Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Squamous cell carcinoma (SCC) is the most prevalent form of epithelial cancer. SCC results when normal epithelial cells undergo multiple neoplastic changes that culminate in the evolution of an invasive cancer. Retinoids are commonly used as chemopreventive and treatment agents in skin cancer; however, SCC progression is accompanied by a gradual loss of retinoid responsiveness. The synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) has shown promising anti-neoplastic activity in a variety of tumor cells, including those that are resistant to all-trans retinoic acid (t-RA). We investigated the effect of HPR on growth and apoptosis of squamous cells at different stages of carcinogenesis. We then determined if retinoic acid receptor (RAR) overexpression affected the outcome of HPR treatment. To model SCC malignant progression, we used a panel of murine keratinocytes representing different stages of squamous cell carcinogenesis. This panel consisted of primary keratinocytes, SP1 and 308 papilloma cell lines, the PAM-212 squamous carcinoma cell line, and the spindle I7 cell line. With the exception of the primary keratinocytes, all cells were unresponsive to t-RA treatment. Pharmacological concentrations of HPR were non-cytotoxic to all keratinocytes tested and HPR sensitivity was stage-dependent, with the papilloma cell lines being the most sensitive, and the spindle cells being the most resistant. Overexpression of RARgamma in SP1 papilloma cells enhanced growth suppression and apoptosis induction by HPR. HPR-induced growth suppression was accompanied by a simultaneous block in the G(1) phase of the cell cycle in RAR-transduced and control SP1 cells and differential regulation of cell cycle and apoptotic mediators.
Mol Carcinog 2004 May
PMID:Stage-specific effect of N-(4-hydroxyphenyl)retinamide on cell growth in squamous cell carcinogenesis. 1510 26

Changes in the proteome of colon mucosal cells accompany the transition from normal mucosa via adenoma and invasive cancer to metastatic disease. Samples from 15 patients with sporadic sigmoid cancers were analyzed. Proteins were separated by two-dimensional gel electrophoresis. Relative differences in expression levels between normal tissue, adenoma, carcinoma and metastasis were evaluated in both intra- and inter-patient comparisons. Up- and down-regulated proteins (> twofold) during development to cancer or metastasis were excised and submitted to peptide mass fingerprinting and MS/MS sequence analysis, facilitated by the use of a compact disc workstation. In total, 112 protein spots were found to be differentially regulated, of which 72 were determined as to protein identity, 46 being up-regulated toward the progression of cancer, and 26 down-regulated. Several of the identifications correlate with proteins of the cell cycle, cytoskeleton or metabolic pathways. The pattern changes now identified have the potential for design of marker panels for assistance in diagnostics and therapeutic strategies in colorectal cancer.
Cell Mol Life Sci 2004 May
PMID:Sequential proteome alterations during genesis and progression of colon cancer. 1514 10

Metastatic renal cell carcinoma (RCC) is often resistant to standard treatment, thereby requiring new therapeutic strategies. In this regard, tumor cell migration and metastasis have recently been shown to be regulated by chemokines and their respective receptors (e.g., SDF-1alpha/CXCR4). In the context of RCC, up-regulation of CXCR4 expression is closely related to the development of invasive cancer. Thus, we hypothesized that the CXCR4 pathway could be exploited for RCC targeting with gene therapy vectors. In this regard, targeting adenoviral vectors to tumor cells is critically dependent on tumor-specific gene expression. Toward the end of RCC tumor targeting, we evaluated the utility of the CXCR4 promoter in an adenoviral context. First, overexpression of CXCR4 was confirmed in several RCC cell lines. Next, an adenoviral vector was constructed, whereby the human CXCR4 promoter drives the expression of a reporter gene. We tested the activity of the CXCR4 promoter in vitro and in vivo in relevant models. Our data indicate that the human CXCR4 promoter is highly active in RCC cells but not in normal human cells. Finally, biodistribution studies in mice demonstrated dramatic repression of the CXCR4 promoter in the liver but not in the kidney. In conclusion, the unique activity of the CXCR4 promoter in RCC lines and its repression in normal human cells and in the murine liver underscore its potential utility as a novel candidate for transcriptional targeting of RCC.
Mol Cancer Ther 2004 Jun
PMID:Transcriptional targeting in renal cancer cell lines via the human CXCR4 promoter. 1521 Aug 54

