• CC chemokine
• CC chemokine receptor
• Chemokine
• Inflammation
• Osteoarthritis

• TRP
• gastric cancer
• ion channel
• temperature
• therapeutic target

• Humans
• Transient Receptor Potential Channels/metabolism
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics

Glioblastoma multiforme (GBM) is a brain tumor with a very poor prognosis. For this reason, researchers worldwide study the impact of the tumor microenvironment in GBM, such as the effect of chemokines. In the present study, we focus on the role of the chemokine CCL18 and its receptors in the GBM tumor. We measured the expression of CCL18, CCR8 and PITPNM3 in the GMB tumor from patients (16 men and 12 women) using quantitative real-time polymerase chain reaction. To investigate the effect of CCL18 on the proliferation and migration of GBM cells, experiments were performed using U-87 MG cells. The results showed that CCL18 expression was higher in the GBM tumor than in the peritumoral area. The women had a decreased expression of PITPNM3 receptor in the GBM tumor, while in the men a lower expression of CCR8 was observed. The hypoxia-mimetic agent, cobalt chloride (CoCl₂), increased the expression of CCL18 and PITPNM3 and thereby sensitized U-87 MG cells to CCL18, which did not affect the proliferation of U-87 MG cells but increased the migration of the test cells. The results indicate that GBM cells migrate from hypoxic areas, which may be important in understanding the mechanisms of tumorigenesis.

• CCL18
• CCR8
• HMC3
• PITPNM3
• microglia
• phagocytosis

• cancers
• immunotherapies
• nanotargeting
• nanotherapy
• peptide
• solid tumor
• tumor associated macrophages (TAMS)

This study aimed to explore the role and underlying molecular mechanisms of long non-coding RNA (lncRNA) LINC00342 in gastric cancer (GC).

The expression of LINC00342 in GC tissues was evaluated by Quantitative reverse transcription polymerase chain reaction (qRT-PCR). Silencing of LINC00342 was conducted to investigate the effect of LINC00342 in vitro and in vivo. The underlying molecular mechanisms of LINC00342 were determined by dual luciferase reporter assay, Western blotting analysis and rescue experiments. Biological functions of LINC00342 were evaluated by cell counting kit-8 (CCK-8) assay, colony formation assay, wound healing assay and Transwell assays. In addition, a tumor model was used to verify the effect of LINC00342 in tumorigenesis in vivo.

LINC00342 was significantly upregulated in GC tissues and cell lines. Silencing of LINC00342 efficiently inhibited proliferation, migration and invasion of AGS cells in vitro, and also suppressed the tumorigenesis of GC in vivo. Functional experiments showed that LINC00342 regulated the expression of canopy fibroblast growth factor signaling regulator 2 (CNPY2) by competitively sponging miR-545-5p. Rescue experiments showed that inhibition of miR-545-5p and overexpression of CNPY2 significantly reversed cell phenotypes caused by silencing of LINC00342.

LINC00342 plays a potential oncogenic role in GC by targeting the miR545-5p/CNPY2 axis, and might act as a novel therapeutic target for GC.

• Gastric cancer
• LINC00342
• Tumorigenesis

• Biomarker
• Cancer
• Chemokine
• Immunosuppressive
• Therapeutic target
• Tumor microenvironment

• Chemokines, CC
• Epithelial-Mesenchymal Transition
• Humans
• Neoplasms
• Neovascularization, Pathologic
• Signal Transduction
• Tumor Microenvironment

• chemokine-chemokine receptor
• exosomeimmune suppression
• metabolism
• tumor-associated macrophages
• tyrosine kinase receptor

• Animals
• Disease Models, Animal
• Humans
• Immunotherapy/methods
• Mice
• Neoplasms/immunology
• Neoplasms/therapy
• Tumor Microenvironment/immunology
• Tumor-Associated Macrophages/immunology

• National Natural Science Foundation of China
• Guangdong Science and Technology Department
• Department of Education of Guangdong Province
• Science and Technology Planning Project of Guangdong Province

A neoplastic tumor consists of cancer cells that interact with each other and non-cancerous cells that support the development of the cancer. One such cell are tumor-associated macrophages (TAMs). These cells secrete many chemokines into the tumor microenvironment, including especially a large amount of CCL18. This chemokine is a marker of the M2 macrophage subset; this is the reason why an increase in the production of CCL18 is associated with the immunosuppressive nature of the tumor microenvironment and an important element of cancer immune evasion. Consequently, elevated levels of CCL18 in the serum and the tumor are connected with a worse prognosis for the patient. This paper shows the importance of CCL18 in neoplastic processes. It includes a description of the signal transduction from PITPNM3 in CCL18-dependent migration, invasion, and epithelial-to-mesenchymal transition (EMT) cancer cells. The importance of CCL18 in angiogenesis has also been described. The paper also describes the effect of CCL18 on the recruitment to the cancer niche and the functioning of cells such as TAMs, regulatory T cells (T_reg), cancer-associated fibroblasts (CAFs) and tumor-associated dendritic cells (TADCs). The last part of the paper describes the possibility of using CCL18 as a therapeutic target during anti-cancer therapy.

