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Cytokines are signaling proteins which are produced by white blood cells. They help mediate and regulate immune responses, inflammation, and the formation of new blood cells (hematopoiesis).

There are many different types of cytokines; some of which are synthesised for use in the treatment of cancer (particulaly Interferon Alpha and Interleukin 2. Also, a class of cytokines called hematopoietic growth factors, can be used to promote the production of blood cells to counteract some of the cytotoxic side effects of chemotherapy.

"Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner." (Source: MeSH)

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Web Resources: Cytokines
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Interferon Alpha
Interleukin 2 (Aldesleukin)
Tumor Necrosis Factors

Web Resources: Cytokines (6 links)

Latest Research Publications

Bushehri A, Czarnota G, Zhang L, et al.
Urinary cytokines/chemokines after magnetic resonance-guided high intensity focused ultrasound for palliative treatment of painful bone metastases.
Ann Palliat Med. 2017; 6(1):36-54 [PubMed] Related Publications
BACKGROUND: Pain is experienced by 50-75% of patients with bone metastases, representing a major source of morbidity amongst cancer patients. Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is a new, non-invasive, outpatient treatment modality for painful bone metastases. The aim of this study was to analyze urinary cytokines/chemokines pattern after MRgHIFU for palliative treatment of painful bone metastases. The findings were compared to the cytokines/chemokines pattern post single 8 Gy fraction radiation from our previous study.
METHODS: Urine samples were collected from patients with painful bone metastases 3 days before and 2 days after treatment with MRgHIFU. Each urine sample was tested for pro-inflammatory cytokines and anti-inflammatory cytokines. Patients received teaching on how to collect urine samples on their own. The Millipore Milliplex 42-Plex Cytokine/Chemokine Kit™ was used to measure urinary levels of a panel of cytokines/chemokines.
RESULTS: Ten patients were enrolled for the study. The following 15 cytokines were above the level of detection (LOD) in at least 50% of patients at both pre MRgHIFU and post MRgHIFU: EGF, eotaxin, Fit-3 ligand, fractalkine, G-CSF, GRO, IFNα2, IL-1ra, IL-8, IP-10, MCP-1, PDGF-AA, RANTES, sIL-2Rα, and VEGF. Nine urinary cytokines significantly decreased post MRgHIFU, namely, eotaxin, GRO, IL-8, IL-13, IP-10, MCP-1, MIP-1β, RANTES, and sIL-2Rα. In addition, there were significant differences between post MRgHIFU and post-8 Gy fraction radiation in most urinary cytokines.
CONCLUSIONS: Nine urinary cytokines significantly reduced post-MRgHIFU in patients with painful bone metastases. The significance of cytokines/chemokines pattern for palliative treatment of painful bone metastases is still unknown.

Živný JH, Leahomschi S, Klener P, et al.
Comparison of Plasma Osteopontin Levels between Patients with Borderline Ovarian Tumours and Serous Ovarian Carcinoma.
Folia Biol (Praha). 2016; 62(6):258-262 [PubMed] Related Publications
Osteopontin (OPN) is a novel biomarker of various cancers including ovarian carcinoma. OPN is a promising adjunct to a major biomarker of ovarian cancer, CA125, in diagnosis, differential diagnosis and prognosis. The aim of our study was to measure the plasma level of OPN and CA125 in patients with borderline ovarian tumours (BOTs), serous ovarian carcinoma, and controls to determine its potential role in the differential diagnosis between serous ovarian carcinoma and BOT. The plasma samples of 66 women were analysed using Luminex technology, designed to simultaneously measure multiple specific protein targets. The mean OPN plasma level for the control group was 23.3 ng/ml; for BOT 26.3 ng/ml; and for patients with serous ovarian carcinoma 59.5 ng/ml. Specifically, there was a significant difference between the OPN levels in patients with ovarian carcinoma and BOT (P < 0.001) as well as controls (P < 0.001). There was no difference between the mean levels of OPN in patients with BOT and the control group (P = 0.286). Using the receiver operating characteristic (ROC), we determined the utility of OPN and CA125 to differentiate between BOT and serous ovarian carcinoma. The area under the ROC curve (AUC) for OPN was 0.793 (95% confidence interval (CI) 0.669-0.917, P < 0.001) and for CA125 0.766 (95% CI 0.626-0.907, P = 0.002). Based on our data, we suggest that OPN can be used as a possible differential diagnostic biomarker to distinguish between malignant serous ovarian carcinoma and BOT.

Wichmann G, Cedra S, Schlegel D, et al.
Cilengitide and Cetuximab Reduce Cytokine Production and Colony Formation of Head and Neck Squamous Cell Carcinoma Cells Ex Vivo.
Anticancer Res. 2017; 37(2):521-527 [PubMed] Related Publications
BACKGROUND/AIM: To analyze ex vivo effects of combined targeting of the epidermal growth factor-receptor (EGFR) by cetuximab (E) plus αVβ3 and αVβ5 integrins by cilengitide (Cil) on colony formation of epithelial cells (CFec) and release of pro-angiogenetic and pro-inflammatory cytokines in head and neck squamous cell carcinoma (HNSCC) cells.
MATERIALS AND METHODS: Collagenase-IV digests of 43 histopathological confirmed HNSCC cases were seeded into laminin-coated 96-well plates containing E, Cil, or Cil+E in final concentrations of 66.7 μg/ml, 10 μM, and 10 μM+66.7 μg/ml, respectively. Following the FLAVINO-assay protocol, supernatants were harvested after 3 days and adherent cells fixed in ethanol. Counting of CFec was facilitated by FITC-labeled pan-cytokeratin antibodies. Out of 43 HNSCC cases, 39 had adherent growth (mean CFec≥4/well in triplicate controls). Cytokines in supernatants were measured using ELISA were interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) and vascular endothelial growth factor A (VEGFA).
RESULTS: CFec on laminin was significantly reduced by Cil, E, and Cil+E. Cytokine measurements also revealed significant suppression of MCP-1, IL-6 and VEGFA. The strongest suppression of CFec, MCP-1 and VEGFA release was exerted by Cil and E combined. Efficacy of Cil+E exceeded those of the solely applied pharmaceutics but failed regarding significant synergism of both treatments as E was unable to significantly boost the effects of Cil. In contrast, IL-6 release was significantly suppressed by E but not by Cil, while their combination strongly reduced it.
CONCLUSION: Combined targeting of EGFR and integrins with E and Cil heightens their suppressive effects regarding CFec as well as release of pro-angiogenetic and pro-inflammatory cytokines.

