周围型肺癌SCT征象与VEGF、E-cad表达相关性的研究
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摘要
背景和目的：肺癌是呼吸系统最常见的原发性恶性肿瘤之一。肺癌的浸润和转移是其最本质的生物学特性，也是导致患者死亡的根本原因，肿瘤血管生成(tumorangiogenesis)是其相应的前提条件。肿瘤血管生成受许多相关因子的诱导和调节，血管内皮生长因子(vascular endothelial growth factor，VEGF)及其受体是促进血管生成的关键因素，它主要促使血管内皮生成和血管通透性增加。人血管内皮细胞及肿瘤细胞上分布两种VEGF受体，其中胎儿肝激酶—1含激酶插入功能区受体(fetalliver kinase-1，FLK-1／KDR)为最重要的一种，在促进血管生成中起主要作用。E钙粘蛋白(E—Cadhrine，E-cad)是一类主要介导同型细胞之间粘附的钙依赖性跨膜糖蛋白，它表达的减弱、消失或异位表达与许多肿瘤转移的发生率呈正相关。本研究诣在探讨周围型肺癌SCT征象与VEGF、E—cad表达间的关系，以客观地评价肿瘤的生长、复发和转移。
材料与方法：本组58例周围型肺癌病人术前一周内行SCT平扫，另外21例加做增强扫描，16例经皮穿刺活检病理证实。扫描采用GE Hispeed Advantage Rp22螺旋CT机。病人仰卧位自肺尖至肝顶一次闭气完成扫描，确定病灶部位局部加高分辨扫描。经肘静脉注入非离子型对比剂欧乃派克(300 mg．I．ml~(-1))或优维显(300mg．I．ml~(-1))，剂量按1.5ml／kg体重计算，速度为300 mg．I．ml~(-1)／s，延时40s行增强扫描。
郑州大学2004届硕士学位论文
周围型肺癌螺旋CT征象与VEGF、E-Cad表达相关的研究
扫描参数为120kV，200mAs，层厚10Inln，螺距为1。术后标本全部经10%福尔马
林液固定，常规脱水后石蜡包埋，4um连续切片，每例收集6张，一张行HE染色，
余备免疫组化用。采用免疫组织化学SP(StrePt硕din Peroxidase)法检测肿瘤组织
中vEGF、KDR及E一cad的表达。实验数据经spss10.0统计软件包进行统计学处
理，采用xZ检验、Fishe:精确概率法和sPe~an相关分析，以。=0.05为检验水
准。
结果:1.SCI，对胸膜侵犯判断的准确率为86.67%，淋巴转移总的判断准确率
为88.24%，SCI，对周围性肺癌诊断的总准确率为81.25%。38例行高分辨扫描，周围
型肺癌SCI，征象的显示率均高于单纯平扫。
2.58例周围型肺癌中，VEGF阳性表达35例，阳性率为60.34%，VEGF的表
达与病理类型无关;细胞分化I一n级组和m一w级组阳性表达率分别为46.88%
(巧/32)和76.92%(20/26)，两组比较差异具有统计学意义(尸<0.05)。
3.58例周围型肺癌中，KDR阳性表达28例，阳性率为48.28%，KDR的表达
与病理类型无关;细胞分化I一n级组和111一W级组阳性表达率分别为34.38%
(11/32)和65.38%(17/26)，两组比较差异具有统计学意义(P<0.05)。
4.58例周围型肺癌中，E一cad异常表达32例，异常表达率为55.17%，E一cad
表达与病理类型无关;细胞分化I一n级组和m一w级组阳性表达率分别为40.63%
(13/32)和73.08%(1 9/26)，两组比较差异具有统计学意义(尸<0.05)。
5.肺癌VEGF的表达与周围型肺癌的毛刺征、棘突征、血管集束征、空洞征明
显相关，而与肿瘤的大小、胸膜凹陷征、分叶征无明显相关，VEGF的表达与胸膜
侵犯、淋巴转移相关(尸<0.05)。
6.肺癌E一ead的异常表达与肿瘤的大小、棘突征明显相关(尸<0.05)，而与毛
刺征、血管集中征、空洞征、胸膜凹陷征、分叶征无关;肺癌的E一cad异常表达与
胸膜侵犯、淋巴转移明显相关(P<0.05)。
7.21例行增强扫描的周围型肺癌中，平扫CT值为28HU一46.4HU，平均(36.08
士4.69)HU，增强后CT值增加了23.3 HU一43.0HU，平均(36.66士7.41)HIJ。周
围型肺癌的强化程度与VEGF的表达明显相关(rs=0.533，P<0.05)。
8.VEGF与KDR表达呈正相关(r=0.572，尸<0.05)，VEGF与E一cad表达之间无
郑州大学2(X)4届硕士学位论文
周围型肺癌螺旋Cl，征象与VEGF、E-cad表达相关的研究
明显相关(r=一0.以9，尸>0.05)，KDR与E一cad表达之间无明显相关(r=一0177，P>0.05)。
结论;1.SCI，、HRCI，是周围型肺癌可靠的检查技术。
2.VEGF、KDR与周围型肺癌的分级、浸润及淋巴结转移显著相关，提示血管
生成可能在肺癌进展中起促进作用;vEGF的表达与棘突征、毛刺征、血管集束征等
明显相关，提示可能是SC几，征象形成的分子生物学基础。
3.E一cad的异常表达与周围型肺癌的大小、分级、转移相关，提示E~cad在肿
瘤转移和浸润中起着重要促进作用。E一cad异常表达与棘突征显著相关，提示可能
是SCr征象形成的分子生物学基础。
4.VEGF、KDR和E一cad表达不相关，提示E一cad在促进肺癌浸润、转移的途
径不同与VEGF不同。
5.VEGF、E一cad的表达与SCI，征象相关，提示SCI，可间接反映周围型肺癌的
生物学特性。
