Identification and expansion of the tumorigenic lung cancer stem cell population

Abstract

Lung carcinoma is often incurable and remains the leading cancer killer in both men and women. Recent evidence indicates that tumors contain a small population of cancer stem cells that are responsible for tumor maintenance and spreading. The identification of the tumorigenic population that sustains lung cancer may contribute significantly to the development of effective therapies. Here, we found that the tumorigenic cells in small cell and non-small cell lung cancer are a rare population of undifferentiated cells expressing CD133, an antigen present in the cell membrane of normal and cancer-primitive cells of the hematopoietic, neural, endothelial and epithelial lineages. Lung cancer CD133 þ cells were able to grow indefinitely as tumor spheres in serum-free medium containing epidermal growth factor and basic fibroblast growth factor. The injection of 10 4 lung cancer CD133þ cells in immunocompromised mice readily generated tumor xenografts phenotypically identical to the original tumor. Upon differentiation, lung cancer CD133 þ cells acquired the specific lineage markers, while loosing the tumorigenic potential together with CD133 expression. Thus, lung cancer contains a rare population of CD133 þ cancer stem-like cells able to self-renew and generates an unlimited progeny of non-tumorigenic cells. Molecular and functional characterization of such a tumorigenic population may provide valuable information to be exploited in the clinical setting.

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

“…[5][6][7][8][9] As shown in Figure 1b, all cell lines generated tumorospheres, and flow cytometry analyses showed that CD44 þ CD24 À population was highly enriched in tumorospheres (Supplementary Figure S1A). We sorted CD44 þ CD24 À cells from spheres of prostate and breast cancer using fluorescence-activated cell sorting (FACS) and achieved a purity of 495% as judged by postsorting flow analysis (Figure 1c).…”

“…Collectively, our data suggest that both CSCs and spheres exhibited diverse stem cell-associated characteristics, consistent with previous reports. [5][6][7][8][9] CSCs overexpressed BAD with elevated phosphorylation. As CSCs are resistant to drugs 11 and phosphorylated BAD correlates with drug resistance in cancer patients, 25 we determined the level of BAD expression and phosphorylation in CSCs and tumorospheres.…”

“…1,2 Subsequently, CSCs have been identified in several cancers. [3][4][5][6][7][8][9][10] Accumulating evidence suggests that current cancer therapies can only shrink tumors as they target and kill the differentiated cancer (DC) cells, but are unable to target the rare CSC population. 11,12 Thus, despite a wealth of information on DC cells, the active survival and self-renewal pathways in CSCs have not been characterized thoroughly.…”

Colorectal micropapillary carcinomas are associated with poor prognosis and enriched in markers of stem cells

“…[8][9][10][11] On the other hand, as the identification of tumorinitiating cells, also referred to as cancer stem cells, in acute myeloid leukemia, their presence has also been identified in a number of solid tumor types, such as breast, lung, ovarian, brain, and colon cancer. [12][13][14][15][16][17] Emerging evidence suggests that stem cells have a crucial role not only in the embryonic development and maintenance of mature normal tissues, but also in the development of malignancies and disease progression associated with poor prognosis. In fact, the expression of stem cell markers and their prognostic significance have been reported in several solid tumors, including colorectal cancer.…”

Cucurbitacin I inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer‐derived CD133‐positive cells

“…[6][7][8][9][10] Eramo et al first demonstrated that CD133-positive lung cancer cells have the ability to self-renew and grow indefinitely as a tumor sphere. 11 In another study of small cell lung cancer (SCLC), Jiang et al demonstrated that SCLC cells with high CD133 levels had markedly enhanced tumorigenicity associated with the basic helixloop-helix transcription factor achaete-scute complex homolog 1. 12 In our previous study, we demonstrated that nonsmall cell lung cancer (NSCLC)-derived CD133-positive cells displayed higher octamer-binding transcription factor 4 (Oct-4) expression and possessed the ability to self-renew, potentially representing a reservoir of proliferative potential to generate lung cancer cells.…”