Induction of TRIF- or MYD88-dependent pathways perturbs cell cycle regulation in pancreatic cancer

Zambirinis, Constantinos P.; Ochi, Atsuo; Barilla, Rocky; Greco, Stephanie H.; Deutsch, Michael; Miller, George

doi:10.4161/cc.24488

Cited by 13 publications

(7 citation statements)

References 7 publications

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“…We previously reported that Toll-like receptor (TLR) ligation accelerates pancreatic cancer progression whereas blockade of select TLR signaling pathways can be protective[ 22 , 44 ]. Therefore, we postulated that TLR inhibition may be protective against pancreatic cancer cachexia.…”

Section: Resultsmentioning

confidence: 99%

TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia

et al. 2015

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Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti-TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-β inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.

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Section: Resultsmentioning

confidence: 99%

TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia

et al. 2015

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“…The results of the presented studies suggest that a decreased expression of MyD88 can facilitate the development of pancreatic cancer and should be considered important in the monitoring of disease progression. It should be emphasized that synthetic inhibitors of MyD88 pathway were shown to exacerbate pancreatic fibro-inflammation and accelerate carcinogenesis [ 45 ], while mice deprived of TLR2 and the MyD88 adaptor protein were more susceptible to infections [ 63 ]. The reason for the reduced gene expression of MyD88 is difficult to explain, but it is undoubtedly an alarming symptom associated with the development of pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the lipid A analogue (OM-174) with a dual stimulating effect on TLR2 and TLR4 receptors, induces regression of several tumor types in animal models [ 42 – 44 ]. Induction of MyD88 and TRIF, downstream TLR pathways, perturbs cell cycle regulation in pancreatic cancer [ 45 ]. TRAF6 upregulates the expression of hypoxia-inducible factor (HIF-1α) and promotes tumor angiogenesis [ 46 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical immunology Gene expression disorders of innate antibacterial signaling pathway in pancreatic cancer patients: implications for leukocyte dysfunction and tumor progression

Słotwiński¹,

Dąbrowska²,

Lech³

et al. 2014

cejoi

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The study was carried out to investigate changes in gene expression of innate antibacterial signaling pathways in patients with pancreatic cancer. Expression of the following genes was measured in peripheral blood leukocytes of 55 patients with pancreatic adenocarcinoma using real-time polymerase chain reaction (RT-PCR): TLR4, NOD1, MyD88, TRAF6 and HMGB1. The levels of expression of TLR4, NOD1 and TRAF6 genes were significantly elevated (p = 0.007; p = 0.001 and p = 0.01, respectively), while MyD88 expression was markedly reduced (p = 0.0002), as compared to controls. Expression of TLR4 and NOD1 exceeded the normal level more than 3.5-fold and there was a significant correlation found between the expression of these genes (r = 0.558, p < 0.001). TLR4, NOD1 and MyD88 genes were expressed at a similar level both before and after surgery. No significant changes in the expression of HMGB1 gene were observed. The results of the study clearly indicate abnormal expression of genes belonging to innate antibacterial signaling pathways in peripheral blood leukocytes of patients with pancreatic cancer, which may lead to leukocyte dysfunction. Overexpression of TLR4, NOD1 and TRAF6 genes, and decreased MyD88 gene expression may contribute to chronic inflammation and tumor progression by up-regulation of the innate antibacterial response. The parameters tested are useful for monitoring innate immunity gene disorders and pancreatic cancer progression.

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“…Activation of TLR4 signaling by LPS profoundly increased the EMT of pancreatic cancer cells, and M2-polarized TAMs promoted the EMT in pancreatic cancer cells, partially through the TLR4/IL-10 signaling pathway [69]. TLR4 activation was shown to accelerate pancreatic cancer development, while MyD88 blockade using synthetic inhibitors accelerated pancreatic fibro-inflammation and carcinogenesis [70]. More specifically, this meant that MyD88 blockade resulted in an invasive pancreatic adenocarcinoma within 3 weeks in p48Cre;Kras G12D mice treated with caerulein compared with the development of early PanIN lesions in age-matched mice with intact MyD88 signaling.…”

Section: Innate Antibacterial Signalingmentioning

confidence: 99%

“…In contrast, the lipid A analogue (OM-174), with a dual stimulating effect on TLR2 and TLR4 receptors, induced regression of several tumor types in animal models [75–77]. Induction of MyD88 and TRIF, downstream of TLR pathways, perturbed cell cycle regulation in pancreatic cancer [70]. Other data demonstrated that protein (mRNA) expression of TLR4, NF-κB p65 and HIF-1α (hypoxia-inducible transcription factor 1α) in pancreatic tumor tissues was increased by 69%, 66% and 70%, respectively, which was significantly higher compared to adjacent normal tissues.…”

Section: Innate Antibacterial Signalingmentioning

confidence: 99%

Dysregulation of signaling pathways associated with innate antibacterial immunity in patients with pancreatic cancer

Słotwiński

Słotwińska

2016

cejoi

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Disorders of innate antibacterial response are of fundamental importance in the development of gastrointestinal cancers, including pancreatic cancer. Multi-regulatory properties of the Toll-like receptors (TLRs) (e.g., regulation of proliferation, the activity of NF-κB, gene transcription of apoptosis proteins, regulation of angiogenesis, HIF-1α protein expression) are used in experimental studies to better understand the pathogenesis of pancreatic cancer, for early diagnosis, and for more effective therapeutic intervention. There are known numerous examples of TLR agonists (e.g., TLR2/5 ligands, TLR6, TLR9) of antitumor effect. The direction of these studies is promising, but a small number of them does not allow for an accurate assessment of the impact of TLR expression disorders, proteins of these signaling pathways, or attempts to block or stimulate them, on the results of treatment of pancreatic cancer patients. It is known, however, that the expression disorders of proteins of innate antibacterial response signaling pathways occur not only in tumor tissue but also in peripheral blood leukocytes of pancreatic cancer patients (e.g., increased expression of TLR4, NOD1, TRAF6), which is one of the most important factors facilitating further tumor development. This review mainly focuses on the genetic aspects of signaling pathway disorders associated with innate antibacterial response in the pathogenesis and diagnosis of pancreatic cancer.

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Induction of TRIF- or MYD88-dependent pathways perturbs cell cycle regulation in pancreatic cancer

Cited by 13 publications

References 7 publications

TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia

TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia

Clinical immunology Gene expression disorders of innate antibacterial signaling pathway in pancreatic cancer patients: implications for leukocyte dysfunction and tumor progression

Dysregulation of signaling pathways associated with innate antibacterial immunity in patients with pancreatic cancer

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