Background and purpose: Peripheral pulmonary carcinoma is one of the most common malignant tumors in respiratory system. Invasion and metastasis are initially characteristics of pulmonary carcinoma, which are the ultimately cause of death in pulmonary carcinoma, and tumor angiogenesis is its premise. Vascular endothelial growth factors (VEGF) and its receptors are the most important factors which are controlled by many kinds of related factors, and play an important role in stimulating vascular growth and vascular permeability. There are two kinds of vascular endothelial growth receptors highly expressed in endothelial cell and tumor cell, Kinase insert domain-containing receptor(KDR) is one of the important receptors. E-cadherin(E-cad) is one of the most important adhesive molecules responsible for the calcium-dependent intra-cellular adhesion mechanism, The aberrant expression of E-cad possesses a close relationship with invasion and metastasis of tumor. The purpose of this study is to investigate the corr
elation between SCT features and expressions of VEGF, E-cad to evaluate the growth and the invasion of pulmonary carcinoma.
Materials and methods: Pulmonary carcinoma of 58 cases confirmed by pathology, and was performed SCT within one week before surgery, 16 of the 58 patients were diagnosed by CT-guided biopsy yet. Spiral CT examination was performed with a GE Hispeed advantage RP22 scanner. Scanning parameter of SCT were 120kv, 200mAs, 10 collimation, pitch= 1. The whole lung was examined and the tumor was scanned with high-resolution CT in 38 casses. About 100ml contrast medium was injected via the cubital vein with the speed of 3.0 ml/s, 21 patients were performed enhanced scan. All the specimens were fixed in 10% neutral formalin and embedded in paraffin after operation. Expressions of VEGF, KDR and E-cad in 58 cases of pulmonary carcinoma were
examined with SP immunohistochemical technique. Statistical analysis was performed with SPSS 10.0 software using Chi-square test, Fisher's exact test and Spearman correlation test, and the P values less than 0.05 were considered significantly different.
Results: 1. On SCT scans, the accuracy in diagnosing invasion of pleural and scanning for lymph metastasis was 86.67% and 88.24% respectively, whereas the accuracy of staging in TNM was 81.25%. The malignant features could be seen better on HRCT than that on convention CT.
2. In 58 cases of peripheral pulmonary carcinoma, VEGF positive expression was detected in 35 patients, which was no relationship to the type of tumor cell (P>0.05). The expression of VEGF in III-IV was significantly higher than that in grade I-II (F<0.05).
3. KDR expression was detected in 28 patients, the KDR positive rates is 48.28%, which is closely associated with the grades of cancer cell (P<0.05), but it was not related to the type of carcinoma (P>.05).
