具有腺癌和鳞状细胞癌双向分化免疫表型特征的非小细胞肺癌1例并文献复习

目的探讨具有腺癌和鳞状细胞癌双向分化免疫表型特征的非小细胞肺癌(NSCLC)的临床病理特征及诊断方法。方法回顾性分析徐州市第一人民医院2022年10月收治的1例具有腺癌和鳞状细胞癌双向分化免疫表型特征的NSCLC患者的临床资料, 并结合相关文献复习。结果患者, 男性, 66岁, 2021年2月因偶尔的干咳和胸痛就诊, CT发现左下肺胸膜下结节(长径0.6 cm), 2022年10月复诊发现结节明显增大, 评估后建议手术切除, 光学显微镜下肿瘤呈低分化NSCLC形态, 有局灶的坏死, 未见明确的腺泡、乳头和微乳头结构, 有部分实性巢团结构和部分弥漫散在胞质略嗜酸性、类似角化或非角化型鳞状细胞癌的区域。免疫组织化学TTF1、NapsinA 、p40、CK5/6弥漫阳性表达, 不表达CK7、CgA、INSM1、syn、CD56、PAX8和CDX2, 特殊染色黏液卡红灶性染色, 最终诊断为具有腺癌和鳞状细胞癌双向分化免疫表型特征的NSCLC。结论具有腺癌和鳞状细胞癌双向分化免疫表型的NSCLC肿瘤细胞同时表达TTF1和p40, 此类肿瘤比传统的NSCLC更具有侵袭性, 肿瘤扩散更迅速, 确诊需...     

原发性甲状腺鳞状细胞癌临床病理分析

目的:探讨原发性甲状腺鳞状细胞癌的临床病理特点、病理诊断及鉴别诊断.方法:复习5例原发性甲状腺鳞状细胞癌的临床病理资料,采用HE染色、免疫组化技术和电镜技术进行观察分析.结果:5例中3例为女性.发病中位年龄55岁,术后平均生存3～7个月.临床主要表现为颈部肿块、声嘶、呼吸困难和吞咽困难;光镜下病变多呈高分化鳞状细胞癌,广泛浸润至周围组织;广谱细胞角蛋白(CKpan)、细胞角蛋白19(CK19)5例均弥漫强阳性,细胞增殖标记抗体(Ki-67)的阳性表达率为30%～50%.甲状腺转录因子-1(TTF1)、甲状腺球蛋白(TG)和外套层细胞淋巴瘤标记(CD5)均不表达;超微结构示瘤细胞有异形性,胞质内可见张力原纤维丝,细胞间有发育良好的桥粒.结论:原发性甲状腺鳞状细胞癌是罕见的高度恶性肿瘤,侵袭性强,诊断时应排除继发性鳞状细胞癌以及其他类型甲状腺病变伴鳞化.     

p63和TTF-1在肺癌组织中的表达及鉴别诊断意义

目的:探讨p63和TTF-1蛋白在肺癌不同组织类型中的表达特点及鉴别诊断的价值。方法:应用免疫组织化学S-P法检测116例原发性肺癌组织中p63和TTF-1蛋白的表达情况。结果:p63在肺鳞癌中阳性表达率为100%(47/47),而在其他组织类型肺癌中基本不表达。TTF-1在肺小细胞癌和肺腺癌中阳性表达率分别为93.3%(14/15)和93.5%(43/46),而在鳞癌中未见表达。结论:p63可作为肺鳞状上皮源性肿瘤标记物,是判断鳞癌的可靠指标。TTF-1可作为肺小细胞癌、腺癌的特异性标记。联合检测p63和TTF-1对肺癌不同组织类型的诊断、鉴别诊断具有较高的实用价值,尤其可作为鉴别分化差的鳞癌、腺癌和小细胞癌的指标。     

