The resistance of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has been brought into focus. COX-2 signal pathway was found to be closely related to EGFR signal pathway by recent researches, and there has been a growing interest to focus the researches on whether COX-2 pathway inhibition improves the efficacy of EGFR-TKIs in treating advanced NSCLC. In this review, we will illustrate recent advances of combined inhibition of EGFR and COX-2 signal pathways in NSCLC therapy.
目的 探讨胃癌组织中人表皮生长因子受体（EGFR）、表皮生长因子受体-2（HER-2）和环氧合酶-2（COX-2）的表达及与临床病理特征的关系。 方法 应用免疫组织化学Envision二步法，检测70例胃癌组织中EGFR、HER-2和COX-2的表达情况，并结合其临床病理特点进行分析。 结果 EGFR、HER-2和COX-2在胃癌组织中的表达阳性率分别为35.7%（25/70）、27.1%（19/70）、67.1%（47/70）。阳性表达与肿瘤分化程度、侵袭深度、有无淋巴结转移及TNM分期有关（P＜0.05），而与患者的性别及年龄、肿瘤部位和大小无关（Pgt;0.05）。EGFR、HER-2和COX-2三者之间在胃癌组织中的表达均呈正相关（P＜0.05）。 结论 EGFR、HER-2和COX-2的表达参与胃癌的生长、侵袭和转移过程。它们的联合检测有助于胃癌患者靶向药物的选择，也为胃癌的预后判断提供客观的参考指标。Objective To observe the expressions of epidermal growth factor receptor (EGFR), HER-2 and cyclooxygenase-2 (COX-2) in gastric carcinoma (GC) and to explore the relationship among them. Methods The envision immunohistochemical stain method was used to detect EGFR, HER-2 and COX-2 protein expressions in sample of 70 GC tissues. And their corresponding pathologic features were analyzed. Results The positive expression rates of EGFR, HER-2 and COX-2 protein in GC tissue were 35.7% (25/70), 27.1% (19/70) and 67.1% (47/70), respectively. The positive expression rates were closely relevant to the differentiation of the cancer, invasion depth, lymphatic metastasis and TNM (P＜0.05), but not to the patient’ s sex, age, tumor site and size (P＞0. 05). There was a stable positive correlation among EGFR, HER-2 and COX-2 expressions in GC tissues, respectively. Conclusions EGFR, HER-2 and COX-2 expressions participate in the development, invasion and metastasis process of GC. Combined detection can be regarded as an important symbol for guiding the molecular targeting therapy of GC, and judging the prognosis of GC.
Objective To investigate the relationship between the expressions of P-gp, GST-π and C-erbB-2 and clinicopathologic characteristics as well as prognosis in breast cancer. Methods The expressions of P-gp， GST-π and C-erbB-2 were detected by immunohistochemistry in 48 cases of breast cancer, and histopathologic characteristics as well as 5-year survival rate of these cases were analyzed. Results There was no significant difference in the expressions of P-gp and GST-π with age, histologic grade, number of lymph node metastasis and TNM stage of breast cancer ( P ＞ 0.05). There was significant difference in expression of C-erbB-2 with histologic grade, number of lymph node metastasis and TNM stage of breast cancer （ P ＜ 0.05）. Positive rate of P-gp expression in breast cancer with positive C-erbB-2 expression was remarkably higher than that in breast cancer with negative C-erbB-2 expression ( P ＜ 0.05) . Positive rate of GST-π and C-erbB-2 expression in survivals within 5 years was remarkably lower than that in deaths within 5 years ( P ＜ 0.01). Conclusion P-gp participates primary drug-resistance mechanism of breast cancer. The possibility of primary drug-resistance is higher in breast cancer with positive C-erbB-2 expression. The expression of C-erbB-2 helps to evaluate prognosis and the result of treatment in breast cancer.
To investigate the significance of epidermal growth factor receptor (EGFR) in thyroid carcinoma, the expression of EGFR in 81 samples of thyroid carcinoma were determined by immunohistochemical SP method and comparison among thyroid carcinoma, thyroid adenomas and normal thyroid tissue adjacent to the cancer were made. The results showed: EGFR expression was positive in 45 cases (55.6%) of thyroid carcinoma with no positive expression either in thyroid adenomas or normal thyroid tissue adjacent to the cancer (Ｐ＜0.01). There were no statistical differences between EGFR positive rate and thyroid carcinomatous pathological type, clinical stage, depth of invasion, lymph node metastasis or patients′ postoperative survival time (Ｐ＞0.05). This data suggests that expression of EGFR in thyroid carcinoma is associated with its autonomous growth and malignant phenotype, but it is probably not a useful index for assessing the biological behavious and prognosis of thyroid carcinoma.
