Identification of Tumorigenic Cells in KrasG12D-Induced Lung Adenocarcinoma

HC Cho, CY Lai, LE Shao, J Yu - Cancer research, 2011 - AACR
HC Cho, CY Lai, LE Shao, J Yu
Cancer research, 2011AACR
We established an inducible KrasG12D-driven lung adenocarcinoma in CCSP-rtTA/TetO-
Cre/LSL-KrasG12D mice that enable pursuits of the cellular and molecular processes
involved in Kras-induced tumorigenesis. To investigate the cellular origin of this cancer, we
first report a strategy using fluorescence-activated cell sorting fractionation that could highly
enrich bronchiolar Clara and alveolar type II cells, respectively. The EpCAM+ MHCII− cells
(bronchiolar origin) were more enriched with tumorigenic cells in generating secondary …
Abstract
We established an inducible KrasG12D-driven lung adenocarcinoma in CCSP-rtTA/TetO-Cre/LSL-KrasG12D mice that enable pursuits of the cellular and molecular processes involved in Kras-induced tumorigenesis. To investigate the cellular origin of this cancer, we first report a strategy using fluorescence-activated cell sorting fractionation that could highly enrich bronchiolar Clara and alveolar type II cells, respectively. The EpCAM+MHCII cells (bronchiolar origin) were more enriched with tumorigenic cells in generating secondary tumors than EpCAM+MHCII+ cells (alveolar origin) in primary tumors that had been already initiated with oncogenic Kras activation. In addition, secondary tumors derived from EpCAM+MHCII cells showed diversity of tumor locations compared with those derived from EpCAM+MHCII+ cells. In the alveolar region, secondary tumors from EpCAM+MHCII cells expressed not only bronchiolar epithelial marker, panCK, but also differentiation marker, proSPC, consistent with the notion that cancer-initiating cells display not only the abilities for self-renewal but also the features of differentiation to generate heterogeneous tumors with phenotypic diversity. Furthermore, high level of ERK1/2 activation and colony-forming ability as well as lack of Sprouty-2 expression were also observed in EpCAM+MHCII cells. Therefore, these results suggest that bronchiolar Clara cells are the origin of cells and tumorigenesis for KrasG12D-induced neoplasia in the lungs. Cancer Res; 71(23); 7250–8. ©2011 AACR.
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