The tumor microenvironment in non-small-cell lung cancer

Abstract

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.

Figure 1. Signal transduction pathways in non-small cell lung cancer

Epidermal growth factor receptor (EGFR) activation, which often occurs in NSCLC, leads to upregulation of the PI3K/Akt pathway as well as the Raf/MEK/ERk kinase pathway. Akt pathway activation has been implicated in both resistance of cells to radiation-induced killing and in increased expression of hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF). A number of drugs that can inhibit various points along these pathways have been shown in pre-clinical models to increase the radiation responsiveness of tumors.