Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many malignant tumors including non-small cell lung cancer (NSCLC) express or over-express EGFR that have shown correlations with rapid growth, metastases, resistance to conventional chemotherapy or radiotherapy, and poor prognosis. Gefitinib is a potent and selective inhibitor of EGFR tyrosine kinase (EGFRTK). Gefitinib specifically inhibited EGF-stimulated cell proliferation in vitro and it also exhibited a broad anti-tumor spectrum against NSCLC, prostate, colorectal, and ovarian cancers in vivo. Gefitinib showed dose-dependent and reversible reduction of c-fos mRNA level and decreased Ki67 significantly in tumors in vivo. In in vitro studies, gefitinib arrested the cell cycle at G1 phase by inducing intrinsic cyclin-dependent kinase (cdk) inhibitors and following inhibition of cdk2. Apoptosis was also seen in gefitinib-treated tumor cells and skin biopsy samples from clinical study. Gefitinib inhibited VEGF production in tumor cells through inhibition of EGFR signaling, leading to suppression of angiogenesis. In clinical studies, gefitinib demonstrated therapeutic benefit in patients who failed conventional chemotherapy. No correlation has been established between the anti-tumor activity of gefitinib and EGFR expression level, whilst sensitivity factors to gefitinib are yet to be elucidated. Identification of sensitivity factors will be a key for effective use of EGFRTK inhibitors including gefitinib for cancer treatment.
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PMID:EGFR tyrosine kinase inhibitor "gefitinib (Iressa)" for cancer therapy. 1463 3

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Deregulation of cell-cycle control is thought to be a crucial event in malignant transformation, and CDC25 phosphatases are a family of cyclin-dependent kinase activators, which act at different points of the cell cycle, including G1-S and G2-M transition. Here, we investigated the expression and functional significance of CDC25s in PDAC. CDC25B mRNA expression levels in human pancreatic tissue samples were analysed by cDNA array, quantitative PCR and Northern blotting. Immunohistochemistry was carried out to localize and quantify CDC25B expression. Two specific CDC25B inhibitors were utilized to determine the functional relevance of CDC25B. By quantitative RT-PCR, CDC25B mRNA was overexpressed in pancreatic cancer (7.5-fold) in comparison to the normal pancreas. Strong nuclear CDC25B immunoreactivity was present in both pancreatic and metastatic cancer samples, and there was a marked increase of the percentage of positive cells in primary cancer (48.6+/-16.3%) and metastatic tissues (71.7+/-3.1%) compared to normal samples (8.3+/-1.8%). Two CDC25B inhibitors reduced the growth of pancreatic cancer cell lines, resulting in the accumulation of phosphorylated CDC2 and G2/M arrest. These findings demonstrate an important role of CDC25B in cell-cycle progression, raising the possibility that inhibition of CDC25B may have therapeutic potential in pancreatic cancer.
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PMID:Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma. 1471 12

Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein and promotes progression through the G1-S phase of the cell cycle. Amplification or overexpression of cyclin D1 plays pivotal roles in the development of a subset of human cancers including parathyroid adenoma, breast cancer, colon cancer, lymphoma, melanoma, and prostate cancer. Of the three D-type cyclins, each of which binds cyclin-dependent kinase (CDK), it is cyclin D1 overexpression that is predominantly associated with human tumorigenesis and cellular metastases. In recent years accumulating evidence suggests that in addition to its original description as a CDK-dependent regulator of the cell cycle, cyclin D1 also conveys cell cycle or CDK-independent functions. Cyclin D1 associates with, and regulates activity of, transcription factors, coactivators and corepressors that govern histone acetylation and chromatin remodeling proteins. The recent findings that cyclin D1 regulates cellular metabolism, fat cell differentiation and cellular migration have refocused attention on novel functions of cyclin D1 and their possible role in tumorigenesis. In this review, both the classic and novel functions of cyclin D1 are discussed with emphasis on the CDK-independent functions of cyclin D1.
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PMID:Minireview: Cyclin D1: normal and abnormal functions. 1533 80

