The Tumor Microenvironment in Non–Small-Cell Lung Cancer

Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA.
Seminars in radiation oncology (Impact Factor: 4.03). 07/2010; 20(3):156-63. DOI: 10.1016/j.semradonc.2010.01.003
Source: PubMed


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.

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    • "In classical radiobiology experiments, clonogen survival after 2 Gy in vitro is predictive for intrinsic cellular radiosensitivity [19], although it has not been shown to consistently predict in vivo tumor control [20, 21]. Tumor microenvironment and vasculature may be important to tumor response in addition to cellular radiosensitivity [22, 23]. By assessing the changes of tracer localization over a period of time with dynamic imaging, the RI or SF may capture information regarding both the intrinsic tumor radiosensitivity and vascular/microenvironment changes within the tumor. "
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    • "In these studies, although the individual tumor accumulations of each tracer were well studied, investigators failed to fully understand the differences in intratumoral distribution of each tracer. Solid tumors have complex and highly heterogeneous microenvironment , being composed of viable cancer cells, stroma, and necrotic zones [13] [14] [15]. Viable cancer cells are usually either hypoxic or oxic or either minimally or highly proliferative. "
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