p63和p53及PCNA在肺癌中的表达及意义

目的 检测蛋白p63、p53和PCNA在肺癌组织中的表达情况,并研究三者之间及其与临床病理参数的关系,以探讨三者在肺癌的发生、发展中的生物学作用和临床意义.方法 选取183例肺癌组织(其中54例有癌旁组织),应用组织芯片技术和免疫组织化学方法观察三种蛋白的表达情况.结果 p63在肺癌中的阳性率分别为鳞状细胞癌82.1%(55/67)、腺癌8.8%(7/80)、细支气管肺泡癌4.2%(1/24)、小细胞癌0%(0/12),鳞状细胞癌中的p63表达率显著高于其他类型(P＜0.01),而其他类型间差异无显著性(P＞0.05);p53在肺癌中的阳性率分别为鳞状细胞癌67.2%(45/67)、腺癌48.8%(39/80)、细支气管肺泡癌54.2%(13/24)、小细胞癌41.7%(5/12),鳞状细胞癌显著高于其他类型(P＜0.05),其他类型间差异无显著性(P＞0.05);PCNA在肺癌中3.8%(7/183)呈阴性,31.1%(57/183)呈弱阳性,37.7%(69/183)呈阳性,27.3%(50/183)呈强阳性,小细胞癌PCNA阳性率显著低于其他类型(P＜0.05).统计结果显示,p63在鳞状细胞癌中的表达率显著高于其他类型(P＜0.01),但与p53、PCNA的表达及临床病理参数不相关(P＞0.05),尽管p53和PCNA与肿瘤分化程度相关(P＜0.01).结论 p63基因在不同类型的肺癌中作用不同,其在肺鳞状细胞癌的发生发展中起着重要的作用,机理有待研究,这一结果可为进一步探讨p63在肿瘤中的作用提供依据;另外,p63可作为鉴别肺鳞状细胞癌与其他类型癌的重要参考指标,为临床病理诊断提供有效依据.     

非小细胞肺癌CD44V6和C-erbB-2的表达及其意义

目的 :探讨CD44V6及C erbB 2表达与非小细胞肺癌临床病理特征之间的关系。方法 :采用S P免疫组化法检测 132例非小细胞肺癌、6 6例淋巴结转移癌、95例癌旁肺组织和 2 0例正常肺组织CD44V6和C erbB 2表达的情况。结果 :非小细胞肺癌CD44V6阳性表达率为 48 4 8%,明显高于癌旁肺组织 16 84%和正常肺组织 2 0 0 0 %的阳性有效率。CD44V6阳性表达与淋巴结转移状况、TNM分期、肿瘤大小和组织学类型有显著相关性。非小细胞肺癌淋巴结转移组、TNMⅢ期患者、直径>3cm的肿瘤和鳞癌CD44V6阳性表达率分别明显高于无淋巴结转移组、TNMⅠ、Ⅱ期患者、直径≤ 3cm的肿瘤和腺癌。淋巴结转移癌CD44V6阳性表达率明显高于肺原发癌。CD44V6阳性表达与患者的性别、年龄和组织学分级无显著相关性。非小细胞肺癌C erbB 2阳性表达率为 6 1 36 %,明显高于癌旁肺组织 18 95 %和正常肺组织 10 0 0 %的阳性表达率。C erbB 2阳性表达与临床病理特征无显著相关性。结论 :CD44V6阳性表达预示非小细胞肺癌具有较强的侵袭和转移能力 ,CD44V6可作为一项预测非小细胞肺癌转移潜能及判断预后的生物学指标。C erbB 2作为判断非小细胞肺癌预后的指标不理想     

