Tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through TGFβ2/NF-κB/Kindlin-2 axis

Zhu, Wei; Yang, Yang; Cui, Yancheng; Wang, Chao; Lai, Zhiyong; Li, Yansen; Zhang, Wei; Mustonen, Harri; Puolakkainen, Pauli; Ye, Yingjiang; Jiang, Kewei; Shen, Zhanlong; Wang, Shan

doi:10.21147/j.issn.1000-9604.2020.01.09

Cited by 41 publications

(31 citation statements)

References 49 publications

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“…In addition, the hypoxic tumor microenvironment can also triggers M2-polarized TAMs. 149 – 151 Once polarized, M2 TAMs secrete various growth factors and cytokines, including TGF-β, 152 , 153 interleukin-IL-10, IL-6, TNF-α, 40 , 154 , 155 IL-1β, 156 , 157 migration inhibitory factor (MIF) 158 , and chemokines such as CCL20, 159 which are all capable of promoting EMT as previously described. In addition, gemcitabine treatment results in robust infiltration of M2-polarized TAMs which secrete TNFα, TGF-β, and IL-6, leading to EMT of PDAC cells.…”

Section: Components Of Pdac Tumor Microenvironment (Tme) That Drive Ementioning

confidence: 84%

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Bulle

Lim

2020

Sig Transduct Target Ther

113

123

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Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma (PDAC). Therapeutics that target the driver mutations, especially the KRAS oncoprotein and its effector cascades, have been ineffective. It is increasing clear that the extensive fibro-inflammatory stroma (or desmoplasia) of PDAC plays an active role in the progression and therapeutic resistance of PDAC. The desmoplastic stroma is composed of dense extracellular matrix (ECM) deposited mainly by the cancer-associated-fibroblasts (CAFs) and infiltrated with various types of immune cells. The dense ECM functions as a physical barrier that limits tumor vasculatures and distribution of therapeutics to PDAC cells. In addition, mounting evidence have demonstrated that both CAFs and ECM promote PDAC cells aggressiveness through multiple mechanisms, particularly engagement of the epithelial-mesenchymal transition (EMT) program. Acquisition of a mesenchymal-like phenotype renders PDAC cells more invasive and resistant to therapy-induced apoptosis. Here, we critically review seminal and recent articles on the signaling mechanisms by which each stromal element promotes EMT in PDAC. We discussed the experimental models that are currently employed and best suited to study EMT in PDAC, which are instrumental in increasing the chance of successful clinical translation.

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Section: Components Of Pdac Tumor Microenvironment (Tme) That Drive Ementioning

confidence: 84%

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Bulle

Lim

2020

Sig Transduct Target Ther

113

123

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“…Accumulating evidence has elucidated their clinicopathological significance in predicting the outcomes and therapeutic efficacy in cancer patients ( 18 , 19 ). The infiltration of CD8-positive T cells and tumor-associated macrophages was reported to facilitate the progression of epithelial gastric cancer ( 20 – 22 ). In the present study, infiltration levels of CD8-positive T cells and M1 macrophages were significantly higher in the gastric cancer group with high PAFAH1B3 expression.…”

Section: Discussionmentioning

confidence: 99%

PAFAH1B3 Expression Is Correlated With Gastric Cancer Cell Proliferation and Immune Infiltration

Xie

Guo

et al. 2021

Front. Oncol.

