Hypoxia in models of lung cancer: implications for targeted therapeutics.
OBJECTIVE
To efficiently translate experimental methods from bench to bedside, it is imperative that laboratory models of cancer mimic human disease as closely as possible. In this study, we sought to compare patterns of hypoxia in several standard and emerging mouse models of lung cancer to establish the appropriateness of each for evaluating the role of oxygen in lung cancer progression and therapeutic response.


METHODS
Subcutaneous and orthotopic human A549 lung carcinomas growing in nude mice as well as spontaneous K-ras or Myc-induced lung tumors grown in situ or subcutaneously were studied using fluorodeoxyglucose and fluoroazomycin arabinoside positron emission tomography, and postmortem by immunohistochemical observation of the hypoxia marker pimonidazole. The response of these models to the hypoxia-activated cytotoxin PR-104 was also quantified by the formation of γH2AX foci in vitro and in vivo. Finally, our findings were compared with oxygen electrode measurements of human lung cancers.


RESULTS
Minimal fluoroazomycin arabinoside and pimonidazole accumulation was seen in tumors growing within the lungs, whereas subcutaneous tumors showed substantial trapping of both hypoxia probes. These observations correlated with the response of these tumors to PR-104, and with the reduced incidence of hypoxia in human lung cancers relative to other solid tumor types.


CONCLUSIONS
These findings suggest that in situ models of lung cancer in mice may be more reflective of the human disease, and encourage judicious selection of preclinical tumor models for the study of hypoxia imaging and antihypoxic cell therapies.
Graves
Edward E
EE
Department of Radiation Oncology, Stanford University, California 94305-5847, USA. egraves@stanford.edu
Vilalta
Marta
M
Cecic
Ivana K
IK
Erler
Janine T
JT
Tran
Phuoc T
PT
Felsher
Dean
D
Sayles
Leanne
L
Sweet-Cordero
Alejandro
A
Le
Quynh-Thu
QT
Giaccia
Amato J
AJ
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004566:Electrodes; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology; D009593:Nitroimidazoles / Q000378:metabolism; D010100:Oxygen / Q000032:analysis; D049268:Positron-Emission Tomography; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
C468783:H2AX protein, human; D006657:Histones; D009588:Nitrogen Mustard Compounds; D009593:Nitroimidazoles; C522381:PR-104; D016271:Proto-Oncogene Proteins c-myc; C033815:pimonidazole; D018631:ras Proteins; D010100:Oxygen