TY - JOUR
T1 - Bioluminescent imaging of HPV-positive oral tumor growth and its response to image-guided radiotherapy
AU - Zhong, Rong
AU - Pytynia, Matt
AU - Pelizzari, Charles
AU - Spiotto, Michael
PY - 2014/4/1
Y1 - 2014/4/1
N2 - The treatment paradigms for head and neck squamous cell cancer (HNSCC) are changing due to the emergence of human papillomavirus (HPV)-associated tumors possessing distinctmolecular profiles and responses to therapy. Although patients with HNSCCs are often treated with radiotherapy, preclinical models are limited by the ability to deliver precise radiation to orthotopic tumors and to monitor treatment responses accordingly. To better model this clinical scenario, we developed a novel autochthonous HPV-positive oral tumor model to track responses to small molecules and image-guided radiation. We used a tamoxifen-regulated Cre recombinase system to conditionally express the HPV oncogenes E6 and E7 as well as a luciferase reporter (iHPV-Luc) in the epithelial cells of transgenic mice. In the presence of activated Cre recombinase, luciferase activity, and by proxy, HPV oncogenes were induced to 11-fold higher levels. In triple transgenicmice containing the iHPV-Luc, K14-CreERtam, and LSL-Kras transgenes, tamoxifen treatment resulted in oral tumor development with increased bioluminescent activity within 6 days that reached a maximum of 74.8-fold higher bioluminescence compared with uninduced mice. Oral tumors expressed p16 andMCM7, two biomarkers associated withHPV-positive tumors. After treatment with rapamycin or image-guided radiotherapy, tumors regressed and possessed decreased bioluminescence. Thus, this novel system enables us to rapidly visualize HPV-positive tumor growth to model existing and new interventions using clinically relevant drugs and radiotherapy techniques.
AB - The treatment paradigms for head and neck squamous cell cancer (HNSCC) are changing due to the emergence of human papillomavirus (HPV)-associated tumors possessing distinctmolecular profiles and responses to therapy. Although patients with HNSCCs are often treated with radiotherapy, preclinical models are limited by the ability to deliver precise radiation to orthotopic tumors and to monitor treatment responses accordingly. To better model this clinical scenario, we developed a novel autochthonous HPV-positive oral tumor model to track responses to small molecules and image-guided radiation. We used a tamoxifen-regulated Cre recombinase system to conditionally express the HPV oncogenes E6 and E7 as well as a luciferase reporter (iHPV-Luc) in the epithelial cells of transgenic mice. In the presence of activated Cre recombinase, luciferase activity, and by proxy, HPV oncogenes were induced to 11-fold higher levels. In triple transgenicmice containing the iHPV-Luc, K14-CreERtam, and LSL-Kras transgenes, tamoxifen treatment resulted in oral tumor development with increased bioluminescent activity within 6 days that reached a maximum of 74.8-fold higher bioluminescence compared with uninduced mice. Oral tumors expressed p16 andMCM7, two biomarkers associated withHPV-positive tumors. After treatment with rapamycin or image-guided radiotherapy, tumors regressed and possessed decreased bioluminescence. Thus, this novel system enables us to rapidly visualize HPV-positive tumor growth to model existing and new interventions using clinically relevant drugs and radiotherapy techniques.
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U2 - 10.1158/0008-5472.CAN-13-2993
DO - 10.1158/0008-5472.CAN-13-2993
M3 - Article
C2 - 24525739
AN - SCOPUS:84897397958
SN - 0008-5472
VL - 74
SP - 2073
EP - 2081
JO - Cancer Research
JF - Cancer Research
IS - 7
ER -