CSF1

Gene Summary

Gene:CSF1; colony stimulating factor 1
Aliases: MCSF, CSF-1
Location:1p13.3
Summary:The protein encoded by this gene is a cytokine that controls the production, differentiation, and function of macrophages. The active form of the protein is found extracellularly as a disulfide-linked homodimer, and is thought to be produced by proteolytic cleavage of membrane-bound precursors. The encoded protein may be involved in development of the placenta. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:macrophage colony-stimulating factor 1
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Single Nucleotide Polymorphism
  • Cancer Gene Expression Regulation
  • Lymphatic Metastasis
  • Synovitis, Pigmented Villonodular
  • Adolescents
  • Biomarkers, Tumor
  • Mice, Transgenic
  • Stromal Cells
  • Signal Transduction
  • Vascular Endothelial Growth Factor Receptor-1
  • MicroRNAs
  • p53 Protein
  • Gene Expression Regulation
  • Macrophages
  • Tissue Array Analysis
  • Immunohistochemistry
  • Pancreatic Cancer
  • Disease Progression
  • Macrophage Colony-Stimulating Factor
  • Neoplasm Invasiveness
  • Chromosome 5
  • Breast Cancer
  • Base Sequence
  • Translocation
  • Oligonucleotide Array Sequence Analysis
  • siRNA
  • Giant Cell Tumors
  • Xenograft Models
  • Neoplastic Cell Transformation
  • Tumor Burden
  • Gene Expression Profiling
  • Receptors, Growth Factor
  • Cell Proliferation
  • Molecular Sequence Data
  • Messenger RNA
  • CSF1R
  • Chromosome 1
  • Mutation
  • Cell Movement
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CSF1 (cancer-related)

Hori S, Miyake M, Onishi S, et al.
Evaluation of pro‑ and anti‑tumor effects induced by three colony‑stimulating factors, G‑CSF, GM‑CSF and M‑CSF, in bladder cancer cells: Is G‑CSF a friend of bladder cancer cells?
Int J Oncol. 2019; 54(6):2237-2249 [PubMed] Related Publications
Cytotoxic chemotherapy is the standard treatment for patients with advanced bladder cancer. However, this treatment can cause transient and prolonged neutropenia, which can result in fatal infection. Three recombinant human colony‑stimulating factors (CSFs), granulocyte CSF (G‑CSF), granulocyte‑macrophage CSF (GM‑CSF), and macrophage CSF (M‑CSF), are currently available to reduce the duration and degree of neutropenia. The present study investigated the pro‑ and anti‑tumor effects of these three CSFs and the changes in molecular profiles. Xenograft tumors in athymic mice were generated by subcutaneously inoculating the human bladder cancer cell lines MGH‑U3 and UM‑UC‑3. A total of 2 weeks after cell inoculation, mice were randomly divided into four groups (control, G‑CSF, GM‑CSF and M‑CSF) and treated thrice a week for 2 weeks. Tumor growth during monitoring and tumor weight at the time of euthanization were significantly higher in mice treated with G‑CSF and lower in mice treated with GM‑CSF compared with the control mice. Tumors were examined by immunostaining with antibodies against proteins associated tumor proliferation (Ki‑67), angiogenesis [CD31 and vascular endothelial growth factor (VEGF)], anti‑immunity (CD204) and epithelial‑mesenchymal transition (EMT; E‑cadherin). Immunohistochemical staining revealed that tumor proliferation, angiogenesis, recruitment of M2 macrophages and EMT were promoted by G‑CSF, whereas lymphangiogenesis and recruitment of M2 macrophages were inhibited by GM‑CSF. Treatment‑associated changes in serum pro‑ and anti‑tumoral cytokines and chemokines were evaluated by enzyme‑linked immunosorbent assay (ELISA)‑based arrays. In the ELISA for serum, the levels of cytokines associated with angiogenesis (interleukin‑6 and VEGF), and EMT (transforming growth factor‑β1 and ‑β2) were elevated in mice treated with G‑CSF. Treatment with GM‑CSF and M‑CSF also affected the level of these cytokines characteristically. The current results indicate that administration of exogenous G‑CSF to patients with bladder cancer promotes tumor growth through promotion of cell proliferation, angiogenesis, recruitment of M2 macrophages and enhancement of EMT through the modulation of the tumor microenvironment.

Bencheikh L, Diop MK, Rivière J, et al.
Dynamic gene regulation by nuclear colony-stimulating factor 1 receptor in human monocytes and macrophages.
Nat Commun. 2019; 10(1):1935 [PubMed] Free Access to Full Article Related Publications
Despite their location at the cell surface, several receptor tyrosine kinases (RTK) are also found in the nucleus, as either intracellular domains or full length proteins. However, their potential nuclear functions remain poorly understood. Here we find that a fraction of full length Colony Stimulating Factor-1 Receptor (CSF-1R), an RTK involved in monocyte/macrophage generation, migrates to the nucleus upon CSF-1 stimulation in human primary monocytes. Chromatin-immunoprecipitation identifies the preferential recruitment of CSF-1R to intergenic regions, where it co-localizes with H3K4me1 and interacts with the transcription factor EGR1. When monocytes are differentiated into macrophages with CSF-1, CSF-1R is redirected to transcription starting sites, colocalizes with H3K4me3, and interacts with ELK and YY1 transcription factors. CSF-1R expression and chromatin recruitment is modulated by small molecule CSF-1R inhibitors and altered in monocytes from chronic myelomonocytic leukemia patients. Unraveling this dynamic non-canonical CSF-1R function suggests new avenues to explore the poorly understood functions of this receptor and its ligands.

