Epidermal growth factor receptor controls flat dysplastic aberrant crypt foci development and colon cancer progression in the rat azoxymethane model

Urszula Dougherty, Amikar Sehdev, Sonia Cerda, Reba Mustafi, Nathaniel Little, Weihua Yuan, Sujatha Jagadeeswaran, Anusara Chumsangsri, Jorge Delgado, Maria Tretiakova, Loren Joseph, John Hart, Ezra E W Cohen, Lata Aluri, Alessandro Fichera, Marc Bissonnette

Research output: Contribution to journalArticle

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Abstract

Purpose: Colonic carcinogenesis deranges growth-regulating epidermal growth factor receptors (EGFR). We previously showed that EGFR signals were up-regulated in human aberrant crypt foci (ACF), putative colon cancer precursors. The azoxymethane model of colon cancer recapitulates many aspects of human colonic tumors. Recent studies indicate that flat dysplastic ACF with increased β-catenin are tumor precursors in this model. We asked, therefore, if EGFR signals are required for flat dysplastic ACF development and cancer progression. Experimental Design: Rats received azoxymethane or saline, and standard chow or chow supplemented with gefitinib, an EGFR inhibitor, for 44 weeks. EGFR signals were quantified in normal colon, flat ACF, and tumors by computerized analysis of immunostains and Western blots. K-ras mutations were assessed by PCR and mRNA for egfr ligands by quantitative real-time PCR. Results: EGFR inhibition with gefitinib decreased the incidence of flat dysplastic ACF from 66% to 36% and tumors from 71% to 22% (P < 0.05). This inhibitor also reduced the overexpressions of cyclin D1 and Cox-2 in flat ACF. Furthermore, in flat ACF, EGFR blockade decreased the upregulation of c-Jun, FosB, phosphorylated active signal transducers and activators of transcription 3, and CCAAT/enhancer binding protein-β, potential regulators of cyclin D1 and Cox-2. In colonic tumors, EGFR blockade significantly decreased angiogenesis, proliferation, and progression while also increasing apoptosis (P < 0.05). Gefitinib also inhibited the activations of extracellular signal-regulated kinase, Src, and AKT pathways in tumors. Conclusions: We have shown for the first time that EGFR promotes the development of flat dysplastic ACF and the progression of malignant colonic tumors. Furthermore, we have mechanistically identified several transcription factors and their targets as EGFR effectors in colonic carcinogenesis.

Original languageEnglish (US)
Pages (from-to)2253-2262
Number of pages10
JournalClinical Cancer Research
Volume14
Issue number8
DOIs
StatePublished - Apr 15 2008
Externally publishedYes

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Aberrant Crypt Foci
Azoxymethane
Epidermal Growth Factor Receptor
Colonic Neoplasms
Neoplasms
Cyclin D1
Carcinogenesis
ErbB Receptors
CCAAT-Enhancer-Binding Proteins
Catenins
STAT3 Transcription Factor
Extracellular Signal-Regulated MAP Kinases
Real-Time Polymerase Chain Reaction
Colon
Research Design
Transcription Factors
Up-Regulation
Western Blotting

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Epidermal growth factor receptor controls flat dysplastic aberrant crypt foci development and colon cancer progression in the rat azoxymethane model. / Dougherty, Urszula; Sehdev, Amikar; Cerda, Sonia; Mustafi, Reba; Little, Nathaniel; Yuan, Weihua; Jagadeeswaran, Sujatha; Chumsangsri, Anusara; Delgado, Jorge; Tretiakova, Maria; Joseph, Loren; Hart, John; Cohen, Ezra E W; Aluri, Lata; Fichera, Alessandro; Bissonnette, Marc.

In: Clinical Cancer Research, Vol. 14, No. 8, 15.04.2008, p. 2253-2262.

