Expression of a truncated epidermal growth factor receptor in oral squamous cell carcinomas

Epidermal growth factor receptor (EGFR) frequently overexpresses in cancers, including oral squamous cell carcinomas (OSCC). We previously identified a truncated EGFR (tEGFR) in human oral keratinocytes. In this study, we evaluated the prognostic value of tEGFR in 45 cases of OSCC. tEGFR expression inversely correlated with EGFR expression (r=-0.83, P<0.01), decreased with T-stage progression and lymph-node metastasis (P<0.05). The EGFR/tEGFR ratio correlated with the lymph-node metastasis (P<0.05) and survival outcome (hazard ratio =3.601; P<0.05). These results suggest that tEGFR may play an important roles in oral carcinogenesis and that the EGFR/tEGFR ratio may be a prognostic factor for OSCC.     

Expression of epiregulin, a novel epidermal growth factor ligand associated with prognosis in human oral squamous cell carcinomas

We examined the expression of epiregulin and amphiregulin mRNA in 39 oral SCCs, 2 epithelial dysplasias and 7 normal gingivae by real-time RT-PCR. The mean expression level of epiregulin mRNA was higher in oral SCCs (0.29+/-0.50) than normal gingivae (0.01+/-0.007) and epithelial dysplasias (0.01+/-0.001). The expression level of epiregulin mRNA was significantly higher in oral SCCs than normal gingivae (Mann-Whitney U test, P=0.023). Epiregulin mRNA was higher in stage III/IV than in stage I/II oral SCCs. However, a significant association was not found. The mean expression level of amphiregulin mRNA was higher in oral SCCs (0.18+/-0.24) than normal gingivae (0.002+/-0.003) and epithelial dysplasias (0.01+/-0.001). Amphiregulin mRNA was significantly higher in oral SCCs than normal gingivae (Mann-Whitney U test, P=0.001). We then examined the expression of four EGF receptor mRNA in oral SCCs. The expression levels of HER1, HER2, HER3 and HER4 mRNA in oral oral SCCs were increased compared to those in normal gingivae. A significant correlation was found between the mRNA expression levels of epiregulin and HER2, HER3 and HER4 (Spearman's correlation coefficient by rank test, P=0.031, P=0.004 and P=0.027, respectively). Patients with oral SCC that have a high expression of epiregulin had a significantly shorter survival than those with low a expression (log-rank test, P<0.05). These results indicate that human epiregulin is closely linked to the increased or abnormal cell proliferation in human oral SCC.     

Histological malignancy grading of oral squamous cell carcinomas

A modification of Jakobsson's criteria that determines the mode of cancer invasion (Yamamoto, 1982) has been reported to be useful in predicting the prognosis in patients with an oral squamous cell carcinoma. In this retrospective study, a five-factorial grading system of the histological malignancy (+ the differentiations, the nuclear polymorphism, the mitoses, and the cellular response) was evaluated in relation to clinical course of each patient. Result: 75 cases were classified into four grades from Grade 1, the lowest malignancy, to Grade 4, the highest malignancy. The percentage metastases was 10, 24, 54, and 75% for each grade, respectively. The percentage of survival was 75, 75, 35, and 25% for each grade, respectively. From these results, this grading system was seen to have a close-correlation with the clinical course of each patient.     

Quantitative assay of epidermal growth factor receptor in human squamous cell carcinomas of the oral region by an avidin-biotin method

A quantitative assay method for epidermal growth factor receptors (EGFRs) of human tumor tissues was established, based on enzyme-labeled avidin-biotin (LAB) interaction with anti-human EGFR monoclonal antibody 528IgG. A standard calibration curve for EGFR estimation in human tumor tissues was obtained with A431#8 cells cloned from A431 human epidermoid carcinoma cell line. The coefficient of variance for the standard curve was below 35% in the application to tumor tissues from nude mice implanted with human tumor cell lines. The minimum tissue amount required for the quantitative assay was around 0.1 g (wet weight). Using the LAB method, the correlation between the level of EGFR number and tumor malignancy was examined for 14 human squamous cell carcinomas (SCCs) from the oral region. Seven of the SCCs showed a more than two-fold higher EGFR number compared to normal gingival tissues. Three highly aggressive carcinomas with poor prognosis possessed five to ten times higher levels of EGFR number than normal tissues. The elevated EGFR level in the SCCs seems to correlate to increasing tumor size and the stage of SCCs as clinically classified according to the 1987 UICC TNM system.     

