Stem Cells and Lung Cancer: In Vitro and In Vivo Studies

Summary of Key Points

The use of mouse models to study the initiation and evolution of lung cancers has been crucial in advancing the field through the identification of putative stem cell niches within the lung.
Bronchoalveolar stem cells (BASCs) are the putative cell of origin for lung adenocarcinoma.
The tumor suppressor gene phosphatase and tensin homolog (PTEN) exerts a brake on BASC transformation to adenocarcinoma.
Basal cells of the trachea are the putative cell of origin for squamous lung cancer.
In small cell lung cancer (SCLC), a common neuroendocrine cell of origin may undergo RAS-driven transformation to a CD44-expressing non-neuroendocrine clone.
Hedgehog (Hh) signaling persists in SCLC and is required for tumor growth in mouse xenograft models.

The cancer stem cell hypothesis, when applied to lung cancers, is underpinned by the concept of a cellular hierarchy in which a relatively rare somatic stem cell population with self-renewal capability, differentiation, and innate drug resistance gives rise to the bulk of the cancer. Evidence of this concept has been reported in studies on hematologic malignancies and solid cancers. Lung cancers, like other cancers, are heterogeneous with respect to histology and are spatially associated with the cellular origin of initiation. With the advent of large-scale DNA sequencing, heterogeneity at the genetic level has been observed within these histologic subclasses, especially in adenocarcinomas. This heterogeneity in adenocarcinomas indicates complexity in the mechanisms underlying cellular initiation and evolution of lung cancers as a result of specific mutational processes. This chapter focuses on the evidence supporting the existence of spatially restricted initiator cell populations in lung cancer (cells of origin), including evidence for specific pathways involved in their maintenance, as well as the less well-supported evidence for cancer stem cells.

Normal Lung

Over time, a model has been developed in which the lung is subdivided into regions associated with their own stem cell population capable of rapidly responding to lung injury, thus enabling cellular repopulation. Accordingly, the trachea, bronchus, bronchioles, and alveolus exhibit their own complement of cells capable of repopulation following lung injury.

For the trachea and bronchus, these repopulating cells are the basal mucous secretory cells. Evidence supports the existence of a cellular compartment in the human airway surface epithelium that can restore the full repertoire of epithelial lining cells in a xenograft model in severe combined immunodeficiency mice. By contrast, the basal/parabasal origin of tracheal stem cells has been proposed based on data showing that a cytokeratin 5 (CK5), CK14-, and mindbomb E3 ubiquitin protein ligase 1-positive cell population comprising only 0.87% of lung cells accounts for 48% of proliferating cells with basal localization. Tracheal gland ductal cells that express CK14 and CK18 have been shown to retain sulfur dioxide labeling up to 4 weeks after inhalation damage in adult mice and can repopulate the tracheal surface after injury.

In the bronchioles and alveoli, the club cell (formally known as the Clara cell) and type II pneumocyte have been implicated in repopulation. Accordingly, specific depletion of club cells in rodent models by either intraperitoneal naphthalene or activation of the suicide substrate ganciclovir by Clara cell secretory protein (CCSP)-promoter-driven herpes simplex virus thymidine kinase in transgenic mice is sufficient to cause irreversible, fatal lung injury. In rodent fetal lung, the existence of a possible bipolar stem cell (M3E3/C3) capable of differentiating into club or type II pneumocytes when grown in different media is supported by data from Finkelstein et al. Bleomycin causes specific alveolar type I (AT1) cell injury, and it has been proposed that AT2 cells can repopulate and repair the alveolar epithelium. A unique, naphthalene-resistant stem cell population has been identified at the bronchoalveolar junction and can repopulate the terminal bronchioles after club cell depletion injury. These cells express CCSP and are independent of the neuroepithelial body microenvironment, implicating a distinct stem cell niche. Similarly, a so-called side population of cells (i.e., a rare cellular subset enriched for stem cell activity) exhibiting typical breast cancer-resistant protein-mediated Hoechst dye efflux has been identified in 0.03% to 0.07% of total lung cells.

Nonsmall Cell Lung Cancer

Adenocarcinoma and the Cells of Origin

Nonsmall cell lung cancer (NSCLC) can be subdivided into two distinct subtypes that reflect the histologic characteristics of distinct regions within the lung: 80% are adenocarcinomas and 20% are squamous cell carcinomas. The adenocarcinoma subtype and adenoma precursors exhibit club and AT2 cell markers consistent with a peripheral or endobronchial origin, whereas squamous cell carcinomas exhibit mature epithelial cell characteristics consistent with trachea and proximal airways origin. The AT2-specific marker surfactant protein has been shown to be expressed in lung adenocarcinoma and squamous cell carcinomas. Accordingly, Ten Have-Opbroek et al. postulated that the AT2 cell may be the pluripotential cell for NSCLC in humans.

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