Gutiérrez-Rodríguez A, Hansberg-Pastor V, Camacho-Arroyo I
Proliferative and Invasive Effects of Progesterone-Induced Blocking Factor in Human Glioblastoma Cells.
Biomed Res Int. 2017; 2017:1295087 [PubMed] Free Access to Full Article Related Publications
Progesterone-induced blocking factor (PIBF) is a progesterone (P4) regulated protein expressed in different types of high proliferative cells including astrocytomas, the most frequent and aggressive brain tumors. It has been shown that PIBF increases the number of human astrocytoma cells. In this work, we evaluated PIBF regulation by P4 and the effects of PIBF on proliferation, migration, and invasion of U87 and U251 cells, both derived from human glioblastomas. PIBF mRNA expression was upregulated by P4 (10 nM) from 12 to 24 h. Glioblastoma cells expressed two PIBF isoforms, 90 and 57 kDa. The content of the shorter isoform was increased by P4 at 24 h, while progesterone receptor antagonist RU486 (10 μM) blocked this effect. PIBF (100 ng/mL) increased the number of U87 cells on days 4 and 5 of treatment and induced cell proliferation on day 4. Wound-healing assays showed that PIBF increased the migration of U87 (12-48 h) and U251 (24 and 48 h) cells. Transwell invasion assays showed that PIBF augmented the number of invasive cells in both cell lines at 24 h. These data suggest that PIBF promotes proliferation, migration, and invasion of human glioblastoma cells.

Kim HW, Lee JC, Paik KH, et al.
Serum interleukin-6 is associated with pancreatic ductal adenocarcinoma progression pattern.
Medicine (Baltimore). 2017; 96(5):e5926 [PubMed] Free Access to Full Article Related Publications
Several reports showed that interleukin-6 (IL-6) or -8 (IL-8) might be useful inflammatory biomarkers for pancreatic ductal adenocarcinoma (PDAC), although these clinical impact is still open to debate. The aim of this study was to elucidate whether serum levels of IL-6 and IL-8 at diagnosis could predict the tumor progression pattern of PDAC, especially in extensive hepatic metastasis.According to the tumor burden of hepatic metastasis at the last follow-up, tumor progression pattern was defined as follows: no or limited (unilobar involvement and 5 or less in the within liver, limited group) and extensive hepatic metastasis (bilobar or more than 5, progressed group). Fifty-three PDAC patients with initially no or limited hepatic metastasis were enrolled retrospectively.Around 42 (79.2%) were included in the limited and 11 (20.8%) in the progressed group. The median serum level of IL-6 in the progressed group was elevated significantly compared with the limited group. However, the median serum level of IL-8 was not. Furthermore, multivariate analysis revealed that the elevated serum level of IL-6 was an independent risk factor for progression to extensive hepatic metastasis (odds ratio 1.928, 95% confidence interval 1.131-3.365, P = 0.019), but IL-8 was not. However, higher IL-6 did not predict shorter survival.High serum IL-6 can be an independent risk factor for progression to extensive hepatic metastasis in PDAC patients.

Wang P, Wang J, Yu M, Li Z
Tumor Necrosis Factor-α T-857C (rs1799724) Polymorphism and Risk of Cancers: A Meta-Analysis.
Dis Markers. 2016; 2016:4580323 [PubMed] Free Access to Full Article Related Publications
Objectives. To investigate the potential association of tumor necrosis factor-α T-857C polymorphism with susceptibility to the five common malignant tumors. Materials and Methods. A comprehensive search of PubMed/Medline, Embase, and Web of Science databases was performed up to November 2015. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to assess the strength of the association. Subgroup analysis, heterogeneity analyses, and publication bias were also texted in the meta-analysis. Results. A total of twenty-two publications involving 5215 cases and 6755 controls were recruited. Overall, the meta-analysis revealed an increased risk between the TNF-α T-857C polymorphism and gastric cancer susceptibility in T versus C model, heterozygote genetic model, and dominant genetic model. An increased risk between the TNF-α T-857C polymorphism and hepatocellular cancer susceptibility in homozygote genetic model and recessive genetic model was also found. No significant association was found between the TNF-α T-857C polymorphism and colorectal cancer, cervical cancer, and prostate cancer. Conclusions. Our meta-analyses suggest that TNF-α T-857C polymorphism may be associated with increased risk of gastric cancer and hepatocellular cancer development. Therefore, the TNF-α T-857C polymorphism could be considered as one possible risk factor of gastric cancer and hepatocellular cancer according to our study.

Feng J, Yan PF, Zhao HY, et al.
Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway.
Biomed Res Int. 2016; 2016:1450843 [PubMed] Free Access to Full Article Related Publications
Overcoming temozolomide (TMZ) resistance is a great challenge in glioblastoma (GBM) treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide and has a crucial role in cancer cell metabolism. In this study, we investigated whether FK866 and CHS828, two specific NAMPT inhibitors, could sensitize GBM cells to TMZ. Low doses of FK866 and CHS828 (5 nM and 10 nM, resp.) alone did not significantly decrease cell viability in U251-MG and T98 GBM cells. However, they significantly increased the antitumor action of TMZ in these cells. In U251-MG cells, administration of NAMPT inhibitors increased the TMZ (100 μM)-induced apoptosis and LDH release from GBM cells. NAMPT inhibitors remarkably enhanced the activities of caspase-1, caspase-3, and caspase-9. Moreover, NAMPT inhibitors increased reactive oxygen species (ROS) production and superoxide anion level but reduced the SOD activity and total antioxidative capacity in GBM cells. Treatment of NAMPT inhibitors increased phosphorylation of c-Jun and JNK. Administration of JNK inhibitor SP600125 or ROS scavenger tocopherol with TMZ and NAMPT inhibitors substantially attenuated the sensitization of NAMPT inhibitor on TMZ antitumor action. Our data indicate a potential value of NAMPT inhibitors in combined use with TMZ for GBM treatment.

