Nectin-1 expression in cancer-associated fibroblasts is a predictor of poor prognosis for pancreatic ductal adenocarcinoma

Yamada, Misuzu; Hirabayashi, Kenichi; Kawanishi, Aya; Hadano, Atsuko; Takanashi, Yoshinori; Hayashi, Izumi; Kawaguchi, Yoshindo; Mine, Tetsuya; Nakamura, Naoya; Nakagohri, Toshio

doi:10.1007/s00595-017-1618-3

Cited by 22 publications

(17 citation statements)

References 34 publications

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“…CAFs express various unique proteins, which are related to the prognosis of PDAC. For example, nectin cell adhesion molecule 1 (NECTIN1) + CAFs were an independent prognostic factor in PDAC [ 66 ]. The level of NECTIN1 in the CAFs of PDAC patients was positively correlated with advanced tumor stage ( P = 0.016), PNI ( P = 0.022), and short OS ( P = 0.003) [ 66 ].…”

Section: Cellular Mediators Of Pnimentioning

confidence: 99%

“…For example, nectin cell adhesion molecule 1 (NECTIN1) + CAFs were an independent prognostic factor in PDAC [ 66 ]. The level of NECTIN1 in the CAFs of PDAC patients was positively correlated with advanced tumor stage ( P = 0.016), PNI ( P = 0.022), and short OS ( P = 0.003) [ 66 ]. Fibroblast activation protein alpha was a broad marker of CAFs in various cancers and was closely associated with PNI ( P = 0.009), tumor size ( P < 0.001), and poor prognosis ( P = 0.0085) in PDAC patients [ 67 ].…”

Section: Cellular Mediators Of Pnimentioning

confidence: 99%

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Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

Kang

Tang

2021

Cancer Communications

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a unique tumor microenvironment surrounded by an interlaced network of cancer and noncancerous cells. Recent works have revealed that the dynamic interaction between cancer cells and neuronal cells leads to perineural invasion (PNI), a clinical pathological feature of PDAC. The formation and function of PNI are dually regulated by molecular (e.g., involving neurotrophins, cytokines, chemokines, and neurotransmitters), metabolic (e.g., serine metabolism), and cellular mechanisms (e.g., involving Schwann cells, stromal cells, T cells, and macrophages). Such integrated mechanisms of PNI not only support tumor development, growth, invasion, and metastasis but also mediate the formation of pain, all of which are closely related to poor disease prognosis in PDAC. This review details the modulation, signaling pathways, detection, and clinical relevance of PNI and highlights the opportunities for further exploration that may benefit PDAC patients.

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Section: Cellular Mediators Of Pnimentioning

confidence: 99%

Section: Cellular Mediators Of Pnimentioning

confidence: 99%

Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

Kang

Tang

2021

Cancer Communications

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“…In breast cancer metastatic tumors have increased expression of nectin-1 and nectin-2 [85]. In pancreatic tumors, overexpression of nectin-1 correlates with poor prognosis of the disease [86]. In such pathological situations, nectin-1 could be a target of choice for NK cells aiming at eliminating cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Interaction between nectin-1 and the human natural killer cell receptor CD96

et al. 2019

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Regulation of Natural Killer (NK) cell activity is achieved by the integration of both activating and inhibitory signals acquired at the immunological synapse with potential target cells. NK cells express paired receptors from the immunoglobulin family which share common ligands from the nectin family of adhesion molecules. The activating receptor CD226 (DNAM-1) binds to nectin-2 and CD155, which are also recognized by the inhibitory receptor TIGIT. The third receptor in this family is CD96, which is less well characterized and may have different functions in human and mouse models. Human CD96 interacts with CD155 and ligation of this receptor activates NK cells, while in mice the presence of CD96 correlates with decreased NK cell activation. Mouse CD96 also binds nectin-1, but the effect of this interaction has not yet been determined. Here we show that human nectin-1 directly interacts with CD96 in vitro . The binding site for CD96 is located on the nectin-1 V-domain, which comprises a canonical interface that is shared by nectins to promote cell adhesion. The affinity of nectin-1 for CD96 is lower than for other nectins such as nectin-3 and nectin-1 itself. However, the affinity of nectin-1 for CD96 is similar to its affinity for herpes simplex virus glycoprotein D (HSV gD), which binds the nectin-1 V-domain during virus entry. The affinity of human CD96 for nectin-1 is lower than for its known activating ligand CD155. We also found that human erythroleukemia K562 cells, which are commonly used as susceptible targets to assess NK cell cytotoxicity did not express nectin-1 on their surface and were resistant to HSV infection. When expressed in K562 cells, nectin-1-GFP accumulated at cell contacts and allowed HSV entry. Furthermore, overexpression of nectin-1-GFP led to an increased susceptibility of K562 cells to NK-92 cell cytotoxicity.

