Blocking the FSTL1-DIP2A Axis Improves Anti-tumor Immunity

Kudo-Saito, Chie; Ishida, Akiko; Shouya, Yuji; Teramoto, Koji; Igarashi, Tomoyuki; Kon, Ryoko; Saito, Kenji; Awada, Chihiro; Ogiwara, Yamato; Toyoura, Masayoshi

doi:10.1016/j.celrep.2018.07.043

Cited by 35 publications

(26 citation statements)

References 49 publications

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“…FSTL1 exerts this effect on migration through the reduction of various cytokines, including metalloproteinase-2 (MMP-2), CCL2, and CXCL12 (Chan et al, 2009). Moreover, FSTL1 is considered a determinant of immune dysfunction mediated by mesenchymal stroma/stem cells (MSCs) and immunoregulatory cells, and may therefore represent a target to suppress cancer progression (Kudo-Saito et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Gastric Cancer Tumor Microenvironment Characterization Reveals Stromal-Related Gene Signatures Associated With Macrophage Infiltration

Wei

Lou

et al. 2020

Front. Genet.

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The tumor microenvironment (TME) has attracted attention owing to its essential role in tumor initiation, progression, and metastasis. With the emergence of immunotherapies for various cancers, and their high efficacy, an understanding of the TME in gastric cancer (GC) is critical. The aim of this study was to investigate the effect of various components within the GC TME, and to identify mechanisms that exhibit potential as therapeutic targets. The ESTIMATE algorithm was used to quantify immune and stromal components in GC samples, whose clinicopathological significance and relationship with predicted outcomes were explored. Low tumor mutational burden and high M2 macrophage infiltration, which are considered immune suppressive characteristics and may be responsible for unfavorable prognoses in GC, were observed in the high stromal group (HR = 1.585; 95% CI, 1.112-2.259; P = 0.009). Furthermore, weighted correlation network, differential expression, and univariate Cox analyses were used, along with machine learning methods (LASSO and SVM-RFE), to reveal genome-wide immune phenotypic correlations. Eight stromal-relevant genes cluster (FSTL1, RAB31, FBN1, ANTXR1, LRRC32, CTSK, COL5A2, and ENG) were identified as adverse prognostic factors in GC. Finally, using a combination of TIMER database and single-sample gene set enrichment analyses, we found that the identified genes potentially contribute to macrophage recruitment and polarization of tumor-associated macrophages. These findings provide a different perspective into the immune microenvironment and indicate potential prognostic and therapeutic targets for GC immunotherapies.

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Section: Discussionmentioning

confidence: 99%

Gastric Cancer Tumor Microenvironment Characterization Reveals Stromal-Related Gene Signatures Associated With Macrophage Infiltration

Wei

Lou

et al. 2020

Front. Genet.

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“…Studies have showed that FSTL1 was involved in tumor develop and tumor immunity by variety of mechanisms, such as promotes metastasis and chemoresistance through NFκB-BMP signaling pathway in esophageal squamous cell carcinoma [12], activating the focal adhesion signaling pathway to promotes colorectal cancer [11], causing immune dysfunction in lung cancer [15] and tumor with bone metastasis [32]. From these results, we can speculate that FSTL1 is crucially involved in tumor progression and tumor immunity.…”

Section: Discussionmentioning

confidence: 82%

“…FSTL1 also affects the progression of multiple tumors by modulating the host immune system, leading to immune dysfunction in many cases. FSTL1-induced immune dysfunction leads to tumor bone metastases [14] and activation of immune evasion mechanisms in patients with non-small cell lung cancer (NSCLC) through the FSTL1-DIP2A axis [15]. FSTL1 plays a crucial role in tumor-immune and cancer cell progression.…”

Section: Introductionmentioning

confidence: 99%

Follistatin-like 1 (FSTL1) is a Prognostic Biomarker and Correlated with Immune Cell Infiltration in Gastric Cancer

Huang

Yao

et al. 2020

Preprint

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Background: Follistatin-like 1 (FSTL1) plays a central role in the progression of tumor and tumor immunity. However, the effect of FSTL1 on the prognosis and immune infiltration of gastric cancer (GC) remains to be elucidated.Method: The expression of FSTL1 data was analyzed in Oncomine and TIMER databases. Analyses of clinical parameters and survival data were conducted by Kaplan-Meier plotter and immunohistochemistry. Western blot assay and real‐time quantitative PCR (RT-qPCR) was using to analyzed protein and mRNA expression, respectively. The correlations between FSTL1 and cancer immune infiltrates was analyzed by Tumor Immune Estimation Resource (TIME), Gene Expression Profiling Interactive Analysis (GEPIA) and LinkedOmics database.Results: The expression of FSTL1 was significantly higher in GC tissues than in normal tissues, and bioinformatic analysis and Immunohistochemistry (IHC) indicated that high FSTL1 expression significantly correlated with poor prognosis in GC. Moreover, FSTL1 was predicted as an independent prognostic factor in GC patients. Bioinformatics analysis results suggested that FSTL1 mainly involved in tumor progression and tumor immunity. And significant correlations were found between FSTL1 expression and immune cell infiltration in GC.Conclusion: The study effectively revealed useful information about FSTL1 expression, prognostic values, potential functional networks and impact of tumor immune infiltration in GC. In summary, FSTL1 can be used as a biomarker for prognosis and evaluating immune cell infiltration in GC.

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“…Yonsei datasets, respectively). FSTL1 was reported as a key mediator in immune dysfunction driven by metastasis and aging in mouse cancer models 48 but no functions of it in gastric cancer was reported previously.…”

Section: Clinical Significance Of the Methylation-driven Key Regulatorsmentioning

confidence: 97%

Molecular and cellular heterogeneity of gastric cancer explained by methylation-driven key regulators

Yoo

Chen

Wang

et al. 2020

Preprint

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Gastric cancer (GC) is a heterogeneous disease of diverse genetic, genomic, and epigenetic alterations. Tumor microenvironment (TME) also contributes to the heterogeneity of GC. To investigate GC heterogeneity, we developed an Integrative Sequential Causality Test (ISCT) to identify key regulators of GC by integrating DNA methylation, copy number variation, and transcriptomic data. Applying ISCT to three GC cohorts containing methylation, CNV and transcriptomic data, 11 common methylation-driven key regulators (ADHFE1, CDO1, CRYAB, FSTL1, GPT, PKP3, PTPRCAP, RAB25, RHOH, SFN, and SORD) were identified. Based on these 11 genes, gastric tumors were clustered into 3 clusters which were associated with known molecular subtypes, Lauren classification, tumor stage, and patient survival, suggesting significance of the methylation-driven key regulators in molecular and histological heterogeneity of GC. We further showed that chemotherapy benefit was different in the 3 GC clusters and varied depending on the tumor stage. Both immune/stromal proportions in TME and tumor cell genomic variations contributed to expression variations of the 11 methylation-driven key regulators and to the GC heterogeneity.

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Blocking the FSTL1-DIP2A Axis Improves Anti-tumor Immunity

Cited by 35 publications

References 49 publications

Gastric Cancer Tumor Microenvironment Characterization Reveals Stromal-Related Gene Signatures Associated With Macrophage Infiltration

Gastric Cancer Tumor Microenvironment Characterization Reveals Stromal-Related Gene Signatures Associated With Macrophage Infiltration

Follistatin-like 1 (FSTL1) is a Prognostic Biomarker and Correlated with Immune Cell Infiltration in Gastric Cancer

Molecular and cellular heterogeneity of gastric cancer explained by methylation-driven key regulators

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