Salvagno C, Ciampricotti M, Tuit S, et al.
Therapeutic targeting of macrophages enhances chemotherapy efficacy by unleashing type I interferon response.
Nat Cell Biol. 2019; 21(4):511-521 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
Recent studies have revealed a role for macrophages and neutrophils in limiting chemotherapy efficacy; however, the mechanisms underlying the therapeutic benefit of myeloid-targeting agents in combination with chemotherapy are incompletely understood. Here, we show that targeting tumour-associated macrophages by colony-stimulating factor-1 receptor (CSF-1R) blockade in the K14cre;Cdh1

Hua F, Tian Y, Gao Y, et al.
Colony‑stimulating factor 1 receptor inhibition blocks macrophage infiltration and endometrial cancer cell proliferation.
Mol Med Rep. 2019; 19(4):3139-3147 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
Tumor‑associated macrophages (TAMs) promote the progression of endometrial cancer (EC), but the mechanism of TAM in EC cell proliferation remains unclear. It was found that colony stimulating factor (CSF)‑1 and CSF‑1 receptor (CSF‑1R) were highly expressed in EC tissues of patients and two EC cell lines (ECC‑1 and HEC‑1A). Using wound‑healing and chemotactic migration assays to evaluate the role of EC cells in the induction of macrophage migration, it was found that the supernatant of EC cells promoted macrophage cell line (U937) migration; however, the migration capacity of U937 weakened when CSF‑1R was blocked. Subsequently, inhibition of CSF‑1 expression in EC cells also restrained U937 migration. Additionally, blocking CSF‑1R by PLX3397 treatment in U937 cells inhibited EC cell proliferation in a co‑culture system by inhibiting the expression of proliferation‑associated proteins (Janus kinase‑1, phosphoinositide 3‑kinase, AKT, cyclin kinase 2, 4 and retinoblastoma‑associated protein). Together, these results demonstrated that CSF‑1 secreted by EC cells promoted macrophage migration; similarly, CSF‑1‑stimulated macrophages promoted EC cell proliferation. These results suggested that the interaction between CSF‑1 and its receptor served an important role in promoting macrophage infiltration and progression of EC.

Ungard RG, Linher-Melville K, Nashed M, et al.
xCT knockdown in human breast cancer cells delays onset of cancer-induced bone pain.
Mol Pain. 2019 Jan-Dec; 15:1744806918822185 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
Cancers in the bone produce a number of severe symptoms including pain that compromises patient functional status, quality of life, and survival. The source of this pain is multifaceted and includes factors secreted from tumor cells. Malignant cells release the neurotransmitter and cell-signaling molecule glutamate via the oxidative stress-related cystine/glutamate antiporter, system x

Abiatari I, Midelashvili T, Motsikulashvili M, et al.
OVEREXPRESSED PROGENITOR GENE CSF1R IN PANCREATIC CANCER TISSUES AND NERVE INVASIVE PANCREATIC CANCER CELLS.
Georgian Med News. 2018; (285):96-100 [PubMed] Related Publications
Aim- pancreatic ductal adenocarcinoma is one of the most aggressive oncological disease with early metastasis and high mortality rate. CSF1R is a gene with progenitor activity, which is also associated with different malignant diseases. In this study our objective was to analyze expression of CSF1R in pancreatic cancer tissues and nerve invasive cancer cells. Quantitative real time polymerase chain reaction (QRT-PCR) was used to analyze the expression of CSF1R mRNA in nine cultured pancreatic cancer cell lines and pancreatic bulk tissues of the normal pancreas, chronic pancreatitis (n=20/20) and pancreatic ductal adenocarcinoma (n=58). Nerve invasive clones of two pancreatic cancer cell lines was also used. QRT-PCR analysis revealed a significant up-regulation of CSF1R mRNA expression in pancreatic adenocarcinoma tissues compared to normal tissues and low expression of this gene indicated a tendency for better survival of pancreatic cancer patients. Expression of CSF1R mRNA was present in all tested pancreatic cancer cell lines with comparably low to moderate expression levels. The CSF1R was significantly overexpressed in nerve invasive pancreatic cancer cells. Increased expression of CSF1R in pancreatic cancer might be related to perineural invasion and poor prognosis. CSF1R might be an important factor during the development and malignant transformation of tissues.

