Epidermal growth factor receptor inhibition modulates the microenvironment by vascular normalization to improve chemotherapy and radiotherapy efficacy
| Autor: | Rosemarie Mick, William M. F. Lee, Nabendu Pore, Xiaoman Xing, Turgut Durduran, George J. Cerniglia, Amit M. Maity, Jeff H. Tsai, Harry Quon, Susan M. Schultz, Regine Choe, Cameron J. Koch, Stephen M. Hahn, Chandra M. Sehgal, Sydney M. Evans, Arjun G. Yodh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Vascular Endothelial Growth Factor A
Pathology medicine.medical_specialty medicine.medical_treatment Oncology/Oncology Agents Mice Nude lcsh:Medicine Antineoplastic Agents Cell Biology/Cell Signaling 03 medical and health sciences chemistry.chemical_compound Erlotinib Hydrochloride Mice 0302 clinical medicine Cell Line Tumor medicine Animals Humans Epidermal growth factor receptor lcsh:Science 030304 developmental biology EGFR inhibitors 0303 health sciences Tumor microenvironment Multidisciplinary biology lcsh:R Neoplasms Experimental Hypoxia-Inducible Factor 1 alpha Subunit 3. Good health Radiation therapy Vascular endothelial growth factor ErbB Receptors Oxygen Vascular endothelial growth factor A chemistry Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Quinazolines Female lcsh:Q Erlotinib medicine.drug Research Article |
| Zdroj: | PLoS ONE, Vol 4, Iss 8, p e6539 (2009) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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-a (HIF-1a) 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-1a 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 O2 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. |
| Databáze: | OpenAIRE |
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