Alveolar hypoxia promotes murine lung tumor growth through a VEGFR-2/EGFR-dependent mechanism.
Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for the development of lung cancer, the mechanisms for which are incompletely understood. We hypothesized that the hypoxic pulmonary microenvironment present in COPD would augment lung carcinogenesis. Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia. Mice exposed to chronic hypoxia developed tumors with increased volume compared with normoxic controls. Both lungs and tumors from hypoxic mice showed a preferential stabilization of HIF-2α and increased expression of VEGF-A, FGF2, and their receptors as well as other survival, proliferation, and angiogenic signaling pathways regulated by HIF-2α. We showed that tumors arising in hypoxic animals have increased sensitivity to VEGFR-2/EGFR inhibition, as chemoprevention with vandetanib showed markedly increased activity in hypoxic mice. These studies showed that lung tumors arising in a hypoxic microenvironment express increased growth, angiogenic, and survival signaling that could contribute to the increased lung cancer risk in COPD. Furthermore, the differential sensitivity of tumors arising in hypoxia to VEGFR-2/EGFR inhibition suggests that the altered signaling present in tumors arising in hypoxic lung might be therapeutically exploited in patients with underlying COPD.
Department of Medicine, University of Colorado Denver, Denver, CO, USA.
Vijaya
V
Karoor
Mysan
M
Le
Daniel
D
Merrick
Karen A
KA
Fagan
Edward C
EC
Dempsey
York E
YE
Miller
D000818:Animals; D000975:Antioxidants / Q000633:toxicity; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D002084:Butylated Hydroxytoluene / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D000860:Hypoxia / Q000503:physiopathology*; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D008748:Methylcholanthrene / Q000031:analogs & derivatives / Q000633:toxicity; D051379:Mice; D009389:Neovascularization, Pathologic; D010880:Piperidines / Q000627:therapeutic use; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000503:physiopathology*; D011799:Quinazolines / Q000627:therapeutic use; D012891:Sleep Apnea Syndromes / Q000503:physiopathology; D014520:Urethane / Q000633:toxicity; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
D000975:Antioxidants; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D002084:Butylated Hydroxytoluene; D002273:Carcinogens; D016207:Cytokines; D066246:ErbB Receptors; D008748:Methylcholanthrene; D010880:Piperidines; D016271:Proto-Oncogene Proteins c-myc; D011799:Quinazolines; D014520:Urethane; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099162:Endothelial PAS Domain-Containing Protein 1; C051446:3-methylcholanthrylene; C541485:EGFR protein, mouse; C452423:vandetanib