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Displayed correlation between gene expression profiles and submicroscopic alterations in response to cetuximab, gefitinib and EGF in human colon cancer cell lines

Abstract

EGFR is frequently overexpressed in colon cancer. We characterized HT-29 and Caco-2, human colon cancer cell lines, untreated and treated with cetuximab or gefitinib alone and in combination with EGF. Cell growth was determined using a variation on the MTT assay. Cell-cycle analysis was conducted by flow cytometry. Immunohistochemistry was performed to evaluate EGFR expression and scanning electron microscopy (SEM) evidenced the ultrastructural morphology. Gene expression profiling was performed using hybridization of the microarray Ocimum Pan Human 40 K array A. Caco-2 and HT-29 were respectively 66.25 and 59.24 % in G0/G1. They maintained this level of cell cycle distribution after treatment, suggesting a predominantly differentiated state. Treatment of Caco-2 with EGF or the two EGFR inhibitors produced a significant reduction in their viability. SEM clearly showed morphological cellular transformations in the direction of cellular death in both cell lines treated with EGFR inhibitors. HT-29 and Caco-2 displayed an important reduction of the microvilli (which also lose their erect position in Caco-2), possibly invalidating microvilli absorption function. HT-29 treated with cetuximab lost their boundary contacts and showed filipodi; when treated with gefitinib, they showed some vesicles: generally membrane reshaping is evident. Both cell lines showed a similar behavior in terms  More>>
Authors:
Solmi, Rossella; [1]  Montroni, Isacco; [2]  Mattei, Gabriella; [1]  Taffurelli, Mario; [2]  Santini, Donatella; [3]  Pezzetti, Furio; [1]  Ruggeri, Alessandro; [4]  Castellani, Gastone; [5]  DIMORFIPA, Università di Bologna, Bologna (Italy)]; Guidotti, Lia; [1]  Coppola, Domenico; [6]  Strippoli, Pierluigi; Lauriola, Mattia; [1]  Francesconi, Mirko; [5]  DIMORFIPA, Università di Bologna, Bologna (Italy)]; Martini, Désirée; [4]  Voltattorni, Manuela; [7]  Ceccarelli, Claudio; [3]  Ugolini, Giampaolo; Rosati, Giancarlo; Zanotti, Simone [2] 
  1. Dipartimento di Istologia, Embriologia e Biologia Applicata, Università di Bologna, Via Belmeloro 8, 40126 Bologna (Italy)
  2. Dipartimento Emergenza/Urgenza, Chirurgia Generale e dei Trapianti, Università di Bologna, Bologna (Italy)
  3. Dipartimento di Patologia, Università di Bologna, Bologna (Italy)
  4. Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Università di Bologna, Bologna (Italy)
  5. Centro Interdipartimentale L. Galvani, Università di Bologna, Bologna (Italy)
  6. H. Lee Moffit Cancer Center and Research Institute, University of South Florida, Tampa, FL (United States)
  7. Laboratori di Biotecnologie, Via Beverara 123, Bologna (Italy)
Publication Date:
Aug 08, 2008
Product Type:
Journal Article
Resource Relation:
Journal Name: BMC Cancer (Online); Journal Volume: 8; Other Information: PMCID: PMC2528013; PUBLISHER-ID: 1471-2407-8-227; PMID: 18691415; OAI: oai:pubmedcentral.nih.gov:2528013; Copyright (c) 2008 Solmi et al; licensee BioMed Central Ltd.; This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.; Country of input: International Atomic Energy Agency (IAEA)
Subject:
60 APPLIED LIFE SCIENCES; 62 RADIOLOGY AND NUCLEAR MEDICINE; ABSORPTION; APOPTOSIS; CELL CYCLE; DEATH; DISTRIBUTION; DRUGS; GENES; HYBRIDIZATION; LARGE INTESTINE; MEMBRANES; MORPHOLOGY; NEOPLASMS; SCANNING ELECTRON MICROSCOPY; VIABILITY
OSTI ID:
22386437
Country of Origin:
United Kingdom
Language:
English
Other Identifying Numbers:
Journal ID: ISSN 1471-2407; TRN: GB15$2752092016
Availability:
Available from http://dx.doi.org/10.1186/1471-2407-8-227; Available from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528013
Submitting Site:
INIS
Size:
page(s) 227
Announcement Date:
Oct 16, 2015

