Osteopontin-CD44 Signaling in the Glioma Perivascular Niche Enhances Cancer Stem Cell Phenotypes and Promotes Aggressive Tumor Growth

Pietras, Alexander; Katz, Amanda; Ekström, Elin; Wee, Boyoung; Halliday, John J.; Pitter, Kenneth L.; Werbeck, Jillian L.; Amankulor, Nduka; Huse, Jason T.; Holland, Eric C.

doi:10.1016/j.stem.2014.01.005

Cited by 446 publications

(420 citation statements)

References 47 publications

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“…A previous study revealed that ERRα, combined with PGC1α, activates the promoter of osteopontin (OPN) gene and leads to elevated OPN expression in CRC cells (29). OPN is a glycoprotein secreted by a variety of tissues and enhances cancer stem cell phenotypes in various cancer types (30,31). Higher levels of OPN are produced by macrophages when co-cultured with cluster of differentiation 44-positive CRC stem cells, subsequently increasing the tumorigenicity of the CRC cells (32).…”

Section: Errα Expression (N=128) ------------------------------------mentioning

confidence: 99%

High expression of estrogen-related receptor α is significantly associated with poor prognosis in patients with colorectal cancer

et al. 2018

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Abstract. Colorectal cancer (CRC) is one of the most common types of malignancy with high morbidity and mortality rates worldwide. This biologically heterogeneous disease results in diverse therapeutic responses, thus, novel prognostic biomarkers are required to improve CRC treatment. Estrogen-related receptor α (ERRα) is a nuclear orphan receptor, which is associated with estrogen receptor α. The present study aimed to investigate the expression of ERRα in patients with CRC, and explore the association between ERRα expression and clinicopathological factors, local recurrence and prognosis. In the present study, ERRα expression was detected in 15 fresh CRC tissues using quantitative real-time polymerase chain reaction (RT-qPCR) and in 128 paraffin-embedded CRC tissues using immunohistochemistry. The associations between ERRα expression and prognosis of CRC patients were evaluated by univariate, and multivariate (Cox proportional hazards model) analysis. RT-qPCR demonstrated that the mRNA expression of ERRα in CRC tissues was significantly higher compared with that in matched normal tissues. Immunohistochemistry revealed that ERRα high expression was detected in the nuclei of cancer cells from 39.1% (50/128) of CRC tissues. ERRα expression based on immunohistochemical staining was significantly associated with tumor differentiation, tumor invasion, lymph node status and Dukes stage (all P<0.05). Furthermore, patients with high ERRα expression were significantly associated with an increased risk of recurrence and poor prognosis, compared with patients with low ERRα expression. ERRα expression was identified as an independent prognostic factor for patients with CRC. In conclusion, ERRα serves important roles in the progression of CRC and is a potential prognostic factor for patients with CRC.

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Section: Errα Expression (N=128) ------------------------------------mentioning

confidence: 99%

High expression of estrogen-related receptor α is significantly associated with poor prognosis in patients with colorectal cancer

et al. 2018

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“…Over recent years CD44 along with other cell surface markers like CD133, CD90, CD24, ALDH, Nestin, EpCAM, and CD34 are also associated with CSC isolation and enrichment in various tumors [12]. In addition to its naturally occurring ligand, CD44 interacts with several ECM molecules including fibronectin galectin-8, laminin, fibrinogen, chondroitin sulfate [13], and osteopontin [14].…”

Section: Introductionmentioning

confidence: 99%

Hyaluronic Acid Mediated Enrichment of CD44 Expressing Glioblastoma Stem Cells in U251MG Xenograft Mouse Model

