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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the past few years many encouraging advancements have been made in understanding the molecular mechanisms underlying carcinogenesis and tumor progression. These improvements have led to the identification of promising new targets for cancer therapy. There has been much success with the HER2 targeting antibody trastuzumab (Herceptin) in the treatment of early stage and metastatic breast cancer. Consequently, several antibodies inhibiting cellular signaling of VEGF and EGFR were tested with respect to their efficacy in breast cancer. In phase II and III clinical trials the humanized anti-VEGF antibody bevacizumab (Avastin) alone or in combination with capecitabine exhibited responses in patients with metastatic breast cancer. Recent developments focus on small molecules interfering with different signal transduction pathways in tumor cells. Numerous inhibitors of EGF and VEGF receptor tyrosine kinases and farnesyl transferases are in early stages of clinical development for breast cancer. Another promising approach is the targeting of endothelins and their two G-protein coupled receptors (ET(A)R und ET(B)R). In this article, we will shortly outline well established targeted treatments and discuss the current development of novel agents to be utilized for molecular targeted breast cancer therapy. Due to the heterogeneity of disease and varying response to conventional systemic therapies, these new perceptions may lead to substantial patient benefit and provide a promising basis for future clinical application.
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PMID:Targeted therapies in breast cancer: established drugs and recent developments. 1869 Aug 83

Cortactin, fascin-1 and EGFR are recognized as important factors in tumor progression. We tested the hypothesis that cortactin, fascin-1 and EGFR expression correlates with clinicopathological parameters of the four most common ovarian surface epithelial carcinomas--serous cystadenocarcinoma, mucinous cystadenocarcinoma, endometrioid adenocarcinoma, and clear cell carcinoma. Immunohistochemical analysis of cortactin, fascin-1 and EGFR was performed using tissue microarrays of 172 specimens comprising 69 serous cystadenocarcinomas, 44 mucinous cystadenocarcinomas, 45 endometrioid adenocarcinomas and 14 clear cell carcinomas. All ovarian carcinomas showed significant expression of cortactin, fascin-1 and EGFR in staining intensity, tumor percentages and immunostaining scores. In addition, higher immunostaining scores of fascin-1 correlated with more advanced cancer stages (TNM), poorer histological differentiation and poorer survival rate of mucinous cystadenocarcinoma. Similarly, higher immunostaining scores of cortactin correlated with T stages and histological differentiation of serous cystadenocarcinoma. The immunostaining scores of EGFR did not correlate with TNM stages, tumor differentiation or prognosis in the four ovarian surface epithelial carcinomas. Our findings suggest that cortactin and fascin-1 may serve as good biomarkers in evaluating aggressiveness of ovarian serous and mucinous cystadenocarcinoma. And the pharmacological inhibitors of fascin-1 activity may slow down tumor progression and prolong survival time in patients with mucinous cystadenocarcinoma.
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PMID:Association of cortactin, fascin-1 and epidermal growth factor receptor (EGFR) expression in ovarian carcinomas: correlation with clinicopathological parameters. 1877 88

We generated mice expressing a COX-2 transgene in colon epithelium and found that they did not develop spontaneous colon tumors. But when treated with azoxymethane, a colon carcinogen, COX-2 mice had a higher tumor load compared to wild-type mice. There was no change in the number of pre-neoplastic lesions, indicating that COX-2 does not affect tumor initiation. Tumors in the COX-2 transgenic mice had higher levels of phosphorylated epidermal growth factor receptor and Akt compared to wild-type mice. Collectively, our data indicate that COX-2 promotes colon tumor progression, but not initiation, and it does so, in part, by activating EGFR and Akt signaling pathways.
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PMID:Transgenic expression of cyclooxygenase-2 in mouse intestine epithelium is insufficient to initiate tumorigenesis but promotes tumor progression. 1879 May 60

Inappropriate signalling through the EGFR and ErbB2/HER2 members of the epidermal growth factor family of receptor tyrosine kinases is well recognised as being causally linked to a variety of cancers. Consequently, monoclonal antibodies specific for these receptors have become increasingly important components of effective treatment strategies for cancer. Increasing evidence suggests that ErbB3 plays a critical role in cancer progression and resistance to therapy. We hypothesised that co-targeting the preferred ErbB2/ErbB3 heterodimer with a bispecific single-chain Fv (bs-scFv) antibody would promote increased targeting selectivity over antibodies specific for a single tumour-associated antigen (TAA). In addition, we hypothesised that targeting this important heterodimer could induce a therapeutic effect. Here, we describe the construction and evaluation of the A5-linker-ML3.9 bs-scFv (ALM), an anti-ErbB3/ErbB2 bs-scFv. The A5-linker-ML3.9 bs-scFv exhibits selective targeting of tumour cells in vitro and in vivo that co-express the two target antigens over tumour cells that express only one target antigen or normal cells that express low levels of both antigens. The A5-linker-ML3.9 bs-scFv also exhibits significantly greater in vivo targeting of ErbB2'+'/ErbB3'+' tumours than derivative molecules that contain only one functional arm targeting ErbB2 or ErbB3. Binding of ALM to ErbB2'+'/ErbB3'+' cells mediates inhibition of tumour cell growth in vitro by effectively targeting the therapeutic anti-ErbB3 A5 scFv. This suggests both that ALM could provide the basis for an effective therapeutic agent and that engineered antibodies selected to co-target critical functional pairs of TAAs can enhance the targeting specificity and efficacy of antibody-based cancer therapeutics.
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PMID:Targeting ErbB2 and ErbB3 with a bispecific single-chain Fv enhances targeting selectivity and induces a therapeutic effect in vitro. 1884 Nov 59

