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.
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.
Objective To investigate the effect of topical external administration of recombinant human epidermal growth factor (rhEGF) when controll ing blood sugar on expression of epidermal growth factor receptor (EGFR) and EGFR mRNA of wound in diabetes mell itus (DM) combined with scald. Methods A total of 136 male Wistar rats weighing (188.57 ± 6.59) g were randamly divided into 4 groups (groups A, B, C, and D, n=34). The rats was made DM model by intraperitoneal injected 60 mg/kg streptozocin in groups A, B, and C; rats were injected buffer alone in group D as control group. After 8 weeks, the rats of 4 groups were placed in 80℃ hot water for 6 seconds for preparation of the back deep II degree scald model. In group A, the blood sugar level was controlled at the level of group D 1 week before scald model; within 24 hours after models preparation, rhEGF was sprayed on wound at 150 U/cm2 . In group B, the rats were given the same treatment as group A except not controll ing blood sugar. In group C, the blood sugar was controlled as group A and wound was suture fixation with 1% silver sulfadiazine cream at 24 hours after the model. In group D, the same treatment as group A was given after injury. The heal ing rate of the wound was detected at 3, 7, 11, 15, and 21 days after injury; the EGFR mRNA expression was determined by mRNA hybridization in situ, and the EGFR protein expression was deterimined by immunohistochemistry and Western blot at 1, 3, 5, 7, 11, 15, and 21 days. Results All the rats survived at the end of experiment. There was no significant difference in the heal ing rate of the wound among the 4 groups at 3 days (P gt; 0.05). The heal ing rate of the wound was significantly higher in groups A and D than in groups B and C (P lt; 0.05) at 7, 11, 15, and 21 days. The expession of EGFR mRNA in 4 groups was observed by hybridization in situ, which mainly distributed in the dermal fibroblasts, capillary endothel ial cells and remnants of skin and wound edge epithel ium of the subsidiary; the expessions reached the peak at 5 days in group A, at 7 days in groups B and C, and at 11 days in group D; and the peak level was significantly higher in groups A and D than in groups B and C (P lt; 0.05). Immunohistochemistry and Western blot showed that the expession of EGFR protein was observed in 4 groups and reached the peak level at 7 days in groups A and B, and at 11 days in groups C and D; showing significant difference between groups B, C and groups A, D (P lt; 0.05). Conclusion External appl ication of rhEGF when controll ing blood sugar can accelerate obviously the wound heal ing in DM combined with scald. After controll ing blood sugar, external appl ication of rhEGF can boost obviously the expressions of EGFR mRNA, EGFR, and the extending process of signal conduction.
OBJECTIVE: To explore the expressive characteristics of epidermal growth factor (EGF) and its receptor (EGFR) in tissues of fetal and adult intestines. METHODS: The expression intensity and distribution of EGF and EGFR were detected with pathological and immunohistochemical methods in 6 specimens of adult (16-54 years) intestines and 18 specimens of fetal intestines with different gestational ages (13-31 weeks). RESULTS: Positive protein particles of EGF and EGFR could be detected in tissues of fetal and adult intestines. The protein expressions of EGF and EGFR were elevated progressively with the gestational age. EGF was mainly located in the cytoplasm and extracellular matrix of intestinal villus cells, endothelial cells and tunica serosa epithelial cells, while EGFR chiefly distributed in the cellular membrane of these cells. CONCLUSION: The endogenous EGF and EGFR might be involved in the intestinal development at embryonic stage, in the structural and functional maintenance at adult stage, and in the wound healing after injury.
Objective To explore the effect of membrane surface nucleolin （NCL） on activation of epidermal growth factor receptor （EGFR） signaling. Methods Immunohistochemistry was used to identify the expressions of membrane surface NCL or EGFR in pallilary thyroid carcinoma （PTC） tissues. The level of phosphorlated EGFR in TPC-1 cells was observed by Western blot. TPC-1 cells invasion capacity was detected by Transwell assay. Results The posi-tive expression rates of membrane surface NCL and EGFR in PTC tissues were 100% （56/56） and 80.4% （45/56） respe-ctively， while the expressions of NCL and EGFR were related with lymph node metastasis （P＜0.05）. There was posi-tive correlation between the expressions of NCL and EGFR （r=0.635， P＜0.01）. Western blot showed that anti-NCL or anti-EGFR of TPC-1 cells could inhibit the expression of phosphorlation EGFR （P＜0.01）. Transwell assay showed the number of membrane-invading cells were reduced significantly in anti-NCL group anti-EGFR group （P＜0.01）. Conclusions Membrane surface NCL may be a kind of indispensable component in activation of EGFR signaling， by which EGFR can participate in growth and invasion of tumors. NCL can be used as a target for developing a new field of tumor treatment.