bims-stacyt 2018-11-25 papers

bims-stacyt

Biomed News

on Paracrine crosstalk between cancer and the organism

Issue of 2018‒11‒25
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

Immune regulation and anti-cancer activity by lipid inflammatory mediators.
The effect of low-level laser irradiation on hyperglycemia-induced inflammation in human gingival fibroblasts.
Hyperglycemia aggravates microenvironment hypoxia and promotes the metastatic ability of pancreatic cancer.
Role of endoplasmic reticulum stress in pro-inflammatory cytokine-mediated inhibition of trophoblast invasion in placenta-related complications of pregnancy.
A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia.
Sestrin2 regulates monocyte activation through AMPK-mTOR nexus under high-glucose and dyslipidemic conditions.
Insulin-like growth factor receptor signaling in breast tumor epithelium protects cells from endoplasmic reticulum stress and regulates the tumor microenvironment.

Int Immunopharmacol. 2018 Nov 14. pii: S1567-5769(18)30921-4. [Epub ahead of print]65 580-592

Immune regulation and anti-cancer activity by lipid inflammatory mediators.

Saraswoti Khadge, John Graham Sharp, Timothy R McGuire, Geoffrey M Thiele, Paul Black, Concetta DiRusso, Leah Cook, Lynell W Klassen, James E Talmadge.

  Rodent and clinical studies have documented that myeloid cell infiltration of tumors is associated with poor outcomes, neutrophilia and lymphocytopenia. This contrasts with increased lymphocyte infiltration of tumors, which is correlated with improved outcomes. Lifestyle parameters, such as obesity and diets with high levels of saturated fat and/or omega (ω)-6 polyunsaturated fatty acids (PUFAs), can influence these inflammatory parameters, including an increase in extramedullary myelopoiesis (EMM). While tumor secretion of growth factors (GFs) and chemokines regulate tumor-immune-cell crosstalk, lifestyle choices also contribute to inflammation, abnormal pathology and leukocyte infiltration of tumors. A relationship between obesity and high-fat diets (notably saturated fats in Western diets) and inflammation, tumor incidence, metastasis and poor outcomes is generally accepted. However, the mechanisms of dietary promotion of an inflammatory microenvironment and targeted drugs to inhibit the clinical sequelae are poorly understood. Thus, modifications of obesity and dietary fat may provide preventative or therapeutic approaches to control tumor-associated inflammation and disease progression. Currently, the majority of basic and clinical research does not differentiate between obesity and fatty acid consumption as mediators of inflammatory and neoplastic processes. In this review, we discuss the relationships between dietary PUFAs, inflammation and neoplasia and experimental strategies to improve our understanding of these relationships. We conclude that dietary composition, notably the ratio of ω-3 vs ω-6 PUFA regulates tumor growth and the frequency and sites of metastasis that together, impact overall survival (OS) in mice.

Keywords:  High fat diet; Immune escape; Infiltration; Inflammation; MDSC; PUFA; TAM; Tumor induction; Tumor progression

DOI:  https://doi.org/10.1016/j.intimp.2018.10.026
Lasers Med Sci. 2018 Nov 19.

The effect of low-level laser irradiation on hyperglycemia-induced inflammation in human gingival fibroblasts.

Kun-Tsung Denzel Lee, Min-Hsuan Chiang, Ping-Ho Chen, Mei-Ling Ho, Hong-Zin Lee, Huey-Er Lee, Yan-Hsiung Wang.

  Hyperglycemia-induced inflammation can greatly increase the risk of periodontal disease in people with diabetes. Low-level laser irradiation (LLLI) has been used for wound healing and anti-inflammation in many cases, and LLLI is known to inhibit the lipopolysaccharide (LPS)-stimulated inflammatory response. However, the therapeutic effect of LLLI in diabetes patients with periodontitis remains unknown. In this study, we cultured human gingival fibroblasts (HGFs) in high-glucose medium (35 mM) to mimic a hyperglycemic environment, and then measured the anti-inflammatory effect of LLLI by assessing the expression of pro-inflammatory genes including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-8 by quantitative real-time polymerase chain reaction. The results demonstrated no significant inflammatory response in HGFs cultured in mannitol medium and in those treated only with LLLI. However, HGFs cultured only in high-glucose medium showed significantly higher expression of pro-inflammatory cytokine than in those treated together with LLLI. We then observed that LLLI reduced the expression of pro-inflammatory cytokines in HGFs cultured in high-glucose medium by modulating cAMP signaling. We also investigated whether antioxidant (vitamin C) treatment reduced the inflammatory effect of oxidative stress in HGFs cultured in high-glucose medium but found no additive effect upon co-treatment with LLLI, suggesting that LLLI may activate cAMP signaling, but not reactive oxygen species (ROS) signaling, to reduce the high glucose-induced inflammation. In conclusion, LLLI may have an anti-inflammatory effect on HGFs in a high glucose environment and may benefit the treatment of periodontal disease in diabetes patients.

