Abstract and Introduction
Abstract
Since the application of molecular biology in cancer biology, lung cancer research has classically focused on molecular drivers of disease. One such pathway, the hypoxic response pathway, is activated by reduced local oxygen concentrations at the tumor site. Hypoxia-driven gene and protein changes enhance epithelial-to-mesenchymal transition, remodel the extracellular matrix, drive drug resistance, support cancer stem cells and aid evasion from immune cells. However, it is not the tumor cells alone which drive this response to hypoxia, but rather their interaction with a complex milieu of supporting cells. This review will focus on recent advances in our understanding of how these cells contribute to the tumor response to hypoxia in non-small-cell lung cancer.
Introduction
Lung cancer is the commonest cancer worldwide, with in excess of 1.61 million new cases diagnosed each year. Patients diagnosed with lung cancer have a very poor survival rate, in the United Kingdom, of those presenting with advanced disease (late stage, metastatic disease), fewer than 10% will survive longer than 5 years.[1]
Two main categories of lung cancer have been defined: non-small-cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC can be further subdivided into: lung adenocarcinoma (ADC), large cell carcinoma and squamous cell carcinoma (SCC). These cancer subtypes have distinct morphologies and molecular profiles, and arise from distinct locations within the lung.[2] An increased understanding of how cells within these areas undergo transformation is crucial for improving the early detection and treatment of lung cancer.
The lung epithelium is composed of a number of different cell types including: ciliated, secretory/Clara, undifferentiated columnar and basal cells in the proximal airways and alveolar type I and type II cells in the distal airways.[3] A number of elegant in vivo studies of lung injury involving lineage tracing of cellular repair have elucidated the existence of several tissue resident multi-potent stem cell-like cells within the lung epithelium.[4] These include: basal cells, Clara cells, alveolar type II cells and cells of the bronchioalveolar duct junction, which are responsible for repairing specific regions of the lung epithelium following damage.[4] These cells may also be the source of tumor initiating cancer stem cells (CSCs). CSCs are currently of great interest to the cancer biology research community particularly in the formation of lung cancer.[5,6]
Surrounding these epithelial cells is a microenvironment of supporting cells including stromal cells, such as lung fibroblasts, and tissue resident and transient circulating immune cells. These cells regulate key epithelial cell processes such as proliferation, metabolism, apoptosis, senescence and differentiation. Interestingly, these processes are all sensitive to the concentration of oxygen present in the microenvironment. Rapidly proliferating cells cause the NSCLC tumor to extend beyond the oxygen diffusion limit, therefore the tumor cells themselves and the surrounding cells of the tumor microenvironment are subjected to low oxygen (hypoxia).
Here we present a brief overview of the key tumor suppressors and driver oncogenes involved in NSCLC followed by a review of the most recent and cutting edge studies which are advancing our understanding of the role of hypoxia in the transformation of lung epithelial cells and its critical role in the tumor supporting microenvironment. We will also provide a brief update of the hypoxic response pathway, and hypoxia regulated mechanisms which play a crucial role in tumor growth and govern the processes of CSC survival, Notch signaling and epithelial-to-mesenchymal transition (EMT).
Future Oncol. 2014;10(16):2659-2674. © 2014 Future Medicine Ltd.
