Enhanced IL-34 expression in Nivolumab-resistant metastatic melanoma

Han, Nanumi; Baghdadi, Muhammad; Ishikawa, K.; Endo, Hitomi; Kobayashi, Takuto; Wada, Haruka; Imafuku, Kimiaki; Hata, Hiroo; Seino, Ken‐ichiro

doi:10.1186/s41232-018-0060-2

Cited by 37 publications

(41 citation statements)

References 30 publications

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“…16 Moreover, IL-34 expression is known to be associated with therapeutic resistance in lung cancer and melanoma. 33,36,37 Therefore, in this study, serum IL-34 level could reflect hepatic fibrosis as well as tumor factors, and was associated with the prognosis of patients with nonviral HCC.…”

Section: Discussionmentioning

confidence: 81%

High serum interleukin‐34 level is a predictor of poor prognosis in patients with non‐viral hepatocellular carcinoma

Noda

Kawaguchi

Korenaga

et al. 2019

Hepatology Research

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Aims We aimed to investigate the impact of interleukin (IL)‐34 and YKL‐40, regulators of hepatic fibrosis and tumor growth, on the prognosis of patients with non‐viral hepatocellular carcinoma (HCC). Methods We enrolled 159 non‐viral HCC patients (age, 70.8 ± 8.5 years; female/male, 43/116). Of these, 86 patients were alive and 73 patients had died at the censor time point. Serum IL‐34 and YKL‐40 levels were quantified by enzyme‐linked immunosorbent assay. Patients were stratified by the median level of serum IL‐34 to examine its effect on survival. Multivariate analysis and random forest analysis were used to evaluate the impact of IL‐34 and YKL‐40 on the prognosis of non‐viral HCC patients. Results Interleukin‐34 (hazard ratio [HR] 1.30; 95% confidence interval [CI], 1.13–1.49; P ≤ 0.01), tumor size (HR 1.63; 95% CI, 1.37–1.94; P ≤ 0.01), and tumor number (HR 1.53; 95% CI, 1.25–1.87; P ≤ 0.01) were independent predictive factors for survival. Furthermore, the survival rates were significantly lower in the high IL‐34 group than in the low IL‐34 group (5‐year survival rates, 34.7% vs. 59.8%, respectively; P < 0.05). In the random forest analysis for survival, IL‐34 was the third‐highest ranking factor, following tumor size and number. In a stratification analysis, serum α‐fetoprotein level and Fibrosis‐4 index were independent positive risk factors for high serum IL‐34 level. YKL‐40 was not associated with prognosis in either the multivariate or random forest analysis. Conclusion Interleukin‐34 was an independent factor for survival of non‐viral HCC patients. Interleukin‐34 might be associated with prognosis through tumor and hepatic fibrosis factors.

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Section: Discussionmentioning

confidence: 81%

High serum interleukin‐34 level is a predictor of poor prognosis in patients with non‐viral hepatocellular carcinoma

Noda

Kawaguchi

Korenaga

et al. 2019

Hepatology Research

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“…Since IL‐34 is expressed at mRNA level in various tissues, this expression is expected to be changed under pathological conditions. Indeed, several studies have confirmed the enhancement of IL‐34 expression at mRNA and protein levels in the context of various diseases including autoimmune disorders, inflammation, infections, metabolic diseases, neurological disorders, and cancer . At the cellular level, IL‐34‐producing cells include synovial fibroblasts, immune cells, epithelial cells, endothelial cells, adipocytes, and cancer cells.…”

Section: Il‐34 Biologymentioning

confidence: 95%

“…CSF‐1R is expressed in a subset of cancer cells or can be induced upon exposure to chemotherapeutic agents . Similarly, IL‐34 is expressed in various types of cancer cells and can be induced by chemotherapy treatment . In an autocrine fashion, cancer cell‐derived IL‐34 induces strong activation of ERK1/2 and AKT downstream of CSF‐1R, thus providing CSF‐1R‐expressing cancer cells with a critical survival signaling that help them to survive under strict chemotherapeutic conditions, such as in pemetrexed‐treated pleural malignant mesothelioma cells, doxorubicin‐ or cisplatin‐treated lung cancer cells, and oxaliplatin‐treated colon cancer cells .…”

Section: Pathological Roles Of Il‐34mentioning

confidence: 99%

“…have suggested the potential involvement of IL‐34 in resistance to immunotherapy. In a clinical case of a patient with melanoma that acquired resistance to anti‐PD‐1 immunotherapy, IL‐34 showed enhanced expression in metastatic refractory melanoma compared to melanoma from primary sites, which correlates positively with increased infiltration of CD163 + TAMs, which have high potential to suppress effective antitumor immune responses . In addition to TAMs, CSF‐1R expression can be detected on tumor‐associated dendritic cells, tumor‐associated neutrophils, and myeloid‐derived suppressor cells.…”