Prognostic significance of epidermal growth factor receptor in esophageal squamous cell carcinomas

The prognostic value of epidermal growth factor (EGF) receptor level was studied in 32 patients with esophageal squamous cell carcinoma. The EGF receptor levels of tumors were measured by iodine 125 (125I)-EGF binding assay, and the patients subsequently were divided into two groups: a group with high EGF binding capacities (greater than or equal to 2.5% of input), and a group with low EGF binding capacities (less than 2.5% of input). The cumulative survival rates for the two groups were calculated by the Kaplan-Meier method. The generalized Wilcoxon test indicated that the survival rate of the high EGF binding group was significantly lower than that of the low EGF binding group (P less than 0.05). In tumors from two patients with the highest EGF receptor levels, EGF receptor gene amplification was observed. These patients developed mediastinal lymph node metastasis and died 4 and 11 months after surgery, respectively. These results suggest that elevated EGF receptor level is a significant prognostic indicator for esophageal squamous cell carcinoma.     

Hyperproduction and gene amplification of the epidermal growth factor receptor in squamous cell carcinomas

Human squamous cell carcinoma tissue was screened to determine the epidermal growth factor (EGF) receptor level. In 9 out of 15 cases, increased EGF binding was observed relative to normal adjacent tissue. In two tissue samples (SCE1 and SCL1), amplification of the EGF receptor gene and increased mRNA level were also observed. In two other cases (SCE2 and SCL3), EGF receptor gene amplification did not occur. We propose that there is an alternative mechanism for EGF receptor hyperproduction, independent of gene content, active in these tissues. A possible role of EGF receptor hyperproduction is envisioned in human neoplasia.     

Expression of epidermal growth factor receptor in human gastric and colonic carcinomas

The expression of epidermal growth factor (EGF) receptor was examined immunohistochemically in a total of 122 gastric and 61 colonic carcinomas, out of which 16 gastric and 8 colonic carcinomas were also examined by 125I-labeled EGF binding analysis and Western blotting. The values of EGF binding were 12.68 +/- 1.98 (SE; n = 16) fmol/mg protein in gastric carcinomas and 5.72 +/- 2.15 (n = 8) fmol/mg protein in nonneoplastic gastric mucosa, the difference being significant (P less than 0.01). In the colonic tissue, the binding capacities in carcinomas and nonneoplastic mucosa were 13.29 +/- 4.17 (n = 8) and 10.68 +/- 0.41 (n = 3) fmol/mg protein, respectively. Scatchard analysis of 125I-labeled EGF binding indicated a single class of receptors in gastric and colonic carcinomas with an apparent Kd value of from 111 to 277 (n = 4) and from 87.4 to 341 fM (n = 5), respectively, except for one gastric carcinoma having two classes of receptors (Kd = 15.9 and 896 fM). In Western blotting using monoclonal anti-EGF receptor antibody, various levels of EGF receptor expression were detected in 12 (85.7%) of the 14 gastric carcinomas and in 7 (87.5%) of the 8 colonic carcinomas. Immunohistochemically, EGF receptor immunoreactivity was detected in one (3.8%) of the 26 early gastric carcinomas, while it was observed in 33 (34.4%) of the 96 advanced gastric carcinomas, the incidence between the two being significantly different (P less than 0.01). In the colonic carcinomas, 47 (77.1%) of the 61 cases showed positive immunoreactivity to EGF receptor, which did not differ by histological type.     

表皮生长因子受体在人头颈部鳞状细胞癌中的作用研究进展

头颈部鳞状细胞癌（head and neck squamous cell carcinoma,HNSCC）是常见的恶性肿瘤,恶性程度较高,患者常出现复发和转移。表皮生长因子受体（epidermal growth factor receptor,EGFR）是重要的癌基因,在头颈鳞癌中广泛过表达,且与HNSCC患者的预后呈负相关,是重要的治疗靶点。但HNSCC中的EGFR靶向治疗效果却不如在非小细胞肺癌治疗中那么有效。近几年的研究发现,EGFR促进肿瘤细胞对治疗耐受的机制可能与其过表达、突变、单核苷酸多态性、入核和自噬有关。本文将就这几个方面进行综述,并探讨如何在HNSCC的治疗中更有效地利用EGFR这一靶点,为探索HNSCC的治疗策略提供新的方向。      

