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Protein expression signatures for inhibition of epidermal growth factor receptor-mediated signaling.
Myers MV, Manning HC, Coffey RJ, Liebler DC
(2012) Mol Cell Proteomics 11: M111.015222
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Blotting, Western, Cell Line, Tumor, Cell Proliferation, Cetuximab, Chromatography, Liquid, Colorectal Neoplasms, Epidermal Growth Factor, ErbB Receptors, Gastritis, Hypertrophic, Gefitinib, Humans, Mice, Neoplasms, Neoplasms, Glandular and Epithelial, Phosphorylation, Prospective Studies, Proteomics, Quinazolines, Signal Transduction, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Transplantation, Heterologous
Show Abstract · Added March 5, 2014
Analysis of cellular signaling networks typically involves targeted measurements of phosphorylated protein intermediates. However, phosphoproteomic analyses usually require affinity enrichment of phosphopeptides and can be complicated by artifactual changes in phosphorylation caused by uncontrolled preanalytical variables, particularly in the analysis of tissue specimens. We asked whether changes in protein expression, which are more stable and easily analyzed, could reflect network stimulation and inhibition. We employed this approach to analyze stimulation and inhibition of the epidermal growth factor receptor (EGFR) by EGF and selective EGFR inhibitors. Shotgun analysis of proteomes from proliferating A431 cells, EGF-stimulated cells, and cells co-treated with the EGFR inhibitors cetuximab or gefitinib identified groups of differentially expressed proteins. Comparisons of these protein groups identified 13 proteins whose EGF-induced expression changes were reversed by both EGFR inhibitors. Targeted multiple reaction monitoring analysis verified differential expression of 12 of these proteins, which comprise a candidate EGFR inhibition signature. We then tested these 12 proteins by multiple reaction monitoring analysis in three other models: 1) a comparison of DiFi (EGFR inhibitor-sensitive) and HCT116 (EGFR-insensitive) cell lines, 2) in formalin-fixed, paraffin-embedded mouse xenograft DiFi and HCT116 tumors, and 3) in tissue biopsies from a patient with the gastric hyperproliferative disorder Ménétrier's disease who was treated with cetuximab. Of the proteins in the candidate signature, a core group, including c-Jun, Jagged-1, and Claudin 4, were decreased by EGFR inhibitors in all three models. Although the goal of these studies was not to validate a clinically useful EGFR inhibition signature, the results confirm the hypothesis that clinically used EGFR inhibitors generate characteristic protein expression changes. This work further outlines a prototypical approach to derive and test protein expression signatures for drug action on signaling networks.
1 Communities
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25 MeSH Terms
A microRNA gene expression signature predicts response to erlotinib in epithelial cancer cell lines and targets EMT.
Bryant JL, Britson J, Balko JM, Willian M, Timmons R, Frolov A, Black EP
(2012) Br J Cancer 106: 148-56
MeSH Terms: Antineoplastic Agents, Cell Line, Tumor, Epithelial-Mesenchymal Transition, ErbB Receptors, Erlotinib Hydrochloride, Gene Expression Profiling, Humans, MicroRNAs, Neoplasms, Glandular and Epithelial, Quinazolines
Show Abstract · Added March 10, 2014
BACKGROUND - Treatment with epidermal growth factor receptor (EGFR) inhibitors can result in clinical response in non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) for some unselected patients. EGFR and KRAS mutation status, amplification of EGFR, or gene expression predictors of response can forecast sensitivity to EGFR inhibition.
METHODS - Using an NSCLC cell line model system, we identified and characterised microRNA (miRNA) gene expression that predicts response to EGFR inhibition.
RESULTS - Expression of 13 miRNA genes predicts response to EGFR inhibition in cancer cell lines and tumours, and discriminates primary from metastatic tumours. Signature genes target proteins that are enriched for epithelial-to-mesenchymal transition (EMT) genes. Epithelial-to-mesenchymal transition predicts EGFR inhibitor resistance and metastatic behaviour. The EMT transcription factor, ZEB1, shows altered expression in erlotinib-sensitive NSCLC and PDAC, where many signature miRNA genes are upregulated. Ectopic expression of mir-200c alters expression of EMT proteins, sensitivity to erlotinib, and migration in lung cells. Treatment with TGFβ1 changes expression of signature miRNA and EMT proteins and modulates migration in lung cells.
