The epithelial lining of the adult airway progresses from proximal to distal in a stereotyped fashion. Proximal airways consist of pseudostratified epithelium, middle airways consist of a simple columnar epithelium, and the most distal airways consist of a cuboidal epithelium. Multiple studies indicate that cells capable of stem-like behavior in response to airway injury are present throughout the airway.
In proximal airways, studies of airway repair in the trachea have identified two cellular populations that act as stem cells in response to injury. Borthwick et al.
identified a population of tracheal basal cells that are pluripotent, retain bromodeoxyuridine, and express keratin-5 (K5). A second study using a naphthalene inhalation injury model identified an additional population of tracheal basal cells, this time expressing the keratin-14 (K14) marker
. These K14+
cells were able to proliferate to give rise to cells of multiple phenotypes in response to airway injury. It appears that in the trachea, basal cell populations expressing either K5 or K14 are capable of the functional aspects of stem cell niches. This finding has implications for the origins of squamous cell carcinoma. Squamous cell carcinoma frequently arises from the more proximal tracheobronchial airways, yielding centrally located tumors that often exhibit elevated levels of K5+
. As such, it appears that cancers with histology consistent with squamous cell carcinoma are more likely to arise from K5+
stem cells. Although there is no targeted therapy available against K5+
cells to date, this stem cell niche of squamous cell carcinoma may provide a worthwhile direction for targeted research, providing a unique biomarker that can be used to target the cell of origin in these tumors.
In the middle airways, two potential stem cell niches have also been identified. A rat model of nitrogen dioxide (NO2
) inhalation injury revealed that mature rat Clara cells could proliferate into phenotypically diverse progeny
. This ability to move from quiescent and fully differentiated epithelial cells to actively proliferating multipotent cells led Evans et al
to deem these Clara cells “facultative progenitor cells,” as they are capable of but not limited to behavior indicative of a stem cell. In the setting of injury to a Clara cell-depleted airway, as is the case with the naphthalene model of injury, Clara-cell secretory protein (CCSP)-positive cells located within neuroepithelial bodies (NEB) have been shown to proliferate to repair the airway
. These NEB CCSP+
cells are able to independently repopulate the middle airways with phenotypically diverse progeny after naphthalene injury, characteristic of true bronchial airway stem cells. Small cell lung carcinomas, frequently arising in the mid-level bronchioles, have been shown to contain fractions of cells expressing cell surface markers associated with mid-airway stem cell subpopulations. In particular, the cell surface markers CD44 and multidrug resistance 1 (MDR1) have previously been identified in a series of small cell lung carcinoma cell lines
. Cells expressing CD44 have also very recently been implicated in lung cancer progression and metastasis by the epithelial-to-mesenchymal transition (EMT)
. In their 2011 study, Tellez et al
found that bronchial epithelial cells exposed to carcinogens gained stem-like properties and that EMT led to a progressively motile and invasive phenotype. Again, while no targeted therapies are presently available to target cells expressing CD44 and MDR1, the potential exists for improved delivery by using agents directed at this cell or origin in conjunction with the current standard of care.
For the most distal airway, there is no consensus on the cell surface marker phenotype of representative lung stem cells. Stripp et al
first identified pluripotent, NEB-independent, CCSP+
cells in the bronchoalveolar duct junction (BADJ) that could, in response to naphthalene injury, yield diverse populations of cells. Cells expressing surface markers surfactant protein C (SP-C), stem cell antigen-1 (SCa-1), and CD34—but not expressing CD45 or Pecam—were shown to act as pluripotent and to have the ability to proliferate and self-renew in culture. However, others have argued that these CCSP+
cells are insufficient as the distal lung stem cell population because they are unable to differentiate into type II alveolar cells. Rawlins et al
instead promoted Id2+
as a more suitable cell surface marker for distal lung epithelial stem cells. Thus, while there is consensus that stem cells form a niche population in the BADJ, the cell marker phenotype remains under debate. Carcinomas of the distal airway—most frequently lung adenocarcinoma and bronchioloalveolar carcinoma—have been associated with stem cells from the BADJ region