Yan J, Zhao Q, Gabrusiewicz K, et al.
FGL2 promotes tumor progression in the CNS by suppressing CD103
Nat Commun. 2019; 10(1):448 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
Few studies implicate immunoregulatory gene expression in tumor cells in arbitrating brain tumor progression. Here we show that fibrinogen-like protein 2 (FGL2) is highly expressed in glioma stem cells and primary glioblastoma (GBM) cells. FGL2 knockout in tumor cells did not affect tumor-cell proliferation in vitro or tumor progression in immunodeficient mice but completely impaired GBM progression in immune-competent mice. This impairment was reversed in mice with a defect in dendritic cells (DCs) or CD103

Haralambiev L, Wien L, Gelbrich N, et al.
Effects of Cold Atmospheric Plasma on the Expression of Chemokines, Growth Factors, TNF Superfamily Members, Interleukins, and Cytokines in Human Osteosarcoma Cells.
Anticancer Res. 2019; 39(1):151-157 [PubMed] Related Publications
BACKGROUND/AIM: Therapeutic options for osteosarcoma (OS) are still limited. Cold atmospheric plasma (CAP) leads to inhibition of tumor growth and metastasis, but underlying mechanisms are not fully understood. The aim of this study was to investigate CAP-induced changes in cytokine expression in OS cells.
MATERIALS AND METHODS: OS cell lines (U2-OS, MNNG/HOS) were treated with CAP and administered to an RT2 Profiler PCR Array (Qiagen, Hilden, Germany) detecting 84 chemokines, growth factors, TNF superfamily members, interleukins, and cytokines.
RESULTS: The analyses showed that 15 factors (C5, CCL5, CNTF, CSF1, CSF3, CXCL1, IL-1A, IL-1B, IL-18, IL-22, IL23A, MSTN, NODAL, TGFβ2, THPO) were induced, but only one factor (VEGFA) was suppressed after CAP treatment.
CONCLUSION: No extensive systemic cell response with presumably far-reaching consequences for neighboring cells was detectable after CAP treatment. Since the antitumoral effect of CAP on OS cells has already been demonstrated, intraoperative treatment with CAP represents a promising and systemic safe option for the therapy of OS.

Ma W, He H, Wang H
Oncolytic herpes simplex virus and immunotherapy.
BMC Immunol. 2018; 19(1):40 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
BACKGROUND: Oncolytic viruses have been proposed to be employed as a potential treatment of cancer. Well targeted, they will serve the purpose of cracking tumor cells without causing damage to normal cells. In this category of oncolytic viral drugs human pathogens herpes simplex virus (HSV) is especially suitable for the cause. Although most viral infection causes antiviral reaction in the host, HSV has multiple mechanisms to evade those responses. Powerful anti-tumor effect can thus be achieved via genetic manipulation of the HSV genes involved in this evading mechanism, namely deletions or mutations that adapt its function towards a tumor microenvironment. Currently, oncolytic HSV (oHSV) is widely use in clinical; moreover, there's hope that its curative effect will be further enhanced through the combination of oHSV with both traditional and emerging therapeutics.
RESULTS: In this review, we provide a summary of the HSV host antiviral response evasion mechanism, HSV expresses immune evasion genes such as ICP34.5, ICP0, Us3, which are involved in inducing and activating host responses, so that the virus can evade the immune system and establish effective long-term latent infection; we outlined details of the oHSV strains generated by removing genes critical to viral replication such as ICP34.5, ICP0, and inserting therapeutic genes such as LacZ, granulocyte macrophage colony-stimulating factor (GM-CSF); security and limitation of some oHSV such G207, 1716, OncoVEX, NV1020, HF10, G47 in clinical application; and the achievements of oHSV combined with immunotherapy and chemotherapy.
CONCLUSION: We reviewed the immunotherapy mechanism of the oHSV and provided a series of cases. We also pointed out that an in-depth study of the application of oHSV in cancer treatment will potentially benefits cancer patients more.

Komohara Y, Noyori O, Saito Y, et al.
Potential anti-lymphoma effect of M-CSFR inhibitor in adult T-cell leukemia/lymphoma.
J Clin Exp Hematop. 2018; 58(4):152-160 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
The c-fms proto-oncogene is also known as macrophage colony stimulating factor receptor (M-CSFR) or colony-stimulating factor-1 receptor (CSF-1R), and is expressed on several types of malignant tumor cells and myeloid cells. In the present study, we found that overexpression of M-CSFR was present in adult T-cell leukemia/lymphoma (ATLL) cases. M-CSFR signaling was associated with lymphoma cell proliferation, and M-CSFR inhibition induced apoptosis in lymphoma cells. The ATLL cell line ATL-T expressed M-CSF/CSF-1 and interleukin (IL)-34, which are both M-CSFR ligands. M-CSF and IL-34 expression was seen in ATLL cases, and co-expression of these ligands was detected in 11 of 13 ATLL cases. M-CSFR inhibition suppressed programmed death-1 and -2 ligand in ATL-T cells and macrophages stimulated with conditioned medium from ATL-T cells. Thus, an M-CSFR inhibitor may be useful as additional therapy against ATLL due to direct and indirect mechanisms.

