Identification of Bronchioalveolar Stem Cells in Normal Lung and Lung Cancer

Abstract

Injury models have suggested that the lung contains anatomically and functionally distinct epithelial stem cell populations. We have isolated such a regional pulmonary stem cell population, termed bronchioalveolar stem cells (BASCs). Identified at the bronchioalveolar duct junction, BASCs were resistant to bronchiolar and alveolar damage and proliferated during epithelial cell renewal in vivo. BASCs exhibited self-renewal and were multipotent in clonal assays, highlighting their stem cell properties. Furthermore, BASCs expanded in response to oncogenic K-ras in culture and in precursors of lung tumors in vivo. These data support the hypothesis that BASCs are a stem cell population that maintains the bronchiolar Clara cells and alveolar cells of the distal lung and that their transformed counterparts give rise to adenocarcinoma. Although bronchiolar cells and alveolar cells are proposed to be the precursor cells of adenocarcinoma, this work points to BASCs as the putative cells of origin for this subtype of lung cancer.

Oncogenic KRAS Induces Progenitor Cell Expansion and Malignant Transformation in Zebrafish Exocrine Pancreas

“…While the effects of oncogenic Ras proteins on cellular differentiation have frequently been examined in the context of mammalian tissue culture 18 , previous in vivo studies have typically been limited by an inability to examine defined progenitor populations. However, a similar blockade in progenitor cell differentiation has recently been reported following expression of oncogenic KRAS in either hematopoietic or bronchoaveolar stem cells 19,20 . In both of these settings, inhibition of differentiation was associated with expansion of an undifferentiated progenitor pool, similar to the expansion of ptf1a-positive, CPA-negative cells observed in our Tg (ptf1a:eGFP-KRAS G12V ) embryos.…”

Attributes of adult stem cells

“…Pollutant resistance of CE cells is related to a deficiency in the phase I drug-metabolizing enzyme CYP450 2F2. At the bronchiolar alveolar duct junction (BADJ), the branch point between terminal bronchioles lined mostly by Clara cells and the alveolar spaces lined by pneumocytes, stem cells expressing both CCSP and surfactant protein C have been identified [159]. In the alveoli, type II pneumocytes are widely believed to be the stem/progenitor cells, undergoing hyperplasia in response to the loss of the squamous type I pneumocytes, giving rise to type I cells as well as selfrenewing.…”

K-ras activation generates an inflammatory response in lung tumors

“…Additionally, these tumors express SPC (Figure 2h). It is likely that SPC expression by CC10-Cre/LSL-K-ras tumors is reflective of the fact that these lung tumors in mice arise from stem cells located at the bronchoalveolar duct junction, which are known to express both CC10 and SPC (Kim et al, 2005) and/or that there is active downregulation of the CC10 promoter as CC10 expression has been associated with tumor suppression (Linnoila et al, 2000).…”