Although the health benefits of dietary antioxidants have been extensively studied, their potential negative effects remain unclear. L-Ascorbic acid 6-palmitate (AAP), a synthetic derivative of ascorbic acid (AA), is widely used as an antioxidant and preservative in foods, vitamins, drugs, and cosmetics. Previously, we found that AA exerted an antitumor effect by protecting inhibition of gap-junctional intercellular communication (GJIC), which is closely associated with tumor progression. In this study, we examined whether AAP, an amphipathic derivative of AA, has chemopreventive effects using a GJIC model. AAP and AA exhibited dose-dependent free radical-scavenging activities and inhibited hydrogen peroxide (H(2)O(2))-induced intracellular reactive oxygen species (ROS) production in normal rat liver epithelial cells. Unexpectedly, however, AAP did not protect against the inhibition of GJIC induced by H(2)O(2); instead, it inhibited GJIC synergistically with H(2)O(2). AAP inhibited GJIC in a dose-dependent and reversible manner. This inhibitory effect was not due to the conjugated lipid structure of AAP, as treatment with palmitic acid alone failed to inhibit GJIC under the same conditions. The inhibition of GJIC by AAP was restored in the presence of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126, but not in the presence of other signal inhibitors and antioxidant (PKC inhibitors, EGFR inhibitor, NADPH oxidase inhibitor, catalase, vitamin E, or AA), indicating the critical involvement of MEK signaling in the GJIC inhibitory activity of AAP. Phosphorylation of ERK and connexin 43 (Cx43) was observed following AAP treatment, and this was reversed by U0126. These results suggest that the AAP-induced inhibition of GJIC is mediated by the phosphorylation of Cx43 via activation of the MEK-ERK pathway. Taken together, our results indicate that AAP has a potent carcinogenic effect, and that the influence of dietary antioxidants on carcinogenesis may be paradoxical.
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PMID:Ascorbic acid 6-palmitate suppresses gap-junctional intercellular communication through phosphorylation of connexin 43 via activation of the MEK-ERK pathway. 1902 67

Glycosphingolipids (GSLs) are present in all eukaryotic membranes and are implicated in neuropathologies and tumor progression in humans. Nevertheless, their in vivo functions remain poorly understood in vertebrates, partly owing to redundancy in the enzymes elongating their sugar chains. In Drosophila, a single GSL biosynthetic pathway is present that relies on the activity of the Egghead and Brainiac glycosyltransferases. Mutations in these two enzymes abolish GSL elongation and yield oogenesis defects, providing a unique model system in which to study GSL roles in signaling in vivo. Here, we use egghead and brainiac mutants to show that GSLs are necessary for full activation of the EGFR pathway during oogenesis in a time-dependent manner. In contrast to results from in vitro studies, we find that GSLs are required in cells producing the TGFalpha-like ligand Gurken, but not in EGFR-expressing cells. Strikingly, we find that GSLs are not essential for Gurken trafficking and secretion. However, we characterize for the first time the extracellular Gurken gradient and show that GSLs affect its formation by controlling Gurken planar transport in the extracellular space. This work presents the first in vivo evidence that GSLs act in trans to regulate the EGFR pathway and shows that extracellular EGFR ligand distribution is tightly controlled by GSLs. Our study assigns a novel role for GSLs in morphogen diffusion, possibly through regulation of their conformation.
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PMID:Glycosphingolipids control the extracellular gradient of the Drosophila EGFR ligand Gurken. 1914 19

SOX4 is a critical developmental transcription factor in vertebrates and is required for precise differentiation and proliferation in multiple tissues. In addition, SOX4 is overexpressed in many human malignancies, but the exact role of SOX4 in cancer progression is not well understood. Here, we have identified the direct transcriptional targets of SOX4 using a combination of genome-wide localization chromatin immunoprecipitation-chip analysis and transient overexpression followed by expression profiling in a prostate cancer model cell line. We have also used protein-binding microarrays to derive a novel SOX4-specific position-weight matrix and determined that SOX4 binding sites are enriched in SOX4-bound promoter regions. Direct transcriptional targets of SOX4 include several key cellular regulators, such as EGFR, HSP70, Tenascin C, Frizzled-5, Patched-1, and Delta-like 1. We also show that SOX4 targets 23 transcription factors, such as MLL, FOXA1, ZNF281, and NKX3-1. In addition, SOX4 directly regulates expression of three components of the RNA-induced silencing complex, namely Dicer, Argonaute 1, and RNA Helicase A. These data provide new insights into how SOX4 affects developmental signaling pathways and how these changes may influence cancer progression via regulation of gene networks involved in microRNA processing, transcriptional regulation, the TGFbeta, Wnt, Hedgehog, and Notch pathways, growth factor signaling, and tumor metastasis.
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PMID:Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells. 1914 88

