Special Issue "Structure and Function of Podoplanin (PDPN) in Disease"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (30 September 2020).

Special Issue Editor

Prof. Yukinari Kato
Website
Guest Editor
Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2‐1 Seiryo‐machi, Aoba‐ku, Sendai, Miyagi 980‐8575, Japan
Interests: monoclonal antibody (mAb); antibody therapy; podoplanin (PDPN); cancer-specific mAb (CasMab); anti-glycopeptide mAb (GpMab); cell-based immunization and screening (CBIS)

Special Issue Information

Dear Colleagues,

Podoplanin (PDPN), also known as T1alpha or Aggrus, is a type I transmembrane sialoglycoprotein that is expressed not only in normal tissues, such as pulmonary type I alveolar cells, renal podocytes, and lymphatic endothelial cells, but also in cancer tissues, including brain tumor, malignant mesothelioma, oral cancer, and lung cancer. PDPN is associated with tumor cell-induced platelet aggregation and hematogenous metastasis through interactions with the C-type lectin-like receptor 2 (CLEC-2). Recent clinical studies have shown the association between increased PDPN expression and poor disease prognosis, indicating that the establishment of anti-PDPN mAbs is critical for developing novel therapeutic strategies against cancer development and metastatic progression. This Special Issue of Cells should improve our understanding of PDPN by including researchers working not only with structure and function of PDPN but also diagnosis and therapy targeting PDPN, including antibody-drug conjugate (ADC), chimeric antigen receptor-T (CAR-T) therapy, radioimmunotherapy (RIT), photoimmunotherapy (PIT), and liquid biopsy.

Prof. Yukinari Kato
Guest Editor

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Keywords

  • podoplanin (PDPN)
  • platelet aggregation
  • antibody
  • cancer

Published Papers (7 papers)

