bims-stacyt 2017-12-24 papers

Immunol Rev. 2018 Jan;281(1): 57-61

IL-1 and IL-1 regulatory pathways in cancer progression and therapy.

Alberto Mantovani, Isabella Barajon, Cecilia Garlanda.

Inflammation is an important component of the tumor microenvironment. IL-1 is an inflammatory cytokine which plays a key role in carcinogenesis and tumor progression. IL-1 is subject to regulation by components of the IL-1 and IL-1 receptor (ILR) families. Negative regulators include a decoy receptor (IL-1R2), receptor antagonists (IL-1Ra), IL-1R8, and anti-inflammatory IL-37. IL-1 acts at different levels in tumor initiation and progression, including driving chronic non-resolving inflammation, tumor angiogenesis, activation of the IL-17 pathway, induction of myeloid-derived suppressor cells (MDSC) and macrophage recruitment, invasion and metastasis. Based on initial clinical results, the translation potential of IL-1 targeting deserves extensive analysis.

Keywords: inflammation; inflammation-associated cancer; interleukin-1; therapy

DOI: https://doi.org/10.1111/imr.12614

Immunol Rev. 2018 Jan;281(1): 138-153

Interleukin-18: Biological properties and role in disease pathogenesis.

Gilles Kaplanski.

Initially described as an interferon (IFN)γ-inducing factor, interleukin (IL)-18 is indeed involved in Th1 and NK cell activation, but also in Th2, IL-17-producing γδ T cells and macrophage activation. IL-18, a member of the IL-1 family, is similar to IL-1β for being processed by caspase 1 to an 18 kDa-biologically active mature form. IL-18 binds to its specific receptor (IL-18Rα, also known as IL-1R7) forming a low affinity ligand chain. This is followed by recruitment of the IL-18Rβ chain. IL-18 then uses the same signaling pathway as IL-1 to activate NF-kB and induce inflammatory mediators such as adhesion molecules, chemokines and Fas ligand. IL-18 also binds to the circulating high affinity IL-18 binding protein (BP), such as only unbound free IL-18 is active. IL-18Rα may also bind IL-37, another member of the IL-1 family, but in association with the negative signaling chain termed IL-1R8, which transduces an anti-inflammatory signal. IL-18BP also binds IL-37 and this acts as a sink for the anti-inflammatory properties of IL-37. There is now ample evidence for a role of IL-18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease. However, IL-18 plays a very specific role in the pathogenesis of hemophagocytic syndromes (HS) also termed Macrophage Activation Syndrome. In children affected by NLRC4 gain-of-function mutations, IL-18 circulates in the range of tens of nanograms/mL. HS is treated with the IL-1 Receptor antagonist (anakinra) but also specifically with IL-18BP. Systemic juvenile idiopathic arthritis or adult-onset Still's disease are also characterized by high serum IL-18 concentrations and are treated by IL-18BP.

Keywords: hemophagocytic syndromes; inflammatory diseases; interferon γ; interleukin-1; interleukin-18; interleukin-18 binding protein

DOI: https://doi.org/10.1111/imr.12616

Semin Oncol. 2017 Jun;pii: S0093-7754(17)30133-1. [Epub ahead of print]44(3): 198-203

Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development.

Lindsay Wilde, Megan Roche, Marina Domingo-Vidal, Katherina Tanson, Nancy Philp, Joseph Curry, Ubaldo Martinez-Outschoorn.

