Coordinated epidermal growth factor receptor pathway gene overexpression predicts epidermal growth factor receptor inhibitor sensitivity in pancreatic cancer

The epidermal growth factor receptor (EGFR) inhibitor erlotinib is approved for treatment of pancreatic cancer but the overall activity is minimal, and known predictive factors for EGFR inhibitor efficacy are infrequent in this disease. We tested the hypothesis that global activation of the EGFR pathway is predictive of EGFR inhibitor efficacy. Pancreatic cancer tumors directly xenografted at surgery were treated with the EGFR inhibitors erlotinib and cetuximab and analyzed for biological features. Two of 10 tumors were sensitive, and by global gene expression profiling with gene set enrichment analysis, the EGFR pathway was highly expressed in sensitive compared with resistant tumors. The core gene components driving EGFR pathway overexpression were pathway ligands and positive effectors. In a prospective validation, the EGFR pathway-based signature correctly predicted anti-EGFR treatment response in eight additional tumors and was not predictive of response to gemcitabine and CI1040 (a MEK inhibitor). Analysis of EGFR, KRAS, and PIK3CA mutations and gene amplification by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification showed that none of these genetic abnormalities were neither predictive nor responsible for the EGFR pathway activation. Coordinated overexpression of the EGFR pathway predicts susceptibility to EGFR inhibitors in pancreatic cancer. These results suggest a phenomenon of pathway addiction and support the value of unbiased system biology approaches in drug development.     

Protein overexpression and gene amplification of epidermal growth factor receptor in adult testicular germ cell tumors: Potential role in tumor progression

Little is known about the pathologic significance of epidermal growth factor receptor (EGFR) expression in malignant testicular germ cell tumors (TGCTs) in adults. From the primary tumor sites of a cohort of 110 TGCT cases, we obtained 209 histologically distinct components: 53 intratubular germ cell neoplasia unclassified (IGCNU) lesions, 83 seminomas (66 pure‐form seminomas and 17 seminoma components in the mixed‐form with nonseminomatous TGCTs), 27 embryonal carcinomas, eight choriocarcinomas, 18 yolk sac tumors, and 20 immature teratomas. Samples were analyzed for expression of EGFR protein and EGFR gene amplification by immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. Overexpression of the EGFR protein was detected in 28% of seminomas (27% in the pure‐form and 29% in the mixed‐form), 11% of embryonal carcinomas, 88% of choriocarcinomas, 44% of yolk sac tumors, and none of the IGCNU lesions or immature teratomas. A higher copy number (≥4 copies per cell) and amplification of the EGFR gene were detected in 20% and 10% of seminomas, 13% and 0% of embryonal carcinomas, 71% and 60% of choriocarcinomas, 15% and 8% of yolk sac tumors, and none of the IGCNU lesions or immature teratomas, respectively. Both higher copy number and amplification of the EGFR gene were positively correlated with immunohistochemical overexpression of EGFR protein (each P < 0.0001). These results suggest that overexpression of EGFR protein and increased copy number or amplification of the EGFR gene occur relatively frequently in primary TGCTs, and may play roles in the formation of invasive cancer and in the progression, especially morphological evolution, of tumors. (Cancer Sci 2010)     

Human epidermal growth factor receptor 2 overexpression in breast cancer of patients with anti-Yo--associated paraneoplastic cerebellar degeneration

Isolated case reports suggest that breast tumors from patients with paraneoplastic cerebellar degeneration (PCD) and Yo antibodies overexpress human epidermal growth factor receptor 2 (HER2). HER2 overexpression is present in 15%-25% of breast cancers and is associated with poor prognosis. We retrospectively analyzed the status of HER2 in breast tumors of 27 patients with anti-Yo-associated PCD to evaluate whether HER2 overexpression in this group of patients is higher than expected. In addition, we analyzed HER2 status of 19 breast tumors from patients with paraneoplastic neurological syndromes and Ri antibodies to see whether HER2 was specifically related to anti-Yo-associated PCD. We also assessed cdr2 expression (the onconeural antigen recognized by Yo antibodies) in 21 HER2-positive breast tumors from patients without paraneoplastic neurological syndromes. HER2 was overexpressed in 26 patients (96.3%) with anti-Yo-associated PCD but only in 2 patients (10.5%) with paraneoplastic neurological syndromes associated with Ri antibodies (P< .0001). Only 5 (23.8%) of the 21 HER2-positive breast tumors showed cdr2 immunoreactivity. This study shows a very high frequency of HER2 overexpression in breast cancers in patients with anti-Yo-associated PCD but not in those from patients with Ri antibodies. Although the expression of cdr2 onconeural antigen is not high in HER2-positive breast cancers, HER2 overexpression seems to be an important requirement to develop an anti-Yo-associated PCD.     

