Prognostic significance of CD44 variant 2 upregulation in colorectal cancer

Ozawa, Mahito; Ichikawa, Yasushi; Zheng, Yun‐Wen; Oshima, Takashi; Miyata, Hidetoshi; Nakazawa, Kenichi; Hb, Guan; Shiozawa, Manabu; Amaki, Makoto; Watanabe, Kazuteru; M, Ota; Fujii, Satoshi; Kunisaki, Chikara; Ishikawa, Takashi; Tanaka, Kuniya; Akiyama, Hirotoshi; Endo, Itaru; Taniguchi, Hideki

doi:10.1038/bjc.2014.253

Cited by 52 publications

(46 citation statements)

References 30 publications

(39 reference statements)

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“…Similar observations were made in non-small cell lung cancer [74]. However, another report showed that patients with colorectal cancer with high expression of CD44v2 had a poorer prognosis than patients with other CD44v isoforms [75]. The discrepancy in prognostic value between CD44s and CD44v isoforms among different reports and in different tumor types awaits further clarification.…”

Section: Clinical Significance Of Cd44 In Cancer Cd44 As a Valuable Bsupporting

confidence: 64%

Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target

Yan

Zuo

Wei

2015

Stem Cells Translational Medicine

531

435

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The reception and integration of the plethora of signals a cell receives from its microenvironment determines the cell's fate. CD44 functions as a receptor for hyaluronan and many other extracellular matrix components, as well as a cofactor for growth factors and cytokines, and thus, CD44 is a signaling platform that integrates cellular microenvironmental cues with growth factor and cytokine signals and transduces signals to membrane-associated cytoskeletal proteins or to the nucleus to regulate a variety of gene expression levels related to cell-matrix adhesion, cell migration, proliferation, differentiation, and survival. Accumulating evidence indicates that CD44, especially CD44v isoforms, are cancer stem cell (CSC) markers and critical players in regulating the properties of CSCs, including selfrenewal, tumor initiation, metastasis, and chemoradioresistance. Furthermore, there is ample evidence that CD44, especially CD44v isoforms, are valuable prognostic markers in various types of tumors. Therefore, therapies that target CD44 may destroy the CSC population, and this holds great promise for the cure of life-threatening cancers. However, many challenges remain to determining how best to use CD44 as a biomarker and therapeutic target. Here we summarize the current findings concerning the critical role of CD44/CD44v in the regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer. We also discuss the current challenges and future directions that may lead to the best use of CD44/CD44v for clinical applications. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1033-1043 SIGNIFICANCEMounting evidence indicates that cancer stem cells (CSCs) are mainly responsible for cancer aggressiveness, drug resistance, and tumor relapse. CD44, especially CD44v isoforms, have been identified as CSC surface markers for isolating and enriching CSCs in different types of cancers. The current findings concerning the critical role of CD44/CD44v in regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer are summarized. The current challenges and future directions that may lead to best use of CD44/CD44v for clinical applications are also discussed.

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Section: Clinical Significance Of Cd44 In Cancer Cd44 As a Valuable Bsupporting

confidence: 64%

Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target

Yan

Zuo

Wei

2015

Stem Cells Translational Medicine

531

435

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“…Anti‐CD44 exon 10 antibody blocked metastasis . Patients having colorectal cancer with high expression of CD44 exon 6 had a poor prognosis . This study identified a novel splicing isoform, CD44v, which does not have exon 8 and 9.…”

Section: Discussionmentioning

confidence: 84%

SALL4 ‐ KHDRBS3 network enhances stemness by modulating CD44 splicing in basal‐like breast cancer

