Identification of the prognostic value of elevated ANGPTL4 expression in gallbladder cancer‐associated fibroblasts

Wang, Fang‐Tao; Li, Xinping; Pan, Mu-Su; Hammami, Mohamed; Sun, Wei; Fan, Yonggang

doi:10.1002/cam4.4150

Cited by 6 publications

(5 citation statements)

References 51 publications

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“…Analogously, CAF was reported to secrete ANGPTL4, MMP13, and STC1, which could promote proliferation of breast cancer cells (23). In gallbladder cancer, the expression of ANGPTL4 was also upregulated in CAFs, and in the stroma of xenograft tumors in nude mice and in human gallbladder cancer, ANGPTL4 was significantly upregulated (24). In addition, IL1RAP was identified as a CAF-associated gene in our study.…”

Section: Discussionsupporting

confidence: 66%

Bioinformatic analysis of cancer-associated fibroblast related gene signature as a predictive model in clinical outcomes and immune characteristics of gastric cancer

Zhang¹,

Zhang²,

Fu³

et al. 2022

Ann Transl Med

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Background: Gastric cancer (GC) has a high incidence and high mortality rate among Asian countries, and distinguishing predictive prognosis biomarkers for GC are essential. Cancer-associated fibroblasts (CAFs) play a significant role in the progression, immune evasion, and therapeutic resistance of GC. Therefore, CAF-associated genes might have huge potential as prognostic biomarkers for predicting tumor progression and survival rate in GC pateints.Methods: A sum of 1,134 GC patients from the The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD), GSE62254, and GSE84437 datasets as well as GC cohorts from Xijing hospital were included. Firstly, we performed univariate Cox regression analysis to identify CAF-associated prognostic genes. Subsequently, the Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was used to develop a CAF gene signature (CAFGS) in the TCGA-STAD training cohort. CAFGS's predictive performance was examined in both the training and validation cohorts, and the relationship between CAFGS and the tumor microenvironment (TME) was investigated by ssGSEA, CIBERSORT, TIMER, and ESTIMATE. Finally, a nomogram of CAFGS was established.Results: Ten CAF-associated genes (ANGPTL4, CPNE8, CST2, HTR1F, IL1RAP, NR1D1, NTAN1, OLFML2B, TMEM259, and VTN) were identified to develop CAFGS. A high CAFGS score represented a worse outcome for GC patients in four cohorts, and a strong correlation was found between CAFGS and the infiltration of immune cells. We showed that CAFs contribute to immune evasion and unfavorable prognoses of GC patients by promoting the formation of an immunosuppressive microenvironment, and a high level of CAF infiltration may attenuate the efficacy of immunotherapy. The nomogram based on CAFGS showed reasonable predictive ability and may deliver great clinical net benefits. Conclusions:We established a CAFGS model with 10 CAF-associated genes that had a great predictive ^ ORCID: 0000-0001-7059-6995.

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Section: Discussionsupporting

confidence: 66%

Bioinformatic analysis of cancer-associated fibroblast related gene signature as a predictive model in clinical outcomes and immune characteristics of gastric cancer

Zhang¹,

Zhang²,

Fu³

et al. 2022

Ann Transl Med

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“…ANGPTL4 is a multi-faceted protein that functions in the tumor microenvironment to promote tumor growth, angiogenesis and chemoresistance (39)(40)(41)(42)(43). ANGPTL4 is secreted by multiple cell types in the tumor microenvironment, including adipocytes and cancer-associated fibroblasts, and is associated with a poor prognosis in breast, gallbladder, and ovarian cancers (19,41,(44)(45)(46). Furthermore, ANGPTL4 has been implicated in carboplatin resistance and hypoxia-induced anoikis resistance (40,41).…”

Section: Discussionmentioning

confidence: 99%

Cancer-associated mesothelial cell–derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis

Bajwa¹,

Kordylewicz²,

Bilecz³

et al. 2023

JCI Insight

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Ovarian cancer (OvCa) preferentially metastasizes in association with mesothelial cell-lined surfaces. We sought to determine if mesothelial cells are required for OvCa metastasis and detect alterations in mesothelial cell gene expression and cytokine secretion upon interaction with OvCa cells. Using omental samples from patients with high-grade serous OvCa and mouse models with Wt1-driven GFP-expressing mesothelial cells, we validated the intratumoral localization of mesothelial cells during human and mouse OvCa omental metastasis. Removing mesothelial cells ex vivo from human and mouse omenta or in vivo using diphtheria toxin mediated ablation in Msln-Cre mice, significantly inhibited OvCa cell adhesion and colonization. Human ascites induced angiopoietinlike 4 (ANGPTL4) and stanniocalcin 1 (STC1) expression and secretion by mesothelial cells. Inhibition of STC1 or ANGPTL4 via RNAi, obstructed OvCa cell-induced mesothelial cell to mesenchymal transition while inhibition of ANGPTL4 alone obstructed OvCa cell-induced mesothelial cell migration and glycolysis. Inhibition of mesothelial cell ANGPTL4 secretion via RNAi prevented mesothelial cell induced monocyte migration, endothelial cell vessel formation and OvCa cell adhesion, migration, and proliferation. In contrast, inhibition of mesothelial cell STC1 secretion via RNAi prevented mesothelial cell induced endothelial cell vessel formation and OvCa cell adhesion, migration, proliferation, and invasion. Additionally, blocking ANPTL4 function with antibodies reduced the ex vivo colonization of three different OvCa cell lines on human omental tissue explants and in vivo colonization of ID8 p53-/-Brca2-/cells on mouse omenta. These findings indicate that mesothelial cells are important to the initial stages of OvCa metastasis, and that the crosstalk between mesothelial cells and the tumor microenvironment, promotes OvCa metastasis through the secretion of ANGPTL4.

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“…MDK is a heparin-binding growth factor implicated in several physiological processes including development, reproduction, repair and angiogenesis 38 , 39 . As MDK is a stimulator of collagen and glycosaminoglycan synthesis 40 , it seems reasonable to infer that MDK regulates vascular endothelial function through a stimulus-induced production of collagen in fibroblasts. ANGPTL4 can regulate several aspects of fibroblast functions, such as orienting the configuration of fibrous matrices, activation of cancer-associated fibroblasts in tumors and co-localization with fibroblast secreted protein-1 and α-smooth muscle actin 41 – 43 .…”

Section: Discussionmentioning

confidence: 99%

Integrated single-cell and spatial transcriptomics reveals heterogeneity of fibroblast and pivotal genes in psoriasis

He,

Song,

et al. 2023

Sci Rep

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Psoriasis, which is one of the most common skin diseases, involves an array of complex immune constituents including T cells, dendritic cells and monocytes. Particularly, the cytokine IL17A, primarily generated by TH17 cells, assumes a crucial function in the etiology of psoriasis. In this study, a comprehensive investigation utilizing bulk RNA analysis, single-cell RNA sequencing, and spatial transcriptomics was employed to elucidate the underlying mechanisms of psoriasis. Our study revealed that there is an overlap between the genes that are differentially expressed in psoriasis patients receiving three anti-IL17A monoclonal antibody drugs and the genes that are differentially expressed in lesion versus non-lesion samples in these patients. Further analysis using single-cell and spatial data from psoriasis samples confirmed the expression of hub genes that had low expressions in psoriasis tissue but were up-regulated after anti-IL17A treatments. These genes were found to be associated with the treatment effects of brodalumab and methotrexate, but not adalimumab, etanercept, and ustekinumab. Additionally, these genes were predominantly expressed in fibroblasts. In our study, fibroblasts were categorized into five clusters. Notably, hub genes exhibited predominant expression in cluster 3 fibroblasts, which were primarily engaged in the regulation of the extracellular matrix and were predominantly located in the reticular dermis. Subsequent analysis unveiled that cluster 3 fibroblasts also established communication with epithelial cells and monocytes via the ANGPTL-SDC4 ligand-receptor configuration, and their regulation was governed by the transcription factor TWIST1. Conversely, cluster 4 fibroblasts, responsible for vascular endothelial regulation, were predominantly distributed in the papillary dermis. Cluster 4 predominantly engaged in interactions with endothelial cells via MDK signals and was governed by the distinctive transcription factor, ERG. By means of an integrated analysis encompassing bulk transcriptomics, single-cell RNA sequencing, and spatial transcriptomics, we have discerned genes and clusters of fibroblasts that potentially contribute to the pathogenesis of psoriasis.

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Identification of the prognostic value of elevated ANGPTL4 expression in gallbladder cancer‐associated fibroblasts

Abstract: Yue-Zu Fan 1This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 6 publications

References 51 publications

Bioinformatic analysis of cancer-associated fibroblast related gene signature as a predictive model in clinical outcomes and immune characteristics of gastric cancer

Bioinformatic analysis of cancer-associated fibroblast related gene signature as a predictive model in clinical outcomes and immune characteristics of gastric cancer

Cancer-associated mesothelial cell–derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis

Integrated single-cell and spatial transcriptomics reveals heterogeneity of fibroblast and pivotal genes in psoriasis

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