Liu M, Sun X, Shi S
MORC2 Enhances Tumor Growth by Promoting Angiogenesis and Tumor-Associated Macrophage Recruitment via Wnt/β-Catenin in Lung Cancer.
Cell Physiol Biochem. 2018; 51(4):1679-1694 [PubMed] Related Publications
BACKGROUND/AIMS: In this study, we aimed to investigate how MORC family CW-type zinc finger 2 (MORC2) affects tumor progression of lung cancer.
METHODS: The MORC2 level was analyzed by real-time RT-PCR and immunohistochemistry (IHC) in normal control tissues and lung cancers. LL/2 cells overexpressing MORC2 were used to study how MORC2 expression influences lung cancer progression. The effects of MORC2 on cell viability, migration and invasion were assessed by MTT assay, Western blotting, and transwell assays, respectively. Afterwards, the effects of MORC2 on the activation of the Wnt/β-catenin pathway were explored by Western blotting. The effects of MORC2 on tumor-associated macrophages (TAM) were determined by immunofluorescence (IF) staining, real-time RT-PCR and Western blotting.
RESULTS: Our results showed that MORC2 was upregulated in lung cancers relative to adjacent tissues. The results also demonstrated that MORC2 promoted lung cancer tumor growth in vivo. Additionally, MORC2 overexpression stimulated the upregulation of vascular endothelial growth factor (VEGF), driving angiogenesis. MORC2 overexpression in LL/2 also increased the amount of aldehyde dehydrogenase-1 (ALDH1) protein, indicating that MORC2 increased cancer stem cell features. We further determined that MORC2 activated Wnt/β-catenin signaling in lung cancer cells. Upregulation of macrophage-recruiting genes including VEGF and Macrophage-specific colony stimulating factor (CSF-1) recruits TAMs to the tumor site, which has the net effect of promoting additional tumor growth and metastasis.
CONCLUSION: Our data suggest that MORC2 overexpression can drive lung cancer growth by stimulating the recruitment of TAMs in addition to angiogenesis and that activation of Wnt/β-signaling may be a key pathway underlying this phenotype that is amenable to pharmacological intervention.

Di K, Lomeli N, Bota DA, Das BC
Magmas inhibition as a potential treatment strategy in malignant glioma.
J Neurooncol. 2019; 141(2):267-276 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
PURPOSE: Magmas (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a nuclear gene that encodes the mitochondrial import inner membrane translocase subunit Tim16. Magmas is highly conserved, ubiquitously expressed in mammalian cells, and is essential for cell viability. Magmas expression levels are increased in prostate cancers and pituitary adenomas. Moreover, silencing Magmas by RNAi sensitizes pituitary adenoma cells to pro-apoptotic stimuli and induces a G0/G1 accumulation. The aim of this study was to examine whether inhibition of Magmas by small molecule inhibitors could be beneficial for the treatment of malignant gliomas.
METHODS: We evaluated the expression of Magmas in patient-derived glioblastoma tissue samples and xenograft models. We studied the feasibility of a small molecule Magmas inhibitor (BT#9) as a therapeutic agent in stable human glioma cell lines and high-grade patient derived glioma stem-like cells.
RESULTS: Magmas was overexpressed in tissue sections from glioma patients and xenografts. In vivo studies revealed that BT#9 could cross the blood-brain barrier in the animal model. Magmas inhibition by BT#9 in glioma cell lines significantly decreased cell proliferation, induced apoptosis along with vacuole formation, and blocked migration and invasion. In addition, BT#9 treatment decreased the respiratory function of glioma cells, supporting the role that Magmas serves as a reactive oxygen species regulator.
CONCLUSIONS: This is the first study on the role of Magmas in glioma. Our findings suggest that Magmas plays a key role in glioma cell survival and targeting Magmas by small molecule inhibitors may be a therapeutic strategy in gliomas.

Bagley SJ, Hwang WT, Brem S, et al.
RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma.
J Neurooncol. 2019; 141(1):95-102 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
INTRODUCTION: We sought to determine which therapeutically targetable immune checkpoints, costimulatory signals, and other tumor microenvironment (TME) factors are independently associated with immune cytolytic activity (CYT), a gene expression signature of activated effector T cells, in human glioblastoma (GBM).
METHODS: GlioVis was accessed for RNA-seq data from The Cancer Genome Atlas (TCGA). For subjects with treatment-naïve, primary GBM, we quantified mRNA expression of 28 therapeutically targetable TME factors. CYT (geometric mean of GZMA and PRF1 expression) was calculated for each tumor. Multiple linear regression was performed to determine the relationship between the dependent variable (CYT) and mRNA expression of each of the 28 factors. Variables associated with CYT in multivariate analysis were subsequently evaluated for this association in an independent cohort of newly diagnosed GBMs from the Chinese Glioma Cooperative Group (CGCG).
RESULTS: 109 TCGA tumors were analyzed. The final multiple linear regression model included the following variables, each positively associated with CYT except VEGF-A (negative association): CSF-1 (p = 0.003), CD137 (p = 0.042), VEGF-A (p < 0.001), CTLA4 (p = 0.028), CD40 (p = 0.023), GITR (p = 0.020), IL6 (p = 0.02), and OX40 (p < 0.001). In CGCG (n = 52), each of these variables remained significantly associated with CYT in univariate analysis except for VEGF-A. In multivariate analysis, only CTLA4 and CD40 remained statistically significant.
CONCLUSIONS: Using multivariate modeling of RNA-seq gene expression data, we identified therapeutically targetable TME factors that are independently associated with intratumoral cytolytic T-cell activity in human GBM. As a myriad of systemic immunotherapies are now available for investigation, our results could inform rational combinations for evaluation in GBM.

