High expression of Nectin-4 is associated with unfavorable prognosis in gastric cancer

Zhang, Yan; Zhang, Jiaxuan; Shen, Qin; Yin, Wei Hsian; Huang, Hua; Liu, Yifei; Ni, Qingfeng

doi:10.3892/ol.2018.8365

Cited by 34 publications

(37 citation statements)

References 40 publications

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“…The NECTIN family comprises Ca 2+ -independent immunoglobulin-like cell adhesion molecules and includes four members (NECTIN1-4) [22,23]. They are involved in several functional processes, including cell adhesion, movement, proliferation, differentiation, and polarization [17,18]. Nectin cell adhesion molecule 4, also known as poliovirus receptor-related protein 4, is involved in the formation and maintenance of adherens junctions in cooperation with cadherins, and it is also a receptor for measles virus, mediating its endocytosis [24,25].…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, nectin cell adhesion molecule 4 (NECTIN4) has been identified as an important factor in several malignant tumors, including urothelial carcinoma, gastric cancer, thyroid cancer, breast cancer, esophageal cancer, and ovarian cancer [15][16][17][18][19][20][21]. Nectin cell adhesion molecule 4 is a member of the NECTIN family of immunoglobulin-like adhesion molecules [22,23].…”

Section: Introductionmentioning

confidence: 99%

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NECTIN4 Expression in Extramammary Paget’s Disease: Implication of a New Therapeutic Target

Murata

Ito

Tanaka

et al. 2020

IJMS

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Extramammary Paget’s disease (EMPD) is a rare skin cancer arising in the anogenital area. Most EMPD tumors remain dormant as in situ lesions, but the outcomes of patients with metastatic EMPD are poor because of the lack of effective systemic therapies. Nectin cell adhesion molecule 4 (NECTIN4) has attracted attention as a potential therapeutic target for some cancers. Urothelial cancer is one such cancer, and clinical trials of enfortumab vedotin, a drug-conjugated anti-NECTIN4 antibody, are ongoing. However, little is known regarding the role of NECTIN4 in EMPD. In this study, we conducted immunohistochemical analysis of NECTIN4 expression in 110 clinical EMPD samples and normal skin tissue. In normal skin, positive signals were observed in epidermal keratinocytes (particularly in the lower part of the epidermis), eccrine and apocrine sweat glands, inner and outer root sheaths, and matrix of the hair follicles. The most EMPD lesions exhibited strong NECTIN4 expression, and high NECTIN4 expression was significantly associated with increased tumor thickness, advanced TNM stage, and worse disease-specific survival. These results support the potential use of NECTIN4-targeted therapy for EMPD. Our report contributes to the better understanding of the pathobiology of NECTIN4 in the skin and the skin-related adverse effects of NECTIN4-targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NECTIN4 Expression in Extramammary Paget’s Disease: Implication of a New Therapeutic Target

Murata

Ito

Tanaka

et al. 2020

IJMS

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“…The latter study was carried out by using the same polyclonal antibody applied in the present investigation. In several human cancers, Nectin immunostaining has been described as predominantly cytoplasmic or both membranous and cytoplasmic, although the significance of this different distribution is still debated. M‐Nectin‐4 expression was significantly associated with a lower metastasis‐free survival rate in breast cancer patients with luminal‐A (oestrogen receptor‐positive [ER+], and/or progesterone receptor‐positive [PR+], human epidermal growth factor receptor 2 [HER−]) tumours, whereas high c‐Nectin‐4 expression was significantly associated with higher rates of disease‐free survival and local relapse‐free survival.…”

Section: Discussionmentioning

confidence: 99%

“…The latter study was carried out by using the same polyclonal antibody applied in the present investigation. In several human cancers, 29 Nectin immunostaining has been described as predominantly cytoplasmic or both membranous and cytoplasmic, 30 Abbreviation: PC, prostatic carcinoma. Nectin 4 expression was classified as membranous (localized at cell-cell boundaries) or cytoplasmic (uniformly distributed throughout the cytoplasm).…”

