The tumor microenvironment in non-small-cell lung cancer.
The tumor microenvironment (TME) of NSCLC is heterogeneous with variable blood flow through leaky immature vessels resulting in regions of acidosis and hypoxia. Hypoxia has been documented in NSCLC directly by polarographic needle electrodes and indirectly by assessing tissue and plasma hypoxia markers. In general, elevated expression of these markers portends poorer outcomes in NSCLC. Impaired vascularity and hypoxia can lead to increased metastasis and treatment resistance. Compounds that directly target hypoxic cells such as tirapazamine have been tested in clinical trials for NSCLC with mixed results. Preclinical data, however, suggest other ways of exploiting the abnormal TME in NSCLC for therapeutic gain. The inhibition of hypoxia-inducible factor-1alpha or vascular endothelial growth factor may increase local control after radiation. Inhibitors of the epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K)/Akt pathway, such as erlotinib or PI-103, may "normalize" tumor vessels, allowing for increased chemotherapy delivery or improved oxygenation and radiation response. To select patients who may respond to these therapies and to evaluate the effects of these agents, a noninvasive means of imaging the TME is critical. Presently, there are several promising modalities to image hypoxia and the tumor vasculature; these include dynamic perfusion imaging and positron emission tomography scanning with radiolabled nitroimidazoles.
Graves
Edward E
EE
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA.
Maity
Amit
A
Le
Quynh-Thu
QT
D000138:Acidosis / Q000000981:diagnostic imaging / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D000860:Hypoxia / Q000000981:diagnostic imaging / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism / Q000528:radiation effects; D008168:Lung / Q000000981:diagnostic imaging; D008175:Lung Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000528:radiation effects; D049268:Positron-Emission Tomography; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism / Q000528:radiation effects; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000528:radiation effects
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases; D040262:Receptors, Vascular Endothelial Growth Factor