Keywords:  Hyperglycemia; Low level laser irradiation; Pro-inflammatory cytokines; Reactive oxygen species; Vitamin C

DOI:  https://doi.org/10.1007/s10103-018-2675-6
Comput Struct Biotechnol J. 2018 ;16 479-487

Hyperglycemia aggravates microenvironment hypoxia and promotes the metastatic ability of pancreatic cancer.

Wei Li, Han Liu, Weikun Qian, Liang Cheng, Bin Yan, Liang Han, Qinhong Xu, Qingyong Ma, Jiguang Ma.

  Background: Diabetes mellitus and pancreatic cancer are intimately related. Our previous studies showed that high levels of blood glucose promote epithelial-mesenchymal transition of pancreatic cancer. In this study, we evaluated the relationship between hyperglycemia and hypoxic tumor microenvironments.Methods: HIF-1α expression was evaluated by immunohistochemistry in clinical pancreatic cancer tissues with or without diabetes mellitus. Statistcal analysis was performed to explore the relationship between HIF-1α expression and pathological features of patients with pancreatic cancer. In vivo and in vitro models was established to detect whether a hyperglycemia environment could cause hypoxia in the pancreatic parenchyma and promote pancreatic cancer. In addition, we also tested the effect of HIF-1α siRNA on the high glucose-induced invasive and migratory abilities of BxPC-3 cells in culture.
Result: Our data showed that pancreatic cancer patients with diabetes had a higher level of HIF-1α expression as well as biliary duct invasion and larger tumor volumes than individuals in the euglycemic group. Diabetic nude mice treated with streptozotocin (STZ) exhibited larger tumors and were more likely to develop liver metastasis than control mice. Acinar cells of the pancreas in diabetic mice showed an obvious expansion of the endoplasmic reticulum and increased nuclear gaps as well as chromatin close to the cellular membrane in some acinar cells. The expression area for Hypoxyprobe-1 and HIF-1α in the diabetic orthotopic xenograft group was larger than that in the control group. The expression level of HIF-1α in the BxPC-3 cancer cell line increased in response to high glucose and CoCl2 concentrations. The high glucose-induced invasive ability, migratory capacity and MMP-9 expression were counter-balanced by siRNA specific to HIF-1α.
Conclusion: Our results demonstrate that the association between hyperglycemia and poor prognosis can be attributed to microenvironment hypoxia in pancreatic cancer.

Keywords:  CCL2, chemical chemokine 2; CoCl2, cobalt chloride; ECM, endothelial cells, extracellular matrix; EGF, epidermal growth factor; EMT, epithelial-mesenchymal transition; GDNF, glial cell line-derived neurotrophic factor; H2O2, hydrogen peroxide; HIF-1α; HIF-1α, hypoxia-inducible factor 1α; Hyperglycemia; Hypoxia; Metastasis; PNI, perineural invasion; PSC, pancreatic stellate cells; Pancreatic cancer; SOD, superoxide dismutase; STZ, streptozotocin; TEM, transmission electron microscopy; VEGF, vascular endothelial growth factor

DOI:  https://doi.org/10.1016/j.csbj.2018.10.006
Am J Pathol. 2018 Nov 15. pii: S0002-9440(18)30582-0. [Epub ahead of print]

Role of endoplasmic reticulum stress in pro-inflammatory cytokine-mediated inhibition of trophoblast invasion in placenta-related complications of pregnancy.

Cheuk-Lun Lee, Jan H W Veerbeek, Tirtha K Rana, Bas B van Rijn, Graham J Burton, Hong Wa Yung.

