with poorer prognoses in maxillary sinus squamous cell carcinoma (SCC)(Cancer 94: 1968-1980, 2002). In the present study, we analyzed tumor angiogenesis monitored by expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and tumor microvessel density, in correlation with p53 status, spontaneous apoptosis or disease prognosis in the same group of 70 maxillary sinus SCC patients. Tumor biopsy specimens obtained prior to initiation of treatment were examined for expression of VEGF and bFGF and tumor microvessel density using immunohistological methods. Average vessel density (AVD) (range: 3-75; median: 25) and maximum vessel density (MVD) (range: 4-125; median: 53) were assessed by the number of microvessels stained with anti-CD31 mAb in tumor lesions. VEGF was expressed in 35 (50%) of 70 patients and bFGF was in 43 (61%). Patients with VEGF expression showed significantly higher levels of MVD than those without VEGF expression (57 vs. 38; P=0.019). The VEGF expression was observed more frequently in patients with p53 overexpression and/or mutation than in those with normal p53 status (P=0.048). The MVD inversely correlated with the apoptotic index (AI) defined as the number of single stranded (ss)-DNA-positive cells per 1000 tumor cells (r= -0.23; P=0.022). Patients with neck lymph node and/or distant metastases after surgery showed significantly higher levels of MVD than patients without any metastasis (64 vs. 42; P=0.048). Low histological effectiveness of radiochemotherapy correlated with bFGF expression (P=0.0059). To clarify actual prognostic factors for maxillary sinus SCC, we selected 57 patients treated uniformly with preoperative radiochemotherapy followed by maxillectomy. Kaplan-Meier analysis showed that survival was significantly worse in patients with high MVD (> or =80) than in those with low MVD (<80) (P=0.042). These data suggest that the VEGF expression in association with the p53 overexpression and/or mutations may cause increased microvascularity, decreased spontaneous apoptosis or metastases, while the bFGF expression may be associated with resistance to radiochemotherapy, thereby resulting in poorer prognoses in maxillary sinus SCC. VEGF and bFGF expression and tumor microvessel density in tumor lesions were analyzed in 70 patients with maxillary sinus squamous cell carcinoma. The VEGF expression dependent of p53 overexpression and/or mutations was associated with angiogenesis, decreased spontaneous tumor apoptosis and metastases, while the bFGF expression was associated with resistance to radiochemotherapy, resulting in poor prognosis.     

Maspin,VEGF and p53 Expression in Small Biopsies of Primary Advanced Lung Cancer and Relationship with Clinicopathologic Parameters

Maspin, one of the serine protease inhibitors, has been shown to inhibit tumor progression and metastasis. We aimed to investigate maspin, p53 and VEGF expression in patients with squamous cell carcinoma (SCC), adenocarcinoma (AC) and small cell lung carcinoma (SCLC). The study included 28 SCC, 18AC, 17 SCLC biopsy samples. We used the streptavidin biotin immunoperoxidase method to test for maspin, p53 and VEGF antibodies. Medical records of these patients were reviewed from archival files. Cytoplasmic maspin expression was detected in 89.3%, 77.8%, 52.9% of SCC, AC and SCLC, respectively. The rate was significantly higher in non-small cell lung cancer (NSCLC) and SCC than SCLC (p = 0.013, p = 0.021, respectively). The mean percentages of maspin expression were significantly higher in NSCLC, SCC and AC than in SCLC (p = 0.0001, p = 0.0001, p = 0.038, respectively). In ACs, maspin and p53 expressions were correlated, although this was not statistically significant (p = 0.053, r = 0.464), and maspin positive cases had a significantly higher T status compared to negative cases (p = 0.036). In SCC, the stage of disease was positively correlated with p53 (p = 0.007, r = 0.536) and negatively correlated with VEGF expression (p = 0.013, r = −0.498). Multivariate analysis demonstrated that stage of disease was a significant independent prognostic parameter in NSCLC (95% confidence interval: 1.067–3.969; p = 0.031). Although maspin expression is higher in SCC and AC, and is related with higher T status in AC, our data did not indicate its prognostic significance. Larger scale studies are needed to reveal the exact role of maspin in lung cancer pathogenesis.     