• CCL18
• PITPNM3
• cancer
• chemokine
• metastasis
• regulatory T cells
• tumor
• tumor-associated macrophages

• Calcium-Binding Proteins/metabolism
• Cancer-Associated Fibroblasts/metabolism
• Chemokines, CC/blood
• Chemokines, CC/metabolism
• Disease Progression
• Epithelial-Mesenchymal Transition
• Gene Expression Regulation, Neoplastic
• Humans
• Macrophages/metabolism
• Membrane Proteins/metabolism
• Neoplasms/blood
• Neoplasms/metabolism
• Prognosis
• Tumor Escape
• Tumor Microenvironment
• Up-Regulation

• Helicobacter pylori
• cancer biomarker
• children
• gastric cancer biomarker
• gastric damage
• oncogene

• Animals
• Apoptosis
• Cells, Cultured
• Chemokine CCL4/genetics
• Chemokine CCL4/metabolism
• Chondrocytes/metabolism
• Collagen/metabolism
• Male
• Mice
• MicroRNAs/genetics
• MicroRNAs/metabolism
• NF-kappa B/genetics
• NF-kappa B/metabolism
• Osteoarthritis/metabolism

• CCL18
• DLBCL
• bioinformatics
• immunohistochemistry
• meta-analysis

• Adult
• Aged
• Biomarkers, Tumor/analysis
• Chemokines, CC/biosynthesis
• Disease Progression
• Female
• Humans
• Lymphoma, Large B-Cell, Diffuse/pathology
• Male
• Middle Aged
• Prognosis
• Up-Regulation

• Erk1/Erk2
• angiogenesis
• cancer progression
• cell invasion
• cell phone
• radiofrequency

• CCL18
• Cancer
• Fibrosis
• Inflammation
• Tolerance

The CC chemokine ligand 18 (CCL18) is produced by alveolar macrophages in patients with fibrosing lung disease and its concentration is increased in various fibrotic lung diseases. Furthermore CCL18 is elevated in several malignancies as it is produced by tumor associated macrophages. In this study we aimed to analyze the role of CCL18 as a prognostic biomarker for the development of early radiation induced lung toxicity (RILT), i.e. radiation pneumonitis after thoracic irradiation and its significance in the course of the disease. Sixty seven patients were enrolled prospectively in the study. Patients were treated with irradiation for several thoracic malignancies (lung cancer, esophageal cancer, thymoma), either with conventionally fractionated or hypo-fractionated radiotherapy. The CCL18 serum levels were quantified with ELISA (enzyme-linked immunosorbent assay) at predefined time points: before, during and at the end of treatment as well as in the first and second follow-up. Treatment parameters and functional tests were also correlated with the development of RILT.Fifty three patients were evaluable for this study. Twenty one patients (39%) developed radiologic signs of RILT Grade >1 but only three of them (5.6%) developed clinical symptoms (Grade 2). We could not find any association between the different CCL18 concentrations and a higher incidence of RILT. Statistical significant factors were the planning target volume (odds ratio OR: 1.003, p = 0.010), the volume of the lung receiving > 20 Gy (OR: 1.132 p = 0.004) and age (OR: 0.917, p = 0.008). There was no association between serial CCL18 concentrations with tumor response and overall survival.In our study the dosimetric parameters remained the most potent predictors of RILT. Further studies are needed in order to estimate the role of CCL18 in the development of early RILT.

• Adult
• Aged
• Aged, 80 and over
• Biomarkers/blood
• Chemokines, CC/blood
• Female
• Humans
• Lung Diseases/blood
• Lung Diseases/etiology
• Lung Diseases/therapy
• Male
• Middle Aged
• Neoplasm Recurrence, Local/pathology
• Prognosis
• Radiation Injuries/blood
• Radiation Injuries/complications
• Radiation Injuries/diagnosis

