Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The translation initiation factor eIF4E is a novel protooncogene found over expressed in most breast carcinomas (Kerekatte et al., 1995), but the pathology where this elevation is initially manifested and its possible role in cancer progression are unknown. We report that eIF4E is markedly increased in vascularized malignant ductules of invasive carcinomas, whereas necrotic and avascular ductal carcinomas in situ display significantly lower levels. eIF4E facilitates the synthesis of FGF-2, a powerful tumor angiogenic factor. Conversely, reducing eIF4E with antisense RNA in MDA-435 cells suppresses their tumorigenic and angiogenic properties, consistent with loss of FGF-2 synthesis. These findings suggest a causal role for eIF4E in tumor vascularization.
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PMID:Elevated expression of eIF4E and FGF-2 isoforms during vascularization of breast carcinomas. 928 63

The translation-initiation factor eIF4E is rate-limiting for protein synthesis, and its over-expression results in oncogenic transformation of mammalian cells. eIF4E facilitates the synthesis of several powerful tumor angiogenic factors (FGF-2 and VEGF) by selectively enhancing their translation. In breast carcinomas, eIF4E is commonly over-expressed, but the pathology where this elevation is initially manifested is presently unknown. To probe whether the elevation of eIF4E marks an early stage of cancer development, we focused our research on early cancerous lesions. We have analyzed 70 invasive ductal carcinomas (IDCs), 78 ductal carcinomas in situ (DCIS), 51 benign lesions and 4 model cell lines for elevated expression of eIF4E by several different methods: Northern/Western blots, immuno-histochemistry and in situ RT-PCR. eIF4E expression was markedly increased in IDC and in islets of viable cells in the center of poorly vascularized DCIS, which are not easily identifiable by standard histological stains. We also show that expression of eIF4E is increased by hypoxia and, presumably, in hypoxic areas of these lesions. We propose that clonal expansion of cancer cells, permanently over-expressing eIF4E, gives them a critical advantage to survive hypoxia and marks the transition toward the vascular phase of cancer progression. Hence, eIF4E may be useful in stratifying DCIS lesions according to their malignant stage.
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PMID:Elevated expression of eIF4E in confined early breast cancer lesions: possible role of hypoxia. 993 50

A central issue in the study of neoplastic transformation is to understand how proto-oncogene products deregulate normal processes of cell growth and differentiation: an intrinsic aspect of this is to probe the sequence of events leading to altered expression of proto-oncogenes. In the past few years, studies aimed at understanding the regulation and function of protein synthesis initiation factors, eIF4E initially, culminated in the unexpected finding that a moderate overexpression of this factor results in dramatic phenotypic changes, including rapid proliferation and malignant transformation. Conversely, the tumorigenic properties of cancer cells can be strongly inhibited by antisense-RNA against eIF4E, or overexpression of the inhibitory proteins: 4E-BPs. Furthermore, eIF4E is elevated in carcinomas of the breast, head and neck (HNSCC) and prostate, but not in typical benign lesions. This is a strong indication that elevated eIF4E expression may mark a critical transition in cancer progression. Establishing a greater protein synthesis output may be a necessary step for cancer cells in order to sustain their rapid proliferation. However, analysis of cells transformed by eIF4E revealed that the synthesis of only a few proteins was greatly enhanced, while synthesis of most was minimally increased. One possible explanation is that eIF4E causes these effects by specifically increasing the translational efficiency of several oncogene transcripts, leading to overexpression of their products. The feasibility of this hypothesis was confirmed experimentally with the identification of several important products that are specifically upregulated in eIF4E-overexpressing cells. These include: c-Myc, cyclin DI and ODC, which control cycle progression and tumorigenesis; basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF), which are powerful promoters of cell growth and angiogenesis. A deeper understanding of the mRNAs that are strongly dependent on excess eIF4E/F for efficient translation will eventually result in fuller understanding of the fundamental role of translational control in different pathophysiological conditions, including malignancy.
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PMID:eIF4E expression in tumors: its possible role in progression of malignancies. 1021 44