FLI-1、p63蛋白在肺癌中表达的研究

目的研究FLI-1、p63蛋白在肺鳞状细胞癌、腺癌及小细胞癌中表达情况及其意义.方法收集52例肺癌（鳞癌24例、腺癌18例、小细胞癌10例）及20例正常肺组织,采用免疫组化（EnVision-plus法）进行FLI-1、p63抗体标记.结果 FLI-1抗体阳性细胞定位在细胞核,在鳞癌、腺癌和小细胞癌的阳性率分别为9.1%、5.9%和90.0%,肺小细胞癌分别与肺鳞癌及腺癌相比差异具有显著性（P＜0.01）.FLI-1抗体诊断小细胞癌的敏感性为90.0%,特异性为92.8%;p63抗体阳性细胞定位在细胞核,在正常支气管黏膜、肺鳞癌、腺癌和小细胞癌阳性率分别为20.0%、91.7%、16.7%和80.0%,肺鳞癌与正常支气管上皮及腺癌比较差异有显著性（P＜0.05）,与小细胞癌相比差异无显著性（P＞0.05）.结论 FLI-1为诊断小细胞肺癌有用的抗体,p63在肺鳞状细胞癌及小细胞癌中表达上调,两者联合运用可以对肺癌鉴别诊断.     

促泌素在小细胞癌中的表达及其临床意义

目的:比较促泌素（secretagogin ，SCGN）与传统神经内分泌标记物在小细胞癌中的表达差异。方法:收集诊断为小细胞癌的标本共39例，其中包括26例小细胞肺癌，13例食管小细胞癌。同时选取肺非典型类癌10例、鳞状细胞癌和腺癌各5 例，食管非典型类癌3 例、鳞状细胞癌和腺癌各5 例作为对照。所有标本均使用SCGN、PGP 9.5、CD56、NSE 、Syn 及CgA 进行SP两步法免疫组织化学染色。结果:97.4%（38/39）小细胞癌表达SCGN，在所有标记中的表达率最高，与NSE 、PGP 9.5 及CgA 比较有显著性差异（P<0.01）；其中SCGN 在肺和食管小细胞癌中的阳性表达率分别为100%（26/26）、92.3%（12/13），两者差异统计学意义（P>0.05）；余标记在肺和食管小细胞癌的表达率也无器官差异性（P>0.05）。 SCGN 在肺和食管非典型类癌中的阳性表达率分别为80.0%（8/10）33.3%（1/3），与相应部位小细胞癌表达率无统计学差异（P>0.05）；余标记在肺非典型类癌与小细胞癌、食管非典型类癌与小细胞癌中的表达率也均无统计差异（P>0.05）。 所有肺和食管的鳞状细胞癌、腺癌均不表达SCGN。结论:SCGN 可作为一种新型的神经内分泌标记物应用于小细胞癌的临床病理诊断，推荐选择SCGN、CD56和Syn 免疫标记组合。同时需要注意的是，SCGN 在肺和食管小细胞癌中的表达无器官差异性，且对小细胞癌与非典型类癌无鉴别诊断价值。      

甲状腺转录因子-1在肺癌细胞核中表达的定量研究

目的: 观察甲状腺转录因子-1 (TTF-1) 在正常成人肺泡Ⅱ型上皮细胞、人胚胎肺泡上皮细胞、肺癌以及淋巴结转移癌癌细胞胞核中的表达, 从量化角度探讨其在肺癌发生及其转移过程中的意义。方法: 石蜡包埋切片, 应用免疫组织化学SP法及LeicaQ500MC图像分析系统,对TTF- 1表达强度进行定量分析。结果: 胚胎肺泡上皮细胞胞核TTF 1阳性单位(PU) 值小于正常成人肺泡Ⅱ型上皮细胞胞核TTF- 1的PU值, 差异具有极显著性(P<0 .001); 不同类型肺癌癌细胞胞核TTF 1的PU值均小于胚胎肺泡上皮细胞和正常成人肺泡Ⅱ型上皮细胞胞核TTF -1的PU值, 且差异具有极显著性(P<0. 001); 肺腺癌和肺小细胞癌癌细胞胞核TTF 1的PU值均大于肺鳞癌和肺大细胞癌癌细胞胞核TTF 1的PU值, 且差异均具有极显著性(P<0 .001); 肺鳞癌癌细胞胞核TTF 1的PU值大于肺大细胞癌癌细胞胞核TTF- 1的PU值, 差异具有极显著性(P<0. 001)。肺腺癌、肺鳞癌和肺大细胞癌淋巴结转移灶中癌细胞胞核TTF 1的PU值均大于其癌原发灶癌细胞胞核TTF 1的PU值, 差异具有显著性(P<0 .001, P<0 .001,P<0. 05); 肺小细胞癌淋巴结转移灶癌细胞胞核与其原发灶癌细胞胞核TTF 1的PU值基本相同, 差异无显著性(P>0 .05)。有淋巴结转移的肺癌癌细胞胞核TTF 1的PU值大于无淋巴结转移     

