Maintenance of tumor initiating cells of defined genetic composition by nucleostemin

Okamoto, Nobuhiko; Yasukawa, Mami; Nguyen, Christine L.; Kasim, Vivi; Maida, Yoshiko; Possemato, Richard; Shibata, Tatsuhiro; Ligon, Keith L.; Fukami, Kiyoko; Hahn, William C.; Masutomi, Kenkichi

doi:10.1073/pnas.1015171108

Cited by 102 publications

(137 citation statements)

References 45 publications

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“…In this vein, Bill Hahn explored the activity of an alternative complex formed by TERT, BRG1 (a chromatin remodeling ATPase implicated in the transcriptional regulation of many target genes), and NS/ GNL3L (two related proteins that are highly expressed in proliferative, multipotential cells). He found that overexpression of NS or GNL3L increased the fraction of TICs (tumor initiating cells or tumor stem cells) in a cell population (61). Consistent with working through a nontelomere-related pathway, the effect was not accompanied by telomere length alterations and was abolished by knockdown of BRG1 and TERT but not TERC (the TER gene).…”

Section: Regulation By Telomere Proteins and Accessory Factorsmentioning

confidence: 55%

Telomerase and retrotransposons: Reverse transcriptases that shaped genomes

Belfort

Curcio

Lue

2011

Proc. Natl. Acad. Sci. U.S.A.

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Section: Regulation By Telomere Proteins and Accessory Factorsmentioning

confidence: 55%

Telomerase and retrotransposons: Reverse transcriptases that shaped genomes

Belfort

Curcio

Lue

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…As a result, chromatin regulators Bmi1 and HMGA2 demonstrated a tendency to be highly expressed in tumors. In addition, CD44, 15 GNL3L/ nucleostemin, 16 and YBX1 17 showed higher average expression in tumors. By contrast, EpCAM, CD133 (Prominin 1), 18 and SHH expression levels showed great variability among individual cases.…”

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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“…Okamoto and coworkers identified TERT as a necessary component to maintain a stem cell state of the tumour-initiating cells (TIC) (Okamoto et al 2011). The formation of a complex TERT-GNL3L/NS, which are proposed as markers for TICs in highly aggressive tumours, seems to contribute directly to cancer stem cell formation (Okamoto et al 2011).…”

Section: Role Of Tert In Proliferation Invasion and Tumourigenesismentioning

confidence: 99%

“…The formation of a complex TERT-GNL3L/NS, which are proposed as markers for TICs in highly aggressive tumours, seems to contribute directly to cancer stem cell formation (Okamoto et al 2011).…”

Section: Role Of Tert In Proliferation Invasion and Tumourigenesismentioning

confidence: 99%

TERT biology and function in cancer: beyond immortalisation

Pestana

Vinagre

Sobrinho-Simões

et al. 2017

Journal of Molecular Endocrinology

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Evasion of replicative senescence and proliferation without restriction, sometimes designated as immortalisation, is one of the hallmarks of cancer that may be attained through reactivation of telomerase in somatic cells. In contrast to most normal cells in which there is lack of telomerase activity, upregulation of TERT transcription/activity is detected in 80-90% of malignant tumours. In several types of cancer, there is a relationship between the presence of TERT promoter mutations, TERT mRNA expression and clinicopathological features, but the biological bridge between the occurrence of TERT promoter mutations and the aggressive/invasive features displayed by the tumours remains unidentified. We and others have associated the presence of TERT promoter mutations with metastisation/survival in several types of cancer. In follicular cell-derived thyroid cancer, such mutations are associated with worse prognostic features (age of patients, tumour size and tumour stage) as well as with distant metastases, worse response to treatment and poorer survival. In this review, we analyse the data reported in several studies that imply TERT transcription reactivation/activity with cell proliferation, tumour invasion and metastisation. A particular attention is given to the putative connections between TERT transcriptional reactivation and signalling pathways frequently altered in cancer, such as c-MYC, NF-κB and B-Catenin.

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Maintenance of tumor initiating cells of defined genetic composition by nucleostemin

Cited by 102 publications

References 45 publications

Telomerase and retrotransposons: Reverse transcriptases that shaped genomes

Telomerase and retrotransposons: Reverse transcriptases that shaped genomes

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

TERT biology and function in cancer: beyond immortalisation

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