Kamal A, Darwish RK, Saad S, et al.
Association of Osteopontin Gene Polymorphisms with Colorectal Cancer.
Cancer Invest. 2017; 35(2):71-77 [PubMed] Related Publications
We investigated the association of the Osteopontin (OPN) (rs9138 and rs1126616) polymorphisms with colorectal cancer (CRC). One hundred CRC patients and 112 healthy individuals were subjected to OPN (rs9138 and rs1126616) genotyping and measurement of OPN protein plasma level. The C allele of OPN rs1126616 and the CC haplotype were significantly higher in CRC patient (p = 0.036, 0.003, respectively). In females, the C allele of OPN rs9318 (A/C) polymorphism was significantly associated with increased CRC risk (p = 0.036). The plasma OPN level >104.35 ng/mL was significantly associated with CRC. Our findings suggest a significant role played by OPN (rs9138 and rs1126616) in colorectal carcinogenesis.

Liu W, Liu SY, He YB, et al.
MiR-451 suppresses proliferation, migration and promotes apoptosis of the human osteosarcoma by targeting macrophage migration inhibitory factor.
Biomed Pharmacother. 2017; 87:621-627 [PubMed] Related Publications
Previous studies have shown that MiR-451 plays an important role in human osteosarcoma carcinogenesis, but the underlying mechanism by which MiR-451 affects the osteosarcoma has not been fully understood. This study intends to uncover the mechanism by which MiR-451 functions as a tumor suppressor. The expression of MiR-451 in osteosarcoma tissues and osteosarcoma cell lines was monitored by real-time PCR. The proliferation ability was examined by MTT and cell cycle assay. The migration and apoptosis of cells were monitored by migration assay and flow cytometry, respectively. Moreover, the angiogenesis of HUVEC cells transfected with MiR-451 mimics was examined by tube formation assay. The effect of MiR-451 on MIF was determined by luciferase assays and Western blot assay. The results showed that MiR-451 expression level was significantly reduced in the osteosarcoma compared with normal bone tissues. Overexpression of MiR-451 significantly attenuated the proliferation and migration, and induced the apoptosis of osteosarcoma cells. Furthermore, the angiogenesis of HUVEC cells transfected with MiR-451 mimics was assayed and the decreased angiogenic ability was detected compared to the controls. Finally, we demonstrated that MiR-451 overexpression inhibited the malignant behavior of osteosarcoma by downregulating MIF. These findings suggest that MiR-451 may act as a tumor suppressor in osteosarcoma. MiR-451 inhibited cell proliferation, migration and angiogenesis and promoted apoptosis of human osteosarcoma cells, at least partially, by inhibiting the expression of MIF. MiR-451/MIF may be a novel therapeutic target in treatment of osteosarcoma.

Makowiecka A, Simiczyjew A, Nowak D, Mazur AJ
Varying effects of EGF, HGF and TGFβ on formation of invadopodia and invasiveness of melanoma cell lines of different origin.
Eur J Histochem. 2016; 60(4):2728 [PubMed] Free Access to Full Article Related Publications
The understanding of melanoma malignancy mechanisms is essential for patient survival, because melanoma is responsible for ca. 75% of deaths related to skin cancers. Enhanced formation of invadopodia and extracellular matrix (ECM) degradation are two important drivers of cell invasion, and actin dynamics facilitate protrusive activity by providing a driving force to push through the ECM. We focused on the influence of epidermal growth factor (EGF), hepatocyte growth factor (HGF) and transforming growth factor β (TGFβ) on melanoma cell invasiveness, since they are observed in the melanoma microenvironment. All three factors stimulated invasion of A375 and WM1341D cells derived from primary tumor sites. In contrast, only EGF and HGF stimulated invasion of WM9 and Hs294T cells isolated from lymph node metastases. Enhanced formation of invadopodia and ECM degradation underlie the increased amount of invasive cells after stimulation with the tested agents. Generally, a rise in invasive potential was accompanied by a decrease in actin polymerization state (F:G ratio). The F:G ratio remained unchanged or was even increased in metastatic cell lines treated with TGFβ. Our findings indicate that the effects of stimulation with EGF, HGF and TGFβ on melanoma cell invasiveness could depend on melanoma cell progression stage.

Zuo ZK, Gong Y, Chen XH, et al.
TGFβ1-Induced LncRNA UCA1 Upregulation Promotes Gastric Cancer Invasion and Migration.
DNA Cell Biol. 2017; 36(2):159-167 [PubMed] Related Publications
According to recent studies, long noncoding RNA urothelial carcinoma associated 1 (UCA1) is involved in the development and progression of many malignant tumors, including gastric cancer (GC). We validated the detailed role of UCA1 in human GC cell lines and GC tissues so as to determine its exact function and the underlying mechanism of GC invasion and migration. In our research, lncRNA-UCA1 was specifically upregulated in GC tissues and cell lines, and augmented GC cell proliferation, and invasive and migratory capabilities. High UCA1 expression in GC was related with poorer prognosis (poorer invasion depth, lymph node metastasis, advanced TNM [T is for the original (primary) tumor, N for nearby (regional) lymph nodes that are involved, and M for distant metastasis] stage, and shorter overall survival). Epithelial mesenchymal transition (EMT), associated with malignancy of cancers, was reported to be responsible for invasion and migration of cancer cells. Transforming growth factor β1 (TGFβ1)-induced EMT was well evaluated. UCA1 silence reduced the protein levels of EMT-related factors, vimentin and snail, while promoted E-cadherin and zonula occludens-1 protein levels in GC cells; the effect of UCA1 could be partly restored by TGFβ1 treatment. Taken together, UCA1 might regulate the tumor proliferation, invasion, and metastasis under TGFβ1 induction. Taken together, UCA1 might present a potential oncogenic factor by promoting GC cell proliferation, invasion, and migration. UCA1 could serve as a novel biomarker for prognosis and a novel therapeutic target of GC treatment.