4. The E-cad abnormal expression was detected in 32 patients. The abnormal expression of E-cad in grade III-IV was obviously higher than that in grade I-II.
5. The VEGF positive expression closely correlated with the CT features, such as spicular sign, cavity sign et al, and was apparently associated with pleural invasion and lymph node metastasis, but it was not related to pleural retraction sign, lobulation sign, and the diameter of tumor.
6. The abnormal expression of E-cad was associated with the CT features, such as lymph node metastasis, pleural invasion and the size of tumor, but was not related to cavity sign, spicular sign, vessel convergence sign et al,
7. On non-enhanced SCT scans, the CT attenuation values of tumors ranges from 28.0Hu to 46.4Hu with a mean of 36.08(36.08 +4.69)HU, the CT attenuation ranges from 23.3HU to 43.0HU with a mean of 36.66HU(36.66+7.41HU); the expression of VEGF was closely associated with the enhanced degree of CT attenuation value (P<0.05).
8. Expression of VEGF positively correlated with expression of KDR (rs=0.572), but their expression was not related to the expression of E-cad (-0.049 and -0.177). Conclusion: 1. SCT
材料与方法：本组58例周围型肺癌病人术前一周内行SCT平扫，另外21例加做增强扫描，16例经皮穿刺活检病理证实。扫描采用GE Hispeed Advantage Rp22螺旋CT机。病人仰卧位自肺尖至肝顶一次闭气完成扫描，确定病灶部位局部加高分辨扫描。经肘静脉注入非离子型对比剂欧乃派克(300 mg．I．ml~(-1))或优维显(300mg．I．ml~(-1))，剂量按1.5ml／kg体重计算，速度为300 mg．I．ml~(-1)／s，延时40s行增强扫描。
郑州大学2004届硕士学位论文
周围型肺癌螺旋CT征象与VEGF、E-Cad表达相关的研究
扫描参数为120kV，200mAs，层厚10Inln，螺距为1。术后标本全部经10%福尔马
林液固定，常规脱水后石蜡包埋，4um连续切片，每例收集6张，一张行HE染色，
余备免疫组化用。采用免疫组织化学SP(StrePt硕din Peroxidase)法检测肿瘤组织
中vEGF、KDR及E一cad的表达。实验数据经spss10.0统计软件包进行统计学处
理，采用xZ检验、Fishe:精确概率法和sPe~an相关分析，以。=0.05为检验水
准。
结果:1.SCI，对胸膜侵犯判断的准确率为86.67%，淋巴转移总的判断准确率
为88.24%，SCI，对周围性肺癌诊断的总准确率为81.25%。38例行高分辨扫描，周围
型肺癌SCI，征象的显示率均高于单纯平扫。
2.58例周围型肺癌中，VEGF阳性表达35例，阳性率为60.34%，VEGF的表
达与病理类型无关;细胞分化I一n级组和m一w级组阳性表达率分别为46.88%
(巧/32)和76.92%(20/26)，两组比较差异具有统计学意义(尸<0.05)。
3.58例周围型肺癌中，KDR阳性表达28例，阳性率为48.28%，KDR的表达
与病理类型无关;细胞分化I一n级组和111一W级组阳性表达率分别为34.38%
(11/32)和65.38%(17/26)，两组比较差异具有统计学意义(P<0.05)。
4.58例周围型肺癌中，E一cad异常表达32例，异常表达率为55.17%，E一cad
表达与病理类型无关;细胞分化I一n级组和m一w级组阳性表达率分别为40.63%
(13/32)和73.08%(1 9/26)，两组比较差异具有统计学意义(尸<0.05)。
5.肺癌VEGF的表达与周围型肺癌的毛刺征、棘突征、血管集束征、空洞征明
显相关，而与肿瘤的大小、胸膜凹陷征、分叶征无明显相关，VEGF的表达与胸膜
侵犯、淋巴转移相关(尸<0.05)。
6.肺癌E一ead的异常表达与肿瘤的大小、棘突征明显相关(尸<0.05)，而与毛
刺征、血管集中征、空洞征、胸膜凹陷征、分叶征无关;肺癌的E一cad异常表达与
胸膜侵犯、淋巴转移明显相关(P<0.05)。
7.21例行增强扫描的周围型肺癌中，平扫CT值为28HU一46.4HU，平均(36.08
士4.69)HU，增强后CT值增加了23.3 HU一43.0HU，平均(36.66士7.41)HIJ。周
围型肺癌的强化程度与VEGF的表达明显相关(rs=0.533，P<0.05)。
8.VEGF与KDR表达呈正相关(r=0.572，尸<0.05)，VEGF与E一cad表达之间无
郑州大学2(X)4届硕士学位论文
周围型肺癌螺旋Cl，征象与VEGF、E-cad表达相关的研究
明显相关(r=一0.以9，尸>0.05)，KDR与E一cad表达之间无明显相关(r=一0177，P>0.05)。
结论;1.SCI，、HRCI，是周围型肺癌可靠的检查技术。
2.VEGF、KDR与周围型肺癌的分级、浸润及淋巴结转移显著相关，提示血管
生成可能在肺癌进展中起促进作用;vEGF的表达与棘突征、毛刺征、血管集束征等
明显相关，提示可能是SC几，征象形成的分子生物学基础。
3.E一cad的异常表达与周围型肺癌的大小、分级、转移相关，提示E~cad在肿
瘤转移和浸润中起着重要促进作用。E一cad异常表达与棘突征显著相关，提示可能
是SCr征象形成的分子生物学基础。
4.VEGF、KDR和E一cad表达不相关，提示E一cad在促进肺癌浸润、转移的途
径不同与VEGF不同。
5.VEGF、E一cad的表达与SCI，征象相关，提示SCI，可间接反映周围型肺癌的
生物学特性。
