Abstract
There is increasing evidence that many solid tumors are hierarchically organized with the bulk tumor cells having limited replication potential, but are sustained by a stem-like cell that perpetuates the tumor. These cancer stem cells have been hypothesized to originate from transformation of adult tissue stem cells, or through re-acquisition of stem-like properties by progenitor cells. Adenosquamous carcinoma (ASC) is an aggressive type of lung cancer that contains a mixture of cells with squamous (cytokeratin 5+) and adenocarcinoma (cytokeratin 7+) phenotypes. The origin of these mixtures is unclear as squamous carcinomas are thought to arise from basal cells in the upper respiratory tract while adenocarcinomas are believed to form from stem cells in the bronchial alveolar junction. We have isolated and characterized cancer stem-like populations from ASC through application of selective defined culture medium initially used to grow human lung stem cells. Homogeneous cells selected from ASC tumor specimens were stably expanded in vitro. Primary xenografts and metastatic lesions derived from these cells in NSG mice fully recapitulate both the adenocarcinoma and squamous features of the patient tumor. Interestingly, while the CSLC all co-expressed cytokeratins 5 and 7, most xenograft cells expressed either one, or neither, with <10% remaining double positive. We also demonstrated the potential of the CSLC to differentiate to multi-lineage structures with branching lung morphology expressing bronchial, alveolar and neuroendocrine markers in vitro. Taken together the properties of these ASC-derived CSLC suggests that ASC may arise from a primitive lung stem cell distinct from the bronchial-alveolar or basal stem cells.
Highlights
The cancer stem cell hypothesis states that cancers arise from mutational or epigenetic changes in tissue stem cells, which allow these cells to escape intrinsic and extrinsic growth controls and become invasive [1]
It has been suggested that within lung cancers, NSCLC adenocarcinomas arise from stem cells (SC) at the bronchial alveolar junction (BASC), squamous carcinomas arise from basal SC of the bronchi and trachea, and small cell carcinomas arise from pulmonary neuroendocrine cells [11,12]
No successful cultures were obtained from squamous carcinoma tissue samples (4 separate attempts) using this same medium
Summary
The cancer stem cell hypothesis states that cancers arise from mutational or epigenetic changes in tissue stem (or progenitor) cells, which allow these cells to escape intrinsic and extrinsic growth controls and become invasive [1]. The source of stem cells (SC) involved in normal lung development, maintenance, and repair following injury is somewhat more complicated than tissues such as the skin or colon (for reviews see: [11,12]), where multiple “conditional” stem cells have been thought to be involved in the repair of different portions of the lung after injury [13]. These may, or may not, be the same stem cells responsible for tissue maintenance [14]. It has been suggested that within lung cancers, NSCLC (non small cell lung cancer) adenocarcinomas arise from SC at the bronchial alveolar junction (BASC), squamous carcinomas arise from basal SC of the bronchi and trachea, and small cell carcinomas arise from pulmonary neuroendocrine cells [11,12]
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