抑癌基因PRDM1在肺癌组织中的表达

目的探讨抑癌基因PRDM1在肺癌组织中的表达情况及其意义。方法45例肺癌患者中,鳞状细胞癌20例、腺癌15例、小细胞肺癌10例。用免疫组织化学方法,研究肺癌石蜡包埋组织中PRDM1蛋白的表达情况;激光微切割技术捕捉冰冻肺癌组织中的肿瘤细胞,抽提RNA、采用逆转录聚合酶链式反应(RT-PCR)技术研究PRDM1基因表达;Western blot技术研究冰冻肺癌组织中PRDM1蛋白表达。结果(1)免疫组织化学结果表明鳞状细胞癌、腺癌、小细胞肺癌患者的PRDM1蛋白阳性率分别为90.0%(18/20)、13.3%(2/15)和0(0/10),统计学分析显示,PRDM1蛋白主要在鳞状细胞癌患者中表达(P<0.01)。(2)激光微切割技术联合RT-PCR证实,PRDM1基因特异表达于鳞状细胞癌患者中,腺癌和小细胞肺癌中未发现其基因表达。进一步研究发现,鳞状细胞肺癌患者中,PRDM1基因的DNA结合区表达缺陷。Western blot在鳞状细胞肺癌组织中检测出约70 000的异常PRDM1蛋白。结论PRDM1在鳞状细胞肺癌中优势表达,可作为肺癌诊断的新的肿瘤标志;鳞状细胞肺癌中PRDM1在转录和蛋白水平上均存在异常,失去了抑癌基因的正常功能,可能成为新的研究治疗靶点。     

肺鳞状细胞癌组织中p63、CK5/6和p40的表达及其病理诊断价值

目的:探讨p63蛋白、细胞角蛋白5/6（cytokeratin5/6,CK5/6）和p40（ΔNp63）蛋白在人非小细胞肺癌（non-small cell lung cancer,NSCLC）组织中的表达及其表达对于肺鳞状细胞癌和肺腺癌的诊断和鉴别诊断价值。方法:采用免疫组化（SP法）检测p63、CK5/6和p40在100例病理确诊的NSCLC组织中的表达情况,并结合NSCLC的临床病理特征进行分析。结果:p63、CK5/6和p40在肺鳞状细胞癌组织中的阳性表达率分别为98.28%、100.00%和98.28%。p63、CK5/6和p40在肺腺癌组织中的阳性表达率分别为45.24%、30.95%和21.43%。肺鳞状细胞癌组织中p63、CK5/6和p40的阳性表达率明显高于肺腺癌组织（P<0.01）。p63、CK5/6和p40诊断肺鳞癌的灵敏度分别为98.28%、100.00%和98.28%,特异度分别为54.76%、69.05%和78.57%。p63、CK5/6和p40在肺鳞状细胞癌中的诊断准确率分别为80%、87%和90%。三者联合检测时三项均阳性诊断肺鳞癌的特异度达90.48%,诊断准确率为95%;三项中至少一项阳性诊断肺鳞癌的灵敏度达100.00%,诊断准确率为75%。结论:p63、CK5/6和p40主要表达在肺鳞状细胞癌组织中。单个指标中p40对诊断肺鳞状细胞癌具有较高的灵敏度和特异度。p63、CK5/6和p40联合检测对肺鳞状细胞癌与肺腺癌的鉴别诊断有重要价值。     

