The field of tissue injury in the lung and airway

Abstract

The concept of field cancerization was first introduced over 6 decades ago in the setting of oral cancer. Later, field cancerization involving histologic and molecular changes of neoplasms and adjacent tissue began to be characterized in smokers with or without lung cancer. Investigators also described a diffuse, nonneoplastic field of molecular injury throughout the respiratory tract that is attributable to cigarette smoking and susceptibility to smoking-induced lung disease. The potential molecular origins of field cancerization and the field of injury following cigarette smoke exposure in lung and airway epithelia are critical to understanding their potential impact on clinical diagnostics and therapeutics for smoking-induced lung disease.

Fig. 1

Hypotheses about the origins of the smoking-related field of epithelial injury in the lungs and airway. A) Based on the observation of p53 mutations throughout the airway epithelium of a smoker without overt lung cancer, Franklin et al. proposed that a malignant epithelial cell clone (green) propagates throughout the entire airway epithelium (14). B) Other studies have suggested that the field of epithelial injury reflects the host response (light blue- and orange-shaded areas) to the lung tumor itself (dark blue). This is supported by numerous observations of a gradient of changes radiating from the lung tumor throughout the adjacent noncancerous lung (17, 31), including tumor-associated macrophages (32). C) The field effect has been described not only in association with smoking-induced lung disease, but also in healthy and phenotypically normal smokers (16, 24, 34-36, 39). This suggests that the field effect represents the host’s response (the purple-to-yellow gradient in the airway) to toxins in cigarette smoke. It is likely that these mechanisms act together in varying degrees to create the field of injury observed in numerous studies.

Fig. 2

Pivotal descriptions of the smoking-related field of injury in the lungs and airway. Although field cancerization was first described by Slaughter in 1944 for patients with oral cancer, the smoking-related field of injury in the human lungs and airway was not described until 1996. Initial studies (shown in red) were aimed at linking genetic changes in tumor tissue to noncancerous adjacent and peripheral lung. Later studies (shown in blue) described the epigenetic changes in both tumor tissue and bronchial epithelia. With the advent of microarray technology, large-scale gene expression studies further characterized the field effect previously observed and an initial push to move to sites distal from the tumor was made (shown in purple). The most recent studies (shown in green) have focused on applying this field of injury to a variety of clinical questions.