Glucose is a key metabolite used by cancer cells to generate ATP, maintain redox state and create biomass. Glucose can be catabolized to lactate in the cytoplasm, which is termed glycolysis, or alternatively can be catabolized to carbon dioxide and water in the mitochondria via oxidative phosphorylation. Metabolic heterogeneity exists in a subset of human tumors, with some cells maintaining a glycolytic phenotype while others predominantly utilize oxidative phosphorylation. Cells within tumors interact metabolically with transfer of catabolites from supporting stromal cells to adjacent cancer cells. The Reverse Warburg Effect describes when glycolysis in the cancer-associated stroma metabolically supports adjacent cancer cells. This catabolite transfer, which induces stromal-cancer metabolic coupling, allows cancer cells to generate ATP, increase proliferation, and reduce cell death. Catabolites implicated in metabolic coupling include the monocarboxylates lactate, pyruvate, and ketone bodies. Monocarboxylate transporters (MCT) are critically necessary for release and uptake of these catabolites. MCT4 is involved in the release of monocarboxylates from cells, is regulated by catabolic transcription factors such as hypoxia inducible factor 1 alpha (HIF1A) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and is highly expressed in cancer-associated fibroblasts. Conversely, MCT1 is predominantly involved in the uptake of these catabolites and is highly expressed in a subgroup of cancer cells. MYC and TIGAR, which are genes involved in cellular proliferation and anabolism, are inducers of MCT1. Profiling human tumors on the basis of an altered redox balance and intra-tumoral metabolic interactions may have important biomarker and therapeutic implications. Alterations in the redox state and mitochondrial function of cells can induce metabolic coupling. Hence, there is interest in redox and metabolic modulators as anticancer agents. Also, markers of metabolic coupling have been associated with poor outcomes in numerous human malignancies and may be useful prognostic and predictive biomarkers.

Keywords: TIGAR; caveolin 1; glycolysis; hypoxia inducible factor; lactate; oxidative phosphorylation

DOI: https://doi.org/10.1053/j.seminoncol.2017.10.004

Cancer Lett. 2017 Dec 13. pii: S0304-3835(17)30790-5. [Epub ahead of print]

Hypoxia-induced microRNA-590-5p promotes colorectal cancer progression by modulating matrix metalloproteinase activity.

Chan Woo Kim, Eun-Taex Oh, Joon Mee Kim, Jin-Seok Park, Don Haeng Lee, Jae-Seon Lee, Kyung Keun Kim, Heon Joo Park.

Hypoxia leads to cancer progression and promotes the metastatic potential of cancer cells. MicroRNAs (miRNAs) are small non-coding RNA that have emerged as key players involved in cancer development and progression. Hypoxia alters a set of hypoxia-mediated miRNAs expression during tumor development and it may function as oncogenes or tumor-suppressors. However, the roles and molecular mechanisms of hypoxia-regulatory miRNAs in colorectal cancer (CRC) progression remain poorly understood. Here we firstly identified miR-590-5p as hypoxia-sensitive miRNAs which was upregulated in colon cancer cells under hypoxia. Hypoxia-induced miR-590-5p suppressed the expression of RECK, in turn, promoting cell invasiveness and migratory abilities via activation of matrix metalloproteinases (MMPs) and filopodia protrusion in vitro. Inhibition of miR-590-5p suppressed tumor growth and metastasis in mouse xenograft and CRC liver metastasis models via inhibition of MMPs activity. Clinical analysis revealed higher miR-590-5p expression in CRC, compared to normal specimens. Furthermore, miR-590-5p expression was significantly increased in liver metastasis as compared to their matched primary CRC. Taken together, our findings provide the first evidence that miR-590-5p may have potential as a therapeutic target for CRC patients with metastasis.

Keywords: Colorectal cancer; Hypoxia; Metastasis; Tumor progression; microRNA

DOI: https://doi.org/10.1016/j.canlet.2017.12.018

Mol Immunol. 2017 Dec 14. pii: S0161-5890(17)30610-7. [Epub ahead of print]94 27-35

Fatty acid oxidation contributes to IL-1β secretion in M2 macrophages and promotes macrophage-mediated tumor cell migration.

Qi Zhang, Herui Wang, Chengyuan Mao, Mitchell Sun, Gifty Dominah, Liyuan Chen, Zhengping Zhuang.