Shallow extravillous trophoblast (EVT) invasion is central to the pathophysiology of many pregnancy complications. Invasion is mediated partially by matrix metalloproteinases (MMPs). MMP-2 is highly expressed in early pregnancy. MMP activity can be regulated by pro-inflammatory cytokines, which also induce endoplasmic reticulum (ER) stress in other cells. We investigated whether pro-inflammatory cytokines regulate MMP-2 activity through ER stress response pathways in trophoblast, before exploring potential regulatory mechanisms. There was increased immunoreactivity of HSPA5, also known as GRP78, in cells of the placental bed, including EVTs, in cases of early-onset preeclampsia compared to normotensive controls. Treating EVT-like JEG3 and HTR8/SVneo cells with ER stress inducers, tunicamycin and thapsigargin, suppressed MMP2 mRNA and protein expression, secretion, activity, and reduced their invasiveness. A cocktail of pro-inflammatory cytokines, interleukin-1β, tumor necrosis factor-α, and interferon-γ, suppressed MMP-2 activity in JEG-3 cells, and was accompanied by activation of the PERK-EIF2A arm of the ER stress pathway. Knockdown of ATF4, a downstream transcriptional factor of the PERK-EIF2A pathway, by small interference RNA, restored MMP2 expression but not cellular proteins. However, suppression of EIF2A phosphorylation with a PERK inhibitor, GSK2606414, under ER stress, restored MMP-2 protein. ER stress regulates MMP-2 expression at both the transcriptional and translational levels. This study provides the first mechanistic linkage by which pro-inflammatory cytokines may modulate trophoblast invasion through ER stress pathways.

DOI: https://doi.org/10.1016/j.ajpath.2018.10.015
Cell Rep. 2018 Nov 20. pii: S2211-1247(18)31696-6. [Epub ahead of print]25(8): 2044-2052.e5

A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia.

Jeroen Baardman, Sanne G S Verberk, Koen H M Prange, Michel van Weeghel, Saskia van der Velden, Dylan G Ryan, Rob C I Wüst, Annette E Neele, Dave Speijer, Simone W Denis, Maarten E Witte, Riekelt H Houtkooper, Luke A O'neill, Elena V Knatko, Albena T Dinkova-Kostova, Esther Lutgens, Menno P J de Winther, Jan Van den Bossche.

  Metabolic reprogramming has emerged as a crucial regulator of immune cell activation, but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic, and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory macrophage responses. In addition to diminished maximal mitochondrial respiration, hypercholesterolemia reduces the LPS-mediated induction of the pentose phosphate pathway (PPP) and the Nrf2-mediated oxidative stress response. Our observation that suppression of the PPP diminishes LPS-induced cytokine secretion supports the notion that this pathway contributes to inflammatory macrophage responses. Overall, this study reveals that systemic and cellular metabolism are strongly interconnected, together dictating macrophage phenotype and function.

Keywords:  Nrf2; atherosclerosis; cardiovascular disease; foam cells; hypercholesterolemia; immunometabolism; inflammation; macrophages; meta-inflammation; metabolic disease; pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.celrep.2018.10.092
J Cell Biochem. 2018 Nov 18.

Sestrin2 regulates monocyte activation through AMPK-mTOR nexus under high-glucose and dyslipidemic conditions.

Saravanakumar Sundararajan, Isaivani Jayachandran, Muthuswamy Balasubramanyam, Viswanathan Mohan, Balachandar Venkatesan, Nagaraj Manickam.

