Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant cells may escape from the immune response in vivo because of a defective differentiation of professional antigen-presenting cells (APCs), i.e., dendritic cells (DCs). We recently reported that tumor cells release interleukin (IL)-6 and macrophage colony stimulating factor (M-CSF), which inhibit the differentiation of CD34+ cells into DCs and promote their commitment toward monocytic lineage with a poor APC function. The results presented here show that both IL-4 and IL-13 reverse the inhibitory effects of renal cell carcinoma conditioned media (RCC CM) or IL-6+M-CSF on the phenotypic and functional differentiation of CD34+ into DCs. IL-4 was found to act through a rapid blockade of the expression of M-CSF and the IL-6 receptor-transducing chain (gp130), along with a decrease of the secondary production of M-CSF, thereby preventing the loss of granulocyte macrophage colony stimulating factor (GM-CSF) receptor alpha chain expression on differentiating CD34+ cells. Consistent with these observations, the differentiation of DCs from monocytes cultured with GM-CSF and IL-4 was also impaired by RCC CM, but the minimal inhibitory concentrations of RCC CM were 10-fold higher than for CD34+ cells. In these conditions, monocytes cultured with GM-CSF and IL-4 also exhibited profound phenotypic changes (CD14+ D32+ CD86+ HLA-DR+ CD115(low) CD23(low) CD1a-) and a poor APC function. These alterations were overcome in a dose-dependent manner by IL-4 (5-500 IU/ml), although not beyond a 40% final concentration of RCC CM. The capacity of RCC CM to block DC differentiation from monocytes strongly correlated with IL-6 and M-CSF concentrations in medium. Taken together, these results demonstrate that IL-4 and IL-13 reverse the inhibitory effect of tumor cells on DC differentiation.
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PMID:IL-4 prevents the blockade of dendritic cell differentiation induced by tumor cells. 1130 93

We report the use of spectral karyotyping (SKY) and comparative genomic hybridization (CGH) to describe the numerous genomic imbalances characteristic of stage IV clear cell renal cell carcinoma (CCRCC). SKY and CGH were performed on 10 cell lines established from nephrectomy specimens, and CGH on uncultured material from five of the primary renal tumors. The mutational status of VHL (3p25) and MET (7q31), genes implicated in renal carcinogenesis, were determined for each case. Each case showed marked aneuploidy, with an average number of copy alterations of 14.6 (+/-2.7) in the primary tumors and 19.3 (+/-4.6) in the cell lines. Both whole-chromosome and chromosome-segment imbalances were noted by CGH: consistent losses or gains included +5q23-->ter (100%), -3p14-->ter (80%), and +7 (70%). All VHL mutations and 83% of the genomic imbalances found in the primary tumors were also found in the cell lines derived from them. SKY showed many complex structural rearrangements that were undetected by conventional banding analysis in these solid tumors. All cases with VHL inactivation had 3p loss and 5q gain related primarily to unbalanced translocations between 3p and 5q. In contrast, gains of chromosome 7 resulted primarily from whole-chromosome gains and were not associated with mutations of MET. SKY and CGH demonstrated that genomic imbalances in advanced RCC were the result of either segregation errors [i.e., whole chromosomal gains and losses (7.8/case)] or chromosomal rearrangements (10.7/case), of which the majority were unbalanced translocations.
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PMID:Patterns of aneuploidy in stage IV clear cell renal cell carcinoma revealed by comparative genomic hybridization and spectral karyotyping. 1275 23

