Podoplanin: An emerging cancer biomarker and therapeutic target

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Abstract

Podoplanin ( PDPN) is a transmembrane receptor glycoprotein that is upregulated on transformed cells, cancer associated fibroblasts and inflammatory macrophages that contribute to cancer progression. In particular, PDPN increases tumor cell clonal capacity, epithelial mesenchymal transition, migration, invasion, metastasis and inflammation. Antibodies, CAR‐T cells, biologics and synthetic compounds that target PDPN can inhibit cancer progression and septic inflammation in preclinical models. This review describes recent advances in how PDPN may be used as a biomarker and therapeutic target for many types of cancer, including glioma, squamous cell carcinoma, mesothelioma and melanoma.

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Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells.

Yukinari Kato, Yutaka Yatomi, Katsue Suzuki-Inoue … (2007)

Podoplanin (aggrus), a transmembrane sialoglycoprotein, is involved in tumor cell-induced platelet aggregation, tumor metastasis, and lymphatic vessel formation. However, the mechanism by which podoplanin induces these cellular processes including its receptor has not been elucidated to date. Podoplanin induced platelet aggregation with a long lag phase, which is dependent upon Src and phospholipase Cgamma2 activation. However, it does not bind to glycoprotein VI. This mode of platelet activation was reminiscent of the snake toxin rhodocytin, the receptor of which has been identified by us as a novel platelet activation receptor, C-type lectin-like receptor 2 (CLEC-2) (Suzuki-Inoue, K., Fuller, G. L., Garcia, A., Eble, J. A., Pohlmann, S., Inoue, O., Gartner, T. K., Hughan, S. C., Pearce, A. C., Laing, G. D., Theakston, R. D., Schweighoffer, E., Zitzmann, N., Morita, T., Tybulewicz, V. L., Ozaki, Y., and Watson, S. P. (2006) Blood 107, 542-549). Therefore, we sought to evaluate whether CLEC-2 serves as a physiological counterpart for podoplanin. Association between CLEC-2 and podoplanin was confirmed by flow cytometry. Furthermore, their association was dependent on sialic acid on O-glycans of podoplanin. Recombinant CLEC-2 inhibited platelet aggregation induced by podoplanin-expressing tumor cells or lymphatic endothelial cells, suggesting that CLEC-2 is responsible for platelet aggregation induced by endogenously expressed podoplanin on the cell surfaces. These findings suggest that CLEC-2 is a physiological target protein of podoplanin and imply that it is involved in podoplanin-induced platelet aggregation, tumor metastasis, and other cellular responses related to podoplanin.

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Podoplanin: emerging functions in development, the immune system, and cancer

Jillian L. Astarita, Sophie E. Acton, Shannon Turley (2012)

Podoplanin (PDPN) is a well-conserved, mucin-type transmembrane protein expressed in multiple tissues during ontogeny and in adult animals, including the brain, heart, kidney, lungs, osteoblasts, and lymphoid organs. Studies of PDPN-deficient mice have demonstrated that this molecule plays a critical role in development of the heart, lungs, and lymphatic system. PDPN is widely used as a marker for lymphatic endothelial cells and fibroblastic reticular cells of lymphoid organs and for lymphatics in the skin and tumor microenvironment. Much of the mechanistic insight into PDPN biology has been gleaned from studies of tumor cells; tumor cells often upregulate PDPN as they undergo epithelial-mesenchymal transition and this upregulation is correlated with increased motility and metastasis. The physiological role of PDPN that has been most studied is its ability to aggregate and activate CLEC-2-expressing platelets, as PDPN is the only known endogenous ligand for CLEC-2. However, more recent studies have revealed that PDPN also plays crucial roles in the biology of immune cells, including T cells and dendritic cells. This review will provide a comprehensive overview of the diverse roles of PDPN in development, immunology, and cancer.

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Podoplanin binds ERM proteins to activate RhoA and promote epithelial-mesenchymal transition.

Miguel Quintanilla, María Yurrita, Ester Martin-Villar … (2006)

Podoplanin is a small membrane mucin expressed in tumors associated with malignant progression. It is enriched at cell-surface protrusions where it colocalizes with members of the ERM (ezrin, radixin, moesin) protein family. Here, we found that human podoplanin directly interacts with ezrin (and moesin) in vitro and in vivo through a cluster of basic amino acids within its cytoplasmic tail, mainly through a juxtamembrane dipeptide RK. Podoplanin induced an epithelial-mesenchymal transition in MDCK cells linked to the activation of RhoA and increased cell migration and invasiveness. Fluorescence time-lapse video observations in migrating cells indicate that podoplanin might be involved in ruffling activity as well as in retractive processes. By using mutant podoplanin constructs fused to green fluorescent protein we show that association of the cytoplasmic tail with ERM proteins is required for upregulation of RhoA activity and epithelial-mesenchymal transition. Furthermore, expression of either a dominant-negative truncated variant of ezrin or a dominant-negative mutant form of RhoA blocked podoplanin-induced RhoA activation and epithelial-mesenchymal transition. These results provide a mechanistic basis to understand the role of podoplanin in cell migration or invasiveness.

