Metastatic Cancer Stem Cells: An Opportunity for Improving Cancer Treatment?

Cancer Center, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
Cell stem cell (Impact Factor: 22.27). 06/2010; 6(6):502-3. DOI: 10.1016/j.stem.2010.05.001
Source: PubMed


Many human cancers are driven by cancer stem cells (CSCs) whose connection to metastatic spread remains incompletely understood. In this issue of Cell Stem Cell, Pang et al. (2010) isolate a subpopulation of human colorectal CSCs that uniquely possesses metastatic potential.

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    • "Interest in epithelial stem cell (SC) maintenance, proliferation, and differentiation has exploded since regulation and function of these stem cells has been implicated in tumor malignancy and cancer stem cells (Reya et al., 2001; Dean, 2006; Kangsamaksin et al., 2007; Bonnet, 2008; Eyler et al., 2008; Fillmore and Kuperwasser, 2008; Todaro et al., 2008; Diehn and Majeti, 2010; Forsberg et al., 2010; Moore, 2010; Karamboulas and Ailles, 2012). Drosophila intestinal SCs (ISCs) are an attractive system for the study of adult somatic stem cells in vivo. "
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    ABSTRACT: Accumulating evidence suggests the involvement of tumor-initiating cells (T-ICs) in cancer genesis, but whether liver T-ICs contribute to HCC invasion and metastasis remains unclear. OV6(+) T-ICs were isolated from SMMC7721 and HuH7 cell lines by magnetic sorting. Characteristics of T-ICs were assessed by in vitro and mouse xenograft assays. Expression of OV6 was determined by immunostaining in specimens from 218 HCC patients, and Kaplan-Meier survival analysis was used to determine the correlation of OV6 expression with prognosis. OV6(+) T-ICs isolated from HCC cell lines not only possess a higher capacity to form tumor spheroids in vitro, but also had a greater potential to form tumors when implanted in non-obese diabetic/severe combined immunodeficient mice, suggesting their elevated self-renewal capacity and tumorigenicity. Moreover, OV6(+) T-ICs exhibited more invasive and metastatic potentials both in vitro and in vivo. Patients with more OV6(+) tumor cells were associated with aggressive clinicopathologic features and poor prognosis. CXCR4 is expressed at higher levels in OV6(+) cells. Recombinant stromal cell-derived factor-1 (SDF-1) treatment expanded the OV6(+) HCC T-ICs population, by sustaining the stem cell property of OV6(+) cells. The SDF-1 effect was blocked by a specific CXCR4 inhibitor, AMD3100, or transfection of siRNA targeting CXCR4. OV6(+) HCC cells may represent a subpopulation of T-ICs with augmented invasion and metastasis potential, which contribute to progression and metastasis of HCC. The SDF-1/CXCR4 axis also provides therapeutic targets for elimination of liver T-ICs.
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    ABSTRACT: Several human cancer types consist of diverse cell populations that can differ in their tumor-driving potential. One breakthrough has been the identification of poorly differentiated tumor cells, herein termed cancer stem cells (CSCs). CSCs have been shown to initiate tumors in different model systems and have been implicated in cancer resistance to conventional therapies. The clinical relevance of CSCs has been increasingly recognized, and recent progress in their enrichment and characterization has paved the way for exploring CSC biology with high-throughput screening technologies. This article focuses on functional chemical and RNAi screens that have led to the identification of factors that control the CSC phenotype. Different experimental strategies, current challenges and perspectives in CSC drug discovery are discussed.
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