The overexpression of c-Kit in chromophobe renal cell carcinoma (ChRCC) has been described by comparative gene expression analyses and has been proposed as a possible specific hallmark of this neoplasm. The aim of our study was to establish its immunohistochemical expression in a large series of ChRCC and to compare it with other renal neoplasms. In our study, immunohistochemical characterization of KIT was performed in 87 renal neoplasms including 25 cases of ChRCC, 13 cases of renal oncocytoma, and 39 renal cell carcinomas (21 cases of conventional RCC [CRCC], 8 cases of CRCC with granular cell differentiation, and 10 cases of papillary RCC [PRCC]). Eighty-eight percent ChRCC and 71% oncocytomas showed immunohistochemical expression of KIT, while the other types of RCC studied were all negative. The meaning of immunohistochemical expression of KIT in ChRCC and oncocytomas is still unknown, but its immunohistochemical staining appears to be useful in distinguishing ChRCC from PRCC, CRCC, and its granular cell variant. Moreover, our findings support current models that consider that there is a histopathogenic relationship between oncocytoma and ChRCC. Finally, it should be determined whether KIT plays a role in the tumorigenesis of ChRCC and oncocytoma and whether targeted therapy with STI-571, an inhibitor of KIT, could be effective in exceptional cases of ChRCC with metastatic extension or recurrence.
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PMID:KIT expression in chromophobe renal cell carcinoma: comparative immunohistochemical analysis of KIT expression in different renal cell neoplasms. 1589 59

Renal cell carcinoma accounts for approximately 3% of adult malignancies and 90%-95% of neoplasms arising from the kidney. It is characterized by a lack of early warning signs, diverse clinical manifestations, resistance to radiation and chemotherapy, and infrequent but reproducible responses to immunotherapy with agents such as interferon alpha (IFNa) and interleukin 2 (IL-2). International studies have shown objective response rates of < 15% in patients with advanced and metastatic disease, with 5-year disease-specific survival ranging between 0-20%. Considering these poor outcomes, renal cancers' very vascular nature and overexpression of receptors for vascular endothelial growth factor (VEGF), various biologic and angio-suppressive therapies are being evaluated in clinical trials. Promising results in terms of overall response rate and median time to progression have been reported especially as second-line therapy following cytokine failure, a setting where no effective systemic therapy has been recognized (SU011248, Bay 43-9006, Bevacizumab and Erlotinib). While confirmatory studies are ongoing, other novel treatments in first line trials (CCI-779, Infliximab, PTK-787, and Thalidomide) have drawn international attention. This review, analyzing basic translational research principles, will summarize the available data on the use of these new therapeutic approaches in RCC.
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PMID:New treatments for metastatic kidney cancer. 1578 Jan 70

The distinction between chromophobe renal cell carcinoma, the granular cell variant of clear cell renal cell carcinoma, and renal oncocytoma is a common diagnostic dilemma. The usefulness of KIT, CD10, RCC, and RON in the differential diagnosis of these renal epithelial tumors was investigated. KIT was 100% positive in chromophobe renal cell carcinoma (11 of 11) and renal oncocytoma (12 of 12). The KIT staining pattern was identical in both tumor types, with cytoplasmic membrane attenuation, and fine granular cytoplasmic staining. In contrast, KIT was absent in all granular cell variants of clear cell renal cell carcinoma (0 of 6). RCC was observed in more than 80% of the granular cell variant of clear cell renal cell carcinoma (5 of 6) but was negative in all chromophobe renal cell carcinomas (0 of 11) and renal oncocytomas (0 of 12). CD10 was expressed in 100% of the granular cell variant of clear cell renal cell carcinoma (6 of 6), 72% of chromophobe renal cell carcinomas (8 of 11), and 58% of renal oncocytomas (7 of 12). RON was 100% positive in the chromophobe renal cell carcinomas (11 of 11) and renal oncocytomas (12 of 12) but only 50% positive in the granular cell variant of clear cell renal cell carcinoma (3 of 6). Colloidal iron was diffusely and strongly positive in more than 80% of the chromophobe renal cell carcinomas (9 of 11), focally and weakly positive in 41% of the renal oncocytomas (5 of 12) but negative in all granular cell variant of clear cell renal cell carcinoma (0 of 6). The above results demonstrate that: 1) KIT is a very sensitive marker for both chromophobe renal cell carcinoma and renal oncocytoma; 2) immunohistochemistry using antibodies to KIT combined with RCC was sufficient to discriminate between chromophobe renal cell carcinoma and the granular cell variant of clear cell renal cell carcinoma; and 3) neither RON, nor KIT, nor a combination of this panel can be used to distinguish chromophobe renal cell carcinoma from renal oncocytoma. Colloidal iron staining aided in this distinction for the majority of the chromophobe renal cell carcinomas (more than 80% positive) and renal oncocytomas (close to 60% negative).
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PMID:KIT and RCC are useful in distinguishing chromophobe renal cell carcinoma from the granular variant of clear cell renal cell carcinoma. 1583 88

