Faculty Opinions recommendation of Stem cell-like properties of the endometrial side population: implication in endometrial regeneration.

The hematopoietic stem cell underlying acute myeloid leukemia (AML) is controversial. Flow cytometry and the DNA-binding dye Hoechst 33342 were previously used to identify a distinct subset of murine hematopoietic stem cells, termed the side population (SP), which rapidly expels Hoechst dye and can reconstitute the bone marrow of lethally irradiated mice. Here, the prevalence and pathogenic role of SP cells in human AML were investigated. Such cells were found in the bone marrow of more than 80% of 61 patients and had a predominant CD34low/− immunophenotype. Importantly, they carried cytogenetic markers of AML in all 11 cases of active disease examined and in 2 out of 5 cases in complete hematological remission. Comparison of daunorubicin and mitoxantrone fluorescence emission profiles revealed significantly higher drug efflux from leukemic SP cells than from non-SP cells. Three of 28 SP cell transplants generated overt AML-like disease in nonobese diabetic–severe combined immunodeficient mice. Low but persistent numbers of leukemic SP cells were detected by molecular and immunological assays in half of the remaining mice. Taken together, these findings indicate that SP cells are frequently involved in human AML and may be a target for leukemic transformation. They also suggest a mechanism by which SP cells could escape the effects of cytostatic drugs and might eventually contribute to leukemia relapse.

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Characterization of stem cell–like cancer cells in immune-competent mice

Blood ◽

10.1182/blood-2006-05-024687 ◽

2006 ◽

Vol 108 (12) ◽

pp. 3906-3912 ◽

Cited By ~ 63

Author(s):

Jorg A. Kruger ◽

Charles D. Kaplan ◽

Yunping Luo ◽

He Zhou ◽

Dorothy Markowitz ◽

...

Keyword(s):

Stem Cell ◽

Cancer Cells ◽

Cell Lines ◽

Carcinoma Cell ◽

Side Population ◽

Carcinoma Cell Lines ◽

Tumorigenic Potential ◽

4T1 Cells

AbstractRecently, the cancer stem cell hypothesis has gained significant recognition as the descriptor of tumorigenesis. Although previous studies relied on transplanting human or rat tumor cells into immunecompromised mice, our study used the Hoechst 33342 dye–based side population (SP) technique to isolate and transplant stem cell–like cancer cells (SCLCCs) from the 4T1 and NXS2 murine carcinoma cell lines into the immune-competent microenvironment of syngeneic mice. 4T1 cells displayed an SP of 2% with a Sca-1highc-Kit–CD45– phenotype, whereas NXS2 cells contained an SP of 0.2% with a Sca-1highCD24highc-Kit–CD45–GD high2 phenotype. Reverse transcription–polymerase chain reaction (RT-PCR) further revealed up-regulation in SP cells of ABCG2, Sca-1, Wnt-1, and TGF-β2. Additionally, 4T1 and NXS2 SP cells exhibited increased resistance to chemotherapy, and 4T1 SP cells also showed an increased ability to efflux doxorubicin, which correlated with a selective increase in the percentage of SP cells found in the tumors of doxorubicin-treated mice. Most importantly, SP cells showed a markedly higher repopulation and tumorigenic potential in vivo, which correlated with an increased number of cells in the SP compartment of SP-derived tumors. Taken together, these results show that we successfully characterized SCLCCs from 2 murine carcinoma cell lines in the immune-competent microenvironment of syngeneic mice.