Woo HH, Chambers SK
Human ALKBH3-induced m
Biochim Biophys Acta Gene Regul Mech. 2019; 1862(1):35-46 [PubMed] Related Publications
In ovarian and breast cancers, the actions of the cytokine CSF-1 lead to poor prognosis. CSF-1 expression can be regulated post-transcriptionally. RNA methylation is another layer of posttranscriptional regulation. The methylation of N

Mastboom MJL, Hoek DM, Bovée JVMG, et al.
Does CSF1 overexpression or rearrangement influence biological behaviour in tenosynovial giant cell tumours of the knee?
Histopathology. 2019; 74(2):332-340 [PubMed] Related Publications
AIMS: Localised- and diffuse-type tenosynovial giant cell tumours (TGCT) are regarded as different clinical and radiological TGCT types. However, genetically and histopathologically they seem indistinguishable. We aimed to correlate CSF1 expression and CSF1 rearrangement with the biological behaviour of different TGCT-types with clinical outcome (recurrence).
METHODS AND RESULTS: Along a continuum of extremes, therapy-naive knee TGCT patients with >3-year follow-up, mean age 43 (range = 6-71) years and 56% females were selected. Nine localised (two recurrences), 16 diffuse-type (nine recurrences) and four synovitis as control were included. Rearrangement of the CSF1 locus was evaluated with split-apart fluorescence in-situ hybridisation (FISH) probes. Regions were selected to score after identifying CSF1-expressing regions, using mRNA ISH with the help of digital correlative microscopy. CSF1 rearrangement was considered positive in samples containing >2 split signals/100 nuclei. Irrespective of TGCT-subtype, all cases showed CSF1 expression and in 76% CSF1 rearrangement was detected. Quantification of CSF1-expressing cells was not informative, due to the extensive intratumour heterogeneity. Of the four synovitis cases, two also showed CSF1 expression without CSF1 rearrangement. No correlation between CSF1 expression or rearrangement with clinical subtype and local recurrence was detected. Both localised and diffuse TGCT cases showed a scattered distribution in the tissue of CSF1-expressing cells.
CONCLUSION: In diagnosing TGCT, CSF1 mRNA-ISH, in combination with CSF1 split-apart FISH using digital correlative microscopy, is an auxiliary diagnostic tool to identify rarely occurring neoplastic cells. This combined approach allowed us to detect CSF1 rearrangement in 76% of the TGCT cases. Neither CSF1 expression nor presence of CSF1 rearrangement could be associated with the difference in biological behaviour of TGCT.

Barve A, Casson L, Krem M, et al.
Comparative utility of NRG and NRGS mice for the study of normal hematopoiesis, leukemogenesis, and therapeutic response.
Exp Hematol. 2018; 67:18-31 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Cell-line-derived xenografts (CDXs) or patient-derived xenografts (PDXs) in immune-deficient mice have revolutionized our understanding of normal and malignant human hematopoiesis. Transgenic approaches further improved in vivo hematological research, allowing the development of human-cytokine-producing mice, which show superior human cell engraftment. The most popular mouse strains used in research, the NOG (NOD.Cg-Prkdc

Benkheil M, Paeshuyse J, Neyts J, et al.
HCV-induced EGFR-ERK signaling promotes a pro-inflammatory and pro-angiogenic signature contributing to liver cancer pathogenesis.
Biochem Pharmacol. 2018; 155:305-315 [PubMed] Related Publications
HCV is a major risk factor for hepatocellular carcinoma (HCC). HCC development in chronically infected HCV patients has until now been attributed to persistent inflammation and interference of viral proteins with host cell signaling. Since activation of the epidermal growth factor receptor (EGFR) presents a crucial step in HCV entry, we aimed at investigating whether EGFR signaling may contribute to the pathogenesis of HCV-related HCC. By applying microarray analysis, we generated a gene expression signature for secreted proteins in HCV-infected hepatoma cells. This gene signature was enriched for inflammatory and angiogenic processes; both crucially involved in HCC development. RT-qPCR analysis, conducted on the entire list of upregulated genes, confirmed induction of 11 genes (AREG, IL8, CCL20, CSF1, GDF15, IGFBP1, VNN3, THBS1 and PAI-1) in a virus titer- and replication-dependent manner. EGFR activation in hepatoma cells largely mimicked the gene signature seen in the infectious HCV model. Further, the EGFR-ERK pathway, but not Akt signaling, was responsible for this gene expression profile. Finally, microarray analysis conducted on clinical data from the GEO database, revealed that our validated gene expression profile is significantly represented in livers of patients with HCV-related liver pathogenesis (cirrhosis and HCC) compared to healthy livers. Taken together, our data indicate that persistent activation of EGFR-ERK signaling in chronically infected HCV patients may induce a specific pro-inflammatory and pro-angiogenic signature that presents a new mechanism by which HCV can promote liver cancer pathogenesis. A better understanding of the key factors in HCV-related oncogenesis, may efficiently direct HCC drug development.

