Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer

Grimmig, Tanja; Moench, Romana; Kreckel, Jennifer; Haack, Stephanie; Rueckert, Felix; Rehder, Roberta; Tripathi, Sudipta; Ribas, Carmen Austrália Paredes Marcondes; Chandraker, Anil; Germer, Christoph T.; Gasser, Martin; Waaga-Gasser, Ana Maria

doi:10.3390/ijms17122060

Cited by 50 publications

(39 citation statements)

References 45 publications

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“…The receptor CAP1 is reported to be universally overexpressed in pancreatic tumors (Yamazaki et al, ) while the receptor TLR4 is expressed in ~69% of pancreatic tumors (Grimmig et al, ). Similar to its ligand resistin, TLR4 has been reported to be expressed in pancreatic tumors and patients with chronic pancreatitis, but not in healthy individuals (Grimmig et al, ). TLR4 can induce angiogenesis through increased VEGF production and Akt phosphorylation, an effect that can be attenuated by its silencing and inhibition of Akt activation (Sun et al, ).…”

Section: Discussionmentioning

confidence: 99%

Retracted: Resistin effects on pancreatic cancer progression and chemoresistance are mediated through its receptors CAP1 and TLR4

Zhang

Yan

Wang

et al. 2018

Journal Cellular Physiology

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Resistin, secreted by macrophages in tumor microenvironment, has never been investigated in pancreatic cancer models, despite a vibrant tumor microenvironment around pancreatic tumors. We evaluated serum resistin levels in healthy individuals versus pancreatic cancer patients representing different tumor grades. In vitro mechanistic analysis involved MiaPaCa‐2 and SW1990 cells. Resistin signaling depends on binding of resistin to its cognitive receptors. Therefore, we silenced adenylyl cyclase‐associated protein 1 (CAP1) and toll‐like receptor 4 (TLR4), its two known receptors, individually as well as in combination, by short hairpin RNA (shRNA). Effect of resistin on cell proliferation, migration, invasion, cell cycle, and sensitivity to gemcitabine was studied without or with silencing of resistin receptors CAP1 and/or TLR4. The results were also confirmed in vivo in mice xenografted with MiaPaCa‐2 cells without or with receptor silencing. We report high resistin levels in pancreatic cancer patients which correlate positively with tumor grades. We observed a marked reduction in the resistin‐induced proliferation, migration, invasion, and cell cycle of pancreatic cancer cells MiaPaCa‐2 and SW1990 when the receptors were silenced. The results were confirmed in vivo wherein resistin effects were significantly attenuated in MiaPaCa‐2 xenografts with silenced receptors. The combined silencing of CAP1 and TLR4 was found to be most effective in vitro and in vivo. We found activation of STAT3 by resistin in vivo and in vitro which was dependent on the presence of CAP1 and TLR4. Further, resistin was found to induce resistance to gemcitabine through its receptors. Our results describe novel functional roles of resistin with implications toward a better understanding of pancreatic tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Retracted: Resistin effects on pancreatic cancer progression and chemoresistance are mediated through its receptors CAP1 and TLR4

Zhang

Yan

Wang

et al. 2018

Journal Cellular Physiology

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“…TLR-specific stimulation resulted in the activation of mitogen-activated protein kinase signaling and expression of VEGF and platelet-derived growth factor (PDGF). Moreover, TLR activation prompted the expression of Bcl-xL to induce tumor cell proliferation in pancreatic cancer 21. TGF-β has a dual role in tumorigenesis, acting as a tumor suppressor in normal cells and in the early stages of tumor development while promoting carcinogenesis and metastasis in advanced tumor stages 22.…”

Section: Pathologic Mechanism Of Pancreatic Carcinogenesismentioning

confidence: 99%

Anti-cancer Mechanism of Docosahexaenoic Acid in Pancreatic Carcinogenesis: A Mini-review

Park

Kim

2017

J Cancer Prev

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Pancreatic cancer is a highly aggressive malignant tumor of the digestive system and radical resection, which is available to very few patients, might be the only possibility for cure. Since therapeutic choices are limited at the advanced stage, prevention is more important for reducing incidence in high-risk individuals with family history of pancreatic cancer. Epidemiological studies have shown that a high consumption of fish oil or ω3-polyunsaturated fatty acids reduces the risk of pancreatic cancers. Dietary fish oil supplementation has shown to suppress pancreatic cancer development in animal models. Previous experimental studies revealed that several hallmarks of cancer involved in the pathogenesis of pancreatic cancer, such as the resistance to apoptosis, hyper-proliferation with abnormal Wnt/β-catenin signaling, expression of pro-angiogenic growth factors, and invasion. Docosahexaenoic acid (DHA) is a ω3-polyunsaturated fatty acid and rich in cold oceanic fish oil. DHA shows anti-cancer activity by inducing oxidative stress and apoptosis, inhibiting Wnt/β-catenin signaling, and decreasing extracellular matrix degradation and expression of pro-angiogenic factors in pancreatic cancer cells. This review will summarize anti-cancer mechanism of DHA in pancreatic carcinogenesis based on the recent studies.