Inactivating mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are associated with clear cell renal cell carcinoma (VHL-/- RCC), the most frequent malignancy of the human kidney. The VHL protein targets the alpha subunits of hypoxia-inducible factor (HIF) transcription factor for ubiquitination and degradation. VHL-/- RCC cells fail to degrade HIF resulting in the constitutive activation of its target genes, a process that is required for tumorigenesis. We recently reported that HIF activates the transforming growth factor-alpha/epidermal growth factor receptor (TGF-alpha/EGFR) pathway in VHL-defective RCC cells. Here, we show that short hairpin RNA (shRNA)-mediated inhibition of EGFR is sufficient to abolish HIF-dependent tumorigenesis in multiple VHL-/- RCC cell lines. The 2alpha form of HIF (HIF-2alpha), but not HIF-1alpha, drives in vitro and in vivo tumorigenesis of VHL-/- RCC cells by specifically activating the TGF-alpha/EGFR pathway. Transient incubation of VHL-/- RCC cell lines with small interfering RNA directed against EGFR prevents autonomous growth in two-dimensional culture as well as the ability of these cells to form dense spheroids in a three-dimensional in vitro tumor assay. Stable expression of shRNA against EGFR does not alter characteristics associated with VHL loss including constitutive production of HIF targets and defects in fibronectin deposition. In spite of this, silencing of EGFR efficiently abolishes in vivo tumor growth of VHL loss RCC cells. These data identify EGFR as a critical determinant of HIF-2alpha-dependent tumorigenesis and show at the molecular level that EGFR remains a credible target for therapeutic strategies against VHL-/- renal carcinoma.
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PMID:Silencing of epidermal growth factor receptor suppresses hypoxia-inducible factor-2-driven VHL-/- renal cancer. 1595 67

To study the effect of Trastuzumab in combination with IFN alpha-2b on HER2 and MRP1 of ACHN in vitro, ACHN cell line of RCC was cultured by employing cell culture. The tetrazolium-based colorimetric assay was used to evaluate the growth-inhibiting effect of Trastuzumab with IFN alpha-2b. SP method was utilized to determine the expression of HER2 and MRP1 of the cells. Our results showed that Trastuzumab had inhibitory effect on the growth of renal tumor cells and reversing effect on the multi-drug-resistance (MDR) in RCC in a time- and dose-dependent manner. Treated with Trastuzumab with or without IFN alpha-2b, the expression of HER2 and MRP1 genes of RCC was decreased significantly (P<0.05). It was concluded that Trastuzumab with IFN alpha-2b could inhibit the proliferation of RCC and the expression of HER2 and MRP1 of ACHN and to some extent, reverse the MDR of the tumor cells.
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PMID:Effect of trastuzumab in combination with IFN alpha-2b on HER2 and- MRP1 of ACHN. 1620 Dec 86