Research output: Contribution to journalArticle

Dougherty, U, Sehdev, A, Cerda, S, Mustafi, R, Little, N, Yuan, W, Jagadeeswaran, S, Chumsangsri, A, Delgado, J, Tretiakova, M, Joseph, L, Hart, J, Cohen, EEW, Aluri, L, Fichera, A & Bissonnette, M 2008, 'Epidermal growth factor receptor controls flat dysplastic aberrant crypt foci development and colon cancer progression in the rat azoxymethane model', Clinical Cancer Research, vol. 14, no. 8, pp. 2253-2262. https://doi.org/10.1158/1078-0432.CCR-07-4926
Dougherty, Urszula ; Sehdev, Amikar ; Cerda, Sonia ; Mustafi, Reba ; Little, Nathaniel ; Yuan, Weihua ; Jagadeeswaran, Sujatha ; Chumsangsri, Anusara ; Delgado, Jorge ; Tretiakova, Maria ; Joseph, Loren ; Hart, John ; Cohen, Ezra E W ; Aluri, Lata ; Fichera, Alessandro ; Bissonnette, Marc. / Epidermal growth factor receptor controls flat dysplastic aberrant crypt foci development and colon cancer progression in the rat azoxymethane model. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 8. pp. 2253-2262.
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abstract = "Purpose: Colonic carcinogenesis deranges growth-regulating epidermal growth factor receptors (EGFR). We previously showed that EGFR signals were up-regulated in human aberrant crypt foci (ACF), putative colon cancer precursors. The azoxymethane model of colon cancer recapitulates many aspects of human colonic tumors. Recent studies indicate that flat dysplastic ACF with increased β-catenin are tumor precursors in this model. We asked, therefore, if EGFR signals are required for flat dysplastic ACF development and cancer progression. Experimental Design: Rats received azoxymethane or saline, and standard chow or chow supplemented with gefitinib, an EGFR inhibitor, for 44 weeks. EGFR signals were quantified in normal colon, flat ACF, and tumors by computerized analysis of immunostains and Western blots. K-ras mutations were assessed by PCR and mRNA for egfr ligands by quantitative real-time PCR. Results: EGFR inhibition with gefitinib decreased the incidence of flat dysplastic ACF from 66{\%} to 36{\%} and tumors from 71{\%} to 22{\%} (P < 0.05). This inhibitor also reduced the overexpressions of cyclin D1 and Cox-2 in flat ACF. Furthermore, in flat ACF, EGFR blockade decreased the upregulation of c-Jun, FosB, phosphorylated active signal transducers and activators of transcription 3, and CCAAT/enhancer binding protein-β, potential regulators of cyclin D1 and Cox-2. In colonic tumors, EGFR blockade significantly decreased angiogenesis, proliferation, and progression while also increasing apoptosis (P < 0.05). Gefitinib also inhibited the activations of extracellular signal-regulated kinase, Src, and AKT pathways in tumors. Conclusions: We have shown for the first time that EGFR promotes the development of flat dysplastic ACF and the progression of malignant colonic tumors. Furthermore, we have mechanistically identified several transcription factors and their targets as EGFR effectors in colonic carcinogenesis.",
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T1 - Epidermal growth factor receptor controls flat dysplastic aberrant crypt foci development and colon cancer progression in the rat azoxymethane model

AU - Dougherty, Urszula

AU - Sehdev, Amikar

AU - Cerda, Sonia

AU - Mustafi, Reba

AU - Little, Nathaniel

AU - Yuan, Weihua

AU - Jagadeeswaran, Sujatha

AU - Chumsangsri, Anusara

AU - Delgado, Jorge

AU - Tretiakova, Maria

AU - Joseph, Loren

AU - Hart, John

AU - Cohen, Ezra E W

AU - Aluri, Lata

AU - Fichera, Alessandro

AU - Bissonnette, Marc

PY - 2008/4/15

Y1 - 2008/4/15

N2 - Purpose: Colonic carcinogenesis deranges growth-regulating epidermal growth factor receptors (EGFR). We previously showed that EGFR signals were up-regulated in human aberrant crypt foci (ACF), putative colon cancer precursors. The azoxymethane model of colon cancer recapitulates many aspects of human colonic tumors. Recent studies indicate that flat dysplastic ACF with increased β-catenin are tumor precursors in this model. We asked, therefore, if EGFR signals are required for flat dysplastic ACF development and cancer progression. Experimental Design: Rats received azoxymethane or saline, and standard chow or chow supplemented with gefitinib, an EGFR inhibitor, for 44 weeks. EGFR signals were quantified in normal colon, flat ACF, and tumors by computerized analysis of immunostains and Western blots. K-ras mutations were assessed by PCR and mRNA for egfr ligands by quantitative real-time PCR. Results: EGFR inhibition with gefitinib decreased the incidence of flat dysplastic ACF from 66% to 36% and tumors from 71% to 22% (P < 0.05). This inhibitor also reduced the overexpressions of cyclin D1 and Cox-2 in flat ACF. Furthermore, in flat ACF, EGFR blockade decreased the upregulation of c-Jun, FosB, phosphorylated active signal transducers and activators of transcription 3, and CCAAT/enhancer binding protein-β, potential regulators of cyclin D1 and Cox-2. In colonic tumors, EGFR blockade significantly decreased angiogenesis, proliferation, and progression while also increasing apoptosis (P < 0.05). Gefitinib also inhibited the activations of extracellular signal-regulated kinase, Src, and AKT pathways in tumors. Conclusions: We have shown for the first time that EGFR promotes the development of flat dysplastic ACF and the progression of malignant colonic tumors. Furthermore, we have mechanistically identified several transcription factors and their targets as EGFR effectors in colonic carcinogenesis.

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