CONCLUSION - From these data, we hypothesise that the tumour microenvironment elicits TGFβ1 and stimulates a miRNA gene expression program that induces resistance to anti-EGFR therapy and drives lung tumour cells to EMT, invasion, and metastasis.
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10 MeSH Terms
Epithelial ovarian cancer.
Morgan RJ, Alvarez RD, Armstrong DK, Boston B, Burger RA, Chen LM, Copeland L, Crispens MA, Gershenson D, Gray HJ, Grigsby PW, Hakam A, Havrilesky LJ, Johnston C, Lele S, Matulonis UA, O'Malley DM, Penson RT, Remmenga SW, Sabbatini P, Schilder RJ, Schink JC, Teng N, Werner TL, National Comprehensive Cancer Network
(2011) J Natl Compr Canc Netw 9: 82-113
MeSH Terms: Carcinoma, Ovarian Epithelial, Female, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms
Added March 10, 2014
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5 MeSH Terms
IGF-II promoter specific methylation and expression in epithelial ovarian cancer and their associations with disease characteristics.
Qian B, Katsaros D, Lu L, Canuto EM, Benedetto C, Beeghly-Fadiel A, Yu H
(2011) Oncol Rep 25: 203-13
MeSH Terms: Adult, Aged, Aged, 80 and over, DNA Methylation, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic, Humans, Insulin-Like Growth Factor II, Middle Aged, Neoplasm Staging, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Promoter Regions, Genetic, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added February 22, 2016
High expression of insulin-like growth factor-II (IGF-II) in epithelial ovarian cancer is associated with aggressive disease and poor prognosis. IGF-II transcription is initiated from multiple promoters. Promoter-specific expression is regulated by DNA methylation, which is often dysregulated in cancer. Here, the effects of promoter-specific methylation on IGF-II expression are investigated in ovarian cancer. Fresh tumor samples were collected from 211 patients for analyses of IGF-II promoter methylation using methylation-specific PCR, and of promoter-specific expression of IGF-II mRNA with qRT-PCR, as well as tissue levels of IGF-II peptide with an ELISA. Cox regression analysis was performed to assess IGF-II methylation and expression in association with progression-free and overall survival. DNA methylation was high in IGF-II promoters 2 (P2, 64.2%) and 3 (P3, 52.1%) and low in promoter 4 (P4, 9.8%). High methylation was associated with low mRNA expression in a promoter-specific manner. P3 methylation and expression appeared to be critical in ovarian cancer compared to other promoters. While methylation in an individual promoter was not associated with the disease, a methylation pattern involving P2 and P3 was significantly different among patients with distinct tumor grade, debulking results, residual tumor size and treatment response. The methylation pattern was also associated with disease progression. The study suggests that DNA methylation regulates IGF-II promoter-specific expression in ovarian cancer and the regulation may play a role in disease progression. Assessing methylation patterns in IGF-II promoters may have clinical implications.
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15 MeSH Terms
Metanephric stromal tumor arising in a patient with neurofibromatosis type 1 syndrome.
McDonald OG, Rodriguez R, Bergner A, Argani P
(2011) Int J Surg Pathol 19: 667-71
MeSH Terms: Female, Humans, Immunohistochemistry, Kidney Neoplasms, Middle Aged, Neoplasms, Glandular and Epithelial, Neurofibromatosis 1
Show Abstract · Added May 5, 2016
Metanephric stromal tumor (MST) is a recently recognized benign renal stromal tumor. MST is thought to be part of a spectrum of benign metanephric renal lesions, which also includes the epithelial lesion metanephric adenoma and the mixed stromal-epithelial lesion metanephric adenofibroma. Metanephric lesions may represent hyperdifferentiated counterparts to Wilms' tumor (WT). MST characteristically shows renovascular angiodysplasia and juxtaglomerular (JG) cell hyperplasia. This is remarkably similar to the renal pathology described in neurofibromatosis-1 (NF-1) syndrome, a condition which is also associated with WT. Here, we report the first case of MST arising in a patient with NF-1. The patient presented with hypertension, and the MST was associated with florid angiodysplasia and JG cell hyperplasia. This case tightens the link between NF-1, WT, and MST.