It is a strong hope that the more we characterize the pathways in an individual tumor, the better we will be able to evaluate the response to a specific therapy. Different array technologies could be powerful tools to achieve this goal, i.e. selecting patients on the basis of the genomic and/or proteomic profiles who would really benefit from the target-designed therapy. Genomic analysis of RCC accumulated ample of data which now can be exploited in clinical management of a previously almost uncontrollable disease. Beside the previously identified genetic abnormalities (VHL, MET, EGFR), CAIX seems to be a novel molecular marker of RCC. Array studies also outlined a small set of tumor markers, vimentin, galectin-3, CD74 and parvalbumin, which can define the individual histologic subtypes of RCC. We are at the beginning to take advantage of the genomic results. Some new approaches will interfere with the progression of RCC (anti-VEGF, anti-VEGFR or anti-EGFR therapies). Further novel molecular targets are available, such as HIF, HSP90 or the IFN-regulated genes, which can be used to the fine-tuning of RCC therapy.
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PMID:Genomics of renal cell cancer-- does it provide breakthrough? 1655 10

Clear cell renal cell cancer (CC-RCC) is a highly chemoresistant tumor characterized by frequent inactivation of the von Hippel-Lindau (VHL) gene. The prognosis is reportedly worse in patients whose tumors express immunoreactive type I insulin-like growth factor receptor (IGF1R), a key mediator of tumor cell survival. We aimed to investigate how IGF1R expression is regulated, and found that IGF1R protein levels were unaffected by hypoxia, but were higher in CC-RCC cells harboring mutant inactive VHL than in isogenic cells expressing wild-type (WT) VHL. IGF1R mRNA and promoter activities were significantly lower in CC-RCC cells expressing WT VHL, consistent with a transcriptional effect. In Sp1-null Drosophila Schneider cells, IGF1R promoter activity was dependent on exogenous Sp1, and was suppressed by full-length VHL protein (pVHL) but only partially by truncated VHL lacking the Sp1-binding motif. pVHL also reduced the stability of IGF1R mRNA via sequestration of HuR protein. Finally, IGF1R mRNA levels were significantly higher in CC-RCC biopsies than benign kidney, confirming the clinical relevance of these findings. Thus, we have identified a new hypoxia-independent role for VHL in suppressing IGF1R transcription and mRNA stability. VHL inactivation leads to IGF1R upregulation, contributing to renal tumorigenesis and potentially also to chemoresistance.
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PMID:The VHL tumor suppressor inhibits expression of the IGF1R and its loss induces IGF1R upregulation in human clear cell renal carcinoma. 1748 80

Genetic aberrations are crucial in renal tumor progression. In this study, we describe loss of heterozygosity (LOH) and DNA-copy number abnormalities in clear cell renal cell carcinoma (cc-RCC) discovered by genome-wide single nucleotide polymorphism (SNP) arrays. Genomic DNA from tumor and normal tissue of 22 human cc-RCCs was analyzed on the Affymetrix GeneChip Human Mapping 10K Array. The array data were validated by quantitative polymerase chain reaction and immunohistochemistry. Reduced DNA copy numbers were detected on chromosomal arm 3p in 91%, on chromosome 9 in 32%, and on chromosomal arm 14q in 36% of the tumors. Gains were detected on chromosomal arm 5q in 45% and on chromosome 7 in 32% of the tumors. Copy number abnormalities were found not only in FHIT and VHL loci, known to be involved in renal carcinogenesis, but also in regions containing putative new tumor suppressor genes or oncogenes. In addition, microdeletions were detected on chromosomes 1 and 6 in genes with unknown impact on renal carcinogenesis. In validation experiments, abnormal protein expression of FOXP1 (on 3p) was found in 90% of tumors (concordance with SNP array data in 85%). As assessed by quantitative polymerase chain reaction, PARK2 and PACRG were down-regulated in 57% and 100%, respectively, and CSF1R was up-regulated in 69% of the cc-RCC cases (concordance with SNP array data in 57%, 33%, and 38%). Genome-wide SNP array analysis not only confirmed previously described large chromosomal aberrations but also detected novel microdeletions in genes potentially involved in tumor genesis of cc-RCC.
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PMID:Loss of heterozygosity and copy number abnormality in clear cell renal cell carcinoma discovered by high-density affymetrix 10K single nucleotide polymorphism mapping array. 1859 4


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