Antisense epidermal growth factor receptor RNA transfection in human glioblastoma cells down-regulates telomerase activity and telomere length

Epidermal growth factor receptor is overexpressed and/or amplified in up to 50% of glioblastomas, suggesting an important role of this gene in glial tumorigenesis and progression. In the present study we demonstrated that epidermal growth factor receptor is involved in regulation of telomerase activity in glioblastoma. Antisense-epidermal growth factor receptor approach was used to inhibit epidermal growth factor receptor expression of glioblastoma U87MG cells. Telomerase activity in antisense-epidermal growth factor receptor cells decreased by up to 54 folds compared with control cells. Moreover, the telomere lengths of antisense-epidermal growth factor receptor cells were shortened. In addition, the tumorigenicity of antisense-epidermal growth factor receptor cells was significantly inhibited. Taken together, there were strong correlations between tumorigenicity and epidermal growth factor receptor expression levels, and between tumorigenicity and telomerase activity. These results provide evidence that epidermal growth factor receptor plays an important role in the regulation of telomerase activity of glioma cells. Our findings provide new insights into both the biological functions of epidermal growth factor receptor and the regulation of telomerase activity. The inhibition of telomerase activity triggered by antisense-epidermal growth factor receptor treatment may reflect yet another mechanism of antisense-epidermal growth factor receptor approach in tumour suppression.     

Amplified and overexpressed epidermal growth factor receptor gene in uncultured primary human breast carcinoma

We analyzed the epidermal growth factor receptor gene using a complementary DNA probe of the epidermal growth factor receptor gene in 21 uncultured primary breast carcinomas and found that the gene was amplified in three of these tumors. We further demonstrated by immunohistochemistry using a monoclonal antibody to the epidermal growth factor receptor that the receptor protein product of this gene was overexpressed and displayed elevated kinase activity. Our data indicate that one of the molecular mechanisms for overexpression of epidermal growth factor receptor in human breast cancer is epidermal growth factor receptor gene amplification without rearrangement in a subset of tumors.     

结直肠癌中表皮生长因子受体靶向治疗的意义

表皮生长因子受体抑制剂在结直肠癌治疗中的应用效果显著,近年来一系列的基础、临床研究表明,抗表皮长因子受体的单克隆抗体(C-225)联合化学治疗其疗效和生存均优于单纯化学治疗。表皮生长因子酪氨酸激酶受体抑制剂的临床研究结果到目前为止还不理想,但就目前的研究结果对其疗效进行评价还为时过早。目前有一些正在进行Ⅰ期临床研究的新型表皮生长因子受体的单克隆抗体和酪氨酸激酶受体抑制剂,有可能给结直肠癌的治疗带来新的希望。     

整合素与生长因子受体之间的交互作用

整合素与生长因子受体之间发生交互作用(cross-talk)对细胞生命活动起着重要的调控作用。本文综述整合素与生长因子受体之间交互作用的确实证据;交互作用后整合素与生长因子受体相互激活的机制;及对下游信号转导通路的调控。同时集中介绍整合素与生长因子之间交互作用对肿瘤新生血管生成的影响。     

人表皮生长因子受体-2及雌激素受体与乳腺癌的关系

乳腺癌与人表皮生长因子受体-2及雌激素受体关系密切,这两种受体也是乳腺癌的分类标准和治疗靶点。在大多数乳腺癌患者中,人表皮生长因子受体-2信号途径和雌激素受体信号途径参与了细胞的增生存活过程。而且在乳腺癌病例中,人表皮生长因子受体-2和雌激素受体呈现出一定程度的负相关。这说明这两种受体活化后有一些联系。本文简要综述了人表皮生长因子受体-2和雌激素受体的联系以及这种联系在乳腺癌治疗中的意义。     

