CD44v8-10 Is a Cancer-Specific Marker for Gastric Cancer Stem Cells

Lau, Wen Min; Teng, Eileen; Chong, Hui Shan; Lopez, Kirsten Anne Pagaduan; Tay, Amy Yuh Ling; Salto-Tellez, Manuel; Shabbir, Asim; So, Jimmy Bok Yan; Chan, Shing Leng

doi:10.1158/0008-5472.can-13-2309

Cited by 173 publications

(156 citation statements)

References 42 publications

(35 reference statements)

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“…Recently, CD44 variable exons 8-10 (present in CD44 isoforms 1, 2, and 3) have been linked to gastric cancer stem cells (33) and associated with tumor progression in bladder cancer (34). In a mouse thymoma cell line, CD44v10 was found to bind more readily to OPN than other adhesion molecules, such as HA, and promoted tumor-infiltrating leukocyte recruitment upon local inflammation (32).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…To overcome the difficulty in obtaining primary tumors of sufficient tumor cellularity from DGC tissues, we collected peritoneal ascites fluid from DGC patients (Supplementary Table S1) and depleted GlyA þ red blood cells and CD45 þ hematopoietic cells. As EpCAM is a tumor-associated antigen that is highly expressed in gastric cancer (23,27), we reasoned that EpCAM þ cells found in ascites fluid of gastric cancer patients would likely be exfoliated tumor cells from the primary tumor site. EpCAM þ cells were observed as viable, single cells and were visibly larger in size than CD45 þ cells as shown in cytospin preparations (Fig.…”

Section: Development and Validation Of Robust Dgc Pdx Modelsmentioning

confidence: 99%

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

Lau

Teng

Huang

et al. 2018

Molecular Cancer Therapeutics

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Preclinical models of diffuse-type gastric cancer (DGC) that reliably predict clinical activity of novel compounds are lacking. To overcome the problem of poor tumor cellularity in DGC, we used cells from malignant ascites to establish DGC patientderived xenograft (PDX) models that recapitulate the primary cancer. Cells in PDX model GAGA6 with FGFR2 amplification were sensitive to AZD4547, a potent FGFR inhibitor that is being clinically evaluated for FGFR-aberrant cancer types. Intermittent in vivo treatment of GAGA6 tumors with AZD4547 gave rise to PDX tumors with acquired resistance to AZD4547, GAGA6-R. Surprisingly, there were no mutations in the FGFR2 gene in GAGA6-R, negating gatekeeper mutations as a mechanism of drug resistance. Phosphorylation of FGFR2 and downstream signaling molecules AKT/PKB and MAPK/ERK remained inhibited by AZD4547. Further analysis of signaling pathways identified AKT-independent phosphorylation and inhibition of GSK3b as a mechanism of drug resistance in GAGA6-R cells. Treatment of GAGA6-R cells with protein kinase C (PKC) inhibitor H7 in combination with AZD4547 led to dephosphorylation and activation of GSK3b with concomitant downregulation of MCL-1 and BCL-XL. Combined treatment with AZD4547 and H7 in vitro synergistically enhanced cell death in GAGA6-R but not GAGA6 cells. Furthermore, midostaurin, a multikinase inhibitor with PKC-inhibiting activity, in part reversed resistance of GAGA6-R tumor to AZD4547 in vivo. Our results suggest that upon challenge with FGFR inhibitors, FGFR2-amplified tumors that are highly dependent on FGFR2 signaling for survival rapidly develop resistance by switching to a PKC-mediated inhibition of GSK3b to gain a survival advantage.

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“…CD44 expression also denotes a subpopulation of gastric cancer cells in which Hedgehog signaling pathway proteins are up‐regulated and also promote chemotherapy resistance and thus a poorer prognosis 21, 38. A variant of CD44 (CD44v8‐10) was identified as the predominant CD44 variant expressed in gastric cancer cells and contributes to tumor initiation, possibly through enhancing oxidative stress defense 39. It has also been demonstrated that CD44 and CD133 expression in gastric cancers is associated with statistically significant histology for intestinal‐type tumors and that CD44v5 is significantly associated with Signet ring histology 21.…”

Section: Cancer Stem Cellsmentioning

confidence: 99%

Identifying and targeting cancer stem cells in the treatment of gastric cancer

Bekaii‐Saab

El‐Rayes²

2017

Cancer

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Current treatment regimens for gastric cancer are not adequate. Cancer stem cells (CSCs) may be a key driving factor for growth and metastasis of this tumor type. In contrast to the conventional clonal evolution hypothesis, CSCs can initiate tumor formation, self‐renew, and differentiate into tumor‐propagating cells. Because gastric cancer can originate from CSCs, it is necessary to review current targets of signaling pathways for CSCs in gastric cancer that are being studied in clinical trials. These pathways are known to regulate the self‐renewal and differentiation process in gastric CSCs. A better understanding of the clinical results of trials that target gastric CSCs will lead to better outcomes for patients with gastric cancer. Cancer 2017;123:1303–1312. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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CD44v8-10 Is a Cancer-Specific Marker for Gastric Cancer Stem Cells

Cited by 173 publications

References 42 publications

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

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

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

Identifying and targeting cancer stem cells in the treatment of gastric cancer

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