Identification of Pancreatic Cancer Stem Cells

Li, Chenwei; Heidt, David G.; Dalerba, Piero; Burant, Charles F.; Zhang, Lanjing; Adsay, Volkan; Wicha, Max S.; Clarke, Michael F.; Simeone, Diane M.

doi:10.1158/0008-5472.can-06-2030

Cited by 2,948 publications

(2,029 citation statements)

References 30 publications

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“…Almost 10 years later, the first solid tumor stem cells were identified in breast cancer when it was demonstrated that a subpopulation of cells expressing the CD44 ϩ CD24 Ϫ phenotype could form tumors with as few as 100 cells, whereas tens of thousands of the bulk tumor cells did not do so (2). Since then, cancer stem cells have been characterized in human brain tumors (3) and colon (4,5), head and neck (6), and pancreatic cancers (7).…”

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confidence: 99%

Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance

Zhou

Wulfkuhle

Zhang

et al. 2007

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

630

486

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Side-population (SP) cells within cancers and cell lines are rare cell populations known to enrich cancer stem-like cells. In this study, we characterized SP cells from the human breast cancer cell line MCF7 as a model for cancer stem-like cells. Compared with non-SP cells, MCF7 SP cells had higher colony-formation ability in vitro and greater tumorigenicity in vivo , suggesting that MCF7 SP cells enrich cancer stem-like cells. cDNA microarray analysis of the SP cells indicated higher expression of ATP-binding cassette transporters and genes involved in quiescence, which were confirmed by quantitative RT-PCR and flow cytometry cell cycle analysis. To identify signal pathways important for cancer stem-like cells, we analyzed cDNA microarray data and identified nine pathways that were altered in the SP cells. To analyze the protein signaling networks, we used reverse-phase signaling pathway protein microarray technology and identified three signaling proteins that are significantly different between MCF7 SP and non-SP cells. Notably, signaling of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR), signal transduction and activator of transcription (STAT3), and phosphatase and tensin homolog (PTEN) was confirmed to be critical for MCF7 SP cell survival and proliferation by pathway specific inhibitors, selected gene knockdown, and in vivo tumorigenicity assay. The STAT3 pathway was found to be positively regulated by mTOR signaling, whereas PTEN served as a negative regulator of both STAT3 and mTOR signaling. This study suggests the existence of prosurvival signaling pathways critical for cancer stem-like cell maintenance, which could be selectively targeted for inhibiting cancer stem-like cells for improved treatment.

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mentioning

confidence: 99%

Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance

Zhou

Wulfkuhle

Zhang

et al. 2007

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

630

486

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“…The earliest evidences of CSCs were reported in a breast cancer 3 and in acute myeloid leukemia. 4 The existence of CSCs was later also reported in neural, 5 colon, 6 pancreatic, 7 head and neck, 8 prostate 9 and other cancers. 10,11 CSCs remain largely resistant to the majority of current anticancer therapeutics (i.e.…”

Section: Introductionmentioning

confidence: 87%

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1

et al. 2015

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Cancer stem-like cells (CSCs) are a rare subpopulation of cancer cells capable of propagating the disease and causing cancer recurrence. In this study, we found that the cellular localization of PKB/Akt kinase affects the maintenance of CSCs. When Akt tagged with nuclear localization signal (Akt-NLS) was overexpressed in SKBR3 and MDA-MB468 cells, these cells showed a 10-15% increase in the number of cells with CSCs enhanced ALDH activity and demonstrated a CD44 CHigh /CD24 ¡Low phenotype. This effect was completely reversed in the presence of Aktspecific inhibitor, triciribine. Furthermore, cells overexpressing Akt or Akt-NLS were less likely to be in G0/G1 phase of the cell cycle by inactivating p21 Waf1/Cip1 and exhibited increased clonogenicity and proliferation as assayed by colony-forming assay (mammosphere formation). Thus, our data emphasize the importance the intracellular localization of Akt has on stemness in human breast cancer cells. It also indicates a new robust way for improving the enrichment and culture of CSCs for experimental purposes. Hence, it allows for the development of simpler protocols to study stemness, clonogenic potency, and screening of new chemotherapeutic agents that preferentially target cancer stem cells. Summary: The presented data, (i) shows new, stemness-promoting role of nuclear Akt/PKB kinase, (ii) it underlines the effects of nuclear Akt on cell cycle regulation, and finally (iii) it suggests new ways to study cancer stem-like cells.

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“…Currently, cancer cell subpopulations selectively endowed with tumorigenic potential are operationally defined as CSCs and have been prospectively identified from selected types of human solid cancer, such as breast (5), brain (6,7), colon (8,9), head and neck (10), and pancreatic cancer (11). However, the CSC working model is still being subjected to intense debate (12), and data published on colorectal cancer (CRC) indicate that a subgroup of primary CRC is likely to be negative for the marker currently used for isolation of colorectal CSCs (Co-CSCs) (9).…”

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confidence: 99%

Phenotypic characterization of human colorectal cancer stem cells

Dalerba

Dylla

Park

et al. 2007

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

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Identification of Pancreatic Cancer Stem Cells

Abstract: Emerging evidence has suggested that

Cited by 2,948 publications

References 30 publications

Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance

Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1

Phenotypic characterization of human colorectal cancer stem cells

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Identification of Pancreatic Cancer Stem Cells

Abstract: Emerging evidence has suggested that

Cited by 2,948 publications

References 30 publications

Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance

Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21Waf1/Cip1and p27kip1

Phenotypic characterization of human colorectal cancer stem cells

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Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1