Background and purpose: Peripheral pulmonary carcinoma is one of the most common malignant tumors in respiratory system. Invasion and metastasis are initially characteristics of pulmonary carcinoma, which are the ultimately cause of death in pulmonary carcinoma, and tumor angiogenesis is its premise. Vascular endothelial growth factors (VEGF) and its receptors are the most important factors which are controlled by many kinds of related factors, and play an important role in stimulating vascular growth and vascular permeability. There are two kinds of vascular endothelial growth receptors highly expressed in endothelial cell and tumor cell, Kinase insert domain-containing receptor(KDR) is one of the important receptors. E-cadherin(E-cad) is one of the most important adhesive molecules responsible for the calcium-dependent intra-cellular adhesion mechanism, The aberrant expression of E-cad possesses a close relationship with invasion and metastasis of tumor. The purpose of this study is to investigate the corr
elation between SCT features and expressions of VEGF, E-cad to evaluate the growth and the invasion of pulmonary carcinoma.
Materials and methods: Pulmonary carcinoma of 58 cases confirmed by pathology, and was performed SCT within one week before surgery, 16 of the 58 patients were diagnosed by CT-guided biopsy yet. Spiral CT examination was performed with a GE Hispeed advantage RP22 scanner. Scanning parameter of SCT were 120kv, 200mAs, 10 collimation, pitch= 1. The whole lung was examined and the tumor was scanned with high-resolution CT in 38 casses. About 100ml contrast medium was injected via the cubital vein with the speed of 3.0 ml/s, 21 patients were performed enhanced scan. All the specimens were fixed in 10% neutral formalin and embedded in paraffin after operation. Expressions of VEGF, KDR and E-cad in 58 cases of pulmonary carcinoma were
examined with SP immunohistochemical technique. Statistical analysis was performed with SPSS 10.0 software using Chi-square test, Fisher's exact test and Spearman correlation test, and the P values less than 0.05 were considered significantly different.
Results: 1. On SCT scans, the accuracy in diagnosing invasion of pleural and scanning for lymph metastasis was 86.67% and 88.24% respectively, whereas the accuracy of staging in TNM was 81.25%. The malignant features could be seen better on HRCT than that on convention CT.
2. In 58 cases of peripheral pulmonary carcinoma, VEGF positive expression was detected in 35 patients, which was no relationship to the type of tumor cell (P>0.05). The expression of VEGF in III-IV was significantly higher than that in grade I-II (F<0.05).
3. KDR expression was detected in 28 patients, the KDR positive rates is 48.28%, which is closely associated with the grades of cancer cell (P<0.05), but it was not related to the type of carcinoma (P>.05).
4. The E-cad abnormal expression was detected in 32 patients. The abnormal expression of E-cad in grade III-IV was obviously higher than that in grade I-II.