Lee SH, Jin YJ, Shin JY, Lee JW
Assessment of hepatocellular carcinoma risk based on peg-interferon plus ribavirin treatment experience in this new era of highly effective oral antiviral drugs.
Medicine (Baltimore). 2017; 96(1):e5321 [PubMed] Free Access to Full Article Related Publications
In this new era of highly effective oral antiviral drugs for chronic hepatitis C virus (HCV), indications for antiviral treatment may be extendable. This study undertaken to identify suitable candidates for peg-interferon plus ribavirin (PEG-IFN/RBV) treatment by evaluating hepatocellular carcinoma (HCC) risk in patients with chronic HCV treated or not with PEG-IFN/RBV.This large-scale retrospective study was conducted on 1176 patients with chronic HCV without a history of HCC (treatment group [n = 489] and no-treatment group [n = 687]). In the treatment group, patients treated with PEG-IFN/RBV were dichotomized based on the achievement of sustained virologic response (SVR) into SVR (+) and SVR (-) groups.Median follow-up for all study subjects was 31 months (range 6-144 months). Three-year cumulative HCC development rates in the SVR (+) (1.1%) and SVR (-) (8.6%) subgroups were significantly lower than in the no-treatment group (13.5%) (P < 0.01 and P < 0.01, respectively). In all study subjects, presence of cirrhosis (hazard ratio [HR], 9.92, P < 0.01), age (HR 1.03, P < 0.01), SVR (-) (HR 7.02, P < 0.01), and no-treatment (HR 6.76, P < 0.01) were found to be independent risk factors of HCC development. In the treatment group, age, the presence of cirrhosis, and SVR (-) were predictors of HCC development. In the no-treatment group, age, male, and the presence of cirrhosis were independent predictors for HCC development.HCC risk increased in patients with chronic HCV with older age, cirrhosis, SVR (-) after PEG-IFN/RBV treatment, and no PEG-IFN/RBV treatment. Active antiviral therapy based on highly effective oral drugs needs to be considered in these patients.

Sagara A, Karasawa T, Igarashi K, et al.
Controlled Secretion of the Anticancer Protein MDA-7 from Engineered Mesenchymal Stem Cells.
Biol Pharm Bull. 2017; 40(1):113-117 [PubMed] Related Publications
Mesenchymal stem cells (MSCs) have been explored as a "live" carrier of cytokines for targeted cancer therapy, but, in earlier reports in the literature, the secretion process of therapeutic cytokines was not regulated. The purpose of this study was to generate MSCs to conditionally secrete the melanoma differentiation-associated gene-7 (MDA-7) tumor-suppressor protein. To control the secretion of MDA-7 from MSCs, a well-established tetracycline-controlled transcriptional activation system was incorporated into MDA-7 plasmid. MDA-7 gene expression was induced in the engineered MSCs only in the presence of doxycycline, as characterized by quantitative reverse transcription (qRT)-PCR. Enzyme-linked immunosorbent assay (ELISA) also revealed that the MDA-7 protein was secreted from the engineered MSCs only after the cells had been exposed to doxycycline. Both recombinant human MDA-7 protein and the conditioned medium from the engineered MSCs in the presence of doxycycline significantly inhibited tube formation of human umbilical vascular endothelial cells (HUVECs), indicating that our system could be used for targeted, antiangiogenic therapy. Overall, this study provides useful information on the potential use of engineered MSCs for the controlled secretion of therapeutic proteins, in this case MDA-7, for targeted cancer therapy.

Liu Y, Wang F, Xu P
miR-590 accelerates lung adenocarcinoma migration and invasion through directly suppressing functional target OLFM4.
Biomed Pharmacother. 2017; 86:466-474 [PubMed] Related Publications
MicroRNA-590 (miR-590) shows oncogenic functions in various tumor types, but little is known about biological functions of miR-590 in lung adenocarcinoma. In this study, we observe that miR-590 is not only overexpressed in lung adenocarcinoma tissues and metastatic lymph nodes, but also significantly increased in lung adenocarcinoma cell lines. Moreover, gain-of-function and loss-of-function studies show miR-590 serve as a tumor suppressor regulating lung adenocarcinoma cells migration and invasion. Furthermore, OLFM4 is proved to as a functional target for miR-590 to regulate lung adenocarcinoma cells migration and invasion. In conclusion, miR-590 regulates lung adenocarcinoma metastasis through directly modulating functional target OLFM4.

Vinzens S, Zindel J, Zweifel M, et al.
Granulocyte Colony-stimulating Factor Producing Anaplastic Carcinoma of the Pancreas: Case Report and Review of the Literature.
Anticancer Res. 2017; 37(1):223-228 [PubMed] Related Publications
We report on the case of a 67-year-old man with granulocyte colony-stimulating factor (G-CSF) producing anaplastic carcinoma of the pancreas. Preoperative routine tests revealed an elevated white blood cell (WBC) count of 25.2 G/l, consisting almost exclusively of neutrophilic granulocytes (23.31 G/l) with a predominance of segmented neutrophils (78% of all neutrophilic granulocytes), and elevated levels of C-reactive protein at 87 mg/l. Upon surgery, local tumour infiltration was more extensive than expected from preoperative imaging. However, no peritoneal dissemination was found and curative resection was attempted. Only seven days after the operation, signs of relapse were seen upon computed tomograpy. Histology revealed an undifferentiated anaplastic carcinoma, on the basis of a poorly differentiated ductal adenocarcinoma. Immunohistochemistry demonstrated G-CSF and G-CSF-Receptor expression in some CD68-positive syncytial macrophages. Granulocyte colony-stimulating factor (G-CSF) in serum was elevated at 5.6 pg/ml, which further raised to 43 pg/ml one week after FOLFIRINOX chemotherapy (oxaliplatin, irinotecan, 5-fluorouracil), while WBC decreased from 103.3 G/l to 59.3 G/l. Granulocyte macrophage-colony stimulating factor (GM-CSF) in serum was normal (<0.5 pg/ml). The patient died on postoperative day 34.