A large amount of data demonstrating the stochastic nature of gene expression and cell differentiation has accumulated during the last 40 years. These data suggest that a gene in a cell always has a certain probability of being activated at any time and that instead of leading to on and off switches in an all-or-nothing fashion, the concentration of transcriptional regulators increases or decreases this probability. In order to integrate these data in an appropriate theoretical frame, we have tested the relevance of the selective model of cell differentiation by computer simulation experiments. This model is based on stochastic gene expression controlled by cellular interactions. Our results show that it is readily able to produce tissue organization. A model involving only two cells generated a bi-layer cellular structure of finite growth. Cell death was not a drawback but an advantage because it improved the viability of this bi-layer structure. However, our results also show that cellular interactions cannot be simply based on raw selection between cells. Instead, tissue coordination includes at least two basic components: phenotypic autostabilization (differentiated cells stabilize their own phenotype) and interdependence for proliferation (differentiated cells stimulate the proliferation of alien phenotypes). In this modified autostabilization-selection model, cellular organization and growth arrest result from a quantitative equilibrium between the parameters controlling these two processes. An imbalance leads to tissue disorganization and invasive cancer-like growth. These findings suggest that cancer does not result solely from mutations in the cancerous cell but from the progressive addition of several small alterations of the equilibrium between autostabilization and interdependence for proliferation. In this frame, it is not solely the cancerous cell that is abnormal. The whole organism is involved. Tumor growth is a local effect of an imbalance between all the factors involved in tissue organization.
Prog Biophys Mol Biol 2005 Sep
PMID:Modeling embryogenesis and cancer: an approach based on an equilibrium between the autostabilization of stochastic gene expression and the interdependence of cells for proliferation. 1582 73

Fundamental differences exist between ulcerative colitis (UC)-associated and sporadic forms of colorectal cancer, including preexisting inflammation, type of dysplasia, and timing of molecular events in carcinogenesis. Transcriptional alterations that occur in UC-associated neoplasia in the progression from normal mucosa through dysplastic epithelium to invasive cancer have not been described. We used Affymetrix U95Av2 microarrays to assess differential gene expression in the neoplastic progression of UC tissue from the colonic mucosa of individuals with benign UC, UC-dysplasia-associated lesions or masses, and UC adenocarcinoma. By correlating transcript alterations across tissue types using a mixed statistical model, we identified 699 genes exhibiting altered expression with dysplasia development. A different expression profile was observed in progression to adenocarcinoma with 392 transcripts exhibiting differential expression. There were 224 transcripts common to both dysplasia and adenocarcinoma. Most of the differentially expressed genes described herein were not previously known to play a role in neoplastic progression in UC, including transcripts affecting cell proliferation and apoptosis, signal transduction and signaling, and DNA repair. The altered expression of five transcripts was confirmed by quantitative real-time reverse-transcription polymerase chain reaction. Based on comparisons with previous studies on sporadic colorectal carcinoma, several similarities were found. There were, however, important differences that suggest that different molecular events may occur in the development of UC-associated neoplasia. Several of these genes demonstrated similar changes in dysplastic and cancerous tissue and may be involved in early cancer formation. Identification of these genes as potential clinical biomarkers may lead to improved early disease diagnosis.
Exp Mol Pathol 2006 Feb
PMID:Molecular profiling of ulcerative colitis-associated neoplastic progression. 1627 83

Most cervical cancers are preventable when the precursor lesions are detected in time. Human papilloma viruses (HPVs) are the main risk factors for cervical cancer development, but there is a high percentage of healthy women infected with HPV that never develop a lesion. Only a small percentage of low-grade dysplasias finally grow out to invasive cancer. Several biomarkers can be used to identify lesions at risk for malignant progression. Overexpression of p16INK4a is induced by the viral oncoprotein E7 and distinguishes dysplastic lesions from benign changes. Integration of human papillomavirus DNA into the host genome is mainly found in high-grade dysplastic lesions and invasive cancers, and points to an increased progression potential.
Methods Mol Med 2005
PMID:Analysis of p16INK4a and integrated HPV genomes as progression markers. 1635 Mar 98

Breast cancer confined within the lactiferous duct or lobule, without invading the stroma, is called ductal carcinoma in situ (DCIS), whereas breast cancer that has invaded the stroma through the basal membrane is called invasive cancer. Heparanase, an endo-beta-D-glucuronidase that specifically degrades heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM), plays an important role when breast cancer cells breach the basal membrane. Recently, we have reported that heparanase is involved in angiogenesis through direct induction of cyclo-oxygenase-2 (COX-2). COX-2 induces vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and is thus involved in neovascularization. The present study was undertaken to analyze surgically resected breast cancer specimens for heparanase and COX-2 expression, using specimens from 59 patients with invasive cancer and 85 patients with DCIS (including 41 cases of DCIS adjacent to invasive cancer). This study yielded the following results: a) the distribution of heparanase within tumor tissue was identical to that of COX-2; b) heparanase expression was more frequent in invasive cancer than in non-invasive cancer; c) a close positive correlation was noted between heparanase and COX-2 expression (this correlation was particularly strong in cases of invasive cancer); and d) COX-2 expression was always seen in cases positive for heparanase expression. Our results indicate that heparanase expression increases during the progression of breast cancer into invasive cancer, and that this change is accompanied by increased COX-2 expression. They also suggest that heparanase may play a novel role for COX-2 mediated tumor angiogenesis in breast-cancer progression.
Int J Mol Med 2006 Feb
PMID:COX-2 induction by heparanase in the progression of breast cancer. 1639 19

