The Polycomb Gene Product BMI1 Contributes to the Maintenance of Tumor-Initiating Side Population Cells in Hepatocellular Carcinoma

Chiba, Tetsuhiro; Miyagi, Satoru; Saraya, Atsunori; Aoki, Ryutaro; Seki, Atsuyoshi; Morita, Yohei; Yonemitsu, Yutaka; Yokosuka, Osamu; Taniguchi, Hideki; Nakauchi, Hiromitsu; Iwama, Atsushi

doi:10.1158/0008-5472.can-07-5882

Cited by 184 publications

(162 citation statements)

References 41 publications

(46 reference statements)

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“…Recently, Bmi1 has been shown to be highly expressed in GSCs and required for GSC self-renewal (Abdouh et al, 2009). In addition, similar finding for an essential role of Bmi1 in maintaining cancer stem cell in hepatocellular carcinomas has been reported (Chiba et al, 2008). These studies suggest that Bmi1 may be a common maker for cancer stem cells in several types of human cancers.…”

Section: Specific Transcription Factors and The Maintenance Of Glioblsupporting

confidence: 85%

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

et al. 2010

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Glioblastomas (GBMs) are highly lethal primary brain tumors. Despite current therapeutic advances in other solid cancers, the treatment of these malignant gliomas remains essentially palliative. GBMs are extremely resistant to conventional radiation and chemotherapies. We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells (GSCs) promotes therapeutic resistance. We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth, which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs. Furthermore, stem cell-like cancer cells (cancer stem cells) have been shown to promote metastasis. Although GBMs rarely metastasize beyond the central nervous system, these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection, and GSCs display an aggressive invasive phenotype. These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment. Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells, but also display critical distinctions that provide important clues into useful therapeutic targets. In this review, we summarize the current understanding and advances in glioma stem cell research, and discuss potential targeting strategies for future development of anti-GSC therapies.

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Section: Specific Transcription Factors and The Maintenance Of Glioblsupporting

confidence: 85%

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

et al. 2010

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“…Our study indicates that ovarian cancer cells are heterogeneous. SP cells are highly proliferative compared with non-SP cells; SP xenogeneic transplant mice grew more tumours than non-SP xenogeneic transplant mice, as shown from other studies (Chiba et al, 2008;Harris et al, 2008;Steiniger et al, 2008). SP cells have characteristics of cancer stem-like cells.…”

Section: Discussionmentioning

confidence: 55%

Ovarian cancer stem-like side-population cells are tumourigenic and chemoresistant

2010

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BACKGROUND: Ovarian cancer is the most lethal gynaecological malignancy. Although ovarian cancer patients often respond initially to chemotherapy, they usually develop chemoresistance. We hypothesised that a small portion of ovarian cancer cells have stem-like cell properties that contribute to tumourigenesis and drug resistance. METHODS: Flow cytometry and Hoechst 33342 efflux isolated side-population (SP) cells from ascites derived from ovarian cancer patients and from mice inoculated with human ovarian cancer cell lines. The SP cells were examined for stem cell markers OCT4, NANOG, STELLAR, and ABCG2/BCRP1 by immunocytochemistry and RT -PCR. The SP cells and non-SP cells were studied for tumourigenesis and chemoresistance in vitro and in vivo. RESULTS: The SP cells expressed ABCG2/BCRP1, OCT4, STELLAR, and NANOG, detected by immunocytochemistry and RT -PCR. ABCG2/BCRP1 expression was higher in SP than in non-SP cells. Xenogeneic mice inoculated with SP cells yielded more tumours than did mice inoculated with non-SP cells. In parallel, SP cell culture resulted in extensive cell proliferation, which was markedly more than in non-SP cells. SP cells resisted chemotherapy compared with non-SP cells, both in vivo and in vitro. CONCLUSION: Ovarian cancer SP cells are tumourigenic and chemoresistant. ABCG2/BCRP1 has an important role in chemoresistance, which has implications for new therapeutic approaches.

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“…Imbalance of the expressions of these molecules causes cancer because of self-renewing and progression capabilities. 26,27 Bmi-1 mRNAs and proteins tend to be expressed in well-differentiated/early and lose expression in poorly differentiated/progressed HNSCC (Tables 1-3). Subsequent identification of Bmi-1 protein expression could distinguish early lesions of cancerous tissue from non-cancerous tissues in HNSCCs (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Stem cell self-renewal factors Bmi1 and HMGA2 in head and neck squamous cell carcinoma: clues for diagnosis

Yamazaki

Mori

Yazawa

et al. 2013

Laboratory Investigation

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Head and neck squamous cell carcinoma (HNSCC) includes both morphological and functional cellular heterogeneity, as would be expected if it arose from dysregulated stem or progenitor cells as opposed to the simple clonal expansion of a mutated cell; however, stemness molecule expression levels and distribution in HNSCC remain unclear. To clarify this, stemness molecule expressions were determined in HNSCC, as well as their properties and prognosis. Two protooncogenic chromatin regulators, Bmi-1 and high-mobility-group A2 (Hmga2), were identified in 12 pair cases of HNSCC tumor regions by comparison with their non-cancerous background tissues using cDNA microarray. Both Bmi-1 and Hmga2 are known to promote stem cell self-renewal by negatively regulating the expressions of Ink4a and Arf tumor suppressors. Despite similar targets, Bmi-1 protein was expressed in an early cancerous region and HMGA2 protein was expressed in a region showing more progression. Similarly, Bmi1 expression had no significance with regard to overall survival (P ¼ 0.67), whereas HMGA2 expression was associated with decreased overall survival (P ¼ 0.05). Quantitative realtime reverse transcription polymerase chain reaction analyses also correlated with protein levels. These findings suggest that Bmi-1 is an early detection marker to distinguish cancerous from non-cancerous regions, whereas HMGA2 is presumed to be a tumor prognosis marker. Among our HNSCC analyses, these stemness molecules expressed fewer primitive rare cells in the tumor than all other cells in the tumor. HNSCC cells with high expression of stemness molecules partly behave like stem cells. Head and neck squamous cell carcinoma (HNSCC) is typically associated with virus infection, persistent chronic inflammation, and tobacco and alcohol use. Survival rates have changed in the last 40 years because of reductions in these factors; 1 however, the mortality rate remains high because advanced and recurrent locoregional control is difficult in many cases. Better understanding of the biology of HNSCC is required to define relevant targets and to develop novel therapeutic approaches. HNSCCs have both morphological and functional cellular heterogeneity, as would be expected if they arose from dysregulated stem or progenitor cells as opposed to the simple clonal expansion of a mutated cell. 2 Recently, numerous reports have shown support for the 'cancer stem cell' theory in many types of tumor, including HNSCC. 3,4,5 Acute and chronic myeloid leukemias follow the cancer stem cell model. Both tumors show robustly hematopoietic hierarchical organization in the tumor cells; 6,7 however, for solid cancers such as squamous cell carcinoma, it is not clear how generalizable the cancer stem cell model is. Not all cancer cells have the same capacity to proliferate. 8 In some cancers, most cancer cells appear to have limited ability to proliferate, while in the same tumors, stochastic minority populations of stemness molecules highly expressed in cancer as a 'stem-like cancer' retain the capacity...

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The Polycomb Gene Product BMI1 Contributes to the Maintenance of Tumor-Initiating Side Population Cells in Hepatocellular Carcinoma

Cited by 184 publications

References 41 publications

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

Ovarian cancer stem-like side-population cells are tumourigenic and chemoresistant

Stem cell self-renewal factors Bmi1 and HMGA2 in head and neck squamous cell carcinoma: clues for diagnosis

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