It has been proposed that the osteoblastic nature of prostate cancer skeletal metastases is due in part to elevated activity of bone morphogenetic proteins (BMPs). BMPs are osteoinductive morphogens, and elevated expression of BMP-6 correlates with skeletal metastases of prostate cancer. In this study, we investigated the expression levels of BMPs and their modulators in prostate, using microarray analysis of cell cultures and gene expression. Addition of exogenous BMP-6 to DU-145 prostate cancer cell cultures inhibited their growth by up-regulation of several cyclin-dependent kinase inhibitors such as p21/CIP, p18, and p19. Expression of noggin, a BMP antagonist, was significantly up-regulated by BMP-6 by microarray analysis and was confirmed by quantitative reverse transcription-polymerase chain reaction and at the protein level. Noggin protein was present in prostate biopsies and localized to the epithelial components of prostate by immunohistochemistry. Recombinant noggin inhibited the function of BMP-6, suggesting a negative feedback regulation of BMP activity and indicating a strategy for the development of a novel therapeutic target in the treatment of painful osteosclerotic bone metastases of prostate cancer.
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PMID:Bone morphogenetic protein (BMP)-6 signaling and BMP antagonist noggin in prostate cancer. 1554 95

Systematic analyses of cancer genomes promise to unveil patterns of genetic alterations linked to the genesis and spread of human cancers. High-density single-nucleotide polymorphism (SNP) arrays enable detailed and genome-wide identification of both loss-of-heterozygosity events and copy-number alterations in cancer. Here, by integrating SNP array-based genetic maps with gene expression signatures derived from NCI60 cell lines, we identified the melanocyte master regulator MITF (microphthalmia-associated transcription factor) as the target of a novel melanoma amplification. We found that MITF amplification was more prevalent in metastatic disease and correlated with decreased overall patient survival. BRAF mutation and p16 inactivation accompanied MITF amplification in melanoma cell lines. Ectopic MITF expression in conjunction with the BRAF(V600E) mutant transformed primary human melanocytes, and thus MITF can function as a melanoma oncogene. Reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents. Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm. Together, these data suggest that MITF represents a distinct class of 'lineage survival' or 'lineage addiction' oncogenes required for both tissue-specific cancer development and tumour progression.
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PMID:Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. 1600 Oct 50

A better understanding of the molecular basis of tumor progression and invasion is needed to improve therapy for malignant tumors. Recently, we established a mouse metastatic MK16 model by transduction of secondary kidney cells with human papillomavirus type 16 (HPV16) E6 and E7 oncogenes and human H-ras activated by G12V mutation. In this study, we extended the model to MK16 cell lines derived from lung metastases and compared the oncogenicity of seven cell lines successively isolated from primary tumors or metastases. By observing the formation and growth of subcutaneous tumors and generation of lung metastasis, we showed a gradual increase in oncogenicity of MK16 cell lines. Interestingly, we demonstrated metastatic potential of MK16/A cells with low oncogenic potential in primary tumor development. To detect changes in gene expression associated with increasing oncogenicity of MK16 cell lines, we performed transcriptional profiling with the Atlas Plastic Mouse 5K microarray. We found that a substantial proportion of up-regulated genes encoded ribosomal proteins. Among the down-regulated genes, the highest number (n=10) belonged to a group coding for transcription factors. Expression of two of these, Pou3f2 and Gtl3, was reduced both in cells derived from primary tumors and those isolated from metastases. Furthermore, microarray hybridization suggested that the down-regulation of cyclin-dependent kinase inhibitors p16(Ink4a) and p57(Kip2) and up-regulation of A6 and A10 members of the S100 protein family might play a role in the increase of MK16 oncogenicity.
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PMID:Analysis of tumor progression by transcriptional profiling of mouse MK16 cell lines transformed with human papillomavirus type 16 E6 and E7 oncogenes and activated H-ras. 1627 73

The p27 tumor suppressor negatively regulates G1 cell cycle progression. However, human malignancies rarely select for deletion/inactivation of p27, a hallmark of tumor suppressor genes. Instead, p27 is degraded or relocalized to the cytoplasm in aggressive malignancies, supporting the notion that p27 sequestration from its nuclear cyclin:cyclin-dependent kinase (cdk) targets is critical. However, emerging cell biology data suggest a novel cdk-independent cytoplasmic function of p27 in cell migration. Here, we find cytoplasmic p27 in 70% of invasive and metastatic melanomas. In contrast, no cytoplasmic p27 was detected in noninvasive, basement membrane-confined melanoma in situ, suggesting a late oncogenic role for cytoplasmic p27 in metastasis. Targeted cytoplasmic expression of wild-type or non-cdk-binding p27 at subphysiologic levels induced melanoma motility and resulted in numerous metastases to lymph node, lung, and peritoneum. These observations point to a prominent role of cytoplasmic p27 in metastatic disease that is independent of cyclin:cdk regulation or mere nuclear loss.
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PMID:Relocalized p27Kip1 tumor suppressor functions as a cytoplasmic metastatic oncogene in melanoma. 1790 30

