| Summary: | 博士 === 國立陽明大學 === 臨床醫學研究所 === 98 === Recent data have demonstrated that tumors contain a crucial subset of cells, i.e., cancer stem-like cells (CSCs) or cancer-initiating cells (CICs), which exhibit a self-renewing capacity and have the ability to reform new tumors in vivo. These properties support the CSC hypothesis of tumorigenesis and tumor relapse as well as tumor metastasis. The most recent theory of cancer stem cells (CSCs) is that cancer arises from a rare population, and these cells are the founders of chemo- and radio-resistance.
CD133 (prominin-1), a 5-transmembrane glycoprotein, has recently been considered to be an important marker that represents the subset population of cancer stem-like cells. Herein we report the isolation of CD133-positive cells (LC-CD133+) and CD133-negative cells (LC-CD133–) from tissue samples of ten patients with non-small cell lung cancer (NSCLC) and two LC cell lines. LC-CD133+ displayed higher Oct-4 expressions with the ability to self-renew and may represent a reservoir with proliferative potential for generating lung cancer cells. Furthermore, LC-CD133+ highly co-expressed the multiple drug-resistant marker ABCG2 and showed significant resistance to chemotherapy agents (ie, cisplatin, etoposide, doxorubicin, and paclitaxel) and radiotherapy compared with LC-CD133–. Oct-4 knockdown with lentiviral vector can specifically block the capability of LC-CD133+ to form spheres and can further facilitate LC-CD133+ differentiating into LC-CD133–. In addition, knock-down of Oct-4 expression in LC-CD133+ can significantly inhibit the abilities of tumor invasion and colony formation. It can increase apoptotic activities of caspase 3 and poly (ADP-ribose) polymerase (PARP). Finally, in vivo studies further confirm that the treatment effect of chemoradiotherapy for LC-CD133+ can be improved by the treatment of Oct-4 siRNA. In conclusion, we demonstrated that Oct-4 expression plays a crucial role in maintaining self-renewing, cancer stem-like, and chemoradioresistant properties of LC-CD133+. Future research is warranted regarding the up-regulated expression of Oct-4 in LC-CD133+ and malignant lung cancer.
In addition, aldehyde dehydrogenase 1 (ALDH1) has been considered to be a marker for cancer stem cells. However, the role of ALDH1 in head and neck squamous cell carcinoma (HNSCC) has yet to be determined. In this study, we isolated ALDH1-positive cells from HNSCC patients and showed that these HNSCC-ALDH1+ cells displayed radioresistance and represented a reservoir for generating tumors. Based on microarray findings, the results of western blotting and immunofluorescent assays further confirmed that ALDH1+-lineage cells showed evidence of having epithelial-mesenchymal transition (EMT) shifting and endogenously co-expressed Snail. Furthermore, the knockdown of Snail expression significantly decreased the expression of ALDH1, inhibited cancer stem-like properties, and blocked the tumorigenic abilities of CD44+CD24-ALDH1+cells. Finally, in a xenotransplanted tumorigenicity study, we confirmed that the treatment effect of chemoradiotherapy for ALDH1+ could be improved by Snail siRNA. In summary, it is likely that ALDH1 is a specific marker for the cancer stem-like cells of HNSCC.
Taken together, we isolated cancer stem-like cells from NSCLC and HNSCC by specific stem cell markers. These cells possess the capability of self-renewal, multi-lineage differentiation, and have the ability to generate a new tumor after xenotransplantation of small amount of CSCs in immunocompromised animals. Blockage of the pathways regulating self-renewal or EMT would effectively inhibit the stem cell properties and improve the outcomes of radio- and chemo-therapy. The phenotypic and genotypic characterization of CSCs are not yet fully understood, and further investigation is needed to determine if targeting the CSC subset and/or radiochemoresistance-associated CSCs will be critical in the treatment of cancer patients.
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