et al. 2018

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Understanding the mechanism by which cancer cells enhance stemness facilitates cancer therapies. Here, we revealed that a stem cell transcription factor, SALL4, functions to enhance stemness in basal‐like breast cancer cells. We used shRNA‐mediated knockdown and gene overexpression systems to analyze gene functions. To evaluate stemness, we performed a sphere formation assay. In SALL4 knockdown cells, the sphere formation ability was reduced, indicating that SALL4 enhances stemness. CD44 is a membrane protein and is known as a stemness factor in cancer. CD44 splicing variants are involved in cancer stemness. We discovered that SALL4 modulates CD44 alternative splicing through the upregulation of KHDRBS3, a splicing factor for CD44. We cloned the KHDRBS3‐regulated CD44 splicing isoform (CD44v), which lacks exons 8 and 9. CD44v overexpression prevented a reduction in the sphere formation ability by KHDRBS3 knockdown, indicating that CD44v is positively involved in cancer stemness. In addition, CD44v enhanced anoikis resistance under the control of the SALL4 ‐ KHDRBS3 network. Basal‐like breast cancer is an aggressive subtype among breast cancers, and there is no effective therapy so far. Our findings provide molecular targets for basal‐like breast cancer therapy. In the future, this study may contribute to the establishment of drugs targeting cancer stemness.

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“…CD44 and activation of WNT, NOTCH1 increases aggressiveness, correlating with progression in colon cancer . CD133 is also associated with enrichment of undifferentiated cells and tumorigenic behavior along with its implication in epithelial dedifferentiation . NOTCH1 signaling has been correlated with normal epithelial differentiation of squamous cells; exogenous expression of the Notch‐Intracellular domain (NICD) enhanced the proliferation/self‐renewal of the head and neck cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…41,42 CD133 is also associated with enrichment of undifferentiated cells and tumorigenic behavior along with its implication in epithelial dedifferentiation. 43,44 NOTCH1 signaling has been correlated with normal epithelial differentiation of squamous cells 45 ; exogenous expression of the Notch-Intracellular domain (NICD) enhanced the proliferation/ self-renewal of the head and neck cancer cells. In our study, Notch1 was deregulated in the epithelial cell lines and an inhibition of its activity using GSI led to a significant decrease in CSC and dysplastic profile, indicating its significance in dysplastic progression of oral cancer.…”

Section: Discussionmentioning

confidence: 99%

Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

Kulsum

Raju²,

Raghavan³

et al. 2019

Molecular Carcinogenesis

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Understanding the cellular interactions during oral carcinogenesis has the potential to identify novel prognostic and therapeutic targets. This study aimed at investigating the cancer stem cell (CSC)‐fibroblast niche interactions using in‐vitro dysplastic cell line models developed from different stages of 4NQO‐induced oral carcinogenic mice model. The spontaneously transformed epithelial cells (DysMSCTR6, 14 and 16) were developed from three time points (mild/moderate/severe), while two fibroblast cell lines (FibroMSCTR12, 16) were developed from moderate and severe dysplastic tissue. The epithelial (Epcam+/Ck+) and the fibroblast cell lines (Vimentin+/α‐SMA+/Ck‐) were authenticated and assessment of cells representing progressive grades of dysplastic severity indicated a significant increase in dysplastic marker profile (P < 0.05). Evaluation of the CSC characteristics showed that an increase in expression of Cd133, Cd44, Aldh1a1, Notch1, and Sox2 was accompanied by an increase in migratory (P > 0.05) and colony formation capacity (P > 0.005). Targeting Notch1 (GSI inhibitor PZ0187; 30 μM), showed a significant reduction in cell proliferation capacity (P < 0.05) and in the dysplastic marker profile. Further, Notch1 inhibition resulted in down regulation of Cd133 and Aldh1a 1 (P < 0.05) and a complete abrogation of colony formation ability (P < 0.0001). The effect of niche interactions evaluated using FibroMSCTR12‐conditioned media studies, revealed an enrichment of ALDH1A1+ cells (P < 0.05), induction of spheroid formation ability (P < 0.0001) and increased proliferation capacity (3.7 fold; P < 0.005). Although PZ0187 reduced cell viability by ∼40%, was unable to abrogate the conditioned‐media induced increase in proliferation capacity completely. This study reports a Notch‐1 dependent enrichment of CSC properties during dysplastic progression and a Notch‐1 independent dysplastic cell‐fibroblast interaction during oral carcinogenesis.

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Prognostic significance of CD44 variant 2 upregulation in colorectal cancer

Cited by 52 publications

References 30 publications

Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target

Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target

SALL4 ‐ KHDRBS3 network enhances stemness by modulating CD44 splicing in basal‐like breast cancer

Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

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