Objective To investigate the feasibility of detection of epidermal growth factor receptor ( EGFR) exon 19 deletions and exon 21 L858R mutations in pleural effusion fromnon-small-cell lung cancer ( NSCLC) patients by mutant enriched PCR assay. Methods The mutations of exon 19 and 21 of EGFR gene in pleural samples fromthirty NSCLC patients were analyzed using both the mutant-enriched PCR assay and the non-enriched PCR assay. Results Ten ( 33. 3% , 10/ 30) exon 19 deletions and five ( 16. 7% , 5/30) exon 21 L858R mutation were detected by the mutant-enriched PCR assay, while only 6 cases ( 20. 0% ) and 1 case ( 3. 3% ) were detected by the non-enriched PCR assay respectively. The difference of mutation detection rate of EGFR gene between the two methods was statistically significant ( P = 0. 032) . Mutations were detected in all of partial responders ( 2 /4) among the four patients who received gefitinib therapy. Conclusions Mutant-enriched PCR assay can detect EGFR exon 19 deletions and exon 21 L858R mutation in pleural effusion from NSCLC patients effectively, economically and accurately. It may be a valuable biomarker for gefitinib therapy in advanced NSCLC.
Objective To explore the effects of prolonged inhalation of Aspergillus fumigatus ( Af)spores on epithelial cell injury and expression of epidermal growth factor receptor( EGFR) in airways of asthmatic rats. Methods 64 male Wistar rats were randomly divided into 8 groups, ie. chronic asthma group ( group A) , chronic asthma plus Af spores inhalation for 1 week ( group B) , 3 weeks ( group C) and 5 weeks ( group D) , chronic asthma plus saline inhalation for 5 weeks ( group E) , OVA-sensitized and salinechallenged group ( group F) , and OVA-sensitized and saline-challenged plus Af spores inhalation for 5 weeks ( group G) ( each n =8) . The airway resistance ( Raw) and change of Raw after acetylcholine provocation were detected using a computerized system. The concentrations of epidermal growth factor ( EGF) andtransforming growth factor alpha( TGF-α) in BALF were measured by ELISA. The extents of epithelial cell injury and goblet cell hyperplasia were evaluated on hematoxylin and eosin-stained( HE) and periodic acidschiff ( PAS) stained lung sections. The expression of EGFR in airway epithelia was demonstrated byimmunohistochemistry, and the level of EGFR protein in the rat lung tissues was measured by western blot.Results The concentration of EGF( pg/mL) ( 51. 72 ±8. 54, 68. 12 ±7. 85, 86. 24 ±9. 12, respectively)and TGF-α( pg/mL) ( 55. 26 ±9. 30, 75. 58 ±11. 56, 96. 75 ±14. 66, respectively) , detached/ inner perimeter of epithelium( % ) ( 11. 25 ±3. 12, 26. 45 ±5. 56, 28. 50 ±7. 50, respectively) , the ratio of goblet cell area to epithelial cell area ( % ) ( 16. 42 ±5. 24, 22. 64 ±6. 82, 36. 38 ±9. 21, respectively) , the integrated optical density ( IOD) of EGFR positive stain in airway epithelial cells ( 82 ±15,120 ±19, 165 ±21, respectively) , and the EGFR protein levels in lung tissues ( 0. 91 ±0. 26, 1. 61 ±0. 52, 2. 52 ±0. 78,respectively) in group B, C, and D were higher than those in group A, E, F and G( P lt; 0. 05 or P lt;0. 01) .The change rates of Raw( % ) ( 61. 91 ±5. 26, 84. 69 ±6. 38) in group C and D were higher than those in group A, E, F and G ( P lt; 0. 05 or P lt;0. 01) . The IOD of EGFR was positively correlated with detached/inner perimeter of epithelium( % ) and the ratio of goblet cell area to epithelial cell area( % ) ( r = 0. 692,P lt;0. 01; r = 0. 657, P lt; 0. 01, respectively) . Conclusion Prolonged inhalation of Aspergillus fumigatus spores can aggravate airway epithelial cell injury, up-regulate the expression of EGFR in airway epithelial cell and induce goblet cell hyperplasia, thus increase the airway responsiveness in rats with chronic asthma.
