Targeting Stem Cells-Clinical Implications for Cancer Therapy

Institute for Systems Biology, Seattle, WA 98103, USA.
Current Stem Cell Research & Therapy (Impact Factor: 2.21). 06/2009; 4(2):147-53. DOI: 10.2174/157488809788167373
Source: PubMed


Cancer stem cells (CSC), also called tumor initiating cells (TIC), are considered to be the origin of replicating malignant tumor cells in a variety of human cancers. Their presence in the tumor may herald malignancy potential, mediate resistance to conventional chemotherapy or radiotherapy, and confer poor survival outcomes. Thus, CSC may serve as critical cellular targets for treatment. The ability to therapeutically target CSC hinges upon identifying their unique cell surface markers and the underlying survival signaling pathways. While accumulating evidence suggests cell-surface antigens (such as CD44, CD133) as CSC markers for several tumor tissues, emerging clinical needs exist for the identification of new markers to completely separate CSC from normal stem cells. Recent studies have demonstrated the critical role of the tumor suppressor PTEN/PI3 kinase pathway in regulating TIC in leukemia, brain, and intestinal tissues. The successful eradication of tumors by therapies targeting CSC will require an in-depth understanding of the molecular mechanisms governing CSC self renewal, differentiation, and escape from conventional therapy. Here we review recent progress from brain tumor and intestinal stem cell research with a focus on the PTEN-Akt-Wnt pathway, and how the components of CSC pathways may serve as biomarkers for diagnosis, prognosis, and therapeutics.