Tumor-associated macrophages (TAMs) are predominantly M2 phenotype in solid cancers including hepatocellular carcinoma (HCC). Though differentiation of M2 macrophages has been recently linked to fatty acid oxidation (FAO), whether FAO plays a role in functional maintenance of M2 macrophages is still unclear. Here, we used an in vitro model to mimic TAM-HCC interaction in tumor microenvironment. We found that M2 monocyte-derived macrophages (MDMs) enhanced the proliferation, migration, and invasion of HCC cells through an FAO-dependent way. Further investigations identified that IL-1β mediated the pro-migratory effect of M2 MDM. Using etomoxir and siRNA to inhibit FAO and palmitate to enhance FAO, we showed that FAO was responsible for the up-regulated secretion of IL-1β and, thus, the pro-migratory effect in M2 MDMs. In addition, we proved that IL-1β induction was reactive oxygen species and NLRP3-dependent. Our study demonstrates that FAO plays a key role in functional human M2 macrophages by enhancing IL-1β secretion to promote HCC cell migration. These findings provide evidence for different dependency of energy sources in macrophages with distinct phenotypes and functions, and suggest a novel strategy to treat HCC by reprogramming cell metabolism or modulating tumor microenvironment.

Keywords: Epithelial-to-mesenchymal transition; Inflammation; Metabolism; Tumor-associated macrophage; β-Oxidation

DOI: https://doi.org/10.1016/j.molimm.2017.12.011

Neoplasia. 2017 Dec 13. pii: S1476-5586(17)30403-7. [Epub ahead of print]20(2): 131-139

Hypoxia Inducible Factors Modify Collagen I Fibers in MDA-MB-231 Triple Negative Breast Cancer Xenografts.

Eibhlin Goggins, Samata Kakkad, Yelena Mironchik, Desmond Jacob, Flonne Wildes, Balaji Krishnamachary, Zaver M Bhujwalla.

Hypoxia inducible factors (HIFs) are transcription factors that mediate the response of cells to hypoxia. HIFs have wide-ranging effects on metabolism, the tumor microenvironment (TME) and the extracellular matrix (ECM). Here we investigated the silencing effects of two of the three known isoforms, HIF-1α and HIF-2α, on collagen 1 (Col1) fibers, which form a major component of the ECM of tumors. Using a loss-of-function approach for HIF-1α or 2α or both HIF-1α and 2α, we identified a relationship between HIFs and Col1 fibers in MDA-MB-231 tumors. Tumors derived from MDA-MB-231 cells with HIF-1α or 2α or both HIF-1α and 2α silenced contained higher percent fiber volume and lower inter-fiber distance compared to tumors derived from empty vector MDA-MB-231 cells. Depending upon the type of silencing, we observed changes in Col1 degrading enzymes, and enzymes involved in Col1 synthesis and deposition. Additionally, a reduction in lysyl oxidase protein expression in HIF-down-regulated tumors suggests that more non-cross-linked fibers were present. Collectively these results identify the role of HIFs in modifying the ECM and the TME and provide new insights into the effects of hypoxia on the tumor ECM.

DOI: https://doi.org/10.1016/j.neo.2017.11.010

Cell Immunol. 2017 Dec 08. pii: S0008-8749(17)30223-X. [Epub ahead of print]

The tumor microenvironment: Thousand obstacles for effector T cells.

Chiara Massa, Barbara Seliger.

The immune system is endowed with the capability to recognize and destroy transformed cells, but even in the presence of an immune infiltrate many tumors do progress. In the last decades new discoveries have shed light into (some of) the underlying mechanisms. Immune effector cells are not only under the influence of immune suppressive cell subsets, but also intrinsically regulated by immune check point molecules that under physiological condition avoid attach of healthy tissue. Moreover, tumor cells are modifying the surrounding microenvironment through secretion of immune modulators as well as via their own metabolism, thus further impairing the development of immune effector functions. Different approaches are currently being evaluated in the clinic to overcome those regulatory mechanisms and to unleash effector T cells.