Objective To evaluate the effects of two different epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR-TKIs) , Gefitinib and Erlotinib, on lung fibrosis induced by bleomycin.Methods Forty BALB/c female mice were randomly divided into four groups, ie. a control group( saline given orally and intratracheally) , a fibrosis group( saline given orally with bleomycin instillation) , a Gefitnib group( Gefitnib 20 mg/kg given orally with bleomycin instillation) , and an Erlotinib group ( Erlotinib25 mg/kg given orally with bleomycin instillation) . Bleomycin ( 3 mg/kg) was intratracheally instilled on the first day. Gefitinib or Erlotinib was given orally daily and normal saline as control. Then they were sacrificed by abdominal aortic bleeding 14 days after the bleomycin instillation. The left lung was stained with HE and Masson’s trichrome staining respectively for pathological examination. Total EGFR and phosphorylated EGFR were detected by immunohistochemistry. Hydroxyproline ( HYP) assay was performed in the right lung.Results Both Gefitinib and Erlotinib significantly reduced lung collagen accumulation and the content of HYP. Immunohistochemistry revealed that phosphorylation of EGFR in lung mesenchymal cells induced by bleomycin was inhibited. Furthermore, there was no difference between Gefitinib and Erlotinib in inhibiting lung fibrosis. Conclusion Our findings suggest that, in the preclinical setting, EGFR-TKIs may have aprotective effect on lung fibrosis induced by bleomycin.
Objective To evaluate the clinical significance of epidermal growth factor receptor EGFR) mutations in the treatment of non-small cell lung cancer ( NSCLC) . Methods Plasma DNAs solated fromblood specimens of 170 NSCLC patients, who were admitted in the First Affiliated Hospital of uangzhou Medical College from December 2005 to December 2007, were subjected to the test of EGFR utant-enriched PCR. The correlation of mutant detection with clinical characteristics was analyzed as well.Results Out of the total 170 patients, EGFR mutations were identified in 77 cases ( 77 /170, 45. 3% ) .EGFR mutations were more frequent in the patients with adenocarcinoma ( P lt; 0. 001) and in the nonsmokers P =0. 001) . In the 33 patients treated with gefitinib, those with mutations ( + ) showed a higher esponse rate and prolonged progression-free survival after the treatment compared with those with mutations( - ) ( P =0. 001 and 0. 001, respectively) . Conclusions EGFR active mutations can be specifically and ensitively detected by EGFR mutant enriched PCR assay. Plasma EGFR mutants detection is valuable in uiding clinical decision.
Abstract： Objective To investigate the expression and correlation of phosphatase and tensin homologue deleted on chromosome ten(PTEN)， epidermal growth factor receptor(EGFR) and Ki-67 in human thymic tumors, and their possible role in tumor genesis， infiltration and metastasis. Methods The expression of PTEN， EGFR and Ki-67 were detected by using SP immunohistochemical technique in 45 cases of thymic tumors and 5 cases of normal thymic tissues. Results In 5 cases of normal thymic tissues, the expression of PTEN was bly positive, whereas EGFR and Ki -67 were weakly positive or negative. In 45 cases of thymic tumors, the positive ratio of PTEN were significantly reduced from benign thymoma， invasive thymoma to thymic carcinoma (χ2=7.808, P=0.020), but the positive ratio of EGFR and Ki-67 were gradually increased(χ2=8.032, 0.018，7.006；P=0.030). The positive ratio of PTEN， EGFR and Ki-67 protein were significantly related to Levine classification, Masaoka staging and lymph node metastasis (Plt;0.05). PTEN positive cases were negatively correlated with EGFR and Ki-67(r=－0.632，－0.653；Plt;0.01), EGFR positive cases were positively correlated with Ki-67 in thymic tumors(r=0.807,Plt;0.01). Conclusions Reduced or absent PTEN and increased EGFR and Ki-67 expression might play an important role in the genesis， invasiveness and metastasis of thymic tumors. The expression of PTEN is bly associated with the expression of abnormal EGFR and Ki-67. Detection of the three protein expressions simultaneously might be more helpful in making an early diagnosis of the tumors jndgement of theirs malignant degree，invasiveness and metastasis capacity, as well as the prognosis.