Recently, we have found dramatic overexpression of ecto-5'-nucleotidase (or CD73), a glycosylphosphatidylinositol-anchored component of lipid rafts, in estrogen receptor-negative [ER-] breast cancer cell lines and in clinical samples. To find out whether there is a more general shift in expression profile of membrane proteins, we undertook an investigation on the expression of selected membrane and cytoskeletal proteins in aggressive and metastatic breast cancer cells. Our analysis revealed a remarkably uniform shift in expression of a broad range of membrane, cytoskeletal, and signaling proteins in ER- cells. A similar change was found in two in vitro models of transition to ER- breast cancer: drug-resistant Adr2 and c-Jun-transformed clones of MCF-7 cells. Interestingly, similar expression pattern was observed in normal fibroblasts, suggesting the commonality of membrane determinants of invasive cancer cells with normal mesenchymal phenotype. Because a number of investigated proteins are components of lipid rafts, our results suggest that there is a major remodeling of lipid rafts and underlying cytoskeleton in ER- breast cancer. To test whether this broadly defined ER- phenotype could be reversed by treatment with differentiating agent, we treated ER- cells with trichostatin A, an inhibitor of histone deacetylase, and observed reversal of mesenchymal and reappearance of epithelial markers. Changes in gene and protein expression also included increased capacity to generate adenosine and altered expression profile of adenosine receptors. Thus, our results suggest that during transition to invasive breast cancer there is a significant structural reorganization of lipid rafts and underlying cytoskeleton that is reversed upon histone deacetylase inhibition.
Mol Cancer Ther 2006 Feb
PMID:Lipid rafts remodeling in estrogen receptor-negative breast cancer is reversed by histone deacetylase inhibitor. 1650 96

The rapidly expanding knowledge of the pathogenesis of pancreatic cancer at the molecular level is providing new targets for disease characterization, early diagnosis, and drug discovery and development. Gene mutation analysis has provided insight on the pathogenesis and progression from preinvasive lesions to invasive cancer. Gene and protein expression profiling has advanced our understanding of pancreatic ductal adenocarcinoma identifying genes that are highly expressed in pancreatic cancers, providing more insight into the clinicopathologic features of pancreatic cancer, and revealing novel features related to the process of tissue invasion by these tumors. The increasing knowledge of the pathway activation profile in pancreatic cancer is yielding new targets but also new markers to select patients and guide and predict therapy efficacy. The discovery of genetic factors of which the presence predisposes pancreatic cancer to successful targeting, such as the association of BRCA2/Fanconi anemia genes defects and sensitivity to mitomycin C, will eventually lead to a more individualized treatment approach. In summary, several decades of intensive research have originated multiple factors or biomarkers that are likely to be helpful in the diagnosis, characterization, and therapy selection of pancreatic cancer patients. A deep understanding of the relative relevance of each biomarker will be key to efficiently diagnose this disease and direct our patients towards the drugs more likely to be of benefit based on their particular profile. The development of new preclinical models is of paramount importance to achieve these goals.
Mol Cancer Ther 2006 Apr
PMID:Molecular biomarkers: their increasing role in the diagnosis, characterization, and therapy guidance in pancreatic cancer. 1664 48

Common fragile site gene WWOX encodes a candidate tumor suppressor WW domain-containing oxidoreductase. Alteration of this gene, along with dramatic downregulation of WWOX protein, is shown in the majority of invasive cancer cells. Ectopic WWOX exhibits proapoptotic and tumor inhibitory functions in vitro and in vivo, probably interacting with growth regulatory proteins p53, p73 and others. Hyaluronidases regulate WWOX expression, increase cancer invasiveness and seem to be involved in the development of hormone-independent growth of invasive cancer cells. Estrogen and androgen stimulate phosphorylation and nuclear translocation of WWOX, although binding of WWOX to these sex hormones is unknown. We propose that suppression of WWOX expression by overexpressed hyaluronidases might contribute in part to the development of hormone independence in invasive cancer.
Trends Mol Med 2007 Jan
PMID:WW domain-containing oxidoreductase: a candidate tumor suppressor. 1714 2


<< Previous 1 2 3 4 5 6 7 8 9 Next >>