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Research

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Open AccessArticle
Phase I/II Clinical Trial of the Anti-Podoplanin Monoclonal Antibody Therapy in Dogs with Malignant Melanoma
Cells 2020, 9(11), 2529; https://doi.org/10.3390/cells9112529 - 23 Nov 2020
Viewed by 659
Abstract
Podoplanin (PDPN), a small transmembrane mucin-like glycoprotein, is ectopically expressed on tumor cells. PDPN is known to be linked with several aspects of tumor malignancies in certain types of human and canine tumors. Therefore, it is considered to be a novel therapeutic target. [...] Read more.
Podoplanin (PDPN), a small transmembrane mucin-like glycoprotein, is ectopically expressed on tumor cells. PDPN is known to be linked with several aspects of tumor malignancies in certain types of human and canine tumors. Therefore, it is considered to be a novel therapeutic target. Monoclonal antibodies targeting PDPN expressed in human tumor cells showed obvious anti-tumor effects in preclinical studies using mouse models. Previously, we generated a cancer-specific mouse–dog chimeric anti-PDPN antibody, P38Bf, which specifically recognizes PDPN expressed in canine tumor cells. In this study, we investigated the safety and anti-tumor effects of P38Bf in preclinical and clinical trials. P38Bf showed dose-dependent antibody-dependent cellular cytotoxicity against canine malignant melanoma cells. In a preclinical trial with one healthy dog, P38Bf administration did not induce adverse effects over approximately 2 months. In phase I/II clinical trials of three dogs with malignant melanoma, one dog vomited, and all dogs had increased serum levels of C-reactive protein, although all adverse effects were grade 1 or 2. Severe adverse effects leading to withdrawal of the clinical trial were not observed. Furthermore, one dog had stable disease with P38Bf injections. This is the first reported clinical trial of anti-PDPN antibody therapy using spontaneously occurring canine tumor models. Full article
(This article belongs to the Special Issue Structure and Function of Podoplanin (PDPN) in Disease)
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Open AccessFeature PaperArticle
Interplay between Podoplanin, CD44s and CD44v in Squamous Carcinoma Cells
Cells 2020, 9(10), 2200; https://doi.org/10.3390/cells9102200 - 29 Sep 2020
Viewed by 651
Abstract
Podoplanin and CD44 are transmembrane glycoproteins involved in inflammation and cancer. In this paper, we report that podoplanin is coordinately expressed with the CD44 standard (CD44s) and variant (CD44v) isoforms in vivo—in hyperplastic skin after a pro-inflammatory stimulus with 12-O-tetradecanoylphorbol-13-acetate (TPA)—and [...] Read more.
Podoplanin and CD44 are transmembrane glycoproteins involved in inflammation and cancer. In this paper, we report that podoplanin is coordinately expressed with the CD44 standard (CD44s) and variant (CD44v) isoforms in vivo—in hyperplastic skin after a pro-inflammatory stimulus with 12-O-tetradecanoylphorbol-13-acetate (TPA)—and in vitro—in cell lines representative of different stages of mouse-skin chemical carcinogenesis, as well as in human squamous carcinoma cell (SCC) lines. Moreover, we identify CD44v10 in the mouse-skin carcinogenesis model as the only CD44 variant isoform expressed in highly aggressive spindle carcinoma cell lines together with CD44s and podoplanin. We also characterized CD44v3-10, CD44v6-10 and CD44v8-10 as the major variant isoforms co-expressed with CD44s and podoplanin in human SCC cell lines. Immunofluorescence confocal microscopy experiments show that these CD44v isoforms colocalize with podoplanin at plasma membrane protrusions and cell–cell contacts of SCC cells, as previously reported for CD44s. Furthermore, CD44v isoforms colocalize with podoplanin in chemically induced mouse-skin SCCs in vivo. Co-immunoprecipitation experiments indicate that podoplanin physically binds to CD44v3-10, CD44v6-10 and CD44v8-10 isoforms, as well as to CD44s. Podoplanin–CD44 interaction is mediated by the transmembrane and cytosolic regions and is negatively modulated by glycosylation of the extracellular domain. These results point to a functional interplay of podoplanin with both CD44v and CD44s isoforms in SCCs and give insight into the regulation of the podoplanin–CD44 association. Full article
(This article belongs to the Special Issue Structure and Function of Podoplanin (PDPN) in Disease)
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Open AccessFeature PaperArticle
Keratinocyte-Expressed Podoplanin is Dispensable for Multi-Step Skin Carcinogenesis
Cells 2020, 9(6), 1542; https://doi.org/10.3390/cells9061542 - 24 Jun 2020
Viewed by 676
Abstract
Podoplanin is a small transmembrane mucin-like glycoprotein that plays a crucial role in the development of the lung, heart and lymphatic vascular system. Its expression is upregulated in several types of human carcinomas and podoplanin levels in squamous cell carcinomas (SCCs) of the [...] Read more.
Podoplanin is a small transmembrane mucin-like glycoprotein that plays a crucial role in the development of the lung, heart and lymphatic vascular system. Its expression is upregulated in several types of human carcinomas and podoplanin levels in squamous cell carcinomas (SCCs) of the oral cavity and the lung correlate with cancer invasiveness, lymph node metastasis and shorter survival time of patients, indicating that podoplanin promotes tumor progression. However, its role during the early stages of carcinogenesis remain unclear. We generated mice with a specific deletion of podoplanin in epidermal keratinocytes (K5-Cre;Pdpnflox/flox mice) and subjected them to a multistep chemical skin carcinogenesis regimen. The rate of tumor initiation; the number, size and differentiation of tumors; and the malignant transformation rate were comparable in K5-Cre;Pdpnflox/flox mice and Pdpnflox/flox control mice. However, tumor cell invasion was reduced in K5-Cre;Pdpnflox/flox mice, in particular single cell invasion. Quantitative immunofluorescence analyses revealed that peritumoral lymphangiogenesis was reduced in K5-Cre;Pdpnflox/flox mice, whereas there were no major changes of tumor-associated immune cell subpopulations. Thus, keratinocyte-expressed podoplanin is dispensable for the early steps of skin carcinogenesis but contributes to the progression of established tumors. Full article