Keywords: Effector T cells; Immune check point; Tumor microenvironment

DOI: https://doi.org/10.1016/j.cellimm.2017.12.004

Semin Oncol. 2017 Jun;pii: S0093-7754(17)30134-3. [Epub ahead of print]44(3): 218-225

Hodgkin lymphoma: A complex metabolic ecosystem with glycolytic reprogramming of the tumor microenvironment.

Lekha Mikkilineni, Diana Whitaker-Menezes, Marina Domingo-Vidal, John Sprandio, Paola Avena, Paolo Cotzia, Alina Dulau-Florea, Jerald Gong, Guldeep Uppal, Tingting Zhan, Benjamin Leiby, Zhao Lin, Barbara Pro, Federica Sotgia, Michael P Lisanti, Ubaldo Martinez-Outschoorn.

BACKGROUND: Twenty percent of patients with classical Hodgkin Lymphoma (cHL) have aggressive disease defined as relapsed or refractory disease to initial therapy. At present we cannot identify these patients pre-treatment. The microenvironment is very important in cHL because non-cancer cells constitute the majority of the cells in these tumors. Non-cancer intra-tumoral cells, such as tumor-associated macrophages (TAMs) have been shown to promote tumor growth in cHL via crosstalk with the cancer cells. Metabolic heterogeneity is defined as high mitochondrial metabolism in some tumor cells and glycolysis in others. We hypothesized that there are metabolic differences between cancer cells and non-cancer tumor cells, such as TAMs and tumor-infiltrating lymphocytes in cHL and that greater metabolic differences between cancer cells and TAMs are associated with poor outcomes.
METHODS: A case-control study was conducted with 22 tissue samples of cHL at diagnosis from a single institution. The case samples were from 11 patients with aggressive cHL who had relapsed after standard treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or were refractory to this treatment. The control samples were from 11 patients with cHL who achieved a remission and never relapsed after ABVD. Reactive non-cancerous lymph nodes from four subjects served as additional controls. Samples were stained by immunohistochemistry for three metabolic markers: translocase of the outer mitochondrial membrane 20 (TOMM20), monocarboxylate transporter 1 (MCT1), and monocarboxylate transporter 4 (MCT4). TOMM20 is a marker of mitochondrial oxidative phosphorylation (OXPHOS) metabolism. Monocarboxylate transporter 1 (MCT1) is the main importer of lactate into cells and is a marker of OXPHOS. Monocarboxylate transporter 4 (MCT4) is the main lactate exporter out of cells and is a marker of glycolysis. The immunoreactivity for TOMM20, MCT1, and MCT4 was scored based on staining intensity and percentage of positive cells, as follows: 0 for no detectable staining in > 50% of cells; 1+ for faint to moderate staining in > 50% of cells, and 2+ for high or strong staining in > 50% of cells.
RESULTS: TOMM20, MCT1, and MCT4 expression was significantly different in Hodgkin and Reed Sternberg (HRS) cells, which are the cancerous cells in cHL compared with TAMs and tumor-associated lymphocytes. HRS have high expression of TOMM20 and MCT1, while TAMs have absent expression of TOMM20 and MCT1 in all but two cases. Tumor-infiltrating lymphocytes have low TOMM20 expression and absent MCT1 expression. Conversely, high MCT4 expression was found in TAMs, but absent in HRS cells in all but one case. Tumor-infiltrating lymphocytes had absent MCT4 expression. Reactive lymph nodes in contrast to cHL tumors had low TOMM20, MCT1, and MCT4 expression in lymphocytes and macrophages. High TOMM20 and MCT1 expression in cancer cells with high MCT4 expression in TAMs is a signature of high metabolic heterogeneity between cancer cells and the tumor microenvironment. A high metabolic heterogeneity signature was associated with relapsed or refractory cHL with a hazard ratio of 5.87 (1.16-29.71; two-sided P < .05) compared with the low metabolic heterogeneity signature.
CONCLUSION: Aggressive cHL exhibits features of metabolic heterogeneity with high mitochondrial metabolism in cancer cells and high glycolysis in TAMs, which is not seen in reactive lymph nodes. Future studies will need to confirm the value of these markers as prognostic and predictive biomarkers in clinical practice. Treatment intensity may be tailored in the future to the metabolic profile of the tumor microenvironment and drugs that target metabolic heterogeneity may be valuable in this disease.

Keywords: Hodgkin lymphoma; glycolysis; ketone bodies; lactate; mitochondria; oxidative phosphorylation

DOI: https://doi.org/10.1053/j.seminoncol.2017.10.003

Immunol Rev. 2018 Jan;281(1): 88-98

Metabolic regulation of NLRP3.

Mark M Hughes, Luke A J O'Neill.

A shift in our understanding of macrophage biology has come about as a result of recent discoveries in the area of metabolic reprogramming of macrophages. The NLRP3 inflammasome drives the activation of caspase-1, leading to the production of IL-1β, IL-18, and a type of cell death termed pyroptosis. The NLRP3 inflammasome has been shown to sense metabolites such as palmitate, uric acid, and cholesterol crystals and is inhibited by ketone bodies produced during metabolic flux. The NLRP3 inflammasome has also been shown to be regulated by mitochondrial reactive oxygen species and components of glycolysis, such as Hexokinase. Here, we review these findings and discuss their importance for inflammation and furthermore discuss potential therapeutic benefits of targeting NLRP3.

Keywords: Krebs cycle; NLRP3; glycolysis; inflammasome; inflammation; metabolism

DOI: https://doi.org/10.1111/imr.12608

Vet Immunol Immunopathol. 2018 Jan;pii: S0165-2427(17)30061-2. [Epub ahead of print]195 1-6

Decreased plasma amino acid concentrations in cats with chronic gastrointestinal diseases and their possible contribution in the inflammatory response.

Kosei Sakai, Shingo Maeda, Tomohiro Yonezawa, Naoaki Matsuki.

In humans, plasma amino acids (AAs) levels are used as dynamic nutritional markers. Moreover, some AAs are associated with chronic inflammation. In this study, we analyzed plasma AA profiles in cats with chronic gastrointestinal (GI) diseases. Eight healthy controls (HCs) and 12 client-owned cats with chronic GI diseases including chronic enteritis (n=8) and neoplasms (n=4) were recruited. Plasma albumin, total protein, and 22 AAs (11 essential and 11 non-essential AAs) levels were estimated. There was no significant difference in plasma albumin and total protein concentrations between the cats with chronic GI diseases and HCs. The plasma concentrations of 7 essential AAs (arginine, histidine, lysine, methionine, phenylalanine, taurine, and tryptophan) and 7 non-essential AAs (asparagine, aspartic acid, glutamic acid, glycine, hydroxyproline, proline, and serine) were significantly decreased in the cats with chronic GI diseases (P<0.05). Moreover, plasma histidine and tryptophan levels were inversely correlated with severity of symptoms (histidine: rs=-0.7781, P<0.005; tryptophan: rs=-0.6040, P<0.05). To examine the contribution of altered AAs levels in the inflammatory response, feline macrophages were stimulated by lipopolysaccharides (LPS) with or without histidine, and the expression of interleukin-8 (IL-8) mRNA was quantified. The expression of IL-8 mRNA was significantly increased in the LPS-stimulated feline macrophages (P<0.05). Histidine almost suppressed the LPS-induced IL-8 expression in the feline macrophages (P<0.05). Our findings suggest that plasma AAs levels are more sensitive nutritional markers than albumin and total protein levels in cats with chronic GI diseases. There is a possibility that the decrease of histidine levels in cats with GI diseases is associated with chronic inflammation.

Keywords: Cats; Chronic enteritis; Histidine; Inflammation; Intestinal neoplasms; Nutritional marker

DOI: https://doi.org/10.1016/j.vetimm.2017.11.001