In a variety of human malignancies, aberrant expression of proteins involved in the control of cell-cycle progression has been reported. In this study, p21cip1, p27kip1, and p16INk4a cyclin-dependent kinase inhibitors were analyzed to evaluate their usefulness in clinical management of papillary thyroid carcinoma (PTC). Archived material derived from 46 cases of PTC was analyzed immunohistochemically. Protein expression was ascertained on tissue microarrays, and results were correlated with clinicopathological features of the patients. Positive immunostaining was observed in 14 (30,4%) p21cip1, 26 (56,5%) p27kip1, and 14 (30,4%) p16INk4a cases. No significant correlation between p21cip1 or p27kip1 and clinical factors was found. In contrast, p16INk4a expression showed a significant correlation with initial extension of the disease. Therefore, 45.8% of patients with loco-regional extension were p16INk4a positive, whereas overexpression was only seen in 15.7% of cases with intrathyroid disease (p < 0.05). Moreover, all patients with simultaneous p16INk4a positivity and lack of p27kip1 staining (four patients) presented lymph node metastases. In contrast, only 12 (28.5%) of the remaining patients showed lymph node tumor involvement. In conclusion, p16INk4a expression suggests extrathyroid neck extension of PTC. This effect is enhanced when p27kip1 is negative. We think that their analysis by immunohistochemistry could be useful in the management of patients with PTC.
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PMID:Expression of p21cip1, p27kip1, and p16INk4a cyclin-dependent kinase inhibitors in papillary thyroid carcinoma: correlation with clinicopathological factors. 1876 73

Mammary cancer is among the most frequently observed canine tumors in unspayed female dogs resulting in death due to metastatic disease. These tumors are excellent models of human breast cancer but until recently there was only anecdotal evidence regarding underlying genetic defects. We recently reported expression defects in the cyclin-dependent kinase p21/Cip1 and p53 among three independent canine mammary tumor (CMT) cell lines derived from spontaneous canine mammary cancers. We investigated further defects in the same three cell lines focusing on additional tumor suppressor gene defects in cyclin-dependent kinase inhibitors. p27/KIP1 appeared normally expressed and did not appear to encode inactivating mutations. In contrast, expression of p16/INK4A was defective/absent in two cell lines and normal/slightly induced in the third cell line. To determine if defects were causative in maintaining the transformed phenotype, a p16/INK4A transgene was permanently transfected followed by selection and single cell cloning. CMT/p16 clones were characterized for transgene expression, p16 protein content and phenotype including proliferation rate, cell cycle phase distribution, contact inhibition, substrate dependent cell growth and cell morphology. All cell lines appeared unique yet clear indications of phenotype rescue due to p16/INK4A transgene complementation were observed suggesting that defects in p16 expression were present in all three. In some cases cellular senescence also appeared to be induced. These data provide evidence supporting p16/INK4A mutations as causative defects promoting transformation in canine mammary cancer and further characterizes tumor suppressor gene defects with functional consequences in these cells supporting their application as spontaneous animal models of human disease.
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PMID:Phenotype-rescue of cyclin-dependent kinase inhibitor p16/INK4A defects in a spontaneous canine cell model of breast cancer. 1913 Apr 92

Cks1 is an essential factor in facilitating Skp2-dependent degradation of p27, but its role in salivary malignancies is unknown. Expression of cyclin-dependent kinase subunit 1 (Cks1) was examined in 64 salivary malignancies, compared with p27, S-phase kinase protein 2 (Skp2), Ki-67, p53, and TDT-mediated dutp-biotin nick end labeling (TUNEL) expression, and with THE patient's clinical and pathological parameters. Cks1 expression was markedly increased in 30 patients (47%) and strongly correlated with increased expression of Skp2, Ki-67, p53, and TUNEL, but inversely with p27 levels. High expression of Cks1 WAS strongly associated with lymph node metastases and poor prognosis and survival. Cks1 alterations may have a significant biological role in the pathogenesis of salivary cancer.
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PMID:The expression and prognostic significance of Cks1 in salivary cancer. 1929 97


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