The biology and role of CD44 in cancer progression: therapeutic implications

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Abstract

CD44, a non-kinase transmembrane glycoprotein, is overexpressed in several cell types including cancer stem cells and frequently shows alternative spliced variants that are thought to play a role in cancer development and progression. Hyaluronan, the main ligand for CD44, binds to and activates CD44 resulting in activation of cell signaling pathways that induces cell proliferation, increases cell survival, modulates cytoskeletal changes, and enhances cellular motility. The different functional roles of CD44 standard (CD44s) and specific CD44 variant (CD44v) isoforms are not fully understood. CD44v contain additional peptide motifs that can interact with and sequester growth factors and cytokines at the cell surface thereby functioning as coreceptors to facilitate cell signaling. Moreover, CD44v were expressed in metastasized tumors, whereas switching between CD44v and CD44s may play a role in regulating epithelial to mesenchymal transition (EMT) and in the adaptive plasticity of cancer cells. Here, we review current data on the structural and functional properties of CD44, the known roles for CD44 in tumorigencity, the regulation of CD44 expression, and the potential for targeting CD44 for cancer therapy.

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CD44: from adhesion molecules to signalling regulators.

Helmut Ponta, Larry Sherman, Peter A Herrlich (2003)

Cell-adhesion molecules, once believed to function primarily in tethering cells to extracellular ligands, are now recognized as having broader functions in cellular signalling cascades. The CD44 transmembrane glycoprotein family adds new aspects to these roles by participating in signal-transduction processes--not only by establishing specific transmembrane complexes, but also by organizing signalling cascades through association with the actin cytoskeleton. CD44 and its associated partner proteins monitor changes in the extracellular matrix that influence cell growth, survival and differentiation.

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CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis.

Matilde Todaro, Miriam Gaggianesi, Veronica Catalano … (2014)

Cancer stem cells drive tumor formation and metastasis, but how they acquire metastatic traits is not well understood. Here, we show that all colorectal cancer stem cells (CR-CSCs) express CD44v6, which is required for their migration and generation of metastatic tumors. CD44v6 expression is low in primary tumors but demarcated clonogenic CR-CSC populations. Cytokines hepatocyte growth factor (HGF), osteopontin (OPN), and stromal-derived factor 1α (SDF-1), secreted from tumor associated cells, increase CD44v6 expression in CR-CSCs by activating the Wnt/β-catenin pathway, which promotes migration and metastasis. CD44v6(-) progenitor cells do not give rise to metastatic lesions but, when treated with cytokines, acquire CD44v6 expression and metastatic capacity. Importantly, phosphatidylinositol 3-kinase (PI3K) inhibition selectively killed CD44v6 CR-CSCs and reduced metastatic growth. In patient cohorts, low levels of CD44v6 predict increased probability of survival. Thus, the metastatic process in colorectal cancer is initiated by CSCs through the expression of CD44v6, which is both a functional biomarker and therapeutic target. Copyright © 2014 Elsevier Inc. All rights reserved.

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Is Open Access

MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells

Qing Ji, Xinbao Hao, Min Zhang … (2009)

Background MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34 family members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are Notch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer stem cells. Methodology/Principal Findings We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines MiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2 and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and G2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+ MiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumor-initiating cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo. Conclusions/Significance Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch, implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination. Restoration of miR-34 may hold significant promise as a novel molecular therapy for human pancreatic cancer with loss of p53–miR34, potentially via inhibiting pancreatic cancer stem cells.

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Author and article information

Contributors

Chen Chen: chenc3@livemail.uthscsa.edu

Shujie Zhao: zhaos@uthscsa.edu

Anand Karnad: karnad@uthscsa.edu

James W. Freeman: freemanjw@uthscsa.edu

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 10 May 2018

Publication date PMC-release: 10 May 2018

Publication date Collection: 2018

Volume: 11

Electronic Location Identifier: 64

Affiliations

[1 ]ISNI 0000 0001 0629 5880, GRID grid.267309.9, Department of Cell Systems & Atanomy, , University of Texas Health Science Center at San Antonio, ; San Antonio, TX USA

[2 ]ISNI 0000 0001 0629 5880, GRID grid.267309.9, Department of Medicine, Division of Hematology and Oncology, , University of Texas Health Science Center at San Antonio, ; San Antonio, TX USA

[3 ]ISNI 0000 0004 0617 9080, GRID grid.414059.d, Research and Development, , Audie Murphy Veterans Administration Hospital, ; San Antonio, TX USA

[4 ]Mays Cancer Center, Experimental and Developmental Therapeutics Program, 7979 Wurzbach Rd, San Antonio, TX 78229 USA

Article

Publisher ID: 605

DOI: 10.1186/s13045-018-0605-5

PMC ID: 5946470

PubMed ID: 29747682

SO-VID: 9401787d-2df3-43a5-b3bc-5e8e3a09f320

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 20 March 2018

Date accepted : 26 April 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;

Award ID: P30CA054174

Award Recipient : James W. Freeman

Funded by: FundRef http://dx.doi.org/10.13039/100000738, U.S. Department of Veterans Affairs;

Award ID: 510BX002962

Award Recipient : James W. Freeman

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cd44,cancer,signaling transduction,tumorigenicity,epithelial to mesenchymal transition (emt),cancer therapy

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cd44, cancer, signaling transduction, tumorigenicity, epithelial to mesenchymal transition (emt), cancer therapy

The biology and role of CD44 in cancer progression: therapeutic implications

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Karger: Oncology

Most cited references 168

CD44: from adhesion molecules to signalling regulators.

CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis.

MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells

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