The Hyaluronic Acid Receptor CD44 Coordinates Normal and Metaplastic Gastric Epithelial Progenitor Cell Proliferation

Khurana, Sakshi; Riehl, Terrence E.; Moore, Ben D.; Fassan, Matteo; Rugge, Massimo; Romero–Gallo, Judith; Noto, Jennifer M.; Peek, Richard M.; Stenson, William F.; Mills, Jason C.

doi:10.1074/jbc.m112.445551

Cited by 105 publications

(119 citation statements)

References 76 publications

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“…CD44 together with other oncoproteins, such as MMP-2 and MMP-9, have been reported to be associated with gastric cancer metastasis (27). Khurana et al recently documented that loss of CD44 in vivo results in decreased proliferation of gastric epithelium and the ERK→CD44→STAT3 signaling pathway regulates normal and atrophy-induced gastric stem/progenitor-cell proliferation (28). Additionally, lines of evidence suggest that MMPs participate in cell growth, angiogenesis and epithelial-mesenchymal transition (3).…”

Section: Discussionmentioning

confidence: 99%

Asporin participates in gastric cancer cell growth and migration by influencing EGF receptor signaling

2015

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Abstract. Asporin (ASPN), a novel member of the small leucine-rich proteoglycan (SLRP) family, serves as a key component of the tumor stroma and has been reported to be abnormally expressed in certain types of tumors. Specifically, the proteoglycan was proven to activate the coordinated invasion of scirrhous gastric cancer and cancer-associated fibroblasts. However, the role of ASPN in cancer cell growth and metastasis has not yet been addressed. In the present study, we aimed to evaluate the tumoricidal benefits of ASPN on tumorigenesis and progression of gastric cancer. Firstly, it was demonstrated that ASPN was overexpressed in gastric carcinoma tissues when compared to the corresponding non-cancerous tissues, and it had varied levels of expression in gastric cancer epithelial cell lines. Additionally, we assessed the effects of transient siRNA-mediated ASPN knockdown on gastric cancer cells. ASPN silencing inhibited proliferation and suppressed the migration of immortalized neoplastic epithelial cells. Furthermore, at the molecular level, we found that downregulation of ASPN blocked the anti-apoptotic molecule Bcl-2, increased the expression of pro-apoptotic molecule Bad, reduced the expression of migration-related proteins CD44 and matrix metalloproteinase (MMP)-2, and abrogated the activation of the phosphorylation status of ERK and epidermal growth factor (EGF) and its receptor (EGFR). Collectively, our findings indicate that ASPN is upregulated and plays an oncogenic role in gastric cancer progression and metastasis by influencing the EGFR signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Asporin participates in gastric cancer cell growth and migration by influencing EGF receptor signaling

2015

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“…Moreover, 80% of eR1 Additional markers have been proposed for gastric stem cells (e.g., DCKL1/DCAMKL1, CD133/PROM1, and CD44), but the multipotency of these cells has not yet been analyzed by lineage tracing [15,16]. Khurana et al found that CD44 (cluster of diferentiation 44) is mainly expressed at the base of antral/pyloric glands, in a region overlapping Lgr5, and in the isthmus region of the corpus glands [17,18]. When parietal cell loss and atrophy were induced chemically or by Helicobacter infection, the CD44 + cells expanded from the isthmus and replenished the base of the gastric units (Figure 2).…”

Section: Discovery Of Gastric Stem Cells and Their Markersmentioning

confidence: 99%

“…Interestingly, the parietal cell atrophy induced after H. pylori infection causes an increase in the proliferation of stem/progenitor cells in the isthmus [37] that is associated with an induction of CD44 expression in this region, which then expands toward the botom of the gastric unit [17,35,36] (Figure 2). Sigal et al also reported an increase of the number of antral Lgr5 + cells in H. pylori-associated gastritis and carcinoma in humans.…”