(This article belongs to the Special Issue Structure and Function of Podoplanin (PDPN) in Disease)
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Open AccessArticle
PDPN Is Expressed in Various Types of Canine Tumors and Its Silencing Induces Apoptosis and Cell Cycle Arrest in Canine Malignant Melanoma
Cells 2020, 9(5), 1136; https://doi.org/10.3390/cells9051136 - 05 May 2020
Cited by 2 | Viewed by 1348
Abstract
Podoplanin (PDPN), a small transmembrane mucin-like glycoprotein, is ectopically expressed. It is also known to be linked with several aspects of tumor malignancy in some types of human tumors, including invasion, metastasis, and cancer stemness. However, there are few reports on the expression [...] Read more.
Podoplanin (PDPN), a small transmembrane mucin-like glycoprotein, is ectopically expressed. It is also known to be linked with several aspects of tumor malignancy in some types of human tumors, including invasion, metastasis, and cancer stemness. However, there are few reports on the expression of dog PDPN (dPDPN) in canine tumors, and the association between dPDPN and tumor malignancy has not been elucidated. We identified that 11 out of 18 types of canine tumors expressed dPDPN. Furthermore, 80% of canine malignant melanoma (MM), squamous cell carcinoma, and meningioma expressed dPDPN. Moreover, the expression density of dPDPN was positively associated with the expression of the Ki67 proliferation marker. The silencing of dPDPN by siRNAs resulted in the suppression of cell migration, invasion, stem cell-like characteristics, and cell viability in canine MM cell lines. The suppression of cell viability was caused by the induction of apoptosis and G2/M phase cell cycle arrest. Overall, this study demonstrates that dPDPN is expressed in various types of canine tumors and that dPDPN silencing suppresses cell viability through apoptosis and cell cycle arrest, thus providing a novel biological role for PDPN in tumor progression. Full article
(This article belongs to the Special Issue Structure and Function of Podoplanin (PDPN) in Disease)
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Open AccessArticle
Targeted Phototherapy for Malignant Pleural Mesothelioma: Near-Infrared Photoimmunotherapy Targeting Podoplanin
Cells 2020, 9(4), 1019; https://doi.org/10.3390/cells9041019 - 20 Apr 2020
Cited by 4 | Viewed by 2772
Abstract
Malignant pleural mesothelioma (MPM) has extremely limited treatment despite a poor prognosis. Moreover, molecular targeted therapy for MPM has not yet been implemented; thus, a new targeted therapy is highly desirable. Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed cancer therapy that combines the [...] Read more.
Malignant pleural mesothelioma (MPM) has extremely limited treatment despite a poor prognosis. Moreover, molecular targeted therapy for MPM has not yet been implemented; thus, a new targeted therapy is highly desirable. Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed cancer therapy that combines the specificity of antibodies for targeting tumors with toxicity induced by the photoabsorber after exposure to NIR-light. In this study, we developed a new phototherapy targeting podoplanin (PDPN) for MPM with the use of both NIR-PIT and an anti-PDPN antibody, NZ-1. An antibody–photosensitizer conjugate consisting of NZ-1 and phthalocyanine dye was synthesized. In vitro NIR-PIT-induced cytotoxicity was measured with both dead cell staining and luciferase activity on various MPM cell lines. In vivo NIR-PIT was examined in both the flank tumor and orthotopic mouse model with in vivo real-time imaging. In vitro NIR-PIT-induced cytotoxicity was NIR-light dose dependent. In vivo NIR-PIT led to significant reduction in both tumor volume and luciferase activity in a flank model (p < 0.05, NIR-PIT group versus NZ-1-IR700 group). The PDPN-targeted NIR-PIT resulted in a significant antitumor effect in an MPM orthotopic mouse model (p < 0.05, NIR-PIT group versus NZ-1-IR700 group). This study suggests that PDPN-targeted NIR-PIT could be a new promising treatment for MPM. Full article
(This article belongs to the Special Issue Structure and Function of Podoplanin (PDPN) in Disease)
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Open AccessArticle
Detection of Circulating Tumor Cells (CTCs) in Malignant Pleural Mesothelioma (MPM) with the “Universal” CTC-Chip and An Anti-Podoplanin Antibody NZ-1.2
Cells 2020, 9(4), 888; https://doi.org/10.3390/cells9040888 - 05 Apr 2020
Cited by 1 | Viewed by 977
Abstract
Circulating tumor cell (CTC) is a potentially useful surrogate of micro-metastasis, but detection of rare tumor cells contaminated in a vast majority of normal hematologic cells remains technical challenges. To achieve effective detection of a variety of CTCs, we have developed a novel [...] Read more.
Circulating tumor cell (CTC) is a potentially useful surrogate of micro-metastasis, but detection of rare tumor cells contaminated in a vast majority of normal hematologic cells remains technical challenges. To achieve effective detection of a variety of CTCs, we have developed a novel microfluidic system (CTC-chip) in which any antibody to capture CTCs is easily conjugated. In previous studies, we employed an antibody (clone E-1) against podoplanin that was strongly expressed on mesothelioma cells. The CTC-chip coated by the E-1 antibody (E1-chip) provided a modest sensitivity in detection of CTCs in malignant pleural mesothelioma (MPM). Here, to achieve a higher sensitivity, we employed a novel anti-podoplanin antibody (clone NZ-1.2). In an experimental model, MPM cells with high podoplanin expression were effectively captured with the CTC-chip coated by the NZ-1.2 antibody (NZ1.2-chip). Next, we evaluated CTCs in the peripheral blood sampled from 22 MPM patients using the NZ1.2-chip and the E1-chip. One or more CTCs were detected in 15 patients (68.2%) with the NZ1.2-chip, whereas only in 10 patients (45.5%) with the E1-chip. Of noted, in most (92.3%, 12/13) patients with epithelioid MPM subtype, CTCs were positive with the NZ1.2-chip. The CTC-count detected with the NZ1.2-chip was significantly higher than that with the E1-chip (p = 0.034). The clinical implications of CTCs detected with the NZ1.2-chip will be examined in a future study. Full article
(This article belongs to the Special Issue Structure and Function of Podoplanin (PDPN) in Disease)
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Review