Frequent overexpression of the c-kit protein in large cell neuroendocrine carcinoma of the lung

Overexpression of receptor-type tyrosine kinases in various cancers is associated with an aggressive tumor phenotype and poor outcome, but their expression had never been evaluated in large cell neuroendocrine carcinoma (LCNEC) of the lung. In the present study, we investigated the expression of three receptor tyrosine kinases, epidermal growth factor receptor (EGFR), c-erbB-2, and c-kit protein, by comparing surgically resected 40 LCNECs with other neuroendocrine (NE) lung tumors: 9 typical carcinoids (TCs), 5 atypical carcinoids (ACs), and 13 small cell lung carcinomas (SCLCs). None of the NE lung tumors showed expression of EFGR or c-erbB-2, but c-kit was overexpressed in 55% of the LCNEC tumor cells and 46% of the SCLC tumor cells. None of the clinicopathologic factors in either the LCNEC or SCLC patients correlated with c-kit overexpression. The finding that c-kit expression in LCNEC is similar to its expression in SCLC suggests that inhibition of c-kit may be effective as a therapy targeting LCNEC as well as SCLC.     

Differential retinoblastoma and p16(INK4A) protein expression in neuroendocrine tumors of the lung

BACKGROUND: Neuroendocrine neoplasms of the lung represent a wide spectrum of phenotypically and biologically distinct entities. Their histopathologic diagnosis, which carries therapeutic and prognostic significance, may sometimes be difficult because of their overlapping features. We previously demonstrated that large cell neuroendocrine carcinomas (LCNECs) and small cell lung carcinomas (SCLCs) failed to show positive nuclear staining of RB protein (RB-), whereas typical and atypical carcinoids (TCs and ACs) showed nuclear RB immunostaining (RB+). METHODS: In the current study, a series of 58 surgically resected lung tumors, of which 33 tumors were initially diagnosed as SCLCs and 25 as TCs or ACs, were studied for RB and p16 protein expression by immunohistochemistry. They were also reviewed for their pathologic diagnosis; the reviewers were blinded to the RB and p16 protein status. RESULTS: Nineteen tumors were diagnosed as TCs, 5 as ACs, 7 as LCNECs, and 27 as SCLCs. Three of seven LCNECs were RB+, whereas the other four were RB-. In contrast, all 19 TCs were RB+ and all 27 SCLCs were RB-. In addition, two of five ACs were RB+, whereas the other three were RB-. Interestingly, all 3 RB+ LCNECs and the 1 RB+ AC tested failed to show nuclear staining of p16 protein in any tumor cells (p16-), although some normal stromal cells showed nuclear staining of p16 protein (p16+) as positive internal controls, indicating loss of p16 function in these tumors. It is also noteworthy that the three RB+ LCNECs were initially diagnosed as SCLCs and one of the RB- ACs was initially considered a TC. With the exception of TCs, tumors were significantly more prevalent among heavy smokers with >20 pack-years compared with nonsmokers and light smokers with < or = 20 pack-years (P < 0.01). CONCLUSIONS: These findings suggest that all SCLCs and LCNECs have abnormalities in the p16:RB pathway, as do at least certain ACs, whereas the p16:RB pathway is normal in TCs.     

Diagnostic findings of bronchial brush cytology for pulmonary large cell neuroendocrine carcinomas: comparison with poorly differentiated adenocarcinomas,squamous cell carcinomas,and small cell carcinomas

