Lung cancer stem cells: Progress and prospects

Abstract

Epithelial stem cells are critical for tissue generation during development and for repair following injury. In both gestational and postnatal stages, the highly branched and compartmentalized organization of the lung is maintained by multiple, resident stem/progenitor cell populations that are responsible for the homeostatic maintenance and injury repair of pulmonary epithelium. Though lung epithelial injury in the absence of oncogenic mutation is more commonly expressed as chronic lung disease, lung cancer is the most common form of death worldwide and poses a highly significant risk to human health. Cancer is defined by the cell of origin, responsible for initiating the disease. The Cancer Stem Cell Hypothesis proposes that cancer stem cells, identified by stem-like properties of self-renewal and generation of differentiated progeny, are responsible for propagating growth and spread of the disease. In lung cancer, it is hypothesized that cancer stem cells derive from several possible cell sources. The stem cell-like resistance to injury and proliferative potentials of bronchioalveolar stem cells (BASCs) and alveolar epithelial type II cells (AEC2), as well as cells that express the cancer stem cell marker glycoprotein prominin-1 (CD133) or markers for side populations make them potential reservoirs of lung cancer stem cells. The abnormal activation of pathways that normally regulate embryonic lung development, as well as adult tissue maintenance and injury repair, including the Wnt, Hedgehog (Hh) and Notch pathways, has also been identified in lung tumor cells. It is postulated that therapies for lung cancer that specifically target stem cell signaling pathways utilized by lung cancer stem cells could be beneficial in combating this disease.

Introduction

Stem cells, which are critical for the generation and regeneration of all tissues, are defined by their undifferentiated phenotype. Stem cells divide both symmetrically and asymmetrically, with the mode of propagation dependent on cell type, differentiation status, niche context and requirements of the tissue dependent on the stem cell pool in question. Symmetrical division, as occurs in the intestinal crypts, produces identical daughter cells that supply the pool needed to generate the rapidly turned over tissue of the gut epithelium [1], [2], [3]. In the distal embryonic lung, the distribution of molecules that specify polarity, including the Notch-binding protein Numb, appears to drive the stem cell decision to divide symmetrically or asymmetrically [4]. Asymmetric division is the method by which stem cells generate both undifferentiated and differentiated offspring during development and in multiple, differentiated tissues. The stem cell ability to self-renew in order to produce an adequate supply of cells that are identical to the cell of origin and to each other allows them to be conserved for future use in tissue repair [2], [5], [6]. The stem cell ability to differentiate into specialized cells when exposed to certain experimental and physiological conditions defines their role in tissue regeneration [5], [6], [7].

In adult organisms, tissue specific stem cells are found throughout the body. The ability to differentiate into a variety of cell types as needed allows the replenishment of damaged or aged cells that is required to withstand normal wear and tear [5], [6], [7], [8]. Each stem cell division involves a decision to self-renew or differentiate. The transcription factors Oct4, Sox2 and Nanog regulate factors that inhibit differentiation and promote self-renewal [5]. Stem cell self-renewal and differentiation are regulated by multiple protein signaling pathways. Pathways of note include the WNT, Hedgehog (Hh), and Notch signaling cascades [8], [9]. These signaling pathways are essential in development during embryogenesis and in the regulation of stem-cell function in adult organs. Stem cells play a critical role in the homeostatic maintenance of functional epithelium. Within adult organs, stem cell activity is specific to discrete compartments of functioning organs. This is particularly true in the highly branched and specialized structures that make up the lung.