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Open AccessReview
Podoplanin as an Attractive Target of CAR T Cell Therapy
Cells 2020, 9(9), 1971; https://doi.org/10.3390/cells9091971 - 26 Aug 2020
Viewed by 669
Abstract
To date, various kinds of cancer immunotherapy methods have been developed, but T cell immunotherapy is one of the most promising strategies. In general, T cell receptor (TCR) or chimeric antigen receptor (CAR) is used to modify the antigen specificity of T cells. [...] Read more.
To date, various kinds of cancer immunotherapy methods have been developed, but T cell immunotherapy is one of the most promising strategies. In general, T cell receptor (TCR) or chimeric antigen receptor (CAR) is used to modify the antigen specificity of T cells. CARs possess an underlying potential with treatment efficacy to treat a broad range of cancer patients compared with TCRs. Although a variety of CAR molecules have been developed so far, the clinical application for solid tumors is limited partly due to its adverse effect known as “on-target off-tumor toxicity”. Therefore, it is very important for CAR T cell therapy to target specific antigens exclusively expressed by malignant cells. Here, we review the application of T cell immunotherapy using specific antigen receptor molecules and discuss the possibility of the clinical application of podoplanin-targeted CAR derived from a cancer-specific monoclonal antibody (CasMab). Full article
(This article belongs to the Special Issue Structure and Function of Podoplanin (PDPN) in Disease)
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