口腔鳞癌组织中基质金属蛋白酶-9和血管内皮生长因子的表达及临床意义

背景与目的:基质金属蛋白酶-9(matrixmetalloproteinase-9,MMP-9)与肿瘤浸润转移密切相关,近年来发现它与肿瘤血管形成也有关。本研究旨在探讨MMP-9和血管内皮生长因子(vascularendothelialgrowthfactor,VEGF)在口腔鳞状细胞癌组织中的表达及与肿瘤浸润、转移的关系。方法:运用免疫组化SP法,对51例口腔鳞状细胞癌、10例口腔鳞状细胞乳头状瘤以及10例正常口腔粘膜的石蜡包埋标本中MMP-9和VEGF表达进行联合检测。结果:MMP-9和VEGF在正常口腔粘膜和口腔鳞状细胞乳头状瘤中均呈阴性或弱阳性表达。口腔鳞状细胞癌中MMP-9的阳性表达率为78.4%(40/51);VEGF阳性表达率为82.4%(42/51);同时表达MMP-9和VEGF的阳性率是66.7%(34/51)。结论:MMP-9和VEGF在口腔鳞状细胞癌组织中有差异性表达;肿瘤细胞浸润与MMP-9表达关系最密切(P<0.01);颈淋巴结转移与否同VEGF表达水平高低密切相关(P<0.01)。MMP-9和VEGF可作为临床评估口腔鳞状细胞癌浸润、转移潜能的生物学指标。     

Immunohistologic detection of the epidermal growth factor receptor in human esophageal squamous cell carcinoma.

Epidermal growth factor receptor (EGF-R) expression was studied immunohistologically in 38 patients with esophageal squamous cell carcinoma. The EGF-R was faintly expressed in basal and parabasal layers of normal esophageal epithelia and in cancer nests of 20 patients; it was strongly expressed in all areas of dysplastic epithelia and in cancer nests of 18 patients. The patients with strongly expressed EGF-R had lymph node metastases more frequently, and their prognosis was poorer than those with faintly expressed EGF-R. The EGF-R expression showed a mosaic pattern in 17 patients and a diffuse pattern in 21 patients. The patients with a mosaic pattern had lymph node metastases more frequently and a worse prognosis than those with a diffuse pattern. Expression of EGF-R in metastatic lymph nodes was similar to that in strongly expressing areas of primary cancers with a mosaic pattern. Thus EGF-R expression may be an important indicator for malignancies of esophageal squamous cell carcinomas because primary cancer cells with strongly expressed EGF-R metastasize to lymph nodes more frequently.     

CD44V3在口腔鳞状细胞癌组织中的表达

目的:研究细胞黏附分子CD44v3在口腔鳞状细胞癌中的表达及其与临床病理因素的关系.方法:采用免疫组织化学法(SP法)检测42例原发口腔鳞状细胞癌及其中13例转移淋巴结内CD44v3的表达,并分析其与口腔鳞癌患者的年龄、性别、肿瘤分化程度、淋巴结转移等临床病理因素的关系.结果:13例发生淋巴结转移的病例中,在原发灶内CD44v3表达强度高于对应的转移灶,差异有统计学意义(P ＜0.05);42例原发灶中CD44v3表达强度,在有淋巴结转移组与无淋巴结转移组之间表达差异无统计学意义(P＞0.05).CD44v3表达与患者的年龄、性别、病理分级等因素均无相关性.结论:CD44v3的表达可能与口腔鳞癌转移有关.     

Cyclin D1在口腔鳞癌中的表达及临床意义

目的 探讨口腔鳞状细胞组织中Cyclin D1的表达与临床和病理学特征之间的关系。方法 应用免疫组化Envision二步法检测43例口腔鳞癌组织中Cyclin D1的表达情况，并将其阳性表达率与口腔鳞癌的患者性别、临床分期、病理分化程度、淋巴结转移情况以及预后做统计学分析。结果 Cyclin D1在口腔鳞癌中的阳性表达率增加，其阳性表达率与颈淋巴结转移和预后相关，但与患者性别、病理分化程度以及临床分期之间无相关性。结论 Cyclin D1异常表达在口腔鳞癌的发生、发展中发挥了重要作用，可作为判断口腔鳞癌颈淋巴结转移和预后的一个重要指标。     

Expression of epidermal growth factor receptors on normal human gastric epithelia and gastric carcinomas

Tissues of normal human gastric mucosae and 15 advanced gastric carcinomas were studied immunohistologically for the presence of receptors for epidermal growth factor (EGF) by use of a murine monoclonal antibody (528IgG), which reacts with the binding domain of human EGF receptor. On normal gastric mucosae, only parietal cells showed positive staining. On cancer tissues, definite staining was observed in 9 of 15 cases. Their staining intensities were variable and weaker in general compared to those of either gastric parietal cells or normal tonsilar squamous epithelium. No apparent correlation of EGF receptor staining with the grade of histologic differentiation or lymph node metastases of these gastric carcinomas was noted.     

Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer.