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7 MeSH Terms
A novel circular invasion assay mimics in vivo invasive behavior of cancer cell lines and distinguishes single-cell motility in vitro.
Kam Y, Guess C, Estrada L, Weidow B, Quaranta V
(2008) BMC Cancer 8: 198
MeSH Terms: Animals, Breast Neoplasms, Cell Line, Tumor, Cell Migration Assays, Cell Transformation, Neoplastic, Colorectal Neoplasms, Female, Humans, Microscopy, Confocal, Neoplasm Metastasis, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Wound Healing
Show Abstract · Added February 27, 2013
BACKGROUND - Classical in vitro wound-healing assays and other techniques designed to study cell migration and invasion have been used for many years to elucidate the various mechanisms associated with metastasis. However, many of these methods are limited in their ability to achieve reproducible, quantitative results that translate well in vivo. Such techniques are also commonly unable to elucidate single-cell motility mechanisms, an important factor to be considered when studying dissemination. Therefore, we developed and applied a novel in vitro circular invasion assay (CIA) in order to bridge the translational gap between in vitro and in vivo findings, and to distinguish between different modes of invasion.
METHOD - Our method is a modified version of a standard circular wound-healing assay with an added matrix barrier component (Matrigel), which better mimics those physiological conditions present in vivo. We examined 3 cancer cell lines (MCF-7, SCOV-3, and MDA-MB-231), each with a different established degree of aggressiveness, to test our assay's ability to detect diverse levels of invasiveness. Percent wound closure (or invasion) was measured using time-lapse microscopy and advanced image analysis techniques. We also applied the CIA technique to DLD-1 cells in the presence of lysophosphatidic acid (LPA), a bioactive lipid that was recently shown to stimulate cancer cell colony dispersal into single migratory cells, in order to validate our method's ability to detect collective and individual motility.
RESULTS - CIA method was found to be highly reproducible, with negligible levels of variance measured. It successfully detected the anticipated low, moderate, and high levels of invasion that correspond to in vivo findings for cell lines tested. It also captured that DLD-1 cells exhibit individual migration upon LPA stimulation, and collective behavior in its absence.
CONCLUSION - Given its ability to both determine pseudo-realistic invasive cell behavior in vitro and capture subtle differences in cell motility, we propose that our CIA method may shed some light on the cellular mechanisms underlying cancer invasion and deserves inclusion in further studies. The broad implication of this work is the development of a reproducible, quantifiable, high-resolution method that can be applied to various models, to include an unlimited number of parameters and/or agents that may influence invasion.
3 Communities
2 Members
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13 MeSH Terms
IGF-II promoter methylation and ovarian cancer prognosis.
Beeghly AC, Katsaros D, Wiley AL, Rigault de la Longrais IA, Prescott AT, Chen H, Puopolo M, Rutherford TJ, Yu H
(2007) J Cancer Res Clin Oncol 133: 713-23
MeSH Terms: Adult, Aged, Aged, 80 and over, DNA Methylation, Female, Humans, Insulin-Like Growth Factor II, Kaplan-Meier Estimate, Middle Aged, Neoplasm Staging, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymerase Chain Reaction, Prognosis, Promoter Regions, Genetic, Survival Analysis
Show Abstract · Added December 6, 2018
PURPOSE - The insulin-like growth factor-II (IGF-II) gene has four promoters that produce distinct transcripts which vary by tissue type and developmental stage. Dysregulation of normal promoter usage has been shown to occur in cancer; DNA methylation regulates promoter use. Thus, we sought to examine if DNA methylation varies among IGF-II promoters in ovarian cancer and if methylation patterns are related to clinical features of the disease.
STUDY DESIGN - Tumor tissue, clinical data, and follow-up information were collected from 215 patients diagnosed with primary epithelial ovarian cancer. DNA extracted from tumor tissues was analyzed for IGF-II promoter methylation with seven methylation specific PCR (MSP) assays: three for promoter 2 (P2) and two assays each for promoters 3 and 4 (P3 and P4).