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“…In previous studies, TLR2 was found to be expressed at a high level in most patients with gastric cancer, and high expression of TLR2 was associated with proliferative genes and indicated a poor prognosis, while other studies have also suggested that TLR2 promotes the development of gastric cancer [15,16]. In pancreatic cancer and breast cancer, TLR2 promotes the proliferation of tumor cells [17,18]. In mantle cell lymphoma, TLR2 promotes the proliferation of tumor cells, and it can also inhibit the cell cycle progression of mantle cell lymphoma, leading to G1 phase arrest [19].…”

Section: Discussionmentioning

confidence: 96%

Effect of TLR2 on the proliferation of inflammation-related colorectal cancer and sporadic colorectal cancer

Meng

Li²,

Zang³

et al. 2020

Cancer Cell Int

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Background: Colitis-associated cancer (CAC) is a complication of inflammatory bowel disease (IBD) with a poor prognosis because it is often diagnosed in advanced stages with local progression or metastasis. Compared with the more common polyp-induced sporadic colorectal cancer (sCRC), CAC has different molecular mechanisms. Toll-like receptor 2 (TLR2) expression is not limited to cells related to inflammation and immune function. High levels of TLR2 expression in tumor tissues of colorectal cancer (CRC) patients have been reported. This report is to investigate the effects of knockout and knockdown of the TLR2 gene on the proliferation of CAC and sCRC. Methods: Twelve C57BL/6 J wild-type mice (WT) and 12 TLR2 knockout mice (TLR2-/-) were used to rapidly establish a colitis-associated cancer (CAC) model via the 1,2-dimethylhydrazine-dextran sodium sulfate (DMH-DSS) method and were divided into the normal WT control group (NC), TLR2 knockout control group (KC), normal wild-type tumor modeling group (NT), and TLR2 knockout tumor modeling group (KT), with 6 mice in each group. The general performance of the mice during modeling, the gross changes of the colon and the rectum, and the pathological score of HE staining were used to observe tumor growth. The expression of TLR2 was detected by immunohistochemistry, and tumor proliferation was detected by Ki67 labeling. Lentivirus carrying TLR2-RNAi was used to stably infect colorectal cancer cells (HCT116 and HT29) to knock down TLR2 gene expression. The experimental groups included the uninfected control group, negative control group, and gene knockdown group. After infection, the expression of TLR2 protein was detected by Western blot, and cell proliferation and the cell cycle were detected by the CCK-8 method and fluorescence-activated cell sorting. Western blot was used to detect the expression levels of p-NF-κβ, cyclin D1 and cyclin D3 protein in each group of cells. Results: TLR2 knockout in the CAC model resulted in greater changes in body weight and more severe diarrhea and colorectal hemorrhage. However, knocking out the TLR2 gene reduced the shortening of colorectal length, the number of tumors, and the total tumor volume and inhibited the growth of CAC. Knocking out the TLR2 gene also reduced the pathological score and tumor severity. TLR2 was localized in the cell membrane of the colorectal epithelium of the NC group and of the colorectal tumors of the NT group and was highly expressed in the NT group, while antigen Ki67 was localized in the nucleus of the colorectal tumor cells of the NT group and the KT group, and its expression was reduced in the KT group. In an in vitro sporadic colorectal cancer cell experiment, TLR2 protein in the TLR2 knockdown group was significantly downregulated, and TLR2 knockdown significantly inhibited the

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Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer

Cited by 50 publications

References 45 publications

Retracted: Resistin effects on pancreatic cancer progression and chemoresistance are mediated through its receptors CAP1 and TLR4

Retracted: Resistin effects on pancreatic cancer progression and chemoresistance are mediated through its receptors CAP1 and TLR4

Anti-cancer Mechanism of Docosahexaenoic Acid in Pancreatic Carcinogenesis: A Mini-review

Effect of TLR2 on the proliferation of inflammation-related colorectal cancer and sporadic colorectal cancer

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