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“…In addition, silencing of Nectin-1 affected the expression of epithelial genes suggesting not only a structural role of Nectin-1 but also a role as a mediator of gene regulation [37]. A recent study [33] proposed Nectin-1 as a novel regulator of the tumor microenvironment of pancreatic ductal adenocarcinoma by demonstrating aggressive clinical features and a significant poor overall survival when Nectin-1 is expressed in cancer-associated fibroblasts. Consequently, Nectin-1 positive cells are either cancer cells or cells of the tumor microenvironment and appear to harbor properties of progenitor/stem cells.…”

Section: Discussionmentioning

confidence: 99%

“…Nectin-1, in particular, regulates axo-glial interactions, Schwann cell differentiation, and myelination [30-32]. Substantial data [33] arising from other studies have demonstrated that expression of Nectin-1 in case of specific malignant tumors is associated with aggressive tumor phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Nectin-1 Expression in Colorectal Cancer: Is There a Group of Patients with High Risk for Early Disease Recurrence?

et al. 2019

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Background: Despite improvements in therapy of colorectal cancer, some patients will present occurrence of recurrence either locally or distantly. Tumor metastasis constitutes the major cause of cancer-associated morbidity and mortality. Nectin-1 belongs to the family of immunoglobulin-like cell adhesion molecules that contribute to the formation of cell-cell adhesions and regulate a series of cellular activities including cell polarization, differentiation, movement, proliferation, and survival. Expression of Nectin-1 in malignant tumors has been associated with aggressive tumor phenotypes. Objectives: The aim of the present study was to assess Nectin-1 expression patterns in colorectal cancer and to investigate its clinical significance. Methods: Nectin-1 expression was assessed via immunohistochemistry in surgical specimens of a cohort comprised of 111 patients with primary resectable colorectal cancer. Results were correlated with clinicopathological characteristics and survival data. Progression-free survival was defined as the primary outcome of the present study. Results: Nectin-1 was strongly expressed in the cytoplasm of colorectal cancer cells. High Nectin-1 expression was associated with advanced stage of disease (p = 0.012) and lymph node metastasis (p = 0.007). Progression-free survival of patients exhibiting high expression of Nectin-1 in the first 36 months after surgery was significantly worse compared to patients with low expression of Nectin-1 (55.7%, 95% CI = 47–70, vs. 82.1%, 95% CI = 69–93, p = 0.014) and independent of other clinicopathological characteristics (HR = 0.389, 95% CI = 0.156–0.972, p = 0.043). Conclusion: Nectin-1 expression in colorectal cancer is associated with a significantly worse 3-year progression-free survival identifying therefore a group of patients with high risk for early disease recurrence.

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Nectin-1 expression in cancer-associated fibroblasts is a predictor of poor prognosis for pancreatic ductal adenocarcinoma

Abstract: Diffuse nectin-1 expression in the CAFs of PDAC patients is associated with invasion, metastasis, and shorter survival.

Cited by 22 publications

References 34 publications

Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

Interaction between nectin-1 and the human natural killer cell receptor CD96

Nectin-1 Expression in Colorectal Cancer: Is There a Group of Patients with High Risk for Early Disease Recurrence?

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