表皮生长因子、雄激素受体和表皮生长因子受体在肝癌组织中的表达及影响因素分析

目的探讨肝癌患者肝癌组织中的表皮生长因子(EGF)、雄激素受体(AR)、表皮生长因子受体(EGFR)的表达情况及临床意义。方法采用免疫组织化学染色法检测EGF、AR、EGFR在90例肝癌患者的肝癌组织和90例非肝癌患者的非肝癌组织中的表达情况,比较不同临床特征肝癌患者肝癌组织中EGF、AR、EGFR的表达情况,分析肝癌患者肝癌组织中EGF、AR、EGFR表达的影响因素。结果肝癌组织中的EGF、AR、EGFR的阳性表达率均明显高于非肝癌组织,差异均有统计学意义(P﹤0.01)。有肝炎史、Ⅲ+Ⅳ期、中低分化、有淋巴结转移的肝癌患者肝癌组织中EGF、AR、EGFR的阳性表达率均高于无肝炎史、Ⅰ+Ⅱ期、高分化、无淋巴结转移的肝癌患者,差异均有统计学意义(P﹤0.05);不同年龄、性别、肿瘤直径的肝癌患者肝癌组织中EGF、AR、EGFR的阳性表达率比较,差异均无统计学意义(P﹥0.05)。Logistic回归分析结果显示,有淋巴结转移、TNM分期为Ⅲ+Ⅳ期是肝癌患者肝癌组织中EGF、AR、EGFR表达的独立危险因素。结论EGF、AR、EGFR在肝癌患者的肝癌组织中呈高表达,且其表达与肝癌患者的淋巴结转移情况和TNM分期密切相关。     

Involvement of epidermal growth factor receptor overexpression in the promotion of breast cancer brain metastasis

BACKGROUND:

Brain‐metastatic breast cancer (BMBC) is increasing and poses a severe clinical problem because of the lack of effective treatments and because the underlying molecular mechanisms are largely unknown. Recent work has demonstrated that deregulation of epidermal growth factor receptor (EGFR) may correlate with BMBC progression. However, the exact contribution that EGFR makes to BMBC remains unclear.

METHODS:

The role of EGFR in BMBC was explored by serial analyses in a brain‐trophic clone of human MDA‐MB‐231 breast carcinoma cells (231‐BR cells). EGFR expression was inhibited by stable short‐hairpin RNA transfection or by the kinase inhibitor erlotinib, and it was activated by heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF). Cell growth and invasion activities also were analyzed in vitro and in vivo.

RESULTS:

EGFR inhibition or activation strongly affected 231‐BR cell migration/invasion activities as assessed by an adhesion assay, a wound‐healing assay, a Boyden chamber invasion assay, and cytoskeleton staining. Also, EGFR inhibition significantly decreased brain metastases of 231‐BR cells in vivo. Surprisingly, changes to EGFR expression affected cell proliferation activities less significantly as determined by a 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay, an anchorage‐independent growth assay, and cell cycle analysis. Immunoblot analysis suggested that EGFR drives cells' invasiveness capability mainly through phosphoinositide 3‐kinase/protein kinase B and phospholipase C γ downstream pathways. In addition, EGFR was involved less in proliferation because of the insensitivity of the downstream mitogen‐activated protein kinase pathway.

CONCLUSIONS:

The current results indicated that EGFR plays more important roles in cell migration and invasion to the brain than in cell proliferation progression on 231‐BR cells, providing new evidence of the potential value of EGFR inhibition in treating BMBC. Cancer 2012. © 2012 American Cancer Society.     