Expression of HIF-1alpha, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer

Endogenous hypoxia markers have been studied as prognostic indicators because they appear to be associated with tumor aggressiveness. This study was undertaken to compare the expression of two endogenous hypoxia markers, Hypoxia-inducible factor-1alpha (HIF-1alpha) and carbonic anhydrase IX (CA IX), with regard to their prognostic significance. We also compared spatial distribution of HIF-1alpha and CA IX and examined their relationship with expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9, which may be regulated by hypoxia. We studied 74 resected stage I/II non-small cell lung cancers (NSCLCs) for expression of HIF-1alpha, CA IX, VEGF, and MMP-9 by immunohistochemistry, and the extent of tumor necrosis. Univariate and multivariate analyses were performed to assess prognostic implications of these markers for disease free survival. HIF-1alpha expression was strongly correlated with CA IX (r=0.667, p<0.001) and was co-localized with CA IX in corresponding areas. HIF-1alpha and CA IX expression were higher in areas with moderate to severe tumor necrosis relative to areas with minimal necrosis, suggesting their relationship with hypoxia. VEGF expression also showed a modest relationship with HIF-1alpha (p=0.07); however, there was no relationship between HIF-1alpha and MMP-9 expression (p>0.99). Expression of HIF-1alpha and CA IX above the median value was significantly associated with shorter disease free survival in univariate analysis (p<0.05). However, only high CA IX expression and pathologic stage were independent prognostic indicators in a multivariate analysis. Of the markers considered in this study, CA IX expression status was the most reliable hypoxia marker for predicting tumor aggressiveness.     

Vascular endothelial growth factor expression in preoperative biopsy specimens correlates with disease recurrence in patients with early gastric carcinoma.

BACKGROUND: Recently many studies have demonstrated that the degree of tumor angiogenesis is related to the aggressiveness of the tumor and clinical outcome. Vascular endothelial growth factor (VEGF) is a well characterized inducer of angiogenesis. In this study, the authors investigated the prognostic significance of VEGF expression in patients with early gastric carcinoma together with p53 gene abnormality and tumor cell proliferation. METHODS: One hundred ninety-five endoscopically biopsied specimens obtained preoperatively from patients with early gastric carcinoma were studied immunohistochemically. RESULTS: According to conventional clinicopathologic factors, submucosal invasion, lymph node metastases, and tumor size were associated significantly with the incidence of disease recurrence. According to conventional biologic factors, VEGF expression was observed more frequently in patients with disease recurrence compared with those without disease recurrence whereas neither p53 abnormality nor tumor cell proliferation were correlated with prognosis. Moreover, multivariate analysis indicated that VEGF expression (as well as submucosal invasion and lymph node metastases) is an independent predictor of disease recurrence. CONCLUSIONS: The results of the current study show that VEGF expression may be a useful prognostic factor for patients with early gastric carcinoma.     

膀胱移行细胞癌T1期复发的多因素分析

目的：探讨多种临床病理指标和生物学标志物在预测T1期膀胱移行细胞癌复发中的价值。方法：采用免疫组化SP法,对75例原发性T1期膀胱癌患者的3种生物学标记物p53、上皮钙黏附素(E-cadherin)和血管内皮生长因子(VEGF)的表达情况进行检测,通过Kaplan-Meier生存分析和Cox风险比例模型,评估各临床病理指标和生物学标记物对复发的影响。结果：患者的1,3,5年累计无复发生存率分别为68．0％、45．3％和20．9％。单因素生存分析显示,肿瘤的发生情况、p53、E-cadherin和VEGF的表达与复发有相关性。多因素分析提示,肿瘤的发生情况、p53和E-cadherin的表达与复发密切相关,而其他变量均与复发无关。结论：膀胱癌的多灶性、p53和E-cadherin的异常表达是预测T1期膀胱癌复发的独立指标。     

Comparison of p53 mutations between adenocarcinoma and squamous cell carcinoma of the lung: unique spectra involving G to A transitions and G to T transversions in both histologic types