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Author and article information

Contributors

Atsushi Natsume:

ORCID: http://orcid.org/0000-0002-9113-0470

anatsume@med.nagoya-u.ac.jp

Gary S. Goldberg:

ORCID: http://orcid.org/0000-0001-5906-4111

gary.goldberg@rowan.edu

Journal

Journal ID (nlm-ta): Cancer Sci

Journal ID (iso-abbrev): Cancer Sci

Journal ID (doi): 10.1111/(ISSN)1349-7006

Journal ID (publisher-id): CAS

Title: Cancer Science

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 1347-9032

ISSN (Electronic): 1349-7006

Publication date (Print): May 2018

Volume: 109

Issue: 5 ( doiID: 10.1111/cas.2018.109.issue-5 )

Pages: 1292-1299

Affiliations

[ ¹ ] Department of Physiology and Biophysics Stony Brook University Stony Brook NY USA

[ ² ] Institute of Cardiovascular Science College of Medical and Dental Sciences University of Birmingham Edgbaston Birmingham UK

[ ³ ] Division of Pathology Exploratory Oncology Research and Clinical Trial Center National Cancer Center Kashiwa Chiba Japan

[ ⁴ ] Laboratory of Cancer Biology Department of Integrated Biosciences Graduate School of Frontier Sciences The University of Tokyo Kashiwa Chiba Japan

[ ⁵ ] Graduate School of Biomedical Sciences and Department of Molecular Biology Rowan University School of Osteopathic Medicine Stratford NJ USA

[ ⁶ ] Division of Experimental Chemotherapy The Cancer Chemotherapy Center Japanese Foundation for Cancer Research Tokyo Japan

[ ⁷ ] Graduate Institute of Biomedical Sciences College of Medicine Chang Gung University Taoyuan Taiwan China

[ ⁸ ] Second Department of Surgery (Chest Surgery) University of Occupational and Environmental health Kitakyushu Fukuoka Japan

[ ⁹ ] Department of Dermatology Kyoto Prefectural University of Medicine Graduate School of Medical Science Kyoto Japan

[ ¹⁰ ] Division of Cardiovascular Medicine Department of Medical and Health Sciences Linköping University Linköping Sweden

[ ¹¹ ] Department of Neurosurgery Nagoya University School of Medicine Nagoya Japan

Author notes

[*] [* ] Correspondence

Gary S. Goldberg, Molecular Biology, Rowan University, Stratford, NJ, USA.

Email: gary.goldberg@ 123456rowan.edu

and

Atsushi Natsume, Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.

Email: anatsume@ 123456med.nagoya-u.ac.jp

Author information

Atsushi Natsume http://orcid.org/0000-0002-9113-0470

Gary S. Goldberg http://orcid.org/0000-0001-5906-4111

Article

Publisher ID: CAS13580

DOI: 10.1111/cas.13580

PMC ID: 5980289

PubMed ID: 29575529

SO-VID: 720f32b2-1d39-4bd0-9b15-0eb0ca5108e7

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 10 January 2018

Date revision received : 02 March 2018

Date accepted : 10 March 2018

Page count

Figures: 4, Tables: 0, Pages: 8, Words: 5762

Funding

Funded by: JSPS KAKENHI

Award ID: 16H05311

Award ID: 24659185

Award ID: 25461674

Award ID: 2617H06356

Funded by: Proteintech

Funded by: Fox Rothschild

Funded by: VWR

Funded by: Sentrimed

Funded by: Rowan University

Funded by: Osteopathic Heritage Foundation and New Jersey Health Foundation

Funded by: National Cancer Center Research and Development Fund

Award ID: 23‐A‐12

Funded by: Foundation for the Promotion of Cancer Research

Funded by: 3rd Term Comprehensive 10‐Year Strategy for Cancer Control

Funded by: Advanced Research for Medical Products Mining Programme of the National Institute of Biomedical Innovation (NIBIO)

Funded by: Project for Cancer Research and Therapeutic Evolution

Award ID: 17cm0106205 h0002

Funded by: Medical Research and Development Programs Focused on Technology Transfer

Funded by: Acceleration Transformative Research for Medical Innovation

Award ID: 17im0210607 h0002

Funded by: Japan Agency for Medical Research and Development

Funded by: Grant‐in‐Aid for Scientific Research on Innovative Areas “Chemistry for Multimolecular Crowding Biosystems”

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source-schema-version-number 2.0

component-id cas13580

cover-date May 2018

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.0 mode:remove_FC converted:31.05.2018

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cancer,chemotherapy,c‐type lectin‐like receptor 2,podoplanin

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cancer, chemotherapy, c‐type lectin‐like receptor 2, podoplanin

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Podoplanin: An emerging cancer biomarker and therapeutic target

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Karger: Oncology

Most cited references 58

Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells.

Podoplanin: emerging functions in development, the immune system, and cancer

Podoplanin binds ERM proteins to activate RhoA and promote epithelial-mesenchymal transition.

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Cited by 72

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