RESULTS - Methylation was found to vary among the seven assays: 19.3% in P2A, 45.6% in P2B, 50.9% in P2C, 48.4% in P3A, 13.1% in P3B, 5.1% in P4A, and 6.1% in P4B. Methylation in any of the three P2 assays was associated with high tumor grade (P = 0.043), suboptimal debulking (P = 0.036), and disease progression [hazards ratio (HR) = 1.73, 95% confidence interval (CI) 1.09-2.74]. When comparing promoter methylation patterns, differential methylation of P2 and P3 was found to be associated with disease prognosis; patients with P3 but not P2 methylation were less likely to have disease progression (HR = 0.39, 95% CI 0.17-0.91) compared to patients with P2 but not P3 methylation.
CONCLUSIONS - This study shows that methylation varies among three IGF-II promoters in ovarian cancer and that this variation seems to have biologic implications as it relates to clinical features and prognosis of the disease.
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MeSH Terms
Stromal fibroblasts in cancer initiation and progression.
Bhowmick NA, Neilson EG, Moses HL
(2004) Nature 432: 332-7
MeSH Terms: Animals, Cell Transformation, Neoplastic, Disease Progression, Fibroblasts, Humans, Neoplasms, Glandular and Epithelial, Signal Transduction, Stromal Cells
Show Abstract · Added February 17, 2014
It is widely accepted that the development of carcinoma--the most common form of human cancer--is due to the accumulation of somatic mutations in epithelial cells. The behaviour of carcinomas is also influenced by the tumour microenvironment, which includes extracellular matrix, blood vasculature, inflammatory cells and fibroblasts. Recent studies reveal that fibroblasts have a more profound influence on the development and progression of carcinomas than was previously appreciated. These new findings have important therapeutic implications.
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8 MeSH Terms
TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia.
Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL
(2004) Science 303: 848-51
MeSH Terms: Animals, Carcinoma, Squamous Cell, Cell Division, Cell Transformation, Neoplastic, Cells, Cultured, Epithelial Cells, Female, Fibroblasts, Gastric Mucosa, Hepatocyte Growth Factor, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Neoplasms, Glandular and Epithelial, Prostate, Prostatic Intraepithelial Neoplasia, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-met, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Recombination, Genetic, Signal Transduction, Stomach, Stomach Neoplasms, Stromal Cells, Transforming Growth Factor beta
Show Abstract · Added February 17, 2014
Stromal cells can have a significant impact on the carcinogenic process in adjacent epithelia. The role of transforming growth factor-beta (TGF-beta) signaling in such epithelial-mesenchymal interactions was determined by conditional inactivation of the TGF-beta type II receptor gene in mouse fibroblasts (Tgfbr2fspKO). The loss of TGF-beta responsiveness in fibroblasts resulted in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach, both associated with an increased abundance of stromal cells. Activation of paracrine hepatocyte growth factor (HGF) signaling was identified as one possible mechanism for stimulation of epithelial proliferation. Thus, TGF-beta signaling in fibroblasts modulates the growth and oncogenic potential of adjacent epithelia in selected tissues.
1 Communities
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28 MeSH Terms
Tyrosine kinase inhibitors: rationale, mechanisms of action, and implications for drug resistance.
Busse D, Yakes FM, Lenferink AE, Arteaga CL
(2001) Semin Oncol 28: 47-55
MeSH Terms: Animals, Antineoplastic Agents, Breast Neoplasms, Cell Cycle, Clinical Trials as Topic, Drug Evaluation, Preclinical, Drug Resistance, Neoplasm, Enzyme Inhibitors, Humans, Ligands, Neoplasms, Glandular and Epithelial, Protein-Tyrosine Kinases, Receptor Protein-Tyrosine Kinases, Receptor, ErbB-2, Signal Transduction
Show Abstract · Added March 5, 2014
Tyrosine kinases play a role in normal cellular regulatory processes. However, aberrant tyrosine kinase activity can lead to cellular transformation and can be causally associated with tumor maintenance and progression. In the last few years, high-throughput screening and the use of combinatorial, computational, and medicinal chemistry have led to the identification of small molecules that compete with the adenosine triphosphate binding site of the catalytic domain of several oncogenic tyrosine kinases. Some of these compounds are highly specific to a single tyrosine kinase, while others can inhibit several homologous kinase pockets simultaneously. At a practical level, the relative promiscuity of these inhibitors against more than one oncogenic tyrosine kinase may have clinical merit as well as implications for host tissue toxicity. Many of these small molecules are in different stages of preclinical and clinical development against several solid tumors and will be discussed.
Copyright 2001 by W.B. Saunders Company.
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15 MeSH Terms