5. The VEGF positive expression closely correlated with the CT features, such as spicular sign, cavity sign et al, and was apparently associated with pleural invasion and lymph node metastasis, but it was not related to pleural retraction sign, lobulation sign, and the diameter of tumor.
6. The abnormal expression of E-cad was associated with the CT features, such as lymph node metastasis, pleural invasion and the size of tumor, but was not related to cavity sign, spicular sign, vessel convergence sign et al,
7. On non-enhanced SCT scans, the CT attenuation values of tumors ranges from 28.0Hu to 46.4Hu with a mean of 36.08(36.08 +4.69)HU, the CT attenuation ranges from 23.3HU to 43.0HU with a mean of 36.66HU(36.66+7.41HU); the expression of VEGF was closely associated with the enhanced degree of CT attenuation value (P<0.05).
8. Expression of VEGF positively correlated with expression of KDR (rs=0.572), but their expression was not related to the expression of E-cad (-0.049 and -0.177). Conclusion: 1. SCT
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27．周燕发，田芳，陈辉。肺内球形灶棘突征CT征与病理对照研究。临床放射学杂志，2002，21(3)：198-200
28．伍建林，李巍，王克礼等。周围型肺癌CT征象和动态CT增强与微血管密度
关系的研究。中国肺癌杂志，2003，6(1)：30-34
29. Tateishi U, Nishihara H, Watanabe S, et al. Tumor angiogenesis and dynamic CT in lung adenocarcinnoma: Radiologic-patholoic correlation,Journal of Assisted Tomography, 2001, 25(1):23-27
30．许茜，时高峰，李彩英等。肺癌血管内皮生长因子与增强CT的相关性研究。中国临床医学影像学杂志，2002，13(2)：9-11
31. Takeichi M, Cadherin cell adhesion receptors as a morphogenetic regulator. Science, 1999, 251:1451-1455
32．张雪燕。E—cadherin及其相关蛋白在肺癌生物学行为中的意义。国外医学呼吸分册，2002，22(1)：6-8
33. Jiang WG.E-cadherin and its associated protein catenins, cancer invasion and metastasis. Br J Surg. 1996;83(4):437-46.
34. Margulis A, Andriani F, Fusenig N, et al. Abrogation of E-cadherin-mediated adhesion induces tumor cell invasion in human skin-like organotypic culture. J Invest Dermatol. 2003; 121 (5):1182-1190
35. Mcneill H, Ozawa M, Kenner R, et al. Neofunction of the cell adhesion molecule unomrulin as an inducer of cell surface polarity. Cell, 1990, 62:309-316
36. Sulfa MA, Leers MP, van Noord JA, et al. Reduced E-cadherin expression is associated with increased lymph node metastasis and unfavorable prognosis in non-small cell lung cancer. Am J Respir Crit Care Med. 1998;157(4):1319-1323
37. Bohm M, Totzeck B, Birchmeier W, et al. Differences of E-cadherin expression levels and patterns in primary and metastatic human lung cancer. Clin Exp Metastasis.1994,12(1):55-62
38. Shibanuma H, Hirano T, Tsuji K, et al. Influence of E-cadherin dysfunction upon local invasion and metastasis in non-small cell lung cancer. Lung Cancer. 1998; 22(2):85-95.
39. Pignatelli M, Ansari TW, Gunter P, et al. Loss of membrannous E-cad expression in pancreeatic cancer: correlation with lymph no de metastasis, high grade and advanced stage. The Journal of pathology, 1994,174:243-248
40. Nowell PC. Mechanisma of tumor progression. Cancer Res, 1986, 46:2203-2204
41. Millauer B, Shawver LK, Plate KH, et al. Glioblastoma growth inhibited in vivo by a dominnant-negative FLK-1 mutant. Nature, 1994, 367:576-597
42. Kimura K, Endo Y, Yonemura Y, et al. Clinical significance of S100A4 and E-cadherin-related adhesion molecules in non-small cell lung cancer. Int J Oncol, 2000, 16(6):1125-1131
43. Benoliel AM, Pirro N, Marin V, et al. Correlation between invasiveness of colorectal tumor cells and adhesive potential under flow. Anticancer Res. 2003, 23(6):4891-4896