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Antioxidant proteins and reactive oxygen species are decreased in a murine epidermal side population with stem cell-like characteristics

Histochemistry and Cell Biology ◽

10.1007/s00418-011-0786-2 ◽

2011 ◽

Vol 135 (3) ◽

pp. 293-304 ◽

Cited By ~ 16

Author(s):

Wanakee J. Carr ◽

Rebecca E. Oberley-Deegan ◽

Yuping Zhang ◽

Christopher C. Oberley ◽

Larry W. Oberley ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Stem Cell ◽

Side Population ◽

Reactive Oxygen ◽

Oxygen Species ◽

Antioxidant Proteins

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PIWIL1 Drives Chemoresistance in Multiple Myeloma by Modulating Mitophagy and the Myeloma Stem Cell Population

Frontiers in Oncology ◽

10.3389/fonc.2021.783583 ◽

2022 ◽

Vol 11 ◽

Author(s):

Yajun Wang ◽

Lan Yao ◽

Yao Teng ◽

Hua Yin ◽

Qiuling Wu

Keyword(s):

Multiple Myeloma ◽

Drug Resistance ◽

Stem Cell ◽

Cell Population ◽

Side Population ◽

Chemotherapeutic Agents ◽

Stem Cell Population ◽

Exact Function

As an important member of the Argonaute protein family, PIWI-like protein 1 (PIWIL1) plays a key role in tumor cell viability. However, the exact function of PIWIL1 in multiple myeloma (MM) and the underlying mechanism remain unclear. Here, we revealed that PIWIL1 was highly expressed in myeloma cell lines and newly diagnosed MM patients, and that its expression was notably higher in refractory/relapsed MM patients. PIWIL1 promoted the proliferation of MM cells and conferred resistance to chemotherapeutic agents both in vitro and in vivo. More importantly, PIWIL1 enhanced the formation of autophagosomes, especially mitophagosomes, by disrupting mitochondrial calcium signaling and modulating mitophagy-related canonical PINK1/Parkin pathway protein components. Mitophagy/autophagy inhibitors overcome PIWIL1-induced chemoresistance. In addition, PIWIL1 overexpression increased the proportion of side population (SP) cells and upregulated the expression of the stem cell-associated genes Nanog, OCT4, and SOX2, while its inhibition resulted in opposite effects. Taken together, our findings demonstrated that PIWIL1 induced drug resistance by activating mitophagy and regulating the MM stem cell population. PIWIL1 depletion significantly overcame drug resistance and could be used as a novel therapeutic target for reversing resistance in MM patients.

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Baicalein Suppresses Stem Cell-Like Characteristics in Radio- and Chemoresistant MDA-MB-231 Human Breast Cancer Cells through Up-Regulation of IFIT2

Nutrients ◽

10.3390/nu11030624 ◽

2019 ◽

Vol 11 (3) ◽

pp. 624 ◽

Cited By ~ 13

Author(s):

So Koh ◽

Jeong Moon ◽

Tatsuya Unno ◽

Somi Cho

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Molecular Mechanisms ◽

Side Population ◽

Acquired Resistance ◽

Treatment Resistance ◽

Toll Like Receptor ◽

Tetratricopeptide Repeats ◽

Mammosphere Formation ◽

Induced Apoptosis

Resistance to both chemotherapy and radiation therapy is frequent in triple-negative breast cancer (TNBC) patients. We established treatment-resistant TNBC MDA-MB-231/IR cells by irradiating the parental MDA-MB-231 cells 25 times with 2 Gy irradiation and investigated the molecular mechanisms of acquired resistance. The resistant MDA-MB-231/IR cells were enhanced in migration, invasion, and stem cell-like characteristics. Pathway analysis by the Database for Annotation, Visualization and Integrated Discovery revealed that the NF-κB pathway, TNF signaling pathway, and Toll-like receptor pathway were enriched in MDA-MB-231/IR cells. Among 77 differentially expressed genes revealed by transcriptome analysis, 12 genes involved in drug and radiation resistance, including interferon-induced protein with tetratricopeptide repeats 2 (IFIT2), were identified. We found that baicalein effectively reversed the expression of IFIT2, which is reported to be associated with metastasis, recurrence, and poor prognosis in TNBC patients. Baicalein sensitized radio- and chemoresistant cells and induced apoptosis, while suppressing stem cell-like characteristics, such as mammosphere formation, side population, expression of Oct3/4 and ABCG2, and CD44highCD24low population in MDA-MB-231/IR cells. These findings improve our understanding of the genes implicated in radio- and chemoresistance in breast cancer, and indicate that baicalein can serve as a sensitizer that overcomes treatment resistance.