Ma J, Zhang L, Yang P, et al.
Integrated analysis of long noncoding RNA expression profiles in lymph node metastasis of hepatocellular carcinoma.
Gene. 2018; 676:47-55 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and metastasis of HCC is the leading cause of poor prognosis. Among all the extrahepatic metastases, lymph node metastasis (LNM) is common, second only to lung metastasis. However, the pathogenesis of HCC LNM remains largely unknown.
METHODS: Microarray was performed to investigate the long noncoding RNA (lncRNA) and messenger RNA (mRNA) expression profiles in serum samples from HCC LNM patients (N = 4) and HCC non-LNM controls (N = 5). Subsequently, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was applied to validate the expression levels of randomly selected differential lncRNAs and mRNAs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were employed to explore the potential functions of differentially expressed mRNAs. Co-expression networks were further constructed to elucidate the interactions of the differential genes and to speculate on the potential functions of the dominant lncRNAs. In this research, we attempted to illuminate the correlations between lncRNA and HCC LNM.
RESULTS: Compared with the non-LNM group, a total of 234 lncRNAs and 58 mRNAs were obtained as significantly dysregulated genes in LNM group (p < 0.05, fold change ≥ 2). Functional enrichment analyses showed that upregulated mRNAs are mostly enriched for glucose-6-phosphate dehydrogenase activity, biotin binding and AP-3 adaptor complex, while the downregulated mRNAs are enriched for macrophage colony-stimulating factor receptor binding, succinate-CoA ligase activity and palmitoyltransferase activity. In addition, coexpression network revealed that the dominant lncRNAs are potential participants of protein metabolic process, integral component of membrane, RNA binding, Golgi apparatus, as well as focal adhesion pathway.
CONCLUSION: This study first revealed the expression profiles and potential functions of dysregulated lncRNAs and mRNAs in HCC LNM, which may provide novel clues for further studies on HCC LNM.

Galdiero MR, Varricchi G, Loffredo S, et al.
Potential involvement of neutrophils in human thyroid cancer.
PLoS One. 2018; 13(6):e0199740 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Neutrophil functions have long been regarded as limited to acute inflammation and the defense against microbes. The role(s) of neutrophils in cancer remain poorly understood. Neutrophils infiltrate tumors and are key effector cells in the orchestration of inflammatory responses. Thyroid cancer (TC) is the most recurrent endocrine malignant tumor and is responsible for 70% of deaths due to endocrine cancers. No studies are so far available on the role of neutrophils in TC.
OBJECTIVE: Our purpose was to study the involvement of tumor-associated neutrophils in TC.
METHODS: Highly purified human neutrophils (>99%) from healthy donors were stimulated in vitro with conditioned media derived from TC cell lines TPC1 and 8505c (TC-CMs). Neutrophil functions (e.g., chemotaxis, activation, plasticity, survival, gene expression, and protein release) were evaluated.
RESULTS: TC-derived soluble factors promoted neutrophil chemotaxis and survival. Neutrophil chemotaxis toward a TC-CM was mediated, at least in part, by CXCL8/IL-8, and survival was mediated by granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, each TC-CM induced morphological changes and activation of neutrophils (e.g., CD11b and CD66b upregulation and CD62L shedding) and modified neutrophils' kinetic properties. Furthermore, each TC-CM induced production of reactive oxygen species, expression of proinflammatory and angiogenic mediators (CXCL8/IL-8, VEGF-A, and TNF-α), and a release of matrix metalloproteinase 9 (MMP-9). Moreover, in TC patients, tumor-associated neutrophils correlated with larger tumor size.
CONCLUSIONS: TC cell lines produce soluble factors able to "educate" neutrophils toward an activated functional state. These data will advance the understanding of the molecular and cellular mechanisms of innate immunity in TC.