表皮生长因子受体在肿瘤放射治疗中的作用

表皮生长因子受体(EGFR)是调节肿瘤细胞生长的重要因子之一,在肿瘤的恶性生物学行为中发挥重要作用,与肿瘤放疗抗拒密切相关。EGFR过表达的肿瘤放疗效果差,易复发,预后不良。EGFR已成为肿瘤靶向治疗的重要靶标,抗EGFR治疗具有肿瘤放疗增敏作用。     

宫颈癌和宫颈上皮内瘤变中表皮生长因子受体表达与人乳头瘤病毒16和(或)18感染及其相互关系

目的探讨宫颈癌发生发展过程中,表皮生长因子受体(EGFR)与人乳头瘤病毒(HPV)的作用及其相互关系。方法宫颈癌组60例,选自1997年至2001年间中山大学肿瘤防治中心住院初治的宫颈癌病例,临床分期Ⅰa～Ⅱb期;宫颈上皮内瘤变(CIN)组40例;正常上皮对照组30例。以免疫组化S-P法检测宫颈组织EGFR的表达,以PCR检测HPV16和(或)HPV18感染。结果正常上皮组、CIN组和宫颈癌组的EGFR中强表达率呈梯度上升,分别为0、42.5%和76.7%,差异有统计学意义(P<0.05)。正常上皮组、CIN组和宫颈癌组的HPV16和(或)HPV18感染率分别为6.7%、67.5%和58.3%,宫颈癌组和CIN组的感染率均显著高于正常上皮组(P=0.000),但宫颈癌组与CIN组之间,差异无统计学意义(P=0.355)。肿瘤侵袭程度超过宫颈1/2间质者,EGFR中强表达率显著高于未达1/2间质者(89.2%:56.5%,P=0.004)。宫颈管侵袭者HPV16和(或)HPV18感染率显著高于无侵袭者(88.2%:46.5%,P=0.003)。EGFR与HPV之间无显著相关性(P>0.05)。EGFR与HPV均未显示与宫颈癌预后有关。结论EGFR和HPV与宫颈癌的发生发展有关;EGFR、HPV16和(或)HPV18与宫颈癌预后无关,EGFR与HPV16和(或)HPV18无显著相关性。     

Targeting epidermal growth factor receptor in lung cancer

Among the most promising agents in clinical development to treat non-small-cell lung cancer (NSCLC) are the epidermal growth factor receptor (EGFR) targeting agents. A series of recent studies have demonstrated the activity of anti-EGFR targeted therapies for NSCLC. In advanced NSCLC that is refractory to chemotherapy, antitumor responses have been reported with EGFR tyrosine kinase inhibitors (ZD1839 and OSI-774). The role of ZD1839 and OSI-774 as possible additions to standard chemotherapy in the first-line setting has also been evaluated, and the studies conducted to date should respond to the question of whether these compounds could provide a survival benefit. Other areas of research involve looking at the role of EGFR tyrosine kinase inhibitors in the neoadjuvant treatment of stage III NSCLC and the planning of chemoprevention studies. These exciting results and plans are further complemented by an emerging number of compounds in clinical development, including both monoclonal antibodies (ie, IMC-C225) and other tyrosine kinase inhibitors, directed at the EGFR.     

