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Epidermal Growth Factor Receptor Inhibition Modulates the Microenvironment by Vascular Normalization to Improve Chemotherapy and Radiotherapy Efficacy

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors have shown only modest clinical activity when used as single agents to treat cancers. They decrease tumor cell expression of hypoxia-inducible factor 1-α (HIF-1α) and vascular endothelial growth factor (VEGF). Hypothesizing that this mig...

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Autores principales: Cerniglia, George J., Pore, Nabendu, Tsai, Jeff H., Schultz, Susan, Mick, Rosemarie, Choe, Regine, Xing, Xiaoman, Durduran, Turgut, Yodh, Arjun G., Evans, Sydney M., Koch, Cameron J., Hahn, Stephen M., Quon, Harry, Sehgal, Chandra M., Lee, William M. F., Maity, Amit
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716529/
https://www.ncbi.nlm.nih.gov/pubmed/19657384
http://dx.doi.org/10.1371/journal.pone.0006539
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author Cerniglia, George J.
Pore, Nabendu
Tsai, Jeff H.
Schultz, Susan
Mick, Rosemarie
Choe, Regine
Xing, Xiaoman
Durduran, Turgut
Yodh, Arjun G.
Evans, Sydney M.
Koch, Cameron J.
Hahn, Stephen M.
Quon, Harry
Sehgal, Chandra M.
Lee, William M. F.
Maity, Amit
author_facet Cerniglia, George J.
Pore, Nabendu
Tsai, Jeff H.
Schultz, Susan
Mick, Rosemarie
Choe, Regine
Xing, Xiaoman
Durduran, Turgut
Yodh, Arjun G.
Evans, Sydney M.
Koch, Cameron J.
Hahn, Stephen M.
Quon, Harry
Sehgal, Chandra M.
Lee, William M. F.
Maity, Amit
author_sort Cerniglia, George J.
collection PubMed
description BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors have shown only modest clinical activity when used as single agents to treat cancers. They decrease tumor cell expression of hypoxia-inducible factor 1-α (HIF-1α) and vascular endothelial growth factor (VEGF). Hypothesizing that this might normalize tumor vasculature, we examined the effects of the EGFR inhibitor erlotinib on tumor vascular function, tumor microenvironment (TME) and chemotherapy and radiotherapy sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: Erlotinib treatment of human tumor cells in vitro and mice bearing xenografts in vivo led to decreased HIF-1α and VEGF expression. Treatment altered xenograft vessel morphology assessed by confocal microscopy (following tomato lectin injection) and decreased vessel permeability (measured by Evan's blue extravasation), suggesting vascular normalization. Erlotinib increased tumor blood flow measured by Power Doppler ultrasound and decreased hypoxia measured by EF5 immunohistochemistry and tumor O(2) saturation measured by optical spectroscopy. Predicting that these changes would improve drug delivery and increase response to chemotherapy and radiation, we performed tumor regrowth studies in nude mice with xenografts treated with erlotinib and either radiotherapy or the chemotherapeutic agent cisplatin. Erlotinib therapy followed by cisplatin led to synergistic inhibition of tumor growth compared with either treatment by itself (p<0.001). Treatment with erlotinib before cisplatin led to greater tumor growth inhibition than did treatment with cisplatin before erlotinib (p = 0.006). Erlotinib followed by radiation inhibited tumor regrowth to a greater degree than did radiation alone, although the interaction between erlotinib and radiation was not synergistic. CONCLUSIONS/SIGNIFICANCE: EGFR inhibitors have shown clinical benefit when used in combination with conventional cytotoxic therapy. Our studies show that targeting tumor cells with EGFR inhibitors may modulate the TME via vascular normalization to increase response to chemotherapy and radiotherapy. These studies suggest ways to assess the response of tumors to EGFR inhibition using non-invasive imaging of the TME.