Section: Tumors Can Originate From Epithelial Stem Cell Transformationmentioning

confidence: 99%

“…Moreover, in contrast to squamous skin tumors [48] or intestinal adenomas [49], the in vivo contribution of GCSCs to tumorigenesis has not yet been fully elucidated. Nevertheless, regardless of their origin, dysplastic lesions and gastric adenocarcinomas are composed of CD44 + cells (Figure 2) [17,36] that have been recently described to possess cancer stem cell properties [50,51].…”

Section: Tumors Originating From Bone Marrow-derived Cellsmentioning

confidence: 99%

“…Loss of CD44 in mice models results in a decrease in gastric mucosa proliferation in the isthmus region. The critical role of CD44 in proliferation involves its interaction with hyaluronic acid and the downstream activation of the STAT3 signaling pathway [17], RhoGTPases, the PI3K/AKT pathway, and the MAPK signaling pathway [63]. CD44 is encoded by the 20-exon CD44 gene, in which exons 1-5 and 16-20 are spliced together and translated into CD44s, the standard or small isoform.…”

Section: Phenotypic Characterization Of Gastric Cancer Stem Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Gastric Cancer: A Stem Cell Disease?

Giraud¹,

Bessède²,

Mégraud³

et al. 2017

Gastric Cancer

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Gastric stem cells have been recently identiied and are not yet fully characterized. Each gastric gland or unit is composed of diferent specialized cells and a small number of discrete stem cells. These gastric stem cells play key roles. They have self-renewal and multipotent properties and are the origin of specialized gastric epithelial cells. These properties are the basis for the stem cells' role in tissue homeostasis, tissue repair, and cancer. In tumors, growing evidence indicates that a cell subpopulation with stem cell features, the so-called cancer stem cells (CSCs), represents the "fuel" for the tumor: they are at the origin of tumor initiation, growth, and dissemination, and they also display resistance to conventional chemotherapy treatments. The recent identiication of CSCs in gastric carcinoma opens the door to the development of new therapeutic strategies targeting more speciically the CSCs at the origin of the disease, which is the third leading cause of cancer-related deaths worldwide.

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Glioblastoma Spheroid Invasion through Soft, Brain‐Like Matrices Depends on Hyaluronic Acid–CD44 Interactions

Safarians

Sohrabi

Solomon

et al. 2023

Adv Healthcare Materials

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Increased secretion of hyaluronic acid (HA), a glycosaminoglycan abundant in the brain extracellular matrix (ECM), correlates with worse clinical outcomes for glioblastoma (GBM) patients. GBM cells aggressively invade the brain parenchyma while encountering spatiotemporal changes in their local ECM, including HA concentration. To investigate how varying HA concentrations affect GBM invasion, patient‐derived GBM cells are cultured within a soft, 3D matrix in which HA concentration is precisely varied and cell migration observed. Data demonstrate that HA concentration can determine the invasive activity of patient‐derived GBM cells in a biphasic and highly sensitive manner, where the absolute concentration of HA at which cell migration peaked is specific to each patient‐derived line. Furthermore, evidence that this response relies on phosphorylated ezrin, which interacts with the intracellular domain of HA‐engaged CD44 to effectively link the actin cytoskeleton to the local ECM is provided. Overall, this study highlights CD44–HA binding as a major mediator of GBM cell migration that acts independently of integrins and focal adhesion complexes and suggests that targeting HA–CD44–ezrin interactions represents a promising therapeutic strategy to prevent tumor cell invasion in the brain.

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The Hyaluronic Acid Receptor CD44 Coordinates Normal and Metaplastic Gastric Epithelial Progenitor Cell Proliferation

Cited by 105 publications

References 76 publications

Asporin participates in gastric cancer cell growth and migration by influencing EGF receptor signaling

Asporin participates in gastric cancer cell growth and migration by influencing EGF receptor signaling

Gastric Cancer: A Stem Cell Disease?

Glioblastoma Spheroid Invasion through Soft, Brain‐Like Matrices Depends on Hyaluronic Acid–CD44 Interactions

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