The protein synthetic machinery is activated by a variety of genetic alterations during tumor progression and represents an attractive target for cancer therapy. The mammalian target of rapamycin (mTOR) plays an important role in regulating protein translation through phosphorylation of p70 S6 kinase 1 (S6K1), a protein involved in ribosome biogenesis, and 4E-BP1 (eIF-4E binding protein), a translation repressor. It has been shown that mTOR has a direct linkage to the phosphatidylinositol-3'-kinase (PI3K)/PTEN-AKT survival pathway. Recent studies have demonstrated that mTOR inhibition by rapamycin or its analogues have remarkable activity against a wide range of human cancers in vitro and in human tumor xenograft models. Phase I clinical evaluations also suggested an anti-tumor effect of rapamycin analogue such as CCI-779. The clinical challenge for the application of this class of anticancer drug is the ability to prospectively identify which tumors will be sensitive to mTOR inhibition. Recent studies have identified cellular markers that are associated with the in vitro activity of rapamycin or CCI-779. However, there have been no reports on how these cellular markers are expressed together in human tumor specimen. In this study, multiple components of the PI3K/PTEN-AKT-mTOR pathway were evaluated by immunohistochemistry in tissue arrays containing 124 tumors from 8 common tumor types. The results show variable expression of all the signaling proteins. For example, mTOR expression was low in brain tumors, but high in the rest of tumors. High levels of 4E-BP1 were seen in colonic adenocarcinoma and low levels in lymphoma. Phospho-AKT (p-AKT) and phospho-S6K1 (p-S6K1) were the only proteins that had significantly correlated protein expression (rs=0.51, p<0.001). Since low PTEN, high p-AKT and high p-S6K1 expression render tumors sensitive to mTOR inhibition in vitro, these criteria were used to model tumor sensitivity. Overall, 26% of tumors (32/124) are predicted to be sensitive to mTOR inhibition, with variable rates for different tumors (melanoma 0% vs ovarian 41%). This is the first report on the PI3K/PTEN-AKT-mTOR pathway in common human tumors and evaluation of the coordinated expression of different signaling proteins. This study should provide a useful tool for selecting future targeted phase II and III clinical trials in the development of this exciting class of agents.
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PMID:Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common human tumors. 1501 Aug 27

The contribution of the mRNA cap-binding protein, eIF-4E, to malignant transformation and progression has been illuminated over the past decade. eIF-4E overexpression has been demonstrated in human tumors of the breast, head and neck, colon, prostate, bladder, cervix and lung, and has been related to disease progression. Overexpression of eIF-4E in experimental models dramatically alters cellular morphology, enhances proliferation and induces cellular transformation, tumorigenesis and metastasis. Conversely, blocking eIF-4E function by expression of antisense RNA, or overexpression of the inhibitory eIF-4E binding proteins (4E-BPs), suppresses cellular transformation, tumor growth, tumor invasiveness and metastasis. Although eIF-4E regulates the recruitment of mRNA to ribosomes, and thereby globally regulates cap-dependent protein synthesis, eIF-4E contributes to malignancy by selectively enabling the translation of a limited pool of mRNAs--those that generally encode key proteins involved in cellular growth, angiogenesis, survival and malignancy (e.g. cyclin D1, c-myc, vascular endothelial growth factor, matrix metalloprotease 9). A deeper understanding of the role of eIF-4E in regulating the translation of the diverse gene products involved in all aspects of malignancy will improve the capacity to exploit eIF-4E as a therapeutic target and as a marker for human cancer progression.
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PMID:eIF-4E expression and its role in malignancies and metastases. 1509 68

Translation initiation factor eIF-4E (eukaryotic initiation factor 4E) is a 25 kd messenger RNA cap-binding phosphoprotein and is involved in the initiation of protein synthesis. The expression is known to be elevated in several carcinomas as compared with normal tissues and benign lesions. In the present study, we undertook to determine whether eIF-4E expression is associated with progression in cervical neoplasia. eIF-4E expression was evaluated by immunohistochemistry in 88 formalin-fixed, paraffin-embedded cervical tissues; 10 normal cervical specimens; 19 low-grade cervical intraepithelial neoplasias (CINs); 19 high-grade CINs; and 40 invasive squamous cell carcinomas (ISCCs). In addition, eIF-4E expression was evaluated at the RNA level in fresh frozen cervical carcinoma tissues by real-time quantitative reverse transcriptase polymerase chain reaction. Immunohistochemical staining showed that eIF-4E expression was undetectable in most normal cervical squamous epithelial tissues (90%), but variable staining was observed in the basal layer of all normal endocervical glands. eIF-4E expression, which was mainly observed as cytoplasmic staining, gradually increased in accordance with histopathologic grade in the order low-grade CIN < high-grade CIN < ISCC (P < .001) and, in particular, was strongly detected in all ISCC cases. Furthermore, real-time quantitative reverse transcriptase polymerase chain reaction revealed that eIF-4E expression in tumor was significantly enhanced versus normal cervical tissues (P = .037). These results suggest that eIF-4E may play a significant role in tumor progression of cervical neoplasia and may represent useful markers for malignant transformation of cervical squamous cells.
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PMID:eIF-4E expression is associated with histopathologic grades in cervical neoplasia. 1626 Feb 73

Cutaneous squamous cell carcinoma (SCC) is a malignant tumour of keratinising epidermal cells. This type of skin cancer is the second leading cause of death after melanoma, and it is the second most common type of non-melanoma skin cancer after basal cell carcinoma. The cellular and molecular events involved in the progression of skin cancers are largely unknown. Increased protein synthesis is necessary for the transition of cells from quiescence to proliferation. Translational control is critical for the proper regulation of the cell cycle, tissue induction and growth. Eukaryotic initiation factor eIF4E, an important regulator of translation, plays critical roles in neo-plastic transformation and cancer progression. We investigated eIF4E expression in 49 skin samples (six normal tissues, eight Bowen diseases, seven stage I, 10 stage II, 13 stage III and five stage IV SCCs). Results obtained demonstrated that all SCC samples, evaluated by SDS-PAGE, Western blotting and cap-affinity chromatography using m7GTP-sepharose, presented eIF4E expression (13.6+/-1.2), whereas, starting from stage 0 (4.1+/-0.9) to stage I (7.4+/-1.4), stage II (12.1+/-2.4), stage III (18.1+/-3.0) and stage IV (26.2+/-3.8) SCCs, a constant and significant increase of protein over expression (P<0.001) was observed. A high expression of eIF4E is correlated with advanced stages. The results presented in this study demonstrate a possible role of eIF4E in SCC.
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PMID:Significance of eIF4E expression in skin squamous cell carcinoma. 1768 90