Vaidyanath¹,

Mahmud²,

Khayrani³

et al. 2017

J Stem Cell Res Ther

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“…1E]. Binding of CD44 to stem cell niche-related extracellular matrix molecules, such as hyaluronan (HA) (9) and osteopontin (OPN), is in part predicated on the specific transcript variants expressed (10), and OPN-CD44 signaling promotes aggressive tumor growth (11). Although CD44 expression has been shown to promote both chronic and acute myeloid leukemia stem cell (LSC) maintenance in mouse models (12)(13)(14), CD44 splice isoform switching and cognate ligand expression as well as malignant reprogramming of human progenitors into self-renewing LSCs had not been elucidated.…”

mentioning

confidence: 99%

Reversion to an embryonic alternative splicing program enhances leukemia stem cell self-renewal

Holm

Hellqvist

Mason

et al. 2015

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

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Formative research suggests that a human embryonic stem cellspecific alternative splicing gene regulatory network, which is repressed by Muscleblind-like (MBNL) RNA binding proteins, is involved in cell reprogramming. In this study, RNA sequencing, splice isoform-specific quantitative RT-PCR, lentiviral transduction, and in vivo humanized mouse model studies demonstrated that malignant reprogramming of progenitors into self-renewing blast crisis chronic myeloid leukemia stem cells (BC LSCs) was partially driven by decreased MBNL3. Lentiviral knockdown of MBNL3 resulted in reversion to an embryonic alternative splice isoform program typified by overexpression of CD44 transcript variant 3, containing variant exons 8-10, and BC LSC proliferation. Although isoform-specific lentiviral CD44v3 overexpression enhanced chronic phase chronic myeloid leukemia (CML) progenitor replating capacity, lentiviral shRNA knockdown abrogated these effects. Combined treatment with a humanized pan-CD44 monoclonal antibody and a breakpoint cluster region -ABL proto-oncogene 1, nonreceptor tyrosine kinase (BCR-ABL1) antagonist inhibited LSC maintenance in a niche-dependent manner. In summary, MBNL3 down-regulationrelated reversion to an embryonic alternative splicing program, typified by CD44v3 overexpression, represents a previously unidentified mechanism governing malignant progenitor reprogramming in malignant microenvironments and provides a pivotal opportunity for selective BC LSC detection and therapeutic elimination.S ince the discovery of induction of stem cell characteristics in somatic cells by enforced expression of four transcription factors (1, 2), human pluripotent stem cell research has provided key insights into human development. Comparative DNA and RNA sequencing (RNAseq) studies have revealed that humanspecific distal regulatory elements, RNA editing, and alternative splicing play key roles in human embryonic stem cell (hESC) self-renewal and cell fate determination (3-6). Several of the phosphoproteins regulated during differentiation are components of the posttranscriptional RNA modification machinery, including double-stranded RNA-specific adenosine deaminase (ADAR) and serine/arginine-rich splicing factor 7 (SFRS7), thereby highlighting the importance of RNA processing alterations in hESC cell fate determination (5). Another key stem cell regulatory protein, β-catenin, is involved in hESC pluripotency and in the transcriptional regulation of adhesion molecules such as CD44 (5).Increased CD44 expression and splice isoform switching have been linked to enhanced metastatic potential and a poor prognosis in several types of cancer (7,8). Alternative splicing of 9 out of 19 exons in human CD44 pre-mRNA results in expression of different transcript variants, leading to variation in the length and function of the extracellular domain [for National Center for Biotechnology Information (NCBI)-designated CD44 nomenclature, see SI Materials and Methods and Fig. 1E]. Binding of CD44 to stem cell niche-related extracellular ma...

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Osteopontin-CD44 Signaling in the Glioma Perivascular Niche Enhances Cancer Stem Cell Phenotypes and Promotes Aggressive Tumor Growth

Cited by 446 publications

References 47 publications

High expression of estrogen-related receptor α is significantly associated with poor prognosis in patients with colorectal cancer

High expression of estrogen-related receptor α is significantly associated with poor prognosis in patients with colorectal cancer

Hyaluronic Acid Mediated Enrichment of CD44 Expressing Glioblastoma Stem Cells in U251MG Xenograft Mouse Model

Reversion to an embryonic alternative splicing program enhances leukemia stem cell self-renewal

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