Sun Y, Long J, Yin Y, et al.
Characterization of CSF2A fusion gene and its effect on Epstein-Barr virus-positive tumor cells.
J Med Virol. 2018; 90(11):1750-1756 [PubMed] Related Publications
We build the latent membrane protein gene latent membrane protein 2A (LMP2A) and the granulocyte-macrophase colony-stimulating factor (GM-CSF) gene fusion gene (CSF2A) and discuss how the CSF2A fusion protein influenced the proliferation and apoptosis of Epstein-Barr virus-positive (EBV

Lacher MD, Bauer G, Fury B, et al.
SV-BR-1-GM, a Clinically Effective GM-CSF-Secreting Breast Cancer Cell Line, Expresses an Immune Signature and Directly Activates CD4
Front Immunol. 2018; 9:776 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Targeted cancer immunotherapy with irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic cancer cell lines has been an effective approach to reduce tumor burden in several patients. It is generally assumed that to be effective, these cell lines need to express immunogenic antigens coexpressed in patient tumor cells, and antigen-presenting cells need to take up such antigens then present them to patient T cells. We have previously reported that, in a phase I pilot study (ClinicalTrials.gov NCT00095862), a subject with stage IV breast cancer experienced substantial regression of breast, lung, and brain lesions following inoculation with clinical formulations of SV-BR-1-GM, a GM-CSF-secreting breast tumor cell line. To identify diagnostic features permitting the prospective identification of patients likely to benefit from SV-BR-1-GM, we conducted a molecular analysis of the SV-BR-1-GM cell line and of patient-derived blood, as well as a tumor specimen. Compared to normal human breast cells, SV-BR-1-GM cells overexpress genes encoding tumor-associated antigens (TAAs) such as PRAME, a cancer/testis antigen. Curiously, despite its presumptive breast epithelial origin, the cell line expresses major histocompatibility complex (MHC) class II genes (

Yang R, Cai TT, Wu XJ, et al.
Tumour YAP1 and PTEN expression correlates with tumour-associated myeloid suppressor cell expansion and reduced survival in colorectal cancer.
Immunology. 2018; 155(2):263-272 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The expansion of myeloid-derived suppressor cells (MDSCs) correlates with tumorigenesis in colorectal cancer (CRC). Here, we found a significant association between CD33

Okugawa Y, Toiyama Y, Ichikawa T, et al.
Colony-stimulating factor-1 and colony-stimulating factor-1 receptor co-expression is associated with disease progression in gastric cancer.
Int J Oncol. 2018; 53(2):737-749 [PubMed] Related Publications
Colony‑stimulating‑factor‑1 (CSF‑1) is a hematopoietic growth factor that exerts its effects through the c‑fms/CSF‑1 receptor (CSF‑1R). The CSF‑1/CSF‑1R axis is thought to be involved in the development of several types of cancer. This study aimed to clarify the clinical and biological significance of the CSF‑1/CSF‑1R axis in gastric cancer (GC). For this purpose, we evaluated CSF‑1 and CSF‑1R expression in GC tissues from 148 patients by RT‑qPCR and immunohistochemistry. The biological roles of the CSF‑1/CSF‑1R axis were investigated by measuring the cell proliferation and migration, and anoikis resistance in a human GC cell line following treatment with recombinant human CSF‑1 and/or CSF‑1R inhibitor. The results revealed that an elevated expression of CSF‑1 or CSF‑1R significantly correlated with disease progression and with a poor overall survival (OS, P=0.037 and 0.016, respectively) and disease‑free survival (DFS, P<0.001 and <0.001, respectively) of patients with GC. Furthermore, a high co‑expression of CSF‑1 and CSF‑1R was an independent prognostic factor for OS (HR, 1.38; 95% CI, 1.02‑1.88; P=0.038) and DFS (HR, 1.79; 95% CI, 1.21‑2.67; P=0.004), and an independent risk factor for lymph node and peritoneal metastasis. Immunohistochemical analysis revealed an intense CSF‑1/CSF‑1R expression in the cytoplasm of cancer cells in primary GC tissues. CSF‑1 or CSF‑1R expression positively correlated with vascular endothelial growth factor A (VEGFA) or Fms related tyrosine kinase 1 (FLT1) expression in GC tissues. Treatment with recombinant human CSF‑1 promoted proliferation, migration and anoikis resistance in a GC cell line. These effects were generally blocked by CSF‑1R inhibition. On the whole, the findings of this study indicate that the CSF‑1/CSF‑1R axis may be a clinically useful prognostic and predictive biomarker for lymph node and peritoneal metastasis and a potential therapeutic target in GC.