Elevated activity of the eIF4F complex, which controls initiation of cap-dependent mRNA translation, has been linked to cancer progression. eIF4E recruitment to eIF4F is the rate limiting step of complex assembly and is regulated by eIF4E-Binding Proteins (4E-BPs). When stimulated, the mammalian Target of Rapamycin complex 1 (mTORC1) phosphorylates 4E-BP1, which then releases eIF4E. Hypoxia inhibits mTORC1 activity and therefore cap-dependent protein synthesis. To establish a novel genetic test of the role of eIF4F activity in regulating cell division and viability within hypoxic tumor microenvironments, we generated shRNA mediated 4E-BP1 knock-down in Rh30 rhabdomyosarcoma cells. 4E-BP1 knock-down relieved hypoxia-mediated inhibition of cycle progression in vitro and was correlated with increased expression of cyclin D1 and c-Myc. Xenograft tumors derived from these cells also displayed enhanced expression of cyclin D1 and c-Myc along with antiapoptotic genes encoding Bcl-x(L), and XIAP, and failed to develop the extensive necrotic zones and edema observed in control tumors. Surprisingly, 4E-BP1 knock-down also leads to a dramatic increase in aberrant mitoses in vivo and enhanced expression of Mad2 and securin. Thus, reduced expression of the negative regulator of eIF4E has significant effects on tumor development, and is associated with enhanced cell proliferation and survival.
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PMID:Effects of 4E-BP1 expression on hypoxic cell cycle inhibition and tumor cell proliferation and survival. 1870 53

Aberrant activation of the PI3K/Akt/mTOR pathway is found in many types of cancer and thus plays a major role in breast cancer cell proliferation and anti-cancer drug resistance. The mechanisms involved in the activation of this pathway include: constitutively activated receptor tyrosine kinases (IGF/IGFR, ErbB, FGF/FGFR systems) leading to constitutive activation of PI3K; loss of PTEN function; PI3K mutations; aberrant activation of Akt, eIF4E, 4E-BP1 and p70S6K. These alterations trigger a cascade of biological events, from cell growth and proliferation to survival and migration, which contribute to tumor progression. Therefore, the PI3K/AKT/mTOR pathway is considered an attractive target for the development of novel anti-cancer molecules, and several specific tyrosine kinase inhibitors and signal transduction inhibitors specifically targeting the kinases involved in this pathway have been developed. Many of these inhibitors currently under clinical evaluation represent a promising approach for the treatment of breast cancer patients. This review provides an overview of the most recent patents, of pre-clinical and clinical studies of inhibitors targeting the different members and/or activators of the PI3K/Akt/mTOR pathway, used alone or in combination with other targeted agents for the treatment of breast cancer.
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PMID:Inhibitors of the PI3K/Akt/mTOR pathway: new hope for breast cancer patients. 1975 Dec 11

Androgen ablation therapy is currently the primary treatment for metastatic prostate cancer. Unfortunately, in nearly all cases, androgen ablation fails to permanently arrest cancer progression. As androgens like testosterone are withdrawn, prostate cancer cells lose their androgen sensitivity and begin to proliferate without hormone growth factors. In this study, we constructed and analyzed a mathematical model of the integration between hormone growth factor signaling, androgen receptor activation, and the expression of cyclin D and Prostate-Specific Antigen in human LNCaP prostate adenocarcinoma cells. The objective of the study was to investigate which signaling systems were important in the loss of androgen dependence. The model was formulated as a set of ordinary differential equations which described 212 species and 384 interactions, including both the mRNA and protein levels for key species. An ensemble approach was chosen to constrain model parameters and to estimate the impact of parametric uncertainty on model predictions. Model parameters were identified using 14 steady-state and dynamic LNCaP data sets taken from literature sources. Alterations in the rate of Prostatic Acid Phosphatase expression was sufficient to capture varying levels of androgen dependence. Analysis of the model provided insight into the importance of network components as a function of androgen dependence. The importance of androgen receptor availability and the MAPK/Akt signaling axes was independent of androgen status. Interestingly, androgen receptor availability was important even in androgen-independent LNCaP cells. Translation became progressively more important in androgen-independent LNCaP cells. Further analysis suggested a positive synergy between the MAPK and Akt signaling axes and the translation of key proliferative markers like cyclin D in androgen-independent cells. Taken together, the results support the targeting of both the Akt and MAPK pathways. Moreover, the analysis suggested that direct targeting of the translational machinery, specifically eIF4E, could be efficacious in androgen-independent prostate cancers.
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PMID:Analysis of the molecular networks in androgen dependent and independent prostate cancer revealed fragile and robust subsystems. 2012 16


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