Citation Formats

Solmi, Rossella, Montroni, Isacco, Mattei, Gabriella, Taffurelli, Mario, Santini, Donatella, Pezzetti, Furio, Ruggeri, Alessandro, Castellani, Gastone, DIMORFIPA, Università di Bologna, Bologna (Italy)], Guidotti, Lia, Coppola, Domenico, Strippoli, Pierluigi, Lauriola, Mattia, Francesconi, Mirko, DIMORFIPA, Università di Bologna, Bologna (Italy)], Martini, Désirée, Voltattorni, Manuela, Ceccarelli, Claudio, Ugolini, Giampaolo, Rosati, Giancarlo, and Zanotti, Simone. Displayed correlation between gene expression profiles and submicroscopic alterations in response to cetuximab, gefitinib and EGF in human colon cancer cell lines. United Kingdom: N. p., 2008. Web. doi:10.1186/1471-2407-8-227.
Solmi, Rossella, Montroni, Isacco, Mattei, Gabriella, Taffurelli, Mario, Santini, Donatella, Pezzetti, Furio, Ruggeri, Alessandro, Castellani, Gastone, DIMORFIPA, Università di Bologna, Bologna (Italy)], Guidotti, Lia, Coppola, Domenico, Strippoli, Pierluigi, Lauriola, Mattia, Francesconi, Mirko, DIMORFIPA, Università di Bologna, Bologna (Italy)], Martini, Désirée, Voltattorni, Manuela, Ceccarelli, Claudio, Ugolini, Giampaolo, Rosati, Giancarlo, & Zanotti, Simone. Displayed correlation between gene expression profiles and submicroscopic alterations in response to cetuximab, gefitinib and EGF in human colon cancer cell lines. United Kingdom. doi:10.1186/1471-2407-8-227.
Solmi, Rossella, Montroni, Isacco, Mattei, Gabriella, Taffurelli, Mario, Santini, Donatella, Pezzetti, Furio, Ruggeri, Alessandro, Castellani, Gastone, DIMORFIPA, Università di Bologna, Bologna (Italy)], Guidotti, Lia, Coppola, Domenico, Strippoli, Pierluigi, Lauriola, Mattia, Francesconi, Mirko, DIMORFIPA, Università di Bologna, Bologna (Italy)], Martini, Désirée, Voltattorni, Manuela, Ceccarelli, Claudio, Ugolini, Giampaolo, Rosati, Giancarlo, and Zanotti, Simone. 2008. "Displayed correlation between gene expression profiles and submicroscopic alterations in response to cetuximab, gefitinib and EGF in human colon cancer cell lines." United Kingdom. doi:10.1186/1471-2407-8-227. https://www.osti.gov/servlets/purl/10.1186/1471-2407-8-227.
@misc{etde_22386437,
title = {Displayed correlation between gene expression profiles and submicroscopic alterations in response to cetuximab, gefitinib and EGF in human colon cancer cell lines}
author = {Solmi, Rossella, Montroni, Isacco, Mattei, Gabriella, Taffurelli, Mario, Santini, Donatella, Pezzetti, Furio, Ruggeri, Alessandro, Castellani, Gastone, DIMORFIPA, Università di Bologna, Bologna (Italy)], Guidotti, Lia, Coppola, Domenico, Strippoli, Pierluigi, Lauriola, Mattia, Francesconi, Mirko, DIMORFIPA, Università di Bologna, Bologna (Italy)], Martini, Désirée, Voltattorni, Manuela, Ceccarelli, Claudio, Ugolini, Giampaolo, Rosati, Giancarlo, and Zanotti, Simone}
abstractNote = {EGFR is frequently overexpressed in colon cancer. We characterized HT-29 and Caco-2, human colon cancer cell lines, untreated and treated with cetuximab or gefitinib alone and in combination with EGF. Cell growth was determined using a variation on the MTT assay. Cell-cycle analysis was conducted by flow cytometry. Immunohistochemistry was performed to evaluate EGFR expression and scanning electron microscopy (SEM) evidenced the ultrastructural morphology. Gene expression profiling was performed using hybridization of the microarray Ocimum Pan Human 40 K array A. Caco-2 and HT-29 were respectively 66.25 and 59.24 % in G0/G1. They maintained this level of cell cycle distribution after treatment, suggesting a predominantly differentiated state. Treatment of Caco-2 with EGF or the two EGFR inhibitors produced a significant reduction in their viability. SEM clearly showed morphological cellular transformations in the direction of cellular death in both cell lines treated with EGFR inhibitors. HT-29 and Caco-2 displayed an important reduction of the microvilli (which also lose their erect position in Caco-2), possibly invalidating microvilli absorption function. HT-29 treated with cetuximab lost their boundary contacts and showed filipodi; when treated with gefitinib, they showed some vesicles: generally membrane reshaping is evident. Both cell lines showed a similar behavior in terms of on/off switched genes upon treatment with cetuximab. The gefitinib global gene expression pattern was different for the 2 cell lines; gefitinib treatment induced more changes, but directly correlated with EGF treatment. In cetuximab or gefitinib plus EGF treatments there was possible summation of the morphological effects: cells seemed more weakly affected by the transformation towards apoptosis. The genes appeared to be less stimulated than for single drug cases. This is the first study to have systematically investigated the effect of cetuximab or gefitinib, alone and in combination with EGF, on human colon cancer cell lines. The EGFR inhibitors have a weaker effect in the presence of EGF that binds EGFR. Cetuximab treatment showed an expression pattern that inversely correlates with EGF treatment. We found interesting cyto-morphological features closely relating to gene expression profile. Both drugs have an effect on differentiation towards cellular death.}
doi = {10.1186/1471-2407-8-227}
journal = {BMC Cancer (Online)}
volume = {8}
journal type = {AC}
place = {United Kingdom}
year = {2008}
month = {Aug}
}