Section: Discussionmentioning

confidence: 99%

Nectin‐4 and p63 immunohistochemical expression in canine prostate tumourigenesis

Salda

Massimini

Romanucci

et al. 2019

Vet Comparative Oncology

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Nectin‐4 is an E‐cadherin‐based adherens junction protein of normal epithelial cells, as well as a potent mediator of anchorage‐independent cancer colony formation. It is considered a tumour‐associated histological and serological marker in various human cancers. The transcription factor p63 is a basal cell marker in the normal prostate, involved in cell adhesion, as well as in the formation and survival of circulating tumour cell clusters. The aim of this study was to evaluate Nectin‐4 and p63 immunohistochemical expression in 42 canine prostate tissues including 2 normal prostates, 10 benign prostatic hyperplasias (BPHs), 30 prostatic carcinomas (PCs), 1 pulmonary and 1 lymph node metastasis. From normal to neoplastic tissues, Nectin‐4 showed a progressive switching from membranous (m‐Nectin‐4) to cytoplasmic (c‐Nectin‐4), regardless of the histological subtypes, except for lack of expression in solid PCs. Metastatic cells exhibited both strong membranous and cytoplasmic positivity. c‐Nectin‐4 expression was significantly (P < 0.0001) increased in PCs/metastasis compared to BPHs cases and a decrease (P < 0.05) of nuclear p63 immunostaining was also detected in the two groups. Furthermore, data showed a significant association (P < 0.05) between p63 and m‐Nectin‐4 distribution, although their colocalization was detected only in scattered cells by double immunofluorescence. Our results suggest the involvement of m‐Nectin‐4 in canine prostate tumourigenesis and metastatic potential, while the exact role of c‐Nectin‐4 expression detectable in primary PCs requires further investigations.

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“…Finally, we show that high expression of Nectin4 is associated with poor overall survival in cancer patients ( figure 7E) and marks a poorer overall prognosis in several cancer types. 18 Therefore, further investigation of our antibody as a drug for these patients is of great clinical value.…”

Section: Open Accessmentioning

confidence: 99%

Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity

Reches¹,

Ophir²,

Stein³

et al. 2020

J Immunother Cancer

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BackgroundThe use of checkpoint inhibitors has revolutionized cancer therapy. Unfortunately, these therapies often cause immune-related adverse effects, largely due to a lack of tumor specificity.MethodsWe stained human natural killer cells using fusion proteins composed of the extracellular portion of various tumor markers fused to the Fc portion of human IgG1, and identified Nectin4 as a novel TIGIT ligand. Next, we generated a novel Nectin4 blocking antibody and demonstrated its efficacy as a checkpoint inhibitor in killing assays and in vivo.ResultsWe identify Nectin4 to be a novel ligand of TIGIT. We showed that, as opposed to all other known TIGIT ligands, which bind also additional receptors, Nectin4 interacts only with TIGIT. We show that the TIGIT-Nectin4 interaction inhibits natural killer cell activity, a critical part of the innate immune response. Finally, we developed blocking Nectin4 antibodies and demonstrated that they enhance tumor killing in vitro and in vivo.ConclusionWe discovered that Nectin4 is a novel ligand for TIGIT and demonstrated that specific antibodies against it enhance tumor cell killing in vitro and in vivo. Since Nectin4 is expressed almost exclusively on tumor cells, our Nectin4-blocking antibodies represent a combination of cancer specificity and immune checkpoint activity, which may prove more effective and safe for cancer immunotherapy.

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High expression of Nectin-4 is associated with unfavorable prognosis in gastric cancer

Cited by 34 publications

References 40 publications

NECTIN4 Expression in Extramammary Paget’s Disease: Implication of a New Therapeutic Target

NECTIN4 Expression in Extramammary Paget’s Disease: Implication of a New Therapeutic Target

Nectin‐4 and p63 immunohistochemical expression in canine prostate tumourigenesis

Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity

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