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IL23 and TGF-ß diminish macrophage associated metastasis in pancreatic carcinoma.

ABSTRACT: The precise role of tumor associated macrophages remains unclear in pancreatic ductal adenocarcinoma (PDAC) while TGF-ß has an unclear role in metastases formation. In order to understand the role of IL23, an interleukin associated with macrophage polarization, we investigated IL23 in the context of TGF-ß expression in PDAC. We hypothesized that IL23 expression is associated with metastatic development and survival in PDAC. We investigated IL23 and TGF-ß protein expression on resected PDAC patient tumor sections who were divided into short-term (<12 months) survivors and long-term (>30 months) survivors. Panc-1 cells treated with IL23, TGF-ß, macrophages, or combinations thereof, were orthotopically implanted into NSG mice. Patients in the long-term survivor group had higher IL23 protein expression (P?=?0.01). IL23 expression was linearly correlated with TGF-ß expression in patients in the short-term survivor group (P?=?0.038). Macrophages induce a higher rate of PDAC metastasis in the mouse model (P?=?0.02), which is abrogated by IL23 and TGF-ß treatment (P?

SUBMITTER: Hussain SM

PROVIDER: S-EPMC5895618 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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IL23 and TGF-ß diminish macrophage associated metastasis in pancreatic carcinoma.

Hussain S Mazher SM Reed Leighton F LF Krasnick Bradley A BA Miranda-Carboni Gustavo G Fields Ryan C RC Bi Ye Y Elahi Abul A Ajidahun Abidemi A Dickson Paxton V PV Deneve Jeremiah L JL Hawkins William G WG Shibata David D Glazer Evan S ES

Scientific reports 20180411 1

The precise role of tumor associated macrophages remains unclear in pancreatic ductal adenocarcinoma (PDAC) while TGF-ß has an unclear role in metastases formation. In order to understand the role of IL23, an interleukin associated with macrophage polarization, we investigated IL23 in the context of TGF-ß expression in PDAC. We hypothesized that IL23 expression is associated with metastatic development and survival in PDAC. We investigated IL23 and TGF-ß protein expression on resected PDAC patie ...[more]

PMID: 29643359

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Project description:BackgroundPancreatic cancer characterizes high recurrence and poor prognosis. In clinical practice, radiotherapy is widely used for pancreatic cancer treatment. However, the outcome remains undesirable due to tumor repopulation and following recurrence and metastasis after radiation. So, it is highly needed to explore the underlying molecular mechanisms and accordingly develop therapeutic strategies. Our previous studies revealed that dying cells from chemoradiation could stimulate repopulation of surviving pancreatic cancer cells. However, we still knew little how dying cells provoke pancreatic cancer cell repopulation. We herein would explore the significance of TGF-β2 changes and investigate the modulation of microRNA-193a (miR-193a), and identify their contributions to pancreatic cancer repopulation and metastasis.MethodsIn vitro and in vivo repopulation models were established to mimic the biological processes of pancreatic cancer after radiation. Western blot, real-time PCR and dual-luciferase reporter assays were accordingly used to detect miR-193a and TGF-β2/TGF-βRIII signalings at the level of molecular, cellular and experimental animal model, respectively. Flow cytometry analysis, wound healing and transwell assay, vascular endothelial cell penetration experiment, and bioluminescence imaging were employed to assessthe biological behaviors of pancreatic cancer after different treatments. Patient-derived tumor xenograft (PDX) mice models were established to evaluate the therapeutic potential of miR-193a antagonist on pancreatic cancer repopulation and metastasis after radiation.ResultsmiR-193a was highly expressed in the irradiated pancreatic cancer dying cells, accordingly elevated the level of miR-193a in surviving cells, and further promoted pancreatic cancer repopulation and metastasis in vitro and in vivo. miR-193a accelerated pancreatic cancer cell cycle and stimulated cell proliferation and repopulation through inhibiting TGF-β2/TGF-βRIII/SMADs/E2F6/c-Myc signaling, and even destroyed normal intercellular junctions and promoted metastasis via repressing TGF-β2/TGF-βRIII/ARHGEF15/ABL2 pathway. Knockdown of miR-193a or restoration of TGF-β2/TGF-βRIII signaling in pancreatic cancer cells was found to block pancreatic cancer repopulation and metastasis after radiation. In PDX models, the treatment in combination with miR-193a antagonist and radiation was found to dramatically inhibit pancreatic cancer cell repopulation and metastasis, and further improved the survival after radiation.ConclusionsOur findings demonstrated that miR-193a stimulated pancreatic cancer cell repopulation and metastasis through modulating TGF-β2/TGF-βRIII signalings, and miR-193a might be a potential therapeutic target for pancreatic cancer repopulation and metastasis.

