CD40 Expression in Human Esophageal Squamous Cell Carcinoma Is Associated with Tumor Progression and Lymph Node Metastasis

Matsumura, Yuko; Hiraoka, Kenzo; Ishikawa, Kenji; Shoji, Yasushi; Noji, Takehiro; Hontani, Koji; Itoh, Tomoo; Nakamura, Tõru; Tsuchikawa, Takahiro; Shichinohe, Toshiaki; Hirano, Satoshi

doi:10.21873/anticanres.10991

Cited by 21 publications

(14 citation statements)

References 29 publications

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“…Findings on CD40 are consistent with the results published by Keidai et al, in which 51.9% of NSCLC tissue specimens [24] and 78% of lung cancer cell lines (14 of 18) expressed CD40 [25]. Furthermore, the expression of CD40 has been documented in many other carcinomas, such as melanomas [26], hepatocellular carcinomas [27] thyroid [28], bladder [29], colon [30], esophageal squamous cell [31], ovarian [32], gastric [33], cervical [34], breast and pancreatic cancer [35], as well as in the vast majority of hematological malignancies [36,37].…”

Section: Discussionsupporting

confidence: 89%

Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients

Dimitrakopoulos

Κοττόρου

Antonacopoulou

et al. 2019

JCM

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An increasing number of studies implicates the NF-κB (Nuclear Factor of kappa light chain gene enhancer in B cells) alternative pathway in non-small-cell lung cancer (NSCLC). We assessed the clinical significance of CD40 (Tumor necrosis factor receptor superfamily member 5, TNFRSF5), BAFFR (B-cell activating factor receptor), RANK (Receptor activator of NF-κB) and LTβR (lymphotoxin β receptor) receptors, which activate the alternative pathway of NF-κB, in NSCLC. Evaluation of CD40, BAFFR, RANK and LTβR expression was performed based on the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets, while protein expression was assessed by immunohistochemistry in specimens from 119 operated NSCLC patients. CD40 gene overexpression was correlated with improved five-year overall survival (OS) (p < 0.001), while increased BAFFR and LTβR mRNA levels were associated with worse OS in patients with adenocarcinomas (p < 0.001 and p < 0.001, respectively). Similarly, patients with adenocarcinomas exhibited a negative correlation between membranous BAFFR protein expression in carcinoma cells and three- and five-year survival (p = 0.021; HR, 4.977 and p = 0.030; HR, 3.358, respectively) as well as between BAFFR protein overexpression in cancer-associated fibroblasts (CAFs) and two-year survival (p = 0.036; HR, 1.983). Patients with increased LTβR nuclear protein staining or stage II patients with lower cytoplasmic LTβR protein expression had worse five-year OS (p = 0.039 and p = 0.008, respectively). Moreover, CD40 protein expression in tumor infiltrating lymphocytes (TILs) and CAFs was positively associated with metastatic spread while BAFFR protein expression in CAFs was negatively associated with bone metastasis (p = 0.041). Our data suggests that CD40, BAFFR, RANK and LTβR play an important role in NSCLC and further supports the role of NF-κB alternative pathway in NSCLC.

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Section: Discussionsupporting

confidence: 89%

Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients

Dimitrakopoulos

Κοττόρου

Antonacopoulou

et al. 2019

JCM

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“…Furthermore, CD40-CD40L interaction can affect the growth regulation of some tumors. Matsumura et al, proposed that the expression of CD40 is associated with progression of ESCC [23]. Moreover, as one of the apoptosis-related markers, FasL plays an important role in the development of ESCC [24].…”

Section: Discussionmentioning

confidence: 99%

POLE2 knockdown reduce tumorigenesis in esophageal squamous cells

et al. 2020

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Background: Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignant tumors originated from digestive system around the world and the treatment was limited by the unclear mechanism. DNA polymerase epsilon 2, accessory subunit (POLE2) is involved in DNA replication, repair, and cell cycle control, whose association with ESCC is still not clear. Methods: In this study, the expression level of POLE2 in ESCC tissues was detected by IHC. The POLE2 knockdown cell line was constructed, identified by qPCR and western blot and used for detecting cellular functions and constructing xenotransplantation mice model. MTT Assay, colony formation assay, flow cytometry, wound-healing assay and Transwell assay were used to detected cell proliferation, apoptosis and migration. Results: We firstly identified that the expression of POLE2 was overexpressed in ESCC. Moreover, the high expression of POLE2 can predict the tumor deterioration and poor prognosis of ESCC patients. Additionally, downregulation of POLE2 was involved in ESCC progression by promoting proliferation, migration, and inhibiting apoptosis in vitro. In vivo studies proved that POLE2 was positively correlated with ESCC tumor formation, which was consistent with the results in vitro. We also illuminated that POLE2 knockdown upregulated pro-apoptotic proteins (Bax, Caspase3, CD40L, FasL, IGFBP-5 and P21) and downregulated anti-apoptotic proteins (CLAP-2, IGF-I and sTNF-R2). In addition, POLE2 was involved in ESCC via targeting PI3K/Akt, Cyclin D1 signaling pathway. Conclusions: Therefore, POLE2 was proved to be involved in the development of ESCC, which may be a potential therapeutic target and bring new breakthroughs in the treatment of ESCC.

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“…Substantial CD40 expression was detected in a variety of frequent solid cancer types including bladder cancer (102/131, 78%), melanoma (41/71, 57,7%), breast cancer (53%), lung cancer (67/129, 51,9%), colon cancer (87/110, 79%) as well as B-lineage malignancies 14–19. CD40 expression was frequently shown to be associated with prolonged survival; however, contrary results were evident in lung and oesophageal cancer as CD40 expression correlated with poor prognosis 17 20. Interestingly, compared with cancer tissue, normal tissues exhibited very low to no CD40 levels, underscoring the potential of CD40 as a cancer-specific immunological target.…”

Section: Cd40 Expression and Signalling In Cancermentioning

confidence: 99%

New emerging targets in cancer immunotherapy: the role of Cluster of Differentiation 40 (CD40/TNFR5)

Piechutta¹,

Berghoff²

2019

ESMO Open

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Cluster of differentiation 40 (CD40) is a member of the tumour necrosis factor family and a new immune-modulating target in cancer treatment. B cells, myeloid cells and dendritic cells can express CD40 and mediate via the ligand cluster of differentiation 40 ligand (CD40L) cytotoxic T cell priming under physiological conditions. Therapeutically, recombinant CD40L molecules, intratumour application of adenoviral vectors leading to CD40L expression and agonistic monoclonal CD40 antibodies are currently tested in various cancer entities for their immune-modulating potential. Early clinical trials suggest safety for agonistic CD40 antibodies with encouraging antitumour effects. Adverse events encompass cytokine release storm, hepatoxicity, thromboembolic events and were so far reported to be clinically manageable and transient. Ongoing studies investigate CD40 activation in combination with chemotherapy, radiation, targeted therapies and immunomodulatory agents. Further studies are awaited to specifically identify patients with the greatest clinical benefit based on predictive biomarkers.

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CD40 Expression in Human Esophageal Squamous Cell Carcinoma Is Associated with Tumor Progression and Lymph Node Metastasis

Cited by 21 publications

References 29 publications

Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients

Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients

POLE2 knockdown reduce tumorigenesis in esophageal squamous cells

New emerging targets in cancer immunotherapy: the role of Cluster of Differentiation 40 (CD40/TNFR5)

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