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BackgroundPlatelet activating factor acetylhydrolase 1b catalytic subunit 3 (PAFAH1B3) is associated with a variety of human diseases. However, its function in gastric cancer remains uncertain.MethodsPAFAH1B3 expression was analyzed in The Cancer Genome Atlas (TCGA) and genotype-tissue expression pan-cancer data. The association between PAFAH1B3 expression and patient prognosis was evaluated using TCGA clinical survival data. Enrichment analysis of PAFAH1B3 was performed using the clusterProfiler R software package. Moreover, the correlation between PAFAH1B3 expression and immune cell infiltration were evaluated by analyzing TCGA database. CCK8 assay and colony-formation assay were performed to assess the effect of PAFAH1B3 on the proliferation of gastric cancer cells. Transwell assay was used to evaluate the impact of PAFAH1B3 on gastric cancer cell migration. Western blot was performed to evaluate the role of PAFAH1B3 on signaling pathways in gastric cancer cells.ResultsPAFAH1B3 was highly expressed in many types of tumors including gastric cancer. High PAFAH1B3 expression was significantly correlated with proliferation-related gene sets involved in DNA replication, the cell cycle, and cell cycle checkpoints. Further analysis showed that high PAFAH1B3 expression was associated with high M1 macrophage and CD8-positive T cell infiltration scores. PAFAH1B3 knockdown inhibited the proliferation, migration, and the activation of oncogenic signaling in gastric cancer cells.ConclusionsOur findings suggest that PAFAH1B3 may be an oncogene in gastric cancer.

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“…In gastric cancer, Yang et al demonstrated that TGFβ2 played a vital role in linking epithelial–mesenchymal transition and tumor mutational burden, which suggested that TGFβ2 may be a predictive therapeutic target for GC [ 48 ]. Wang et al [ 49 ] showed that the tumor-associated macrophages participated in GC cell invasion and metastasis through the TGFβ2/ nuclear factor kappa B /Kindlin-2 axis, providing a possibility for new treatment options and approaches. In this study, we found the level of TGFβ2 was not only significantly changed among different patients’ tumor stages, states, T categories, and grades as described above, but also up-regulated in patients with GC vs the normal (Additional file 12 : Table S11, Additional file 13 : Table S12, Fig.…”

Section: Discussionmentioning

confidence: 99%

Identification of the subtypes of gastric cancer based on DNA methylation and the prediction of prognosis

Chen

et al. 2020

Clin Epigenet

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Background Gastric cancer (GC) is a digestive system cancer with a high mortality rate globally. Previous experiences and studies have provided clinicians with ample evidence to diagnose and treat patients with reasonable therapeutic options. However, there remains a need for sensitive biomarkers that can provide clues for early diagnosis and prognosis assessment. Results We found 610 independent prognosis-related 5′-cytosine-phosphate-guanine-3′ (CpG) sites (P < 0.05) among 21,121 sites in the training samples. We divided the GC samples into seven clusters based on the selected 610 sites. Cluster 6 had relatively higher methylation levels and high survival rates than the other six clusters. A prognostic risk model was constructed using the significantly altered CpG sites in cluster 6 (P < 0.05). This model could distinguish high-risk GC patients from low-risk groups efficiently with the area under the receiver operating characteristic curve of 0.92. Risk assessment showed that the high-risk patients had poorer prognosis than the low-risk patients. The methylation levels of the selected sites in the established model decreased as the risk scores increased. This model had been validated in testing group and its effectiveness was confirmed. Corresponding genes of the independent prognosis-associated CpGs were identified, they were enriched in several pathways such as pathways in cancer and gastric cancer. Among all of the genes, the transcript level of transforming growth factor β2 (TGFβ2) was changed in different tumor stages, T categories, grades, and patients’ survival states, and up-regulated in patients with GC compared with the normal. It was included in the pathways as pathways in cancer, hepatocellular carcinoma or gastric cancer. The methylation site located on the promoter of TGFβ2 was cg11976166. Conclusions This is the first study to separate GC into different molecular subtypes based on the CpG sites using a large number of samples. We constructed an effective prognosis risk model that can identify high-risk GC patients. The key CpGs sites or their corresponding genes such as TGFβ2 identified in this research can provide new clues that will enable gastroenterologists to make diagnosis or personalized prognosis assessments and better understand this disease.

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Tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through TGFβ2/NF-κB/Kindlin-2 axis

Cited by 41 publications

References 49 publications

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

PAFAH1B3 Expression Is Correlated With Gastric Cancer Cell Proliferation and Immune Infiltration

Identification of the subtypes of gastric cancer based on DNA methylation and the prediction of prognosis

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