The role of EGFR inhibitors in nonsmall cell lung cancer

PURPOSE OF REVIEW: The epidermal growth factor receptor is a cell membrane receptor that plays a key role in cancer development and progression. Ligand-activated epidermal growth factor receptor-dependent signaling is involved in cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. Targeting the epidermal growth factor receptor represents a promising molecular approach in cancer treatment. Several antiepidermal growth factor receptor agents are in clinical development. This review focuses on the available clinical data on epidermal growth factor receptor-targeting drugs in the treatment of nonsmall cell lung cancer. RECENT FINDINGS: Three drugs are currently in phase 2 and phase 3 development as single agents or in combination with other anticancer therapies in nonsmall cell lung cancer patients: cetuximab (Erbitux), a chimeric human-mouse monoclonal IgG1 antibody that blocks ligand binding and functional epidermal growth factor receptor activation; and erlotinib (Tarceva) and gefitinib (Iressa), two orally bioavailable, small-molecule epidermal growth factor receptor inhibitors of tyrosine kinase enzymatic activity that prevent epidermal growth factor receptor autophosphorylation and activation. Single-agent gefitinib treatment has determined a 10 to 20% response rate and a 30 to 50% symptom improvement in previously treated, chemotherapy-refractory advanced nonsmall cell lung cancer patients. Gefitinib has been the first epidermal growth factor receptor-targeting agent to be registered as an anticancer drug in several countries, including Japan, Australia, and the United States, for the third-line treatment of chemoresistant nonsmall cell lung cancer patients. SUMMARY: Antiepidermal growth factor receptor has shown promising antitumor activity in nonsmall cell lung cancer patients with a mild toxicity profile. However, a series of important clinical issues such as selection of potentially responsive patients and optimal combination with conventional anticancer treatments needs to be addressed to use these drugs better in lung cancer.     

Reaction of plasma hepatocyte growth factor levels in non-small cell lung cancer patients treated with EGFR-TKIs

Hepatocyte growth factor induces resistance to epidermal growth factor receptor tyrosine kinase inhibitors. It has been hypothesized that epidermal growth factor receptor tyrosine kinase inhibitors administration may influence the levels of plasma hepatocyte growth factor. Patients with advanced non-small cell lung cancer and relapsed after chemotherapies were eligible. Plasma hepatocyte growth factor levels were analyzed on pretreatment and post-treatment day 15 and 30. We also investigated the correlation between plasma hepatocyte growth factor levels and sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors, tissue immunoreactivity for hepatocyte growth factor and MET gene status. Thirty-one patients were enrolled. Plasma hepatocyte growth factor levels on post-treatment day 15 (630.1 ± 366.9 pg/ml) were significantly higher (p = 0.029) than the pretreatment plasma hepatocyte growth factor levels (485.9 ± 230.2 pg/ml). Plasma hepatocyte growth factor levels on the post-treatment day 30 (581.5 ± 298.1 pg/ml) tend to be higher than those before treatment (p = 0.057). Pretreatment plasma hepatocyte growth factor levels in patients with progressive disease (724.1 ± 216.4 pg/ml) were significantly higher than those in patients with stable disease (396.5 ± 148.3 pg/ml; p = 0.0008) and partial response (381.7 ± 179.0 pg/ml; p = 0.0039). The optimal pretreatment plasma hepatocyte growth factor cut-off value for diagnosis of responder was 553.5 pg/ml, and its sensitivity and specificity were 90% and 65%, respectively. Pretreatment plasma hepatocyte growth factor levels had no correlation with tissue immunoreactivities for hepatocyte growth factor, MET gene status and active EGFR mutations. Administration of epidermal growth factor receptor tyrosine kinase inhibitors significantly increased plasma hepatocyte growth factor levels. High levels of pretreatment plasma hepatocyte growth factor indicated intrinsic resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Plasma hepatocyte growth factor can serve as a useful biomarker for the early diagnosis of tumor relapse treated with epidermal growth factor receptor tyrosine kinase inhibitors.     

Growth-regulating functions of human papillomavirus early gene products in cervical cancer cells acting dominant over enhanced epidermal growth factor receptor expression.

Squamous cell carcinomas of the human anogenital tract are usually associated with infection of specific types of human papillomaviruses (HPV 16, 18, 31, 33, 35). The intracellular concentration of human papillomavirus early gene products E6 and E7 has been directly linked to the proliferative capacity of cervical cancer cells. Since the expression rate of epidermal growth factor receptor correlates to growth properties in squamous carcinoma cell lines, it has been presumed that human papillomavirus early genes influence cell growth via enhanced epidermal growth factor receptor expression. This hypothesis implies that growth regulation by epidermal growth factor receptor overexpression dominates over a growth-regulatory influence of human papillomavirus early gene products in squamous carcinoma cells. To test this hypothesis epidermal growth factor receptor expression was analyzed in various clones of the C4-1 cervical cancer cell line which, upon dexamethasone treatment, express either increased or decreased levels of human papillomavirus 18 early gene products. In C4-1 clones expressing reduced levels of viral E6/E7 gene products upon glucocorticoid treatment expression of epidermal growth factor receptor was the same as in those clones displaying increased levels of papillomavirus proteins under identical culture conditions. The growth rate of the cells correlated with the level of viral gene products rather than with the expression of epidermal growth factor receptor. These findings suggest that unregulated overexpression of epidermal growth factor receptor is not the dominant mechanism of growth control in papillomavirus-positive carcinoma cells. Other, yet unknown pathways associated with papillomavirus early genes are essentially involved in growth control mechanisms of human cervical cancer cells.     