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Molecular characterisation of side population cells with cancer stem cell-like characteristics in small-cell lung cancer

British Journal of Cancer ◽

10.1038/sj.bjc.6605668 ◽

2010 ◽

Vol 102 (11) ◽

pp. 1636-1644 ◽

Cited By ~ 99

Author(s):

C D Salcido ◽

A Larochelle ◽

B J Taylor ◽

C E Dunbar ◽

L Varticovski

Keyword(s):

Lung Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Side Population ◽

Small Cell ◽

Molecular Characterisation ◽

Side Population Cells ◽

Small Cell Lung

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Abstract 3337: TGF-β from niche fibroblasts increases the stemness cancer stem cell-like side population cells in gastric cancer

10.1158/1538-7445.am2012-3337 ◽

2012 ◽

Cited By ~ 10

Author(s):

Tsuyoshi Hasegawa ◽

Masakazu Yashiro ◽

Tamami Morisaki ◽

Naoki Aomatsu ◽

Toshiki Hirakawa ◽

...

Keyword(s):

Gastric Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Side Population ◽

Side Population Cells

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Relationship between CD34/CD38 and side population (SP) defined leukemia stem cell compartments in acute myeloid leukemia

Leukemia Research ◽

10.1016/j.leukres.2019.04.004 ◽

2019 ◽

Vol 81 ◽

pp. 27-34

Author(s):

Bijan Moshaver ◽

Rolf F. Wouters ◽

Angèle Kelder ◽

Gert J. Ossenkoppele ◽

Guus A.H. Westra ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Myeloid Leukemia ◽

Side Population ◽

Leukemia Stem Cell ◽

Cell Compartments ◽

Acute Myeloid

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Enforced P-glycoprotein pump function in murine bone marrow cells results in expansion of side population stem cells in vitro and repopulating cells in vivo

Blood ◽

10.1182/blood.v96.3.902 ◽

2000 ◽

Vol 96 (3) ◽

pp. 902-909 ◽

Cited By ~ 126

Author(s):

Kevin D. Bunting ◽

Sheng Zhou ◽

Taihe Lu ◽

Brian P. Sorrentino

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Bone Marrow Cells ◽

Side Population ◽

Murine Bone Marrow ◽

Stem Cell Expansion ◽

Myeloproliferative Syndrome ◽

P Glycoprotein ◽

Marrow Cells

Abstract The human multidrug resistance-1 (MDR1) gene product, P-glycoprotein (P-gp), is well known for its ability to confer drug resistance; however, recent evidence suggests that P-gp expression can have more general effects on cellular development. In support of this idea, it was previously shown that retroviral-mediated MDR1 expression in murine bone marrow cells resulted in the expansion of stem cells in culture and in the development of a myeloproliferative syndrome in transplanted mice. It is now reported that MDR1-mediated stem cell expansion is associated with an increase in side population (SP) stem cells, defined by Hoechst dye staining. Transduction of murine bone marrow cells with an MDR1 retroviral vector resulted in an almost 2 log increase in SP cell numbers over 12 days in culture, whereas there was a rapid loss of SP cells from control cultures. Stem cell amplification was not limited to ex vivo expansion cultures but was also evident when MDR1-transduced cells were directly transplanted into irradiated mice. In these cases, stem cell expansion was associated with relatively high vector copy numbers in stem cell clones. As previously reported, some cases were associated with a characteristic myeloproliferative syndrome. A functionally inactive MDR1 mutant cDNA was used to show that P-gp pump function was required both for amplification of phenotypically defined SP cells and functionally defined repopulating cells. These studies further support the concept that ABC transporter function can have important effects on hematopoietic stem cell development.

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