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) of the lung has been proposed as a new disease entity. To establish diagnostic features, bronchial brush cytologic findings were evaluated. METHODS: Bronchial brush cytology material of 20 LCNECs was evaluated by light microscopy and stained immunocytochemically with protein gene product 9.5 (PGP9.5), neuron-specific enolase, and neural cell adhesion molecule antibodies. The findings were compared with those for 19 poorly differentiated adenocarcinomas (ACs), 18 poorly differentiated squamous cell carcinomas (SCCs), and 20 small cell lung carcinomas (SCLCs). RESULTS: Frequently observed characteristic cytologic findings of LCNECs were necrotic background (90.0%), large tumor cell size (90.0%), naked nuclei (90.0%), and nuclear streaking (90.0%). Nuclei in all LCNECs showed a fine granular chromatin pattern and possessed one or a few nucleoli. Indian-filing and rosette arrangements were observed in less than one-half of the LCNECs. In poorly differentiated ACs and SCCs, these features were less frequent, whereas thick nuclear membranes were observed more often. In SCLCs, tumor cell adhesions and Indian-filing or nuclear molding were observed more frequently than in LCNECs, whereas a necrotic background, tumor cell clusters, large tumor cells, and nucleoli were less prominent. The majority of LCNECs (80.0%) had a positive immunocytochemical reaction for PGP9.5, in contrast to the low positive reactions for ACs (42.1%) and SCCs (30.8%). CONCLUSIONS: Large cell neuroendocrine carcinomas can be diagnosed preoperatively by bronchial brush cytology using reliable parameters, including tumor cell size, naked nuclei, thin nuclear membranes, nuclear streaking, high PGP9.5 positivity, and a necrotic background.     

Allelic loss on chromosome 10q in human lung cancer: association with tumour progression and metastatic phenotype.

We analysed 78 carcinomas of the lung for allelic losses on chromosome 10q. The tumours were of different stage and grade and comprised 22 small-cell lung carcinomas (SCLC), 40 squamous cell carcinomas (SCC), 11 adenocarcinomas, four large-cell carcinomas and one carcinoid. They were investigated by six polymorphic markers located between 10q21 and 10qter. We observed a high incidence of loss of heterozygosity (LOH) in SCLC (91%) and metastatic SCC (56%). Non-metastatic SCC showed deletions in three cases (14%) and no LOH was found in the other types of non-small-cell lung cancer. The statistical analysis indicated that the presence of LOH correlated significantly with advanced tumour stages in the entire collective and in particular within the SCLC and SCC subgroups. For SCC, a positive association was found between LOH and metastases formation, while in SCLC the number of non-metastatic tumours was too small for a final conclusion. Whereas SCLC was frequently characterized by multiple allelic losses, suggesting the deletion of the entire chromosomal arm, SCC showed interstitial imbalances. A high incidence of allelic loss was observed between the markers D10S677 and D10S1223. The analysis of five informative cases suggested the presence of two non-overlapping regions between the loci D10S677/D10S1237 and D10S1213/D10S1223. In SCLC, we did not find mutations in the putative tumour-suppressor gene MXI1. The data indicate that LOH on chromosome 10q is associated with tumour progression in SCC and SCLC. Thus it may become a useful genetic marker in the assessment of the malignant potential of these tumour types.     

Immunohistochemical detection of cluster 1 small cell lung cancer antigen and chromogranin A in lung carcinomas.

Eighteen small cell lung cancers (SCLCs), 108 non-SCLCs (67 adenocarcinomas, 29 squamous cell carcinomas and 12 large cell carcinomas) were immunohistochemically examined for expressions of cluster 1 SCLC antigen/N-CAM and chromogranin A with monoclonal antibodies NCC-Lu-243 and anti-chromogranin A. The cell membranes of all the SCLCs and three of the 67 adenocarcinomas (4.5%) were stained for cluster 1 SCLC antigen/N-CAM. Eight of the 18 SCLCs (44.4%), and three of the 67 adenocarcinomas (4.5%) were stained for chromogranin A, but no squamous cell carcinoma or large cell carcinoma was stained for both antigens. Two of the three adenocarcinomas which expressed cluster 1 SCLC antigen/N-CAM had been suspected of being either SCLC or poorly-differentiated adenocarcinoma cytologically, and were resected after chemotherapy and radiotherapy. Histologically, they were poorly-differentiated adenocarcinoma with rosette-like tubules. The remaining one was moderately-differentiated papillary adenocarcinoma resembling bronchial surface epithelial cells without mucin (BSE type adenocarcinoma). The three adenocarcinomas which expressed chromogranin A were well- to moderately-differentiated BSE type adenocarcinomas, and stained tumor cells were distributed sparsely as neuroendocrine cells in the normal bronchial mucosa. One of them also expressed cluster 1 SCLC antigen/N-CAM. In the present study, we demonstrated the usefulness of NCC-Lu-243 in the immunohistochemical detection of adenocarcinomas with neuroendocrine features.     