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spelling pubmed-27165292009-08-06 Epidermal Growth Factor Receptor Inhibition Modulates the Microenvironment by Vascular Normalization to Improve Chemotherapy and Radiotherapy Efficacy Cerniglia, George J. Pore, Nabendu Tsai, Jeff H. Schultz, Susan Mick, Rosemarie Choe, Regine Xing, Xiaoman Durduran, Turgut Yodh, Arjun G. Evans, Sydney M. Koch, Cameron J. Hahn, Stephen M. Quon, Harry Sehgal, Chandra M. Lee, William M. F. Maity, Amit PLoS One Research Article BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors have shown only modest clinical activity when used as single agents to treat cancers. They decrease tumor cell expression of hypoxia-inducible factor 1-α (HIF-1α) and vascular endothelial growth factor (VEGF). Hypothesizing that this might normalize tumor vasculature, we examined the effects of the EGFR inhibitor erlotinib on tumor vascular function, tumor microenvironment (TME) and chemotherapy and radiotherapy sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: Erlotinib treatment of human tumor cells in vitro and mice bearing xenografts in vivo led to decreased HIF-1α and VEGF expression. Treatment altered xenograft vessel morphology assessed by confocal microscopy (following tomato lectin injection) and decreased vessel permeability (measured by Evan's blue extravasation), suggesting vascular normalization. Erlotinib increased tumor blood flow measured by Power Doppler ultrasound and decreased hypoxia measured by EF5 immunohistochemistry and tumor O(2) saturation measured by optical spectroscopy. Predicting that these changes would improve drug delivery and increase response to chemotherapy and radiation, we performed tumor regrowth studies in nude mice with xenografts treated with erlotinib and either radiotherapy or the chemotherapeutic agent cisplatin. Erlotinib therapy followed by cisplatin led to synergistic inhibition of tumor growth compared with either treatment by itself (p<0.001). Treatment with erlotinib before cisplatin led to greater tumor growth inhibition than did treatment with cisplatin before erlotinib (p = 0.006). Erlotinib followed by radiation inhibited tumor regrowth to a greater degree than did radiation alone, although the interaction between erlotinib and radiation was not synergistic. CONCLUSIONS/SIGNIFICANCE: EGFR inhibitors have shown clinical benefit when used in combination with conventional cytotoxic therapy. Our studies show that targeting tumor cells with EGFR inhibitors may modulate the TME via vascular normalization to increase response to chemotherapy and radiotherapy. These studies suggest ways to assess the response of tumors to EGFR inhibition using non-invasive imaging of the TME. Public Library of Science 2009-08-06 /pmc/articles/PMC2716529/ /pubmed/19657384 http://dx.doi.org/10.1371/journal.pone.0006539 Text en This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Cerniglia, George J.
Pore, Nabendu
Tsai, Jeff H.
Schultz, Susan
Mick, Rosemarie
Choe, Regine
Xing, Xiaoman
Durduran, Turgut
Yodh, Arjun G.
Evans, Sydney M.
Koch, Cameron J.
Hahn, Stephen M.
Quon, Harry
Sehgal, Chandra M.
Lee, William M. F.
Maity, Amit
Epidermal Growth Factor Receptor Inhibition Modulates the Microenvironment by Vascular Normalization to Improve Chemotherapy and Radiotherapy Efficacy
title Epidermal Growth Factor Receptor Inhibition Modulates the Microenvironment by Vascular Normalization to Improve Chemotherapy and Radiotherapy Efficacy
title_full Epidermal Growth Factor Receptor Inhibition Modulates the Microenvironment by Vascular Normalization to Improve Chemotherapy and Radiotherapy Efficacy
title_fullStr Epidermal Growth Factor Receptor Inhibition Modulates the Microenvironment by Vascular Normalization to Improve Chemotherapy and Radiotherapy Efficacy
title_full_unstemmed Epidermal Growth Factor Receptor Inhibition Modulates the Microenvironment by Vascular Normalization to Improve Chemotherapy and Radiotherapy Efficacy
title_short Epidermal Growth Factor Receptor Inhibition Modulates the Microenvironment by Vascular Normalization to Improve Chemotherapy and Radiotherapy Efficacy
title_sort epidermal growth factor receptor inhibition modulates the microenvironment by vascular normalization to improve chemotherapy and radiotherapy efficacy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716529/
https://www.ncbi.nlm.nih.gov/pubmed/19657384
http://dx.doi.org/10.1371/journal.pone.0006539
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