Side populations of gastrointestinal cancers are not enriched in stem cells

Burkert, Julia; Otto, WR; Wright, Nicholas

doi:10.1002/path.2307

Cited by 102 publications

(79 citation statements)

References 33 publications

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“…Burkert et al 15 found that SP cells derived from gastrointestinal cancers cell lines HT29, HGT101, Caco2, and HRA19a1.1 were not enriched with a CSC/TIC population. In the present study, we were able to isolate SP cells from all six colon cancer cell lines studied (SW480, HT29, HCT15, KM12LM, Lovo, and Colo320).…”

Section: Discussionmentioning

confidence: 99%

“…All these SP cells were specifically inhibited by verapamil, as has been shown previously, 14 suggesting that these SP cells were specific for ABC transporter expression. Because previous studies showed that some colon cancer SP cells were not enriched with a CSC/TIC population, 15 it was essential to confirm the presence of CSCs/TICs in SP cells for further analysis. We inoculated these SP cells subcutaneously into the back of immunodeficient NOD/SCID mice using serial dilution.…”

Section: Isolation Of Colon Cscs/tics As Sp Cellsmentioning

confidence: 99%

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Cytotoxic T Lymphocytes Efficiently Recognize Human Colon Cancer Stem-Like Cells

Inoda

Hirohashi

Torigoe

et al. 2011

The American Journal of Pathology

105

100

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Cancer stem-like cells (CSCs) and tumor-initiating cells (TICs) are a small population of cancer cells that share three properties: tumor initiating ability, self-renewal, and differentiation. These properties suggest that CSCs/ TICs are essential for tumor maintenance, recurrence, and distant metastasis. Here, we show that cytotoxic T lymphocytes (CTLs) specific for the tumor-associated antigen CEP55 can efficiently recognize colon CSCs/ TICs both in vitro and in vivo. Using Hoechst 33342 dye staining, we isolated CSCs/TICs as side population (SP) cells from colon cancer cell lines SW480, HT29, and HCT15. The SP cells expressed high levels of the stem cell markers SOX2, POU5F1, LGR5, and ALDH1A1 and showed resistance to chemotherapeutic agents such as irinotecan or etoposide.To evaluate the susceptibility of SP cells to CTLs, we used CTL clone 41, which is specific for the CEP55-derived antigenic peptide Cep55/ c10orf3_193 ( Colon cancer is one of the most common malignancies worldwide. With recent progress in treatment, the prognosis has improved to some extent. In advanced disease, however, the prognosis remains unfavorable, because of recurrence, distant metastasis, and resistance to treatment. Thus, novel treatment modalities are needed.Cancers contain morphologically heterogeneous populations. This fact has led to the cancer stem cell theory, 1 the idea that cancers are composed of several types of cells, and that only a small population of cancer cells that can regenerate cancer tissues, much as normal tissue can be regenerated only by a small population of stemlike cells. Recently, cancer stem-like cells and tumorinitiating cells (CSCs/TICs) have been isolated from various types of malignancies, including colon cancer.2-6 In colon cancer, CSCs/TICs can reinitiate tumors that resemble mother colon cancer tissues morphologically when transplanted into immunodeficient mice.3 Furthermore, these CSCs/TICs have higher tumorigenic potential than do non-CSCs/TICs. Previous reports have shown that CSCs/TICs are resistant to a variety of treatments, including chemotherapy and radiotherapy, with varied mechanisms of resistance, including high expression of drug transporters, relative cell cycle quiescence, high levels of DNA repair machinery, and resistance to apoptosis. 7 These reports 3-6 support the hypothesis that malignant cancers comprise heterogeneous populations that organize in a hierarchical differentiation model. The CSCs/TICs are located at the top of this hierarchy, and targeting CSCs/TICs is essential to achieve efficient effects for treatment of malignant diseases. Recently, some trials targeting CSCs/TICs have been reported for hema-

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Section: Discussionmentioning

confidence: 99%

Section: Isolation Of Colon Cscs/tics As Sp Cellsmentioning

confidence: 99%

Cytotoxic T Lymphocytes Efficiently Recognize Human Colon Cancer Stem-Like Cells

Inoda

Hirohashi

Torigoe

et al. 2011

The American Journal of Pathology

105

100

View full text Add to dashboard Cite

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“…The ratios of SP cells in Caki1, SMKTR2, and SMKTR3 cells were too low for further analysis, and we therefore used ACHN and RenCa in the following experiments. It has been shown that SP cells were not enriched with CSCs/ CICs in some types of cancer cells (24) We carried out RT-PCR analysis to evaluate genetic characteristics of SP and MP cells derived from ACHN and RenCa cells (Fig. 2C).…”