表皮生长因子受体、血管内皮生长因子受体和BAD在非小细胞肺癌中的表达

背景与目的：表皮生长因子受体（epidermal growth factor receptor，EGFR）和血管内皮生长因子受体（vascular endothelial growth factor receptor，VEGFR）均属酪氨酸激酶受体（receptor tyrosine kinase，RTK），可调控细胞的增殖、分化与生存。BAD是Bcl-2家族中的促凋亡信号成分，在调控细胞凋亡特别是肿瘤细胞凋亡过程中发挥重要作用。但目前人们对上述这些重要蛋白在非小细胞肺癌（non—small—cell lung cancer，NSCLC）中的表达与肿瘤病理学的关系所知甚少。本研究探讨ECFR、VEGFR、BAD和磷酸化BAD在NSCLC中的表达情况以及与肿瘤病理的关系。方法：使用组织微阵列（tissue microarray，TMA）切片的免疫组织化学法，NSCLC患者51例（26例腺癌，16例鳞癌，8例大细胞癌，1例大细胞神经内分泌癌）。结果：51例患者中EGFR和VEGFR分别在10例（加％）和14例（27％）中出现过度表达。大细胞癌中未见VEGFR表达（0／8例），而鳞癌和腺癌患者中VEGFR表达分别为44％（7／16）和27％（7／26）。EGFR和VEGFR的表达与性别，肿瘤细胞分化及肿瘤浸润程度（包括胸膜浸润，血管浸润，淋巴结转移，肺内播散，脑转移情况）无关。51例患者中22例（43％）出现BAD蛋白表达缺失，且NSCLC的不同病理类型间差异有显著性。BAD蛋白表达缺失在16例鳞癌患者中10例（63％），8例大细胞癌患者中5例（63％），26例鳞癌患者中有7例（27％）（P=0．04）。51例患者中25例（49％）出现磷酸化BAD蛋白过度表达[其中26例腺癌患者中有13例（50％），16例鳞癌患者中有8例（50％），8例大细胞癌患者中有4例（50％）]。BAD蛋白的表达缺失与磷酸化BAD蛋白的过度表达经统计检验与上述肿瘤浸润程度无相关性。结论：肺鳞癌出现VEGFR表达增高的可能较大，而大细胞癌出现VEGFR表达增高的可能最小。在鳞癌和大细胞癌中可见BAD蛋白表达的显著缺失。NSCLC患者EGFR，VEGFR，磷酸化BAD蛋白的过度表达以及BAD蛋白表达的缺失与病理浸润程度无关。但这些受体酪氨酸激酶表达以及与NSCLC凋亡直接相关的媒介因子可能成为未来多靶向治疗中的候选靶标。     

Epithelial-mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression

Aberrant activation of a latent embryonic program - known as the epithelial-mesenchymal transition (EMT) - can endow cancer cells with the migratory and invasive capabilities associated with metastatic competence. The induction of EMT entails the loss of epithelial characteristics and the de novo acquisition of a mesenchymal phenotype. In breast cancer, the EMT state has been associated with cancer stem cell properties including expression of the stem cell-associated CD44⁺/CD24^-/low antigenic profile, self-renewal capabilities and resistance to conventional therapies. Intriguingly, EMT features are also associated with stem cells isolated from the normal mouse mammary gland and human breast reduction tissues as well as the highly aggressive metaplastic and claudin-low breast tumor subtypes. This has implications for the origin of these breast tumors as it remains unclear whether they derive from cells that have undergone EMT or whether they represent an expansion of a pre-existing stem cell population that expresses EMT-associated markers to begin with. In the present review, we consider the current evidence connecting EMT and stem cell attributes and discuss the ramifications of these newly recognized links for our understanding of the emergence of distinct breast cancer subtypes and breast cancer progression.     

Cortactin overexpression inhibits ligand-induced down-regulation of the epidermal growth factor receptor

Ligand-induced receptor down-regulation by endocytosis is a critical process regulating the intensity and duration of receptor tyrosine kinase signaling. Ubiquitylation of specific receptor tyrosine kinases, for example, the epidermal growth factor receptor (EGFR) by the E3 ubiquitin ligase c-Cbl, provides a sorting signal for lysosomal degradation and leads to termination of receptor signaling. Cortactin, which couples the endocytic machinery to dynamic actin networks, is encoded by EMS1, a gene commonly amplified in breast and head and neck cancers. One mechanism whereby cortactin overexpression contributes to tumor progression is by enhancing tumor cell invasion and metastasis. However, in this study, we show that overexpression of cortactin in HeLa cells markedly inhibits ligand-induced down-regulation of the EGFR. This is independent of alterations in receptor autophosphorylation and correlates with impaired c-Cbl phosphorylation and association with the EGFR, reduced EGFR ubiquitylation, and sustained EGF-induced extracellular signal-regulated kinase activation. Furthermore, analysis of a panel of head and neck squamous cell carcinoma (HNSCC) cell lines revealed that cortactin overexpression is associated with attenuated ligand-induced EGFR down-regulation. Importantly, RNAi-mediated reduction of cortactin expression in an 11q13-amplified HNSCC cell line accelerates EGFR degradation. This represents the first demonstration of modulation of growth factor receptor signaling by cortactin. Moreover, enhanced EGFR signaling due to cortactin overexpression may provide an alternative explanation for EMS1 gene amplification in human cancers.     