Li X, Qin Z, Xue J, et al.
Genetic variants in macrophage colony-stimulating factor are associated with risk of renal cell carcinoma in a Chinese population.
Int J Biol Markers. 2018; 33(3):321-328 [PubMed] Related Publications
OBJECTIVE: This study was performed to investigate whether CSF-1 polymorphisms influenced the risk of renal cell carcinoma in a Chinese population.
METHODS: The potentially functional polymorphisms in CSF-1 (rs333951 and rs2050462) were genotyped in this hospital-based case-control study, comprising 1512 renal cell carcinoma patients and 1691 controls in a Chinese population using the TaqMan assay. Furthermore, odds ratios (ORs) and 95% confidence intervals (CI) were used to estimate such an association. The logistic regression was used to assess the association between these genetic polymorphisms and the risk of renal cell carcinoma.
RESULTS: We found the genotype and allele frequency distribution of rs2050462 were significantly associated with the increasing risk of renal cell carcinoma ( P = 0.007). However, no statistical significance was found in the association between CSF-1 rs333951 polymorphism and the susceptibility of renal cell carcinoma ( P = 0.589). The analysis of combined risk alleles revealed that patients with two to four risk alleles showed no elevated risk of renal cell carcinoma compared to those with zero to one risk alleles (adjusted OR 1.09; 95% CI 0.95, 1.26; P = 0.226). Furthermore, compared with the genotypes containing A allele (AC and AA), the patients carrying the CC genotype in rs2050462 had a significantly greater prevalence of clinical stage II and IV (adjusted OR 0.67; 95% CI 0.47, 0.94; P = 0.021; adjusted OR 0.50; 95% CI 0.29, 0.88; P = 0.015, respectively).
CONCLUSIONS: The functional rs2050462 in CSF-1 might have a substantial influence on the renal cell carcinoma susceptibility and evolution in the Chinese population.

Shu C, Wang Q, Yan X, Wang J
Prognostic and microRNA profile analysis for CD44 positive expression pediatric posterior fossa ependymoma.
Clin Transl Oncol. 2018; 20(11):1439-1447 [PubMed] Related Publications
BACKGROUND: Ependymoma is the third most common pediatric brain tumor and occurs most frequently in the posterior fossa. However, the lack of immortalized cell lines, xenografts, or animal models has significantly hindered the study of pediatric posterior fossa ependymoma (P-PF-EPN) pathogenesis. This prompted us to use clinical big data to study this rare disease.
METHODS: Application of the robust rank aggregation method revealed CD44 as a reliable biomarker in P-PF-EPN. 120 P-PF-EPN samples after surgical resection were selected for Kaplan-Merier and Cox proportion hazard regression survival analysis. Immunohistochemical analysis was performed to assess CD44 expression in the tumor samples. The miRNA profile was determined using a whole-genome miRNA microarray. The expression patterns of related mRNAs, miRNAs and proteins were validated by qRT-PCR or Western blotting.
RESULTS: CD44 was found to be an independent predictor of prognosis in survival analysis. It improved the accuracy of using LAMA2/NELL2 for classifying P-PF-EPN molecular subgroups. Fourteen miRNAs were underexpressed, and one miRNA was overexpressed in CD44-positive P-PF-EPNs. miR-543, miR-495-3p, miR-299-3p, miR-139-5p and miR-128-3p were identified to have CD44 positively co-regulated potential target oncogenes. Two PI3K-Akt signaling pathway related potential target oncogenes (VEGFA, CSF1) for miR-299-3p and miR-495-3p were validated overexpression in CD44 positive P-PF-EPNs. Abnormal activation of the PI3K-Akt pathway was confirmed in CD44-positive cases.
CONCLUSIONS: CD44 is of great clinical significance as a prognostic biomarker. The survival difference between CD44 positive and negative P-PF-EPN is determined by a complex functional miRNA-mRNA-signaling pathway regulatory network.

Goyal G, Wong K, Nirschl CJ, et al.
PPARγ Contributes to Immunity Induced by Cancer Cell Vaccines That Secrete GM-CSF.
Cancer Immunol Res. 2018; 6(6):723-732 [PubMed] Related Publications
Peroxisome proliferator activated receptor-γ (PPARγ) is a lipid-activated nuclear receptor that promotes immune tolerance through effects on macrophages, dendritic cells (DCs), and regulatory T cells (Tregs). Granulocyte-macrophage colony stimulating factor (GM-CSF) induces PPARγ expression in multiple myeloid cell types. GM-CSF contributes to both immune tolerance and protection, but the role of PPARγ in these pathways is poorly understood. Here, we reveal an unexpected stimulatory role for PPARγ in the generation of antitumor immunity with irradiated, GM-CSF-secreting tumor-cell vaccines (GVAX). Mice harboring a deletion of

Webb MW, Sun J, Sheard MA, et al.
Colony stimulating factor 1 receptor blockade improves the efficacy of chemotherapy against human neuroblastoma in the absence of T lymphocytes.
Int J Cancer. 2018; 143(6):1483-1493 [PubMed] Article available free on PMC after 15/09/2019 Related Publications
Tumor-associated macrophages can promote growth of cancers. In neuroblastoma, tumor-associated macrophages have greater frequency in metastatic versus loco-regional tumors, and higher expression of genes associated with macrophages helps to predict poor prognosis in the 60% of high-risk patients who have MYCN-non-amplified disease. The contribution of cytotoxic T-lymphocytes to anti-neuroblastoma immune responses may be limited by low MHC class I expression and low exonic mutation frequency. Therefore, we modelled human neuroblastoma in T-cell deficient mice to examine whether depletion of monocytes/macrophages from the neuroblastoma microenvironment by blockade of CSF-1R can improve the response to chemotherapy. In vitro, CSF-1 was released by neuroblastoma cells, and topotecan increased this release. In vivo, neuroblastomas formed by subcutaneous co-