Targeting growth factor receptors: integration of novel therapeutics in the management of head and neck cancer

Tyrosine kinase (type 1) growth factor receptors include the erbB family. These cell surface receptors were discovered in the context of cellular transformation and have subsequently been found to be overexpressed in many types of human cancer. Cumulative evidence suggests that upregulation of the most well-characterized receptor, erbB1, also known as the epidermal growth factor receptor, plays a significant role in the development and progression of head and neck squamous cell carcinoma. A variety of strategies have been developed that specifically target epidermal growth factor receptor, including monoclonal antibodies, ligand-linked immunotoxins, tyrosine kinase inhibitors, and antisense approaches. Epidermal growth factor receptor blockade in head and neck squamous cell carcinoma cell lines and preclinical animal models inhibits cell proliferation and tumor growth. Clinical trials are under way to test the safety and efficacy of many of these targeting strategies in head and neck squamous cell carcinoma patients. Encouraging preliminary results combining an epidermal growth factor receptor targeting approaches with chemotherapy or radiotherapy suggest that interference with this growth factor receptor may enhance antitumor efficacy of standard therapies. As erbB family member interactions and downstream signaling pathways are elucidated in head and neck squamous cell carcinoma, specific targeting strategies may become incorporated into standard treatment approaches.     

Antiangiogenic drugs in non-small cell lung cancer treatment

PURPOSE OF REVIEW: A promising therapeutic target is the vascular endothelial growth factor pathway - a key mediator of tumor angiogenesis - which is important in tumor growth, invasion, and metastasis. This review focuses on the available clinical data on drugs targeting the vascular endothelial growth factor - vascular endothelial growth factor receptor pathway in the treatment of non-small cell lung cancer. RECENT FINDINGS: The therapeutic value of inhibiting the vascular endothelial growth factor pathway has been demonstrated by using drugs that prevent vascular endothelial growth factor receptor binding and by using drugs that inhibit receptor activation. Two antiangiogenic drugs exemplify these mechanisms: bevacizumab (Avastin; Genentech, South San Francisco, California, USA), a humanized monoclonal antibody that acts by binding and neutralizing vascular endothelial growth factor; and ZD6474 (Zactima; AstraZeneca, Macclesfield, UK), a small-molecule inhibitor of vascular growth factor receptor and epidermal growth factor receptor tyrosine kinase activity. Recently, the first results of a large, phase III randomized clinical trial of bevacizumab in combination with platinum-based doublet chemotherapy have been reported in patients with nonsquamous non-small cell lung cancer. SUMMARY: The inhibition of tumor angiogenesis is a key therapeutic strategy that holds great promise for the advancement of metastatic lung cancer therapy. The combination of bevacizumab and conventional chemotherapy could offer a new therapeutic option in selected non-small cell lung cancer histotypes.     

Medical treatment for gastro-entero-pancreatic neuroendocrine tumours

Gastro-entero-pancreatic neuroendocrine neoplasms(GEPNENs) represents a various family of rare tumours. Surgery is the first choice in GEP-NENs patients with localized disease whilst in the metastatic setting many other treatment options are available. Somatostatin analogues are indicated for symptoms control in functioning tumours. Furthermore they may be effective to inhibit tumour progression. GEP-NENs pathogenesis has been extensively studied in the last years therefore several driver mutations pathway genes have been identified as crucial factors in their tumourigenesis. GEP-NENs can over-express vascular endothelial growth factor(VEGF), basic-fibroblastic growth factor, transforming growth factor(TGF-α and-β), platelet derived growth factor(PDGF), insulin-like growth factor-1(IGF-1) and their receptors PDGF receptor, IGF-1 receptor, epidermal growth factor receptor, VEGF receptor, and c-kit(stem cell factor receptor) that can be considered as potential targets. The availability of new targeted agents, such as everolimus and sunitinib that are effective in advanced and metastatic pancreatic neuroendocrine tumours, has provided new treatment opportunities. Many trials combing new drugs are ongoing.     