Molecular markers for reinforcement of histological subclassification of neuroendocrine lung tumors

The degree of malignancy of neuroendocrine lung tumors (NEs) increases in this order: from typical carcinoids (TCs) through atypical carcinoids (ACs) to large cell neuroendocrine carcinomas (LCNECs) and small cell lung carcinomas (SCLCs). However, histological classification has sometimes proved difficult. We here investigated loss of heterozygosity (LOH) using eight microsatellite markers and expression of p53, Bcl-2 and Bax proteins using immunohistochemical methods in 57 NEs (19 TCs, 5 ACs, 14 LCNECs and 19 SCLCs), looking for objective genetic markers to distinguish between subtypes. The frequencies of LOHs on D3S1300, RBi2 and TP53, the combinations of LOH status for RBi2 and TP53, and the immunohistochemically demonstrated Bcl-2/Bax ratios and p53-positive rates significantly differed among histopathologically diagnosed NEs. Differentiation between TC and AC was possible with reference to LOH on D3S1300, RBi2 and TP53, and the combined LOH status on RBi2 and TP53 (i.e., both LOH(-) versus one LOH(+)). For comparison between AC and LCNEC + SCLC, LOH on TP53 or the combination of two markers--one LOH(+) versus both LOH(+)--was applied. Furthermore, in three discordant cases of diagnoses based on histology and LOH markers, diagnoses using the latter were considered to be more probable by survival analysis. The present study indicated that assessment of LOHs using microsatellite markers could provide objective markers that can distinguish subtypes of NEs, for which histological assessment may commonly result in disagreement.     

Different roles for caveolin-1 in the development of non-small cell lung cancer versus small cell lung cancer

Caveolin-1 (CAV1), an essential structural constituent of caveolae that plays an important role in cellular processes such as transport and signaling, has been implicated in the development of human cancers. However, it is unclear whether CAV1 is acting like an oncogene or tumor suppressor gene. We found that CAV1 expression was reduced or absent in 95% of small cell lung cancers (SCLCs; n = 21 lines), whereas it was retained in 76% of non-small cell lung cancers (NSCLCs; n = 25 lines) compared with normal human lung epithelial cultures, where it was abundantly expressed. CAV1 expression was tightly linked to the ability to grow attached to the plastic cell culture surface, whereas CAV1-nonexpressing lung cancers of both SCLC and NSCLC type grew as suspension cultures. In addition, attached lung cancer cultures expressed phosphorylated focal adhesion kinase, whereas suspension cultures did not. Lack of CAV1 expression was tightly associated with CAV1 promoter methylation (P < 0.0001) such that CAV1 methylation was found in 93% of SCLCs (n = 15) and 9% of NSCLCs (n = 11), whereas 5-aza-2'deoxycytidine treatment restored CAV1 expression in SCLCs. Exogenous CAV1 expression in SCLCs significantly inhibited soft-agar colony formation but did not lead to attachment. By contrast, CAV1 knockdown in NSCLCs mediated by small interfering RNA against CAV1 led to inhibition of cellular proliferation and soft-agar and liquid colony formation. Importantly, CAV1 knockdown led to reduced phospho-focal adhesion kinase and RalA, but not RalB, levels in NSCLC cells. These results suggest different roles for CAV1 in SCLC, where CAV1 acts like a tumor suppressor gene, and NSCLC, where it appears required for survival and growth.