Maelstrom Directs Myeloid-Derived Suppressor Cells to Promote Esophageal Squamous Cell Carcinoma Progression via Activation of the Akt1/RelA/IL8 Signaling Pathway

Li, Pupu; Chen, Xinfeng; Qin, Guohui; Yue, Dongli; Zhang, Zhen; Yü, Ping; Wang, Dan; Zhao, Xuan; Song, Mengjia; Zhao, Qitai; Li, Jieyao; Li, Shasha; Wang, Dong; Zhang, Chaoqi; Lian, Jingyao; Cao, Liu; Li, Feng; Huang, Lan; Wang, Liping; Li, Yang; Huang, Jianmin; Li, Hong; Zhang, Bin; Zhang, Yi

doi:10.1158/2326-6066.cir-17-0415

Cited by 31 publications

(37 citation statements)

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“…IL8 plays an important role in angiogenesis, survival, tumor stemness, invasion, metastasis, and immune cell infiltration in breast, lung, prostate, and pancreatic cancer 46 . In ESCC, IL8 directly binds to CXCR1/2 to promote invasion and migration 47,48 . IL8 also recruits myeloid-derived suppressor cells by chemotaxis to promote tumor cell growth 48 .…”

Section: Discussionmentioning

confidence: 99%

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PLAU directs conversion of fibroblasts to inflammatory cancer-associated fibroblasts, promoting esophageal squamous cell carcinoma progression via uPAR/Akt/NF-κB/IL8 pathway

et al. 2021

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Cancer-associated fibroblasts (CAFs) plays an important role in the tumor microenvironment. The heterogeneity of CAFs affects the effect of CAFs on promoting or inhibiting tumors, which can be regulated by other cells in the tumor microenvironment through paracrine methods. The urokinase-type plasminogen activator (PLAU) system mediates cell proliferation, migration, adhesion, and other functions through the proteolytic system, intracellular signal transduction, and chemokine activation. PLAU promotes tumor progression in many tumors. We explored the function of PLAU in ESCC and the influence of PLAU secreted by tumor cells on the heterogeneity of CAFs. We found that PLAU is highly expressed in ESCC, which is related to poor prognosis and can be used as a prognostic marker for ESCC. Through loss-of function and gain-of function experiments, we found that PLAU promoted ESCC proliferation and clone formation via MAPK pathway, and promotes migration by upregulating Slug and MMP9, which can be reversed by the MEK 1/2 inhibitor U0126. At the same time, through sequencing, cytokine detection, and RT-qPCR verification, we found that tumor cells secreted PLAU promoted the conversion of fibroblasts to inflammatory CAFs, which upregulated expression and secretion of IL8 via the uPAR/Akt/NF-κB pathway. The IL8 secreted by CAFs in turn promotes the high expression of PLAU in tumor cells and further promoted the progression of ESCC. In summary, PLAU was not only a prognostic marker of ESCC, which promoted tumor cell proliferation and migration, but also promoted the formation of inflammatory CAFs by the PLAU secreted by tumor cells.

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Section: Discussionmentioning

confidence: 99%

“…In ESCC, IL8 directly binds to CXCR1/2 to promote invasion and migration 47,48 . IL8 also recruits myeloid-derived suppressor cells by chemotaxis to promote tumor cell growth 48 . IL8 is associated with progression, metastasis, inflammation, and poor prognosis in ESCC patients 47 .…”

Section: Discussionmentioning

confidence: 99%

PLAU directs conversion of fibroblasts to inflammatory cancer-associated fibroblasts, promoting esophageal squamous cell carcinoma progression via uPAR/Akt/NF-κB/IL8 pathway

et al. 2021

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“…Of its reported actions, IL-8 has been linked to the recruitment and activation of MDSCs, neutrophils, and other myeloid cell populations to the tumor microenvironment, and the serum concentration of IL-8 is predictive of responses to immunotherapies in melanoma and non-small-cell lung cancer (17, 18). Additionally, it has recently been shown that IL-8 recruits PMN-MDSCs to esophageal squamous cell carcinoma tumors, where the MDSCs promote disease progression and decrease overall survival via TGFβ-mediated Smad2/3 signaling (19). Furthermore, in models of pancreatic cancer, recruitment of MDSCs via IL-8 contributes to the establishment of the metastatic niche, and inhibition of IL-8 reduces the frequency of hepatic metastasis (20).…”

