Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/16378
Title: Molecular profiling of cetuximab and bevacizumab treatment of colorectal tumours reveals perturbations in metabolic and hypoxic response pathways
Authors: Greening, David W;Lee, Sze Ting;Ji, Hong;Simpson, Richard J;Rigopoulos, Angela;Murone, Carmel;Fang, Catherine;Gong, Sylvia J;O’Keefe, Graeme J;Scott, Andrew M
Issue Date: 10-Nov-2015
EDate: 2015-10-26
Citation: Oncotarget 2015; 6(35): 38166-38180
Abstract: Angiogenesis and epidermal growth factor receptor (EGFR) inhibition has been shown to have anti-tumour efficacy, and enhance the therapeutic effects of cytotoxic chemotherapy in metastatic colorectal cancer. The interplay of signalling alterations and changes in metabolism and hypoxia in tumours following anti-VEGF and anti-EGFR treatment is not well understood. We aimed to explore the pharmacodynamics of cetuximab and bevacizumab treatment in human colon carcinoma tumour cells in vitro and xenograft models through proteomic profiling, molecular imaging of metabolism and hypoxia, and evaluation of therapy-induced changes in tumour cells and the tumour microenvironment. Both cetuximab and bevacizumab inhibited tumour growth in vivo, and this effect was associated with selectively perturbed glucose metabolism and reduced hypoxic volumes based on PET/MRI imaging. Global proteomic profiling of xenograft tumours (in presence of cetuximab, bevacizumab, and combination treatments) revealed alterations in proteins involved in glucose, lipid and fatty acid metabolism (e.g., GPD2, ATP5B, STAT3, FASN), as well as hypoxic regulators and vasculogenesis (e.g., ATP5B, THBS1, HSPG2). These findings correlated with western immunoblotting (xenograft lysates) and histological examination by immunohistochemistry. These results define important mechanistic insight into the dynamic changes in metabolic and hypoxic response pathways in colorectal tumours following treatment with cetuximab and bevacizumab, and highlight the ability of these therapies to selectively impact on tumour cells and extracellular microenvironment.
URI: http://ahro.austin.org.au/austinjspui/handle/1/16378
DOI: 10.18632/oncotarget.6241
ORCID: 0000-0002-6656-295X
PubMed URL: https://www.ncbi.nlm.nih.gov/pubmed/26517691
Type: Journal Article
Subjects: Bevacizumab
Cancer therapeutics
Cetuximab
Hypoxia
Metabolism
Appears in Collections:Journal articles

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