Receptors for epidermal growth factor and estrogen as predictors of relapse in patients with mammary carcinoma

Analysis of the receptors for estradiol and epidermal growth factor was performed in tumors from 225 breast cancer patients. The tumor cell content of both receptors was independent of clinical stage and lymph node status. There was an inverse correlation between the epidermal growth factor receptor and the estradiol receptor. Either the presence of the epidermal growth factor receptor or the lack of the estradiol receptor was related to a high relapse rate. A combination of these two receptors leads to an increased prognostic predictive capacity. Patients whose tumors contain both the estradiol receptor and epidermal growth factor receptor had a relapse rate similar to those whose tumors were estradiol receptor poor, and are thus high risk patients. Patients whose tumors contain the estradiol receptor and lack the epidermal growth factor receptor belong to a good prognosis group.     

Combined targeted therapies in non-small cell lung cancer: a winner strategy?

PURPOSE OF REVIEW: Current treatment modalities provide limited improvement in the natural course of lung cancer, and prognosis remains poor. Lung cancer is a malignancy with great molecular heterogeneity. The complexity of the signalling process leading to cancer cell proliferation and to the neoplastic phenotype supports the necessity of interfering at different stages to avoid cancer cell resistance to therapy. RECENT FINDINGS: Use of several agents with multiple growth factor receptor or intracellular targets has shown encouraging results in phase I and II clinical trials in non-small cell lung cancer. ZD6474 is a dual epidermal growth factor receptor and vascular endothelial growth factor receptor 2 small-molecule tyrosine kinase inhibitor; sorafenib is an oral kinase inhibitor of Raf-1 and is also active against vascular endothelial growth factor receptors 2 and 3, platelet-derived growth factor receptor beta, and c-KIT. Sunitinib is a vascular endothelial growth factor receptor 1, 2, and 3, c-KIT, and platelet-derived growth factor receptor alpha and beta tyrosine kinase inhibitor. SUMMARY: Combined use of epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib and the humanized vascular endothelial growth factor receptor monoclonal antibody bevacizumab in advanced, chemotherapy-refractory non-small cell lung cancer has shown promising results.     

Epidermal growth factor receptor/angiogenesis dual targeting: preclinical experience

PURPOSE OF REVIEW: This review aims to critically examine the preclinical background regarding the combination of drugs targeting the epidermal growth factor receptor and anti-angiogenic compounds. RECENT FINDINGS: There are studies exploring the anti-tumor efficacy of dual inhibitors, such as the compound ZD6474, which combines in the same molecule an anti-tyrosine kinase activity against the epidermal growth factor receptor and the vascular endothelial growth factor receptor. In addition, several studies have investigated the anti-tumor effects of combinations of an anti-epidermal growth factor receptor agent and a vascular endothelial growth factor receptor inhibitor. In general, in these studies, supra-additive anti-tumor efficacy was apparent when combining anti-epidermal growth factor receptor and anti-angiogenic treatments. Beneficial effects were also observed when combining this dual targeted therapy with either conventional chemotherapy or irradiation. SUMMARY: Early clinical trials combining the anti-epidermal growth factor receptor drug erlotinib (Tarceva) and the anti-angiogenic agent bevacizumab (Avastin) show acceptable toxicity and promising anti-tumor activity (lung cancer), which need to be confirmed in randomized trials.     

Regulatory effects of cell density on the binding of transforming growth factor beta, epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor

The work described in this paper demonstrates that the cellular binding of transforming growth factor beta, epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor is reduced as cell density is increased. The reduction in transforming growth factor beta binding was observed in five different cell lines. Examination of several of the cell lines, under conditions where transforming growth factor beta binding is reduced, revealed that epidermal growth factor binding, platelet-derived growth factor binding, and fibroblast growth factor binding are also reduced. In the case of NRK-49F cells, the reduction in transforming growth factor beta binding results from a decrease in the number of high-affinity receptors and not from a change in receptor affinity. Similarly, it was determined that the reduction in epidermal growth factor binding is due to a selective reduction in the high-affinity receptors for epidermal growth factor. Overall, the data suggest that the effect of cell density on growth factor binding, which we refer to as density-induced down regulation of growth factor receptors, differs both from down regulation induced by a specific growth factor and from receptor transmodulation.     

Targeting the EGF receptor in ovarian cancer with the tyrosine kinase inhibitor ZD 1839 ("Iressa")

The modulating effects of the orally active epidermal growth factor receptor-specific tyrosine kinase inhibitor ZD 1839 ("Iressa") on cell growth and signalling were evaluated in four ovarian cancer cell lines (PE01, PE04, SKOV-3, OVCAR-5) that express the epidermal growth factor receptor, and in A2780, which is epidermal growth factor receptor-negative. Transforming growth factor-alpha stimulated growth was completely inhibited by concentrations of ZD 1839 > or =0.3 microM in the epidermal growth factor receptor-expressing cell lines, as were transforming growth factor-alpha stimulated phosphorylation of the epidermal growth factor receptor and downstream components of the MAP kinase and PI-3 kinase signalling cascades. Growth inhibition in the absence of added transforming growth factor-alpha was also observed which could be consistent with suppression of action of autocrine epidermal growth factor receptor-activating ligands by ZD 1839. In support of this, transforming growth factor-alpha, EGF and amphiregulin mRNAs were detected by RT-PCR in the epidermal growth factor receptor-expressing cell lines. ZD 1839 inhibited growth of the PE04 ovarian cancer xenograft at 200 mg kg(-1)day(-1). These data lend further support to the view that targeting the epidermal growth factor receptor in ovarian cancer could have therapeutic benefit.     