Section: Isolation and Analysis Of Rcc Stem-like Population From Humamentioning

confidence: 99%

HSP DNAJB8 Controls Tumor-Initiating Ability in Renal Cancer Stem–like Cells

et al. 2012

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Cancer stem-like cells (CSC) are a small population of cancer cells with superior tumor initiating, self-renewal, and differentiation properties. In this study, we show that the cancer-testis antigen and HSP40 family member DNAJB8 contributes to the CSC phenotype in renal cell carcinoma (RCC). DNAJB8 overexpression increased the percentage of side population (SP) cells representing CSCs in RCC cells, enhancing their tumor-initiating ability. Conversely, attenuation of DNAJB8 decreased SP cells and reduced tumor-initiating ability. The utility of DNAJB8 as an immunologic target was established in DNA vaccination experiments. Compared with immunization with the tumor-associated antigen survivin, which was expressed in both CSCs and non-CSCs in RCC, immunization with Dnajb8 expression plasmids yielded stronger antitumor effects. Together, our findings suggest that DNAJB8 plays a role in CSC maintenance and that it offers a candidate for CSC-targeting immunotherapy in RCC.

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“…In recent years, it has been shown that SP cells exist in various types of tumours, including the CRC (Haraguchi et al, 2006;Sussman et al, 2007;Burkert et al, 2008). However, it is important to note that these studies are conflicting and stringent functional characterisation of SP cells in CRC is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…However, there are also some studies report that SP cells have not been shown to possess stem cell properties (Triel et al, 2004;Burkert et al, 2008;Lichtenauer et al, 2008;Broadley et al, 2011). There have been few studies directly comparing SP and Non-SP in CRC and yielding inconsistent results (Haraguchi et al, 2006;Burkert et al, 2008). These studies need to be confirmed using more cancer cell lines and especially primary tumour to have a better understanding of the involvement of SP in CRC.…”

mentioning

confidence: 99%

205 MicroRNA Expression Profiling Identifies MiR-328 Regulates Cancer Stem Cell-Like SP Cells in Colorectal Cancer

Xu¹,

Xu²,

Tong³

et al. 2012

Gastroenterology

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BACKGROUND: Side population (SP) cells and their relationship to stem cell-like properties have been insufficiently studied in colorectal cancer (CRC). MicroRNAs (miRNAs) have attracted much attention but their roles in the maintenance of SP phenotype remain unclear. METHODS: The SPs from CRC cell lines and primary cell cultures were analysed for stem cell-like properties. MiRNA microarray analysis identified miR-328 as a potential stemness miRNA of SP phenotype. The level of miR-328 expression in clinical samples and its correlation with SP fraction were determined. Gain-of-function and loss-of-function studies were performed to examine its roles in cancer stem-like SP cells. Furthermore, bioinformatics prediction and experimental validation were used to identify miR-328 target genes. RESULTS: The SP cells sorted from CRC possess cancer stem cell (CSC)-like properties, including self-renewal, differentiation, resistance to chemotherapy, invasive and strong tumour formation ability. MiR-328 expression was significantly reduced in SP cells compared with Non-SP cells (Po0.05). Moreover, miR-328 expression was downregulated in CRC (n ¼ 33, Po0.05) and low miR-328 expression tend to correlate with high SP fraction (n ¼ 15, r ¼ 0.6559, Po0.05, Pearson's correlation). Functional studies indicated that miR-328 expression affects the number of SP cells. In addition, miR-328 overexpression reversed drug resistance and inhibited cell invasion of SP cells. Furthermore, luciferase reporter assay demonstrated that miR-328 directly targets ABCG2 and MMP16 and affects the levels of mRNA and protein expression in SP cells. CONCLUSION: These findings indicate that CRC contain cancer stem-like SP cells. MiR-328 has an important role in maintaining cancer stem-like SP phenotype that may be a potential target for effective CRC therapy.

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Side populations of gastrointestinal cancers are not enriched in stem cells

Cited by 102 publications

References 33 publications

Cytotoxic T Lymphocytes Efficiently Recognize Human Colon Cancer Stem-Like Cells

Cytotoxic T Lymphocytes Efficiently Recognize Human Colon Cancer Stem-Like Cells

HSP DNAJB8 Controls Tumor-Initiating Ability in Renal Cancer Stem–like Cells

205 MicroRNA Expression Profiling Identifies MiR-328 Regulates Cancer Stem Cell-Like SP Cells in Colorectal Cancer

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