de Matos LG, Cândido EB, Vidigal PV, et al.
Association between Toll-like receptor and tumor necrosis factor immunological pathways in uterine cervical neoplasms.
Tumori. 2017; 103(1):81-86 [PubMed] Related Publications
INTRODUCTION: The immune system plays a critical role in the defense against human papillomavirus (HPV) infection and its persistence. Toll-like receptors (TLRs) are membrane receptors responsible for activation of the innate immune response, and an association between TLR expression and uterine cervical cancer has been shown. Tumor necrosis factors (TNFs) are among the main mediators of skin and mucosa inflammation. The aim of this study was to demonstrate the association between TLR and TNF immune expression and cervical cancer and premalignant cervical lesions.
METHODS: A total of 64 embedded tissues were obtained from gynecological procedures, including 35 specimens with cervical intraepithelial neoplasia (CIN) and 10 specimens with cervical squamous cell carcinoma (CSCC) as well as 19 normal cervical samples. The expression of TLR2, TLR3, TLR4, TNF-α and TNF-β was measured by immunohistochemistry and graded into low and high levels of expression.
RESULTS: There was an association between the expression levels of TLR2 and those of TNF-α and TNF-β (p = 0.01 and p = 0.021, respectively) in the cervical cancer and CIN groups. TLR4 expression was associated with TNF-α and TNF-β expression (p = 0.016 and p = 0.025, respectively) in these 2 groups. By contrast, TLR3 was not statistically associated with TNF-α or TNF-β in any of the groups.
CONCLUSIONS: There might be an association of the TLR2 and TLR4 pathways with the immunological response of TNF-α and TNF-β in cervical cancer. These markers are also expressed at higher levels in cervical cancer and premalignant lesions compared to normal controls.

Ning X, Shang XW, Zhuang Y, et al.
Correlation between TRAIL and caspase-8 expression and their relationship with cell proliferation and apoptosis in human osteosarcoma.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Osteosarcoma is a common malignant bone tumor that mainly affects children and adolescents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily. Caspase-8 appears in the upstream of apoptosis signaling pathway among caspases. We investigated TRAIL and caspase-8 levels in osteosarcoma patients to determine their correlation with cell proliferation and apoptosis. Osteosarcoma and osteochondroma patients receiving surgery in our hospital were selected. TRAIL and caspase-8 expression levels in tissue were determined by immunohistochemistry, and protein levels in cells were evaluated by western blotting. Human osteosarcoma cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The osteosarcoma and osteochondroma cell cycles and apoptosis were investigated by flow cytometry. Correlation analysis was applied to TRAIL and caspase-8 levels during cell apoptosis. Positive TRAIL and caspase-8 expression rates in osteosarcoma tissue were significantly lower than in the controls (P < 0.05). TRAIL (0.114 ± 0.002) and caspase-8 (0.352 ± 0.124) levels in experimental cells were obviously lower than in the controls (P < 0.05). Osteosarcoma cells in the experimental group demonstrated higher proliferation and lower apoptosis at 24, 48, and 72 h (P < 0.05). The experimental cell number increased in the G1 stage and decreased in the S stage (P < 0.05). TRAIL and caspase-8 proteins showed positive correlation with apoptosis in osteosarcoma (P < 0.05). Human osteosarcoma presented reduced TRAIL and caspase-8 levels with enhanced cell proliferation and reduced apoptosis. TRAIL and caspase-8 expression levels were positively correlated with apoptosis in osteosarcoma.

Gan WY, Li HM, Zhang YG, et al.
Association between IL18-607C/A and -137G/C polymorphisms and susceptibility to non-small cell lung cancer in a Chinese population.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Lung cancer is one of the main causes of cancer-related mortality in males and females worldwide. A pleiotropic effect has been observed in the interleukin 18 gene (IL18); its effects include the activation of natural killer cell cytotoxicity and the promotion of the Th1 immune response through the alteration of the expression of interferon-γ and TNF-α in humans. IL18 is therefore involved in the elimination of tumor cells in the human body. We recruited 357 patients with non-small cell lung cancer (NSCLC) and 414 controls to evaluate the correlation between two genetic variations (IL18-607C/A and IL18-137G/C) and the pathogenesis of NSCLC. We used polymerase chain reaction-restriction fragment length polymorphism to genotype IL18-607C/A and IL18-137G/C. Statistical analysis revealed that individuals harboring the AA genotype of IL18-607C/A had an increased risk of NSCLC compared to those harboring the CC genotype (OR = 2.20, 95%CI = 1.30-3.74). Individuals expressing the A allele of IL18-607C/A had an elevated risk of developing NSCLC compared to those expressing the C allele (OR = 1.31, 95%CI = 1.06-1.62). In summary, our analysis shows that the IL18-607C/A genetic variation is related to the risk of NSCLC, whereas the IL18-137G/C variation is not. Therefore, the IL18-607C/A variation is related to the pathogenesis of NSCLC in the Chinese population studied.