The p53 gene is frequently mutated in lung tumors, and mutations may be caused by both polycyclic aromatic hydrocarbons (PAHs) and nitrosamines found in tobacco smoke. The two major forms of lung cancer, adenocarcinoma (AC) and squamous cell carcinoma (SCC), are known to differ in the proportion of tumors exhibiting p53 mutation, and may also differ in the mutational spectra produced. Previous studies comparing p53 mutational spectra between AC and SCC of the lung have been limited by small sample size. We examined p53 mutations in exons 5-8 in 202 cases of AC and 82 cases of SCC from smoking lung cancer patients in the Western Pennsylvania region. The percent of cases with p53 mutation was significantly lower in ACs (40/202, 20%) compared to SCCs (29/82, 35%, P=0.006). The proportion of mutations present that were G to T transversions was not significantly different between the two tumor types (52% of p53 mutations in AC compared to 32% in SCC). G to A transitions either did not differ in frequency in the two types of lung cancer (20% of mutations in AC and 24% of mutations in SCC). A distinct spectrum was observed, however, in the p53 mutation pattern in the two types of lung cancer. ACs showed a strong preference for a mutational hotspot at codons 248 and 249, while squamous cell tumors showed mutational events spread throughout exons 5-8, with a preference for codon 267. Mutations at codon 267 in SCC were all C to T transitions that occurred at CpG sites. Both tumor types demonstrated preferential mutation of the non-transcribed strand (100% of all G to T transversions and 55% of the G to A transitions). These results suggest that p53 mutations in both types of lung tumors may arise from adduction by both PAHs and nitrosamines. Mutations arising in ACs appear selectively in regions of p53 that produce more rigid proteins, suggesting a drastic change in p53 function is needed to result in ACs, while less constrained changes in p53 function can result in SCCs. Mutation in p53 was not found to be related to patient survival in this group of patients, while tumor size and degree of differentiation were poor survival predictors.     

Prognostic impact of Notch ligands and receptors in nonsmall cell lung cancer

BACKGROUND:

Notch signaling plays a key role in embryonic vascular development and angiogenesis. The authors aimed to study the prognostic role of the angiogenesis‐related Notch ligands and receptors and investigate the prognostic impact of the coexpression of vascular endothelial growth factor‐A (VEGF‐A) and Notch signaling.

METHODS:

Tumor tissue samples from 335 resected patients with stage I to IIIA nonsmall cell lung cancer (NSCLC) were obtained, and tissue microarrays were constructed from duplicate cores of tumor cells and tumor‐related stroma from each specimen. Immunohistochemistry was used to evaluate the expression of the molecular markers Notch‐1, Notch‐4, Delta‐like ligand 4 (DLL4), and Jagged‐1.

RESULTS:

There were 191 squamous cell carcinomas (SCCs), 113 adenocarcinomas (ACs), and 31 large cell carcinomas. In AC, low tumor cell Delta‐like ligand 4 expression was an independent negative prognostic factor (hazard ratio [HR], 2.9; 95% confidence interval [CI], 1.4‐6.3 [P = .006]), whereas high tumor cell Notch‐1 expression was an independent negative prognostic factor (HR, 2.2; 95% CI, 1.2‐4.1 [P<.001]). In SCC, low stromal Delta‐like ligand 4 expression was an independent indicator of poor prognosis (HR, 3.3; 95% CI, 1.8‐6.1 [P<.001]). The coexpression of Notch‐1 and VEGF‐A had a significant prognostic impact (P<.001). For Notch‐1 and VEGF‐A, low/low (n = 142) versus high/high (n = 35) expression resulted in 5‐year survival rates of 69% and 32%, respectively.

CONCLUSIONS:

Delta‐like ligand 4 and Notch‐1 are independent prognostic factors in NSCLC, but have diverse impacts in SCC and AC. The coexpression of tumor cell Notch‐1/VEGF‐A has a major impact on survival. Cancer 2010. © 2010 American Cancer Society.     

肺癌患者胸水中肿瘤标志物检测的临床意义

[目的]探讨肺癌患者胸水中肿瘤标志物的检测在临床上的应用价值。[方法]应用酶联免疫吸附实验（ELISA）检测170例肺癌患者和58例肺部良性疾病患者胸水中神经元特异性烯醇化酶（NSE）、胃泌素释放肽前体（pro-GRP）、细胞角蛋白19（CYFRA21-1）、鳞癌抗原（SCC）、p53抗体和CA199的水平含量。[结果]肺癌患者胸水的6种肿瘤标志物水平均明显高于肺部良性疾病组,差异有统计学意义（P〈0.01）。NSE、pro-GRP在小细胞肺癌中的水平明显高于其他类型的肺癌（P〈0.01）;CYFRA21-1、鳞癌抗原（SCC）在鳞癌中的水平明显高于其他类型的肺癌（P〈0.01）。[结论]胸水中6种肿瘤标志物对于肺癌的辅助诊断有一定的临床意义。