  The vicious cycle between hyperinsulinemia and insulin resistance results in the progression of atherosclerosis in the vessel wall. The complex interaction between hyperglycemia and lipoprotein abnormalities promotes the development of atherogenesis. In the early phase of atherosclerosis, macrophage-derived foam cells play an important role in vascular remodeling. Mechanistic target of rapamycin (mTOR) signaling pathway has been identified to play an essential role in the initiation, progression, and complication of atherosclerosis. Recently sestrin2, an antioxidant, was shown to modulate TOR activity and thereby regulating glucose and lipid metabolism. But the role of sestrin2 in monocyte activation is still not clearly understood. Hence, this study is focussed on investigating the role of sestrin2 in monocyte activation under hyperglycemic and dyslipidemic conditions. High-glucose and oxidized low-density lipoprotein (LDL) treatments mediated proinflammatory cytokine production (M1) with a concomitant decrease in the anti-inflammatory cytokine (M2) levels in human monocytic THP1 cells. Both glucose and oxidized LDL (OxLDL) in a dose and time-dependent manner increased the mTOR activation with a marked reduction in the levels of pAMPK and sestrin2 expression. Both high-glucose and OxLDL treatment increased foam cell formation and adhesion of THP1 cells to endothelial cells. Experiments employing activator or inhibitor of adenosine monophosphate kinase (AMPK) as well as overexpression or silencing of sestrin2 indicated that high-glucose mediated monocyte polarization and adhesion of monocytes to the endothelial cells were appeared to be programmed via sestrin2-AMPK-mTOR nexus. Our results evidently suggest that sestrin2 plays a major role in regulating monocyte activation via the AMPK-mTOR-pathway under diabetic and dyslipidemic conditions and also AMPK regulates sestrin2 in a feedback mechanism.

Keywords:  atherogenesis; diabetes; dyslipidemia; monocyte activation; sestrin2

DOI:  https://doi.org/10.1002/jcb.28102
Breast Cancer Res. 2018 Nov 20. 20(1): 138

Insulin-like growth factor receptor signaling in breast tumor epithelium protects cells from endoplasmic reticulum stress and regulates the tumor microenvironment.

Alison E Obr, Sushil Kumar, Yun-Juan Chang, Joseph J Bulatowicz, Betsy J Barnes, Raymond B Birge, Deborah A Lazzarino, Emily Gallagher, Derek LeRoith, Teresa L Wood.

  BACKGROUND: Early analyses of human breast cancer identified high expression of the insulin-like growth factor type 1 receptor (IGF-1R) correlated with hormone receptor positive breast cancer and associated with a favorable prognosis, whereas low expression of IGF-1R correlated with triple negative breast cancer (TNBC). We previously demonstrated that the IGF-1R acts as a tumor and metastasis suppressor in the Wnt1 mouse model of TNBC. The mechanisms for how reduced IGF-1R contributes to TNBC phenotypes is unknown.METHODS: We analyzed the METABRIC dataset to further stratify IGF-1R expression with patient survival and specific parameters of TNBC. To investigate molecular events associated with the loss of IGF-1R function in breast tumor cells, we inhibited IGF-1R in human cell lines using an IGF-1R blocking antibody and analyzed MMTV-Wnt1-mediated mouse tumors with reduced IGF-1R function through expression of a dominant-negative transgene.
RESULTS: Our analysis of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset revealed association between low IGF-1R and reduced overall patient survival. IGF-1R expression was inversely correlated with patient survival even within hormone receptor-positive breast cancers, indicating reduced overall patient survival with low IGF-1R was not due simply to low IGF-1R expression within TNBCs. Inhibiting IGF-1R in either mouse or human tumor epithelial cells increased reactive oxygen species (ROS) production and activation of the endoplasmic reticulum stress response. IGF-1R inhibition in tumor epithelial cells elevated interleukin (IL)-6 and C-C motif chemokine ligand 2 (CCL2) expression, which was reversed by ROS scavenging. Moreover, the Wnt1/dnIGF-1R primary tumors displayed a tumor-promoting immune phenotype. The increased CCL2 promoted an influx of CD11b+ monocytes into the primary tumor that also had increased matrix metalloproteinase (MMP)-2, MMP-3, and MMP-9 expression. Increased MMP activity in the tumor stroma was associated with enhanced matrix remodeling and collagen deposition. Further analysis of the METABRIC dataset revealed an increase in IL-6, CCL2, and MMP-9 expression in patients with low IGF-1R, consistent with our mouse tumor model and data in human breast cancer cell lines.
CONCLUSIONS: Our data support the hypothesis that reduction of IGF-1R function increases cellular stress and cytokine production to promote an aggressive tumor microenvironment through infiltration of immune cells and matrix remodeling.

Keywords:  Breast cancer; CCL2; Cellular stress; IGF-1R; IL-6; MMP; Wnt1

DOI:  https://doi.org/10.1186/s13058-018-1063-2