Project description:Tumor microenvironment, and particularly tumor-associated macrophages (TAMs), represent a key contributing factor in pancreatic ductal adenocarcinoma (PDAC) pathogenesis. Here we report that heparanase (predominant enzyme degrading heparan sulfate, the main polysaccharide found at the cell surface and extracellular matrix) directs tumor-promoting behavior of TAM in PDAC. A mouse model of heparanase-overexpressing pancreatic carcinoma (n = 5 mice/group), tumor-associated macrophages ex vivo, primary wild-type and heparanase-null macrophages, and histological specimens from PDAC patients (n = 16), were analyzed, applying immunostaining, enzyme-linked immunosorbent assay, real-time reverse transcription-polymerase chain reaction, cell proliferation, and heparanase activity assays. All statistical tests are two-sided. We found that overexpression of heparanase is associated with increased TAM infiltration in both experimental (P = .002) and human (P = .01) PDAC. Moreover, macrophages derived from heparanase-rich tumors (which grew faster in mouse hosts), display pronounced procancerous phenotype, evidenced by overexpression of MSR-2, IL-10, CCL2, VEGF, and increased production of IL-6, an important player in PDAC pathogenesis. Furthermore, in vitro heparanase enzyme-rendered macrophages (stimulated by necrotic cells which are often present in PDAC tissue) procancerous, as exemplified by their enhanced production of key cytokines implicated in PDAC (including IL-6), as well as by their ability to induce STAT3 signaling and to augment pancreatic carcinoma cell proliferation. In agreement, we observed activation of STAT3 in experimental and clinical specimens of heparanase-overexpressing PDAC. Our findings underscore a novel function of heparanase in molecular decision-making that guides cancer-promoting action of TAM and imply that heparanase expression status may become highly relevant in defining a target patient subgroup that is likely to benefit the most from treatment modalities targeting TAM/IL-6/STAT3.

Project description:BackgroundActivation of NLRP3 in liver macrophages contributes to alcohol-associated liver disease (ALD). Molecular chaperone heat shock protein (HSP) 90 facilitates NLRP3 inflammasome activity during infections and inflammatory diseases. We previously reported that HSP90 is induced in ALD and regulates proinflammatory cytokines, tumor necrosis factor alpha, and IL-6. Whether HSP90 affects IL-1β and IL-18 regulated by NLRP3 inflammasome in ALD is unknown. Here, we hypothesize that HSP90 modulated NLRP3 inflammasome activity and affects IL-1β and IL-18 secretion in ALD.MethodsThe expression of HSP90AA1 and NLRP3 inflammasome genes was evaluated in human alcoholic livers and in mouse model of ALD. The importance of HSP90 on NLRP3 inflammasome activation in ALD was evaluated by administering HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) to mice subjected to ALD, and in vitro to bone marrow-derived macrophages (BMDM) stimulated with LPS and ATP. The effect of activation of HSF1/HSPA1A axis during HSP90 inhibition or direct activation during heat shock of BMDMs on NLRP3 activity and secretion of downstream cytokines was evaluated.ResultsWe found positive correlation between induction of HSP90 and NLRP3 inflammasome genes in human alcoholic cirrhotic livers. Administration of 17-DMAG in mouse model of ALD significantly down-regulated NLRP3 inflammasome-mediated caspase-1 (CASP-1) activity and cytokine secretion, with reduction in ALD. 17-DMAG-mediated decrease in NLRP3 was restricted to liver macrophages. Using BMDMs, we show that inhibition of HSP90 prevented CASP-1 activity, and Gasdermin D (GSDMD) cleavage, important in release of active IL-1β and IL-18. Interestingly, activation of the heat shock factor 1 (HSF1)/HSPA1A axis, either during HSP90 inhibition or by heat shock, decreased NLRP3 inflammasome activity and reduced secretion of cytokines.ConclusionOur studies indicate that inhibition of HSP90 and activation of HSF1/HSPA1A reduce IL-1β and IL-18 via decrease in NLRP3/CASP-1 and GSDMD activity in ALD.

Dataset Information

IL23 and TGF-ß diminish macrophage associated metastasis in pancreatic carcinoma.

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IL23 and TGF-ß diminish macrophage associated metastasis in pancreatic carcinoma.

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