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    • "Cancer arises from a tumorigenic subpopulation of TICs. The identification of molecular signatures of lung TICs provide a key standpoint for better understanding tumorigenesis and developing prognostic biomarkers and targeted therapy [22]. For instance, methylation of TIC-associated Wnt target genes were identified in colorectal tumors and showed the potential for predicting a poor prognosis of colon cancer patients [23]. "
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    ABSTRACT: Background Non-small cell lung cancer (NSCLC) is the number one cancer killer. Tumor-initiating cells (TICs) are responsible for tumor progression and recurrence. Emerging evidences suggest that small nucleolar RNAs (snoRNAs) play malfunctioning roles in lung tumorigenesis. This study aims to determine if snoRNAs have important function in lung TICs by: 1) profiling and comparing snoRNA expression patterns in lung ALDH1+/- cells of 28 primary NSCLC tissues to identify new signatures of TICs; 2) determining prognostic significance of the snoRNA signatures by analyzing the expression in 82 NSCLC tissues with different stages and histological types using quantitative PCR; 3) functionally investigating if the snoRNAs contribute to stemness of lung TICs using in vitro and in vivo assays. Results Twenty-two snoRNAs were identified whose changes were specific to the TICs. The expression of two snoRNAs (snoRA3 and snoRA42) was inversely associated with survival of NSCLC patients (P = 0.002, p = 0.001, respectively). Functional analysis indicated that snoRA42 was upregulated in CD133+ cells isolated from NSCLC cell lines compared with the CD133- counterparts. snoRA42 knockdown reduced the proliferation and self-renewal of TICs in vitro. However, ectopic expression of snoRA42 in non-TICs enhanced the potentials of cell proliferation and self-renewal. snoRA42 expression was associated with expression of stem cell-core transcription factors in lung TICs. Blocking snoRA42 expression in TIC xenografts decreased tumorigenesis in mice. Conclusions The snoRNA signatures of lung TICs provide potential biomarkers for predicting outcome of NSCLC. snoRA42 is one of the important snoRNAs in regulating features of lung TICs, and thus contributes to lung tumorigenesis.
    Full-text · Article · May 2014 · Molecular Cancer
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    • "One surviving CSC has potential to make recurrent tumors after treatments. Therefore, it is tremendously important to eradicate CSCs completely for the cure of cancer.7 Most CSC studies have utilized a magnetic-beads-conjugated anti-CD133 antibody to isolate CSCs in a heterogeneous population.4 "
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    ABSTRACT: Radioresistance, which is a major cause of failure of radiotherapy (RT), is proposed as one of the intrinsic characteristics of cancer stem cells (CSCs) whose unique DNA damage response (DDR), efficient DNA repair and resistance to apoptosis are thought to confer the phenotype. We have isolated surviving CSCs by exposure to long-term fractionated radiation for 82 days from HepG2 and A172 cells (82FR-31NR cells). 82FR-31NR cells exhibited CSC properties, such as high expression of CSC marker CD133 and the ABC transporters (MDR1 and BCRP1), and high tumorigenic potential after transplantation into nude mice. The advantage of our isolated CSCs is that they can proliferate in as the same growth medium as that of parental cells without loss of CSC properties. Therefore, we can analyze DDR of non-stem cells and CSCs without any influences caused by different culture conditions. 82FR-31NR cells showed efficient DNA repair of radiation-induced DNA damage and radioresistance with activation of the AKT/cyclin D1 survival signaling pathway. In contrast, DNA damage persisted for a long time after irradiation in parental cells compared with isolated CSCs. Persisted DNA damage induced apoptosis in parental cells without activation of the AKT/cyclin D1 pathway. Therefore, inhibition of the AKT/cyclin D1 pathway by an AKT inhibitor, API-2, or cyclin D1 siRNA resulted in a loss of efficient DNA repair and radiosensitization of 82FR-31NR cells. Furthermore, knockdown of Cdk4 by its siRNA or a Cdk4 inhibitor was sufficient to suppress radioresistance of CSCs. In this study, we present a newly discovered DDR regarding the AKT/cyclin D1/Cdk4 pathway in response to radiation in CSCs. Combination of fractionated RT and reagents targeting the AKT/cyclin D1/Cdk4 pathway to eradicate CSCs would be effective therapeutic modality.
    Full-text · Article · Jun 2012 · Oncogenesis
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    • "Additionally, CD44 acts as a co-receptor with neighboring receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) [36], hepatocyte growth factor receptor (c-MET) [37] and VEGF receptor (VEGFR) [38], and induces the PI3K/AKT cascade and anti-apoptotic pathway [39], resulting in enhanced aggressiveness and multi-drug resistance [40]. Recently, CD44 has also been reported to be a possible cancer stem cell marker for breast, pancreas, or colorectal cancer [41]. In bronchial cells, CD44 is associated with stem cells, namely basal cells and type 2 pneumocytes, and may act to anchor these cells to the matrix and be important in migration during repair or neoplasia. "
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    ABSTRACT: CD44s is a cell adhesion molecule known to mediate cellular adhesion to the extracellular matrix, a prerequisite for tumor cell migration. CD44s plays an important role in invasion and metastasis of various cancers. In the present study, we sought to determine whether CD44s is involved in clinical outcomes of patients with resected non-small cell lung cancer (NSCLC). Using immunohistochemical staining, we investigated CD44s protein expression using tissue array specimens from 159 patients with resected NSCLC (adenocarcinoma (AC; n=82) and squamous cell carcinoma (SCC; n=77). Additionally, the immunoreactivity of cyclooxygenase (COX)-2 was also studied. The clinicopathological implications of these molecules were analyzed statistically. High CD44s expression was detected more frequently in NSCLC patients with SCC (66/72; 91.7%) than in those with AC histology (P<0.001). Additionally, high CD44s expression was significant correlated with more advanced regional lymph node metastasis (P=0.021). In multivariate analysis of survival in NSCLC patients with AC histology, significant predictors were lymph node metastasis status (P<0.001), high-grade tumor differentiation (P=0.046), and high CD44s expression (P=0.014). For NSCLC patients with SCC histology, the significant predictor was a more advanced tumor stage (P=0.015). No significant association was found between CD44s and clinical outcome (P=0.311). High CD44s expression was a negative prognostic marker with significance in patients with resected NSCLC, particularly those with AC histology, and was independent of tumor stage.
    Full-text · Article · Aug 2011 · BMC Cancer
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