Chemokine (CC motif) ligand 18 (CCL18) is involved in remodeling of the tumor microenvironment and plays critical roles in oncogenesis, invasiveness, and metastasis. We previously investigated the overexpression of CCL18 in primary oral squamous cell carcinoma (OSCC) tissues and its association with advanced clinical stage in OSCC patients. However, the underlying mechanisms of this CCL18‐derived activity remains unidentified. This study showed exogenous CCL18 increased cell migration and invasion and induced cell epithelial–mesenchymal transition (EMT), and that E‐cadherin, an epithelial marker, decreased and N‐cadherin, a mesenchymal marker, increased, compared to negative control in OSCC cells. Furthermore, we detected that CCL18 induced the acquisition of cancer stem(‐like) cell characteristics in oral cancer cells, but also found a significantly positive correlation between the expression of CCL18 and Bmi‐1 (P < 0.001) in OSCC surgical specimens by immunohistochemistry analysis. The expression of octamer‐binding transcription factor 4 and Bmi‐1 were significantly upregulated, and proportions of aldehyde dehydrogenase^high+ cells and CD133⁺ cells were markedly increased in CCL18‐treated cells compared to untreated cells. Sphere formation ability was observably enhanced when cells were continually exposed to high levels of CCL18. Moreover, CCL18 upregulated Slug expression by stimulating the mammalian target of rapamycin (mTOR) signaling pathway in OSCC cell lines. Inhibition of the mTOR pathway by INK128, or Slug knockdown by RNA interference, reversed CCL18‐induced EMT and the stemness response at both molecular and functional levels. In conclusion, our data suggested that CCL18 upregulated Slug expression to promote EMT and stem cell‐like features by activating the mTOR pathway in oral cancer. These findings provide new potential targets for the early diagnosis and treatment of OSCC.

• Cancer stem(-like) cell (CSC)
• Slug
• chemokine (CC motif) ligand 18 (CCL18)
• epithelial-mesenchymal transition (EMT)
• oral squamous cell carcinoma (OSCC)

Ovarian cancer (OC) ascites consist in a proinflammatory tumor environment that is characterized by the presence of various cytokines, chemokines and growth factors. The presence of these inflammatory-related factors in ascites is associated with a more aggressive tumor phenotype. CCL18 is a member of CCL chemokines and its expression has been associated with poor prognosis in some cancers. However, its role in OC progression has not been established. Therefore, the aim of the current study was to elucidate the role of ascites CCL18 in OC progression.

ELISA and tissue microarrays were used to assess CCL18 in ascites and phospho-Pyk2 expression in cancer tissues respectively. Cell migration was assessed using Boyden chambers. CCL18 and ascites signaling was examined in ovarian cancer cells utilizing siRNA and exogenous gene expression.

Here, we show that CCL18 levels are markedly increased in advanced serous OC ascites relative to peritoneal effusions from women with benign conditions. Ascites and CCL18 dose-dependently enhanced the migration of OC cell lines CaOV3 and OVCAR3. CCL18 levels in ascites positively correlated with the ability of ascites to promote cell migration. CCL18 blocking antibodies significantly attenuated ascites-induced cell migration. Ascites and CCL18 stimulated the phosphorylation of proline-rich tyrosine kinase 2 (Pyk2) in CaOV3 and OVCAR3 cells. Most importantly, the expression of phosphorylated Pyk2 in serous OC tumors was associated with shorter progression-free survival. Furthermore, enforced expression of Pyk2 promoted tumor cell migration while siRNA-mediated downregulation of Pyk2 attenuated cell migration. Downregulation of Pyk2 markedly inhibited ascites and CCL18-induced cell migration.

Taken together, our findings establish an important role for CCL18, as a component of ascites, in the migration of tumor cells and identify Pyk2 as prognostic factor and a critical downstream signaling pathway for ascites-induced OC cell migration.

The online version of this article (doi:10.1186/s12943-016-0542-2) contains supplementary material, which is available to authorized users.

• Ascites
• CCL18
• Cell migration
• Ovarian carcinoma
• Pyk2

Gastric cancer (GC) is the fifth most common malignancy in the world. The major cause of GC is chronic infection with Helicobacter pylori (H. pylori). Infection with H. pylori leads to an active inflammatory microenvironment that is maintained by immune cells such as T cells, macrophages, natural killer cells, among other cells. Immune cell dysfunction allows the initiation and accumulation of mutations in GC cells, inducing aberrant proliferation and protection from apoptosis. Meanwhile, immune cells can secrete certain signals, including cytokines, and chemokines, to alter intracellular signaling pathways in GC cells. Thus, GC cells obtain the ability to metastasize to lymph nodes by undergoing the epithelial-mesenchymal transition (EMT), whereby epithelial cells lose their epithelial attributes and acquire a mesenchymal cell phenotype. Metastasis is a leading cause of death for GC patients, and the involved mechanisms are still under investigation. In this review, we summarize the current research on how the inflammatory environment affects GC initiation and metastasis via EMT.

• Gastric cancer
• Inflammation
• Epithelial-mesenchymal transition
• Microenvironment
• Immune cells

• Epithelial-Mesenchymal Transition
• Humans
• Inflammation/pathology
• Macrophages/immunology
• Neoplasm Metastasis
• Stomach Neoplasms/immunology
• Stomach Neoplasms/pathology
• T-Lymphocytes, Cytotoxic/immunology
• Transforming Growth Factor beta1/physiology