Oncogenic fingerprint of epidermal growth factor receptor pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer

Epidermal growth factor receptor (EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer (CRC). Evidence from clinical trials indicates that cetuximab and panitumumab (anti-EGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS (KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency. Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade. Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS, BRAF, PIK3CA and PTEN could be intrinsically resistant to EGFR blockade. Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients. While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC, further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.     

Involvement of growth factor receptors of the epidermal growth factor receptor family in prostate cancer development and progression to androgen independence

The development of prostate cancer and the progression from a normal prostate epithelium to androgen-dependent cancer and eventually to hormone-refractory prostate cancer is a multistep process involving several changes in the function of different growth-regulatory signals. In the past 10 years, conflicting results on epidermal growth factor receptor (EGFR) family expression in prostate cancer have been reported. These differences may result from technical differences, lack of standardization of immunohistochemical assays, or different scoring methodologies. Recently, 4 studies have shown experimental evidence of a role of the EGFR family, particularly ErbB-2, in the development of prostate cancer and, more specifically, in the progression to hormone-refractory clinical behavior. These 4 studies were similar in some relevant aspects, such as the patient population. In fact, the patients in each study were divided into 3 groups that represent the progression of prostate cancer. In 3 of 4 studies, a statistically significant increase in ErbB-2 expression was detected by immunohistochemistry in the progression from hormone-dependent to hormone-independent disease. The expression of EGFR was also evaluated in 1 of the 4 studies. In a recent report from our group, a significant increase in EGFR expression was observed in patients treated with radical surgery, in patients who received hormonal therapy as primary therapy before radical prostatectomy, and, finally, in patients with metastatic and hormone-refractory disease. It has been proposed that EGFR family receptors and androgen receptors function synergistically in the absence of androgen suggesting cross-talk between the ErbB-2 and androgen receptor pathways, and that mitogen-activated protein kinase and phosphatidylinositol 3-kinase can be considered the transduction pathways. Finally, clinical trials are currently in progress in patients with prostate cancer testing novel agents that selectively interfere with these receptors, such as trastuzumab, an anti- ErbB-2 monoclonal antibody, and gefitinib (ZD1839, Iressa), a small-molecule selective EGFR tyrosine kinase inhibitor.     

转录因子Snail与肿瘤的上皮细胞间质化

肿瘤对人体的危害极大,其引起的死亡大多是因为肿瘤转移。肿瘤的转移是一个十分复杂的过程,它是多种基因参与的结果,不仅仅是遗传性状的改变,还包括细胞与细胞之间、细胞与细胞外基质之间的相互作用。一些在胚胎发育中起着重要作用的基因常常在癌组织中重新激活,提示其可能有促进肿瘤发生和/或转移的作用。肿瘤的浸润和转移是通过细胞粘附分子的改变而实现的,这些粘附分子也是许多致癌因素最终的作用位     

Transforming growth factor alpha and epidermal growth factor levels in bladder cancer and their relationship to epidermal growth factor receptor.

We have examined levels of epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) in neoplastic and non-neoplastic bladder tissue using a standard radioimmunoassay technique. Tumour samples had much higher TGF-alpha levels compared with EGF and TGF-alpha levels in malignant tissue were significantly higher than in benign bladder samples. There was, in addition, a difference in mean EGF levels from ''normal'' bladder samples from non-tumour bearing areas of bladder in patients with bladder cancer compared with ''normal'' bladder tissue obtained at the time of organ retrieval surgery. Levels of EGF and TGF-alpha did not correlate with levels of EGF receptor (EGFR) as determined by a radioligand binding method but levels of TGF-alpha > 10 ng gm-1 of tumour tissue did correlate with EGFR positivity defined using immunohistochemistry. These data suggest that TGF-alpha is the likely ligand for EGFR in bladder tumours.     

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.