Section: Pathological Roles Of Il‐34mentioning

confidence: 99%

“…Depleting or repolarizing TAMs showed promising effects in preclinical models . As an important factor that increases TAMs frequencies and enhances their pro‐tumorigenic functions, targeting IL‐34 has a therapeutic potential in TAMs‐targeting strategies . Furthermore, since cancer cells rely on IL‐34‐activated signaling pathways for their survival under chemotherapeutic conditions, targeting IL‐34 may help to sensitize therapeutic‐resistant cancer cells to cancer therapy such in chemoresistant lung cancers, colon cancers, and malignant pleural mesotheliomas .…”

Section: Il‐34 From Bench To Bedsidementioning

confidence: 99%

See 2 more Smart Citations

Interleukin-34, a comprehensive review

Baghdadi

Umeyama

Hama

et al. 2018

Journal of Leukocyte Biology

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117

120

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IL-34 is a novel cytokine that was identified in 2008 in a comprehensive proteomic analysis as a tissue-specific ligand of CSF-1 receptor (CSF-1R). IL-34 exists in all vertebrates including fish, amphibians, birds, and mammals, showing high conservation among species. Structurally, IL-34 belongs to the short-chain helical hematopoietic cytokine family but shows no apparent consensus structural domains, motifs, or sequence homology with other cytokines. IL-34 is synthesized as a secreted homodimeric glycoprotein that binds to the extracellular domains of CSF-1R and receptor-type protein-tyrosine phosphatase-zeta (PTP-ζ) in addition to the chondroitin sulfate chains of syndecan-1. These interactions result in activating several signaling pathways that regulate major cellular functions, including proliferation, differentiation, survival, metabolism, and cytokine/chemokine expression in addition to cellular adhesion and migration. In the steady state, IL-34 contributes to the development and maintenance of specific myeloid cell subsets in a tissue-specific manner: Langerhans cells in the skin and microglia in the brain. In pathological conditions, changes in IL-34 expression-increased or decreased-are involved in disease pathogenesis and correlate with progression, severity, and chronicity. One decade after its discovery, IL-34 has been introduced as a newcomer to the big family of interleukins with specific physiological functions, critical pathological roles, and promising clinical applications in disease diagnosis and treatment. In this review, we celebrate the 10th anniversary of IL-34 discovery, introducing its biological characteristics, and discussing the importance of IL-34 signaling network in health and disease.

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IL‐34 in hepatoblastoma cells potentially promote tumor progression via autocrine and paracrine mechanisms

et al. 2022

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Hepatoblastoma is the most common pediatric liver tumor, but little research has been done on the role of macrophages in hepatoblastoma. The purpose of this study was to gain insight into potential roles for macrophages in hepatoblastoma. Paraffin-embedded specimens from 56 patients who underwent surgical resection were examined with immunohistochemical staining for the macrophage-specific markers, Iba1 and CD163. Significant differences were seen among histological subtypes. Significantly increased numbers of macrophages were detected in embryonal components compared to fetal components in the mixed epithelial type. In vitro studies using human monocyte-derived macrophages and two hepatoblastoma cell lines (HepG2 and Huh6) were performed.Conditioned medium from these cell lines induced increased CD163 expression in macrophages. Direct co-culture with macrophages induced tumor cell proliferation via induction of protumor cytokine secretion from macrophages. Direct co-culture with macrophages also induced interleukin (IL)-34 overexpression by Huh6 cells via Brd4 signaling. IL-34 overexpression promoted tumor cell proliferation and chemoresistance. High IL-34 and Brd4 expression was detected in embryonal components, which have potentially higher proliferation activity than fetal components. In conclusion, IL-34 expression in embryonal components may induce macrophage chemotaxis in a paracrine manner, and tumor cell proliferation and chemoresistance in an autocrine manner. IL-34 is a potential therapeutic target for hepatoblastoma.

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Enhanced IL-34 expression in Nivolumab-resistant metastatic melanoma

Cited by 37 publications

References 30 publications

High serum interleukin‐34 level is a predictor of poor prognosis in patients with non‐viral hepatocellular carcinoma

High serum interleukin‐34 level is a predictor of poor prognosis in patients with non‐viral hepatocellular carcinoma

Interleukin-34, a comprehensive review

IL‐34 in hepatoblastoma cells potentially promote tumor progression via autocrine and paracrine mechanisms

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