Section: Introductionmentioning

confidence: 99%

IL-6 and IL-8 Are Linked With Myeloid-Derived Suppressor Cell Accumulation and Correlate With Poor Clinical Outcomes in Melanoma Patients

et al. 2019

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We sought to identify tumor-secreted factors that altered the frequency of MDSCs and correlated with clinical outcomes in advanced melanoma patients. We focused our study on several of the many factors involved in the expansion and mobilization of MDSCs. These were identified by measuring circulating concentrations of 13 cytokines and growth factors in stage IV melanoma patients (n = 55) and healthy controls (n = 22). Based on these results, we hypothesized that IL-6 and IL-8 produced by melanoma tumor cells participate in the expansion and recruitment of MDSCs and together would be predictive of overall survival in melanoma patients. We then compared the expression of IL-6 and IL-8 in melanoma tumors to the corresponding plasma concentrations and the frequency of circulating MDSCs. These measures were correlated with clinical outcomes. Patients with high plasma concentrations of either IL-6 (40%) or IL-8 (63%), or both (35%) had worse median overall survival compared to patients with low concentrations. Patients with low peripheral concentrations and low tumoral expression of IL-6 and IL-8 showed decreased frequencies of circulating MDSCs, and patients with low frequencies of MDSCs had better overall survival. We have previously shown that IL-6 is capable of expanding MDSCs, and here we show that MDSCs are chemoattracted to IL-8. Multivariate analysis demonstrated an increased risk of death for subjects with both high IL-6 and IL-8 (HR 3.059) and high MDSCs (HR 4.265). Together these results indicate an important role for IL-6 and IL-8 in melanoma patients in which IL-6 potentially expands peripheral MDSCs and IL-8 recruits these highly immunosuppressive cells to the tumor microenvironment. This study provides further support for identifying potential therapeutics targeting IL-6, IL-8, and MDSCs to improve melanoma treatments.

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“…Activation of the NF-κB pathway is often considered an important link between the in ammatory microenvironment and tumor development 41 . The cytokines downstream of NF-κB in ESCC have been reported to be IL-8 and IL1 2,10,24 . IL1 promotes tumor invasion, tumor-mediated immunosuppression, and tumor stem cell self-renewal28.…”

Section: Discussionmentioning

confidence: 99%

LAMC1, Upregulated by TGFβ in Tumor Cells, Contributed to The Formation of Inflammatory Cancer-Associated Fibroblasts Via NF-kB/CXCL1/STAT3 in Esophageal Squamous Cell Carcinoma.

Fang

Che

Zhang

et al. 2021

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Background: The tumor microenvironment (TME) consists of a variety of cells that interact with each other through cytokines. As an important member of the TME, cancer-associated fibroblasts (CAFs) play an important role in the development of tumor cells, which is influenced by the heterogeneity of CAFs. Transforming growth factor β (TGFβ) not only plays a dual role in the progression of tumor cells directly but also influences tumor cells by regulating the heterogeneity of CAFs. Methods: we explored oncogenes regulated by TGFβ, which were involved in signaling molecules and interactions in the TME. We analyzed sequencing data of TCGA and GSE53625, as well as ESCC cell lines with or without TGFβ1 stimulation, and then we focused on laminin subunit gamma 1 (LAMC1). The upregulation of LAMC1 after TGF-β1 stimulation was examined by western blot (WB), quantitative real time PCR (qRT-PCR) and Chromatin immunoprecipitation (ChIP). We performed gain-of-function and loss-of-function assays to examine the effect of LAMC1 on proliferation and migration of ESCC cells. CAFs were isolated and cocultured with ESCC cells. And conditional medium of shLAMC1 ESCC cells and CAFs with different treatments were collected. RNA-seq of those cells were also performed. Luminex liquid suspension chip detection, ELISA, WB, qRT-PCR and rescue experiments were carried out to reveal the interaction of between ESCC cells and CAFs.Results: LAMC1 was highly expressed in ESCC, affecting the prognosis of patients. Moreover, LAMC1 could be upregulated by TGFβ1 through SMAD4 and SP1 synergistic activation. Further experiments showed that LAMC1 would promote the proliferation and migration of tumor cells mainly via Akt/NF-κB/MMP9 and MMP14. Additionally, LAMC1 would promote CXCL1 secretion mainly by activating NF-κB. Tumor-secreted CXCL1 remodeled the formation of inflammatory CAFs (iCAFs) through CXCR2/pSTAT3. The conditioned medium of iCAFs promoted the proliferation and migration of tumor cells.Conclusions: Our study identified the mechanism by which upregulation of LAMC1 by TGFβ in tumor cells not only promoted ESCC progression but also indirectly induced carcinogenesis by stimulating CXCL1 secretion and promoting the formation of iCAFs. This suggests that LAMC1 could be a potential therapeutic target and prognostic marker for ESCC.

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Maelstrom Directs Myeloid-Derived Suppressor Cells to Promote Esophageal Squamous Cell Carcinoma Progression via Activation of the Akt1/RelA/IL8 Signaling Pathway

Cited by 31 publications

References 50 publications

PLAU directs conversion of fibroblasts to inflammatory cancer-associated fibroblasts, promoting esophageal squamous cell carcinoma progression via uPAR/Akt/NF-κB/IL8 pathway

PLAU directs conversion of fibroblasts to inflammatory cancer-associated fibroblasts, promoting esophageal squamous cell carcinoma progression via uPAR/Akt/NF-κB/IL8 pathway

IL-6 and IL-8 Are Linked With Myeloid-Derived Suppressor Cell Accumulation and Correlate With Poor Clinical Outcomes in Melanoma Patients

LAMC1, Upregulated by TGFβ in Tumor Cells, Contributed to The Formation of Inflammatory Cancer-Associated Fibroblasts Via NF-kB/CXCL1/STAT3 in Esophageal Squamous Cell Carcinoma.

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