Immune Response Against Tumor Antigens Expressed on Human Cancer Stem-Like Cells/Tumor-Initiating Cells

Hirohashi, Yoshihiko; Torigoe, Toshihiko; Inoda, Satoko; Takahashi, Akiko; Morita, Rena; Nishizawa, Satoshi; Tamura, Yasuaki; Suzuki, Hiromu; Toyota, Minoru; Sato, Noriyuki

doi:10.2217/imt.10.10

Cited by 52 publications

(46 citation statements)

References 62 publications

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“…15 We previously demonstrated that SOX2-overexpressing lung adenocarcinoma cell lines showed higher rates of side population cells and higher tumorigenecity and that SOX2 mRNA knockdown of side population cells by gene-specific siRNA completely abrogated tumorigenecity in vivo. 33 In this study, we found that SOX2 was associated with cancer-specific survival in patients with upper urinary tract urothelial cell carcinoma.…”

Section: Discussionmentioning

confidence: 95%

“…1 Cancer stem-like cells/tumor-initiating cells are a small population of cancer cells that have the properties of tumor-initiating ability, self-renewal and differentiation. Cancer stem-like cells/tumor-initiating cells are more resistant to chemotherapy and radio-therapy than non-cancer stem-like cell/tumor-initiating cell populations via various mechanisms, 15 suggesting that the existence of these cells is a prognostic factor in cancer patients. In this study, we investigated two cancer stem-like cell/tumor-initiating cell markers.…”

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confidence: 99%

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Prognostic impact of the expression of ALDH1 and SOX2 in urothelial cancer of the upper urinary tract

et al. 2013

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Aldehyde dehydrogenase 1 (ALDH1) and sex determining region-Y-related high mobility group box 2 (SOX2) have been identified as putative cancer stem-like cell/tumor-initiating cell markers in various cancer tissues. The aim of this study was to elucidate the prognostic impact of these putative cancer stem-like cell/tumorinitiating cell markers in upper urinary tract urothelial cell carcinoma. Immunohistochemical staining for ALDH1 and SOX2 was carried out on archival specimens from 125 patients with upper urinary tract urothelial cell carcinoma who underwent radical nephroureterectomy. The prognostic value of ALDH1 and SOX2 expression and other clinicopathological features was evaluated. On univariate analysis, tumor grade, pathological T stage, pathological N stage, lymphovascular invasion, ALDH1 expression and SOX2 expression were associated with a poor prognosis. On multivariate analysis, the independent factors of prognosis were tumor grade (P ¼ 0.014), pathological N stage (P ¼ 0.005) and ALDH1 expression (P ¼ 0.002). In subgroup analysis, those subgroups with no positive, one positive or two positive results in immunohistochemistry for ALDH1 and SOX2 expression had estimated 5-year cancer-specific survival rates of 80%, 49% and 22%, respectively (Po0.001). Neither ALDH1 nor SOX2 expression correlated with intravesical recurrence after radical nephroureterectomy. These findings suggest that cancer stem-like cells/tumor-initiating cells are linked to more aggressive behavior of upper urinary tract urothelial cell carcinoma, supporting the current cancer stem cell hypothesis. Thus, therapeutic targeting of cancer stem-like cells/tumor-initiating cells in upper urinary tract urothelial cell carcinoma is a future possibility.

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Section: Discussionmentioning

confidence: 95%

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confidence: 99%

Prognostic impact of the expression of ALDH1 and SOX2 in urothelial cancer of the upper urinary tract

et al. 2013

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“…Thus, therapy targeting the small population of CSCs/ CICs might be a reasonable approach for treatment of resistant and advanced cancers. Some immunologic effector cells, including natural killer (NK) cells and gdT cells, have been reported to be able to efficiently recognize the CSC/CIC population (14). Furthermore, we have reported that CTLs can efficiently recognize human colon CSCs/CICs (16).…”

Section: Introductionmentioning

confidence: 93%

“…In advanced cases, however, complete Cancer cells in solid carcinomas display heterogeneity in many aspects of their phenotypes, and only a small population of cells, called cancer stem-like cells/cancer-initiating cells (CSC/CIC), express stem cell phenotype and have high tumorinitiating ability (cancer stem cell hypothesis; refs. [12][13][14]. CSCs/CICs are resistant to chemotherapy and radiotherapy by various mechanisms, and these characteristics of CSCs/ CICs are thought to be related to posttherapeutic recurrence (15).…”

Section: Introductionmentioning

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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“…3 At this time, there are no definitive markers of CSCs/CICs; however, three major methods for enriching CSC/CIC population have been described. 4 One is side population (SP) cells based on the efflux of Hoechst 33342 dye. 5 CSCs/CICs were successfully isolated as SP cells in several types of cancers.…”

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SOX2 is overexpressed in stem-like cells of human lung adenocarcinoma and augments the tumorigenicity

Nakatsugawa

Takahashi

Hirohashi

et al. 2011

Laboratory Investigation

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Recently, the SOX2 gene has been reported to be amplified in human lung squamous cell carcinomas. However, its roles in human lung adenocarcinomas are still elusive. In this study, we analyzed the functions of SOX2 in cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) derived from human lung adenocarcinoma. Human lung CSCs/CICs were isolated as higher tumorigenic side population (SP) cells using Hoechst 33342 dye from several lung cancer cell lines. Four of nine lung cancer cell lines were positive for SP cells (LHK2, 1-87, A549, Lc817). The ratios of SP cells ranged from 0.4% for Lc817 to 2.8% for LHK2. To analyze the molecular aspects of SP cells, we performed microarray screening and RT-PCR analysis, and isolated SOX2 as one of a SP cell-specific gene. SOX2 was expressed predominantly in LHK2 and 1-87 SP cells, and was also expressed in several other cancer cell lines. The expression of SOX2 protein in primary human lung cancer tissues were also confirmed by immunohistochemical staining, and SOX2 was detected in more than 80% of primary lung cancer tissues. To address SOX2 molecular functions, we established a SOX2-overexpressed LHK2 and A549 cell line (LHK2-SOX2 and A549-SOX2). LHK2-SOX2 cells showed higher rates of SP cells and higher expression of POU5F1 compared with control cells. LHK2-SOX2 and A549-SOX2 cells showed relatively higher tumorigenicity than control cells. On the other hand, SOX2 mRNA knockdown of LHK2 SP cells by gene-specific siRNA completely abrogated tumorigenicity in vivo. These observations indicate that SOX2 has a role in maintenance of stemness and tumorigenicity of human lung adenocarcinoma CSCs/CICs and is a potential target for treatment.

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Immune Response Against Tumor Antigens Expressed on Human Cancer Stem-Like Cells/Tumor-Initiating Cells

Cited by 52 publications

References 62 publications

Prognostic impact of the expression of ALDH1 and SOX2 in urothelial cancer of the upper urinary tract

Prognostic impact of the expression of ALDH1 and SOX2 in urothelial cancer of the upper urinary tract

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

SOX2 is overexpressed in stem-like cells of human lung adenocarcinoma and augments the tumorigenicity

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