PURPOSE: The transforming growth factor alpha-epidermal growth factor receptor (EGFR) autocrine pathway has been implicated in prostate cancer cell growth. Amplification and/or overexpression of c-erbB-2, a receptor closely related to the EGFR, has been recently involved in prostate cancer progression. We investigated EGFR and c-erbB-2 expression in primary androgen-dependent and in advanced androgen-independent prostate cancer and their potential role as markers of disease progression. EXPERIMENTAL DESIGN: EGFR and c-erbB-2 expression were evaluated by immunohistochemistry in a consecutive series of 74 prostate cancer patients with the following characteristics: 29 patients (group 1) treated with radical prostatectomy; 29 patients (group 2) treated with luteinizing hormone-releasing hormone analogues and antiandrogen therapy followed by radical prostatectomy; and 16 patients with hormone-refractory metastatic disease. In all patients we evaluated: association between EGFR and/or c-erbB-2 expression and clinicopathological parameters; and disease-free survival according to EGFR and c-erbB-2 expression in univariate analysis (Kaplan-Meier product-limit method) and in multivariate analysis (Cox proportional hazards regression model). RESULTS: EGFR expression was found in 12 of 29 (41.4%) group 1 patients, in 22 of 29 (75.9%) group 2 patients (P < 0.0005), and in 16 of 16 (100%) metastatic patients (P < 0.005), whereas c-erbB-2 expression was found in 11 of 29 (37.9%) group 1, in 10 of 29 (34.5%) group 2 patients, and in 9 of 16 (56.3%) metastatic patients. A significant association was found between EGFR expression and a high Gleason score (P < 0.01) and between EGFR expression and higher serum prostate-specific antigen values (P < 0.02) in all groups of patients. Among the 58 patients treated with radical prostatectomy, 23 of 34 EGFR-positive patients (67.6%) relapsed, whereas only 2 of 24 EGFR-negative patients (8.3%) relapsed (P < 0.00004). c-erbB-2 expression did not significantly correlate with disease relapse (P = 0.07). In a Cox multivariate analysis, the only parameter with an independent prognostic effect on disease-free survival was EGFR expression (relative hazard, 11.23; P = 0.0014). CONCLUSIONS: EGFR expression increases during the natural history of prostate cancer. Correlation with disease progression and hormone-refractory disease suggests that EGFR-targeted drugs could be of therapeutic relevance in prostate cancer.     

Expression of the epidermal growth factor receptor in human small cell lung cancer cell lines.

Epidermal growth factor (EGF) receptor expression was evaluated in a panel of 21 small cell lung cancer cell lines with radioreceptor assay, affinity labeling, and Northern blotting. We found high-affinity receptors to be expressed in 10 cell lines. Scatchard analysis of the binding data demonstrated that the cells bound between 3 and 52 fmol/mg protein with a KD ranging from 0.5 x 10(-10) to 2.7 x 10(-10) M. EGF binding to the receptor was confirmed by affinity-labeling EGF to the EGF receptor. The cross-linked complex had a M(r) of 170,000-180,000. Northern blotting showed the expression of EGF receptor mRNA in all 10 cell lines that were found to be EGF receptor-positive and in one cell line that was found to be EGF receptor-negative in the radioreceptor assay and affinity labeling. Our results provide, for the first time, evidence that a large proportion of a broad panel of small cell lung cancer cell lines express the EGF receptor.     

Clinical significance of the epidermal growth factor receptor gene in squamous cell carcinomas of the nasal cavities and paranasal sinuses.

The authors retrospectively analyzed epidermal growth factor receptor (EGFR) gene amplification in 49 cases of squamous cell carcinoma (SCC) arising from the nasal cavities (NC) and paranasal sinuses (PS) by using slot-blot analysis of DNA extracted from formalin-fixed, paraffin-embedded tissues. Also, the relationship between the results of gene analysis and the clinical features of the patients was studied to investigate the clinical significance of the EGFR in SCC of the NC and PS. Amplification of the EGFR gene was detected in 5 of the 49 cases (10%). No significant difference was observed between EGFR gene amplification and the presence of lymph node metastases, local recurrence, or prognosis. This suggests that EGFR gene amplification is not related to the local progression or metastasis of the SCC in the NC and PS. In addition, it appears that amplification of the EGFR gene is not a prognostic indicator for SCC in the NC and PS.     

Expression of vascular endothelial growth factor and prognosis of oral squamous cell carcinoma

The correlation between expression of vascular endothelial growth factor (VEGF) and prognosis for oral squamous cell carcinoma was investigated. Tissue samples of oral squamous cell carcinoma were obtained from 63 patients. Of these patients, 11 had stage I, 17 had stage II, 9 had stage III, and 26 had stage IV tumours. Immunohistochemical expression of VEGF was quantitatively determined by computer-assisted image analysis. The value of VEGF expression was significantly higher for the patients with poor prognosis than for those with good prognosis (P=0.0423). Regarding regional lymph node metastasis, VEGF showed no significant difference between metastasis positive and negative patients. Expression of VEGF may thus be a prognostic marker for oral squamous cell carcinoma.