Despite surgical advances and recent progress in adjuvant therapies, the prognosis for patients with malignant brain tumors such as glioblastoma multiforme has remained poor, and the neurological deterioration suffered by most patients as a consequence of tumor progression is dramatic and severe. In addition, malignant brain tumors have >>95% recurrence close to the primary site of initial resection. Unfortunately, standard imaging techniques do not permit the intraoperative identification of individual or small clusters of residual tumor cells, precluding their selective removal while sparing the surrounding normal brain tissue. In this report, we show that quantum dots (QDs) coupled to epidermal growth factor (EGF) or anti-EGF receptor receptor (EGFR, Her1) specifically and sensitively label glial tumor cells in cell culture, glioma mouse models, and human brain-tumor biopsies. A clear demarcation between brain and tumor tissue at the macroscopic as well as the cellular level is provided by the fluorescence emission of the QDs.
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PMID:Tumor-targeted quantum dots can help surgeons find tumor boundaries. 1930 3

Clinical and animal studies have shown that coexpression of the receptor tyrosine kinases HER2 and epidermal growth factor (EGF) receptor (EGFR) indicates a highly metastatic phenotype of breast cancer. In a cellular model of this phenotype using differential gene expression analysis, we identified TOB1 to be up-regulated depending on EGF stimulation and transduction through phosphorylation of HER2 tyrosine 1248. mRNA expression analysis of breast cancers from a cohort of node-negative patients showed significantly shortened distant metastasis-free survival for patients with high TOB1 expression. In subsequent tissue microarray studies of 725 clinical samples, high HER2 and EGF protein levels were significantly correlated with TOB1 expression in breast cancer, whereas EGFR and EGF levels correlated with TOB1 phosphorylation. We did not observe a correlation between TOB1 expression and cyclin D1, which was previously suggested to mediate the antiproliferative effect of unphosphorylated TOB1. A positive correlation of TOB1 phosphorylation status with proliferation marker Ki67 suggests that elevated TOB1 phosphorylation might abrogate the antiproliferative effect of TOB1 in breast cancer. This suggests a new regulatory role for TOB1 in cancer progression with particular significance in HER2- and/or EGFR-positive breast cancers.
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PMID:TOB1 is regulated by EGF-dependent HER2 and EGFR signaling, is highly phosphorylated, and indicates poor prognosis in node-negative breast cancer. 1949 Dec 69

Previous studies demonstrated that patients with oligodendroglial tumors (OT) have longer overall and recurrence free survival than patients with other glial tumors of the same grade. Recent investigations showed high influence of genetic alterations on patients' outcome: overall and recurrence free survival increased in the case of presence 1p19q deletion and decreased in the presence of 9p or 10q deletion and/or EGFR amplification. In the series of 241 cases (107 male, 134 female patients, median age -- 38 years, (16-73)) we analyzed the impact of histology, tumor grade and genetic alterations on time to tumor progression (TTP). All patients underwent surgical resection of tumor or biopsy from 2000 to 2005. 70 patterns (oligodendroglioma (O) -- 13 cases, oligoastrocytoma (OA) -- 13, anaplastic oligodendroglioma (AO) -- 30, anaplastic oligoastrocytoma (AOA) -- 14) were assessed by fluorescent in situ hybridization. Median follow up was 24 months. The type of tumor (pure or mixed) didn't influence survival. TTP of patients with grade II and grade III tumors was 37.7 and 48.2 months, respectively (p = 0.035). Deletion 1p19q was noted in 34 (49%) cases. In pure O codeletion 1p19q was detected more frequently (in O -- 75%, in AO -- 56%) than in mixed tumors (in OA -- 31%, in AOA -- 35%). Deletions 9p, 10q and EGFR amplification were noted in 5, 6 and 4 cases, respectively. None of the tumors with 1pl9q deletion had other genetic alterations. Thus, we generated three prognostic groups: A -- deletion 1p19q; B -- balanced chromosomal profile; C -- deletion 9p. Median TTP in groups A, B and C was 46.6, 25.3 and 6.4 months, respectively (p < 0.001). The percentage of OT with 1p19q codeletion was lower than in previous studies. Pure O more frequently had 1p19q deletion than mixed tumors. Genetic alterations predict outcome stronger than histological criteria.
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PMID:[Influence of molecular-genetic factors on prognosis in patients with oligodendroglial tumors]. 1950 10


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