Promises and pitfalls in the prediction of antiepidermal growth factor receptor activity

There is a constant examination of the features that may anticipate or predict the likelihood of the clinical benefit that a patient may experience from a given therapy. This is especially true in the case of novel targeted therapies, as proof-of-principle experimental or pilot analyses are increasingly being embedded into clinical protocols. An unprecedented number of significant developments in the field of epidermal growth factor receptor-targeted therapy have occurred in recent months. This is exemplified by the discovery of activating mutations in the catalytic domain of the epidermal growth factor receptor that increase sensitivity to antiepidermal growth factor receptor small-molecule inhibitors. This review discusses the recent advances and controversies of the different approaches to predict the efficacy of antiepidermal growth factor receptor agents and the effectiveness of the tools that we are using to evaluate and predict the efficacy of epidermal growth factor receptor-targeted drugs and their potential pitfalls.     

Promises and pitfalls in the prediction of antiepidermal growth factor receptor activity

There is a constant examination of the features that may anticipate or predict the likelihood of the clinical benefit that a patient may experience from a given therapy. This is especially true in the case of novel targeted therapies, as proof-of-principle experimental or pilot analyses are increasingly being embedded into clinical protocols. An unprecedented number of significant developments in the field of epidermal growth factor receptor-targeted therapy have occurred in recent months. This is exemplified by the discovery of activating mutations in the catalytic domain of the epidermal growth factor receptor that increase sensitivity to antiepidermal growth factor receptor small-molecule inhibitors. This review discusses the recent advances and controversies of the different approaches to predict the efficacy of antiepidermal growth factor receptor agents and the effectiveness of the tools that we are using to evaluate and predict the efficacy of epidermal growth factor receptor-targeted drugs and their potential pitfalls.     

Comprehensive analysis of receptor tyrosine kinase activation in human melanomas reveals autocrine signaling through IGF-1R

Melanomas depend on autocrine signals for proliferation and survival; however, no systematic screen of known receptor tyrosine kinases (RTKs) has been performed to identify which autocrine signaling pathways are activated in melanoma. Here, we performed a comprehensive analysis of 42 RTKs in six individual human melanoma tumor specimens as well as 17 melanoma cell lines, some of which were derived from the tumor specimens. We identified five RTKs that were active in almost every one of the melanoma tissue specimens and cell lines, including two previously unreported receptors, insulin-like growth factor receptor 1 (IGF-1R) and macrophage-stimulating protein receptor (MSPR), in addition to three receptors (vascular endothelial growth factor receptor, fibroblast growth factor receptor, and hepatocyte growth factor receptor) known to be autocrine activated in melanoma. We show, by quantitative real time PCR, that all melanoma cell lines expressed genes for the RTK ligands such as HGF, IGF-1, and MSP. Addition of antibodies to either IGF-1 or HGF, but not to MSP, to the culture medium blocked melanoma cell proliferation, and even caused net loss of melanoma cells. Antibody addition deactivated IGF-1R and hepatocyte growth factor receptors, as well as mitogen-activated protein kinase signaling. Thus, IGF-1 is a new growth factor for autocrine driven proliferation of human melanoma in vitro. Our results suggest that IGF-1-IGF-1R autocrine pathway in melanoma is a possible target for therapy in human melanomas.     

Expression of angiogenic growth factor genes in primary human astrocytomas may contribute to their growth and progression.

Astrocytomas are highly malignant brain tumors and are among the most neovascularized solid tumors. We have investigated the expression of the angiogenic growth factors acidic fibroblast growth factor and transforming growth factor-alpha, together with its receptor epidermal growth factor receptor, in 30 primary astrocytomas. Both acidic fibroblast growth factor and transforming growth factor-alpha, together with epidermal growth factor receptor, are found to be greatly overexpressed in these tumors when compared with normal brain. This overexpression of angiogenic growth factors may underlie the intense neovascularization characteristic of astrocytomas.