Li L, Tang XY, Ye LM, et al.
Investigation on the association between IL-10 C819T gene polymorphisms and susceptibility to gastric cancer.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
We conducted a case-control study to investigate the association between the interleukin-10 (IL-10) C819T polymorphism and susceptibility to gastric cancer in a Chinese population. A total of 157 patients with gastric cancer and 249 controls were consecutively enrolled from the Guizhou Provincial People's Hospital between October 2012 and February 2015. The polymerase chain reaction-restriction fragment length polymorphism technique was used to genotype for IL-10 C819T. As determined by χ(2)-test, there was a significant difference in genotype distributions of IL-10 C819T between gastric cancer patients and controls (χ(2) = 7.09; P = 0.03). Based on unconditional logistic regression analysis, the TT genotype of IL-10 C819T was significantly associated with increased risk of gastric cancer when compared with that of the CC genotype [odds ratio (OR) = 2.24; 95% confidence interval (CI) = 1.17-4.26; P = 0.008]. In a dominant model, we found that the CT + TT genotype of IL-10 C819T was associated with susceptibility to gastric cancer compared to that of the CC genotype (OR = 1.63; 95%CI = 1.02-2.64). In a recessive model, the TT genotype of IL-10 C819T was correlated with a higher risk of gastric cancer when compared with that of the CC + CT genotype (OR = 1.75; 95%CI = 1.01-3.02). In conclusion, our study suggests that the IL-10 C819T polymorphism is associated with an increased risk of gastric cancer in co-dominant, dominant, and recessive models.

Zhuo C, Li X, Zhuang H, et al.
Elevated THBS2, COL1A2, and SPP1 Expression Levels as Predictors of Gastric Cancer Prognosis.
Cell Physiol Biochem. 2016; 40(6):1316-1324 [PubMed] Related Publications
BACKGROUND/AIMS: Gastric cancer (GC) is an important health problem. Classification based on molecular subtypes may help to determine the prognosis of patients with GC. Tumor invasion and metastasis are important factors affecting the prognosis of cancer. We aimed to identify genes related to tumor invasion and metastasis, which may serve as indicators of good GC prognosis.
METHODS: Tumor tissues and adjacent normal tissues were collected from 105 patients with primary GC who were treated by undergoing radical surgery. Samples were used for tissue microarray analysis. Identified genes with altered expression were further analyzed using the Gene Ontology (Go) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The expression levels of THBS2, COL1A2 and SPP1 were analyzed by RT-PCR, western blot and immunohistochemistry. The overall survival curves of patients with high and low expression of each gene of interest were plotted and compared.
RESULTS: Forty-three genes were identified. THBS2, COL1A2 and SPP1 were selected for further analysis. Altered expression levels of THBS2, COL1A2 and SPP1 in tumor tissues were confirmed. Patients with low THBS2 expression had a better prognosis; the expression of COL1A2 and SPP1 might not affect the prognosis of patients with GC.
CONCLUSION: THBS2, but not COL1A2 and SPP1, may serve as an indicator of GC prognosis.

Xiao Q, Fu B, Chen P, et al.
Three polymorphisms of tumor necrosis factor-alpha and hepatitis B virus related hepatocellular carcinoma: A meta-analysis.
Medicine (Baltimore). 2016; 95(50):e5609 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To assess the association between tumor necrosis factor-alpha (TNF-α) G308A, G238A and C863T polymorphisms and hepatitis B virus related hepatocellular carcinoma (HBV-HCC) susceptibility.
METHODS: We interrogated the databases of Pubmed, Sciencedirect and Viley online library up to March 8, 2016. Odds ratios (ORs) and corresponding 95% confidence intervals (95%CIs) were calculated in a fixed-effects model or a random-effects model when appropriate.
RESULTS: In total, 12 case-control studies which containing 1580 HBV-HCC cases, 2033 HBV carrier controls, 395 HBV spontaneously recovered (SR) controls and 1116 healthy controls were included. Compared with GG genotype, the genotypes GA/AA of G308A were associated with a significantly increased HBV-HCC risk when the controls were all healthy individuals (AA vs. GG, OR 2.483, 95%CI 1.243 to 4.959; GA vs. GG, OR 1.383, 95%CI 1.028 to 1.860; GA/AA vs. GG, OR 1.381, 95%CI 1.048 to 1.820). Meanwhile, only the AA vs. GG model of G238A and HBV-HCC showed a statistic significance when the controls were healthy individuals (OR 4.776, 95%CI 1.280 to 17.819). CT genotype of TNF-α C863T could increase HBV-HCC risk whenever the controls were healthy individuals, HBV carriers or HBV recovers.
CONCLUSION: This meta-analysis shows that AA genotype in TNF-α G308A and TNF-α G238A and CT genotype in TNF-α C863T may increase HBV-HCC risk. Therefore, HBV infection seemed to be a more important factor for tumorigenesis of HCC than genetic predisposition in G308A of TNF-α, and interaction between TNF-α C863T polymorphisms and HBV infection might be associated with increased HCC risk.

Xiong B, Lei X, Zhang L, Fu J
The clinical significance and biological function of olfactomedin 4 in triple negative breast cancer.
Biomed Pharmacother. 2017; 86:67-73 [PubMed] Related Publications
Olfactomedin 4 abnormal expression has been observed in several types of human cancer, but the status of olfactomedin 4 in triple negative breast cancer is still unknown. The aim of our study is to explore the clinical significance and biological function of olfactomedin 4 in triple negative breast cancer. The mRNA and protein expression of olfactomedin 4 in triple negative breast cancer tissues and cell lines was detected, and the correlation between olfactomedin 4 expression and clinicopathological factors was analyzed by immunohistochemistry. The biological function of olfactomedin 4 on tumor-metastasis was explored by Transwell migration assay and invasion assay in vitro. In our results, olfactomedin 4 mRNA and protein expression is decreased in triple-negative breast cancer tissues and cell lines. Olfactomedin 4 protein low-expression associated with lymph node metastasis, distant metastasis, clinical stage and poor prognosis of triple-negative breast cancer patients. Up-regulation of olfactomedin 4 suppresseed triple-negative breast cancer cells migration and invasion, and reduced cell metastasis-associated protein MMP 9 expression. In conclusion, olfactomedin 4 is a novel biomarker of triple-negative breast cancer for predicting prognosis and developing targeted molecular therapies.

McCaw L, Shi Y, Wang G, et al.
Low Density Lipoproteins Amplify Cytokine-signaling in Chronic Lymphocytic Leukemia Cells.
EBioMedicine. 2017; 15:24-35 [PubMed] Free Access to Full Article Related Publications
Recent studies suggest there is a high incidence of elevated low-density lipoprotein (LDL) levels in Chronic Lymphocytic Leukemia (CLL) patients and a survival benefit from cholesterol-lowering statin drugs. The mechanisms of these observations and the kinds of patients they apply to are unclear. Using an in vitro model of the pseudofollicles where CLL cells originate, LDLs were found to increase plasma membrane cholesterol, signaling molecules such as tyrosine-phosphorylated STAT3, and activated CLL cell numbers. The signaling effects of LDLs were not seen in normal lymphocytes or glycolytic lymphoma cell-lines but were restored by transduction with the nuclear receptor PPARδ, which mediates metabolic activity in CLL cells. Breakdown of LDLs in lysosomes was required for the amplification effect, which correlated with down-regulation of HMGCR expression and long lymphocyte doubling times (LDTs) of 53.6±10.4months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels in a subgroup of patients. These observations suggest LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Prospective clinical trials are needed to confirm the therapeutic potential of lowering LDL concentrations in CLL, particularly in patients with indolent disease in the "watch-and-wait" phase of management.

Huang Y, Wan G, Tao J
C1q/TNF-related protein-3 exerts the chondroprotective effects in IL-1β-treated SW1353 cells by regulating the FGFR1 signaling.
Biomed Pharmacother. 2017; 85:41-46 [PubMed] Related Publications
Cartilage degeneration is known as a major cause of osteoarthritis (OA). C1q/TNF-related protein-3 (CTRP3) is an adipokine relative to chondrogenesis in vitro. However, its effect on cartilage degeneration in OA remains unclearly. In the present study, SW1353 cells were treated with IL-1β to imitate the microenvironment of OA for vitro research. Then, an obvious down-regulation of CTRP3 were validated in IL-1β-treated SW1353 cells. In addition, CTRP3 overexpression significantly attenuated the decrease in cell proliferation and increase in cell apoptosis triggered by IL-1β. Moreover, CTRP3 up-regulation significantly inhibited the expression of FGFR1, but with slight decrease in FGFR3 levels. Further analysis corroborated that FGFR1 overexpression markedly ameliorated the pro-proliferation and anti-apoptotic effects of CTRP3 elevation in cells upon IL-1β. Down-regulation of FGFR1 attenuated the increase in Ras-GTP expression caused by IL-1β stimulation. Moreover, EGFR1 elevation also abated the inhibitory effect of CTRP3 on Ras expression and the CRTP3-induced activation of PI3K/AKT in cells upon IL-1β. Furthermore, Ras inhibitor manumycin A antagonized the decrease in phosphorylation of PI3K and Akt caused by IL-1β treatment. Both Manumycin A and PI3K/Akt agonist FGF-1 attenuated the inhibitory effect of IL-1β on cell growth. Together, this research suggested that CTRP3 might protect chondrocytes against IL-1β-induced injury by suppressing the FGFR1- Ras/PI3K/Akt signaling-mediated growth inhibitory pathway, indicating a potential agent against osteoarthritis.

Bonovas S, Minozzi S, Lytras T, et al.
Risk of malignancies using anti-TNF agents in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: a systematic review and meta-analysis.
Expert Opin Drug Saf. 2016; 15(sup1):35-54 [PubMed] Related Publications
INTRODUCTION: Malignancies have been reported in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, treated with anti-tumour necrosis factor (anti-TNF) agents. Areas covered: We conducted a systematic review of randomized controlled trials (RCTs) to determine the effect of anti-TNF agents on the occurrence of cancer (any type). Literature databases were searched up to May 2014 to identify relevant studies that evaluated adalimumab, certolizumab, etanercept, golimumab, or infliximab, compared with placebo or no treatment. Data on cancer occurrence were extracted at the maximum follow-up time reported. Expert opinion: Fifty-five RCTs with 20,631 patients met the eligibility criteria. Of these, 32 trials with 15,539 patients reported at least one case of cancer, for a total of 112 malignancies. The degree of variability between studies was consistent with what would be expected to occur by chance alone. There was no evidence of an association between anti-TNF agents and cancer risk (fixed-effects model (OR: 1.31, 95% CI: 0.89, 1.95); a random-effects model (OR: 1.16, 95% CI: 0.75, 1.81)). We found evidence of selective outcome reporting or publication bias suggesting that the pooled effect estimate for cancer may have been overestimated. The evidence is imprecise, and the risk of bias was high or unclear across primary studies.

Shany S, Sigal-Batikoff I, Lamprecht S
Vitamin D and Myofibroblasts in Fibrosis and Cancer: At Cross-purposes with TGF-β/SMAD Signaling.
Anticancer Res. 2016; 36(12):6225-6234 [PubMed] Related Publications
The multifaceted involvement of the active vitamin D metabolite 1,25-dihydroxyvitamin D3 (henceforth referred to by the synonyms 1,25(OH)2D3, calcitriol or vitamin D) in blunting the growth of cancer cells is amply recognized. In this review we focused our attention on the cross-talk between 1,25 (OH)2D3 and the tumor microenvironment (TME), signaling out stromal cancer-associated fibroblasts (CAFs), the most abundant TME population, as a target for calcitriol anticancer action. In view of the commonality of the phenotypic signature in myofibroblasts, resident in the cancer stroma and in non-neoplastic fibrotic loci, we examined modes of action of vitamin D in non-neoplastic chronic diseases and in cancer to assess mechanistic similarities and divergences. A constant observation was that 1,25(OH)2D3 or synthetic ligands via the active vitamin D receptor (VDR) impede transforming growth factor (TGF)-β/mothers against decapentaplegic homologs (SMADs) signaling in myofibroblasts regardless of the initiating insult. The translational impact of 1,25(OH)2D3 in targetting stromal CAFs is discussed.

Patel HJ, Patel BM
TNF-α and cancer cachexia: Molecular insights and clinical implications.
Life Sci. 2017; 170:56-63 [PubMed] Related Publications
Cancer cachexia characterized by a chronic wasting syndrome, involves skeletal muscle loss and adipose tissue loss and resistance to conventional nutritional support. Cachexia is responsible for the reduction in quality and length of life of cancer patients. It also decreases the muscle strength of the patients. The pro-inflammatory and pro-cachectic factors produced by the tumor cells have important role in genesis of cachexia. A number of pro-inflammatory cytokines, like interleukin-1 (IL-1), IL-6, tumor necrosis factor- alpha (TNF-α) may have important role in the pathological mechanisms of cachexia in cancer. Particularly, TNF-α has a direct catabolic effect on skeletal muscle and causes wasting of muscle by the induction of the ubiquitin-proteasome system (UPS). In cancer cachexia condition, there is alteration in carbohydrate, protein and fat metabolism. TNF-α is responsible for the increase in gluconeogenesis, loss of adipose tissue and proteolysis, while causing decrease in protein, lipid and glycogen synthesis. It has been associated with the formation of IL-1 and increases the uncoupling protein-2 (UCP2) and UCP3 expression in skeletal muscle in cachectic state. The main aim of the present review is to evaluate and discuss the role of TNF-α in different metabolic alterations and muscle wasting in cancer cachexia.

Iliaz R, Akyuz U, Tekin D, et al.
Role of several cytokines and adhesion molecules in the diagnosis and prediction of survival of hepatocellular carcinoma.
Arab J Gastroenterol. 2016; 17(4):164-167 [PubMed] Related Publications
BACKGROUND AND STUDY AIMS: There is still need for accurate markers for early diagnosis of hepatocellular carcinoma (HCC) and assessment of prognosis. The aim of this study is to investigate interleukin (IL)-32, IL-1 beta, IL-18, vascular cell adhesion molecule (VCAM)-1, and epithelial cell adhesion molecule (EpCAM) in the diagnosis and assessment of prognosis of HCC.
PATIENTS AND METHODS: Fifty patients with HCC and 15 healthy volunteers were enroled into this prospective study. Serum samples were obtained at the first admission before any treatment was given. Serum IL-32, IL-1 beta, IL-18, VCAM-1, and EpCAM levels were determined using ELISA kits.
RESULTS: The mean age of the patient group and controls was 60±9years and 56±8years, respectively. The mean serum level of IL-32 was higher in patients with HCC than in the control subjects (65.1 vs. 14.1pg/mL; p<0.001). IL-18 levels were significantly higher in the HCC group (546.5 vs. 157.8pg/mL; p<0.001). EpCAM (20.3 vs. 1.5pg/mL; p<0.001) and VCAM (6.5 vs. 1.8μg/mL; p<0.001) levels were also higher in patients with HCC. The mean level of IL-1 beta in the HCC group was similar to that in the control subjects (1.9 vs. 1.9pg/mL; p=0.97). Fifty-eight per cent of the patients with HCC died at 7.3months (median). Cytokine levels except EpCAM did not correlate with survival (p>0.05). Alpha-foetoprotein, IL-32, IL-18, EpCAM, and VCAM had valuable cutoff levels to differentiate between patients with HCC and control group (p<0.001).
CONCLUSIONS: Although cytokines can be a diagnostic marker for HCC, they did not have any significant prognostic value in patients with HCC. Only EpCAM may be used to determine the prognosis of HCC, thereby assisting with treatment management.

Lu E, Su J, Zhou Y, et al.
CCL20/CCR6 promotes cell proliferation and metastasis in laryngeal cancer by activating p38 pathway.
Biomed Pharmacother. 2017; 85:486-492 [PubMed] Related Publications
Chemokine and its receptors play important roles in laryngeal cancer development and progression. CCR6 is the receptor of CCL20 chemokine, but its function in laryngeal cancer is not known. The aim of this study is to explore the roles of CCR6 and its regulation mechanism in laryngeal cancer. We found CCR6 expression was higher in laryngeal cancer tissues compared with their normal controls, so did in laryngeal cancer cells. Cellular function indicated that down-regulation of CCR6 in laryngeal cancer cells could suppress cell proliferation and metastasis. Further research showed that CCR6 could activate p38, which was related with the changes of microRNA (miRNA) profile in laryngeal cancer cells. We also found that CCR6 was positively associated with miR-20a-5p, miR-489 and negatively related to miR-29-3p, miR-632 and miR-1276 in laryngeal cancer tissues.

Atretkhany KN, Drutskaya MS
Myeloid-Derived Suppressor Cells and Proinflammatory Cytokines as Targets for Cancer Therapy.
Biochemistry (Mosc). 2016; 81(11):1274-1283 [PubMed] Related Publications
Myeloid-derived suppressor cells represent a heterogeneous population of immature myeloid cells. Under normal conditions, these cells differentiate into macrophages, dendritic cells, and granulocytes. However, in pathological states such as inflammation, infection, or tumor growth, there is an arrest of their differentiation that results in the accumulation of immature myeloid cells in the organism. In addition, these cells acquire a suppressor phenotype, expressing anti-inflammatory cytokines and reactive oxygen and nitrogen species, and suppress T-cell immune response. Myeloid-derived suppressor cells (MDSC) contribute to cancerogenesis by forming a favorable microenvironment for tumor growth. Proinflammatory cytokines, secreted by tumor cells and the tumor microenvironment, induce angiogenesis and metastasis and promote tumor growth. They also provide signals necessary for survival, accumulation, and function of MDSC. Understanding the mechanisms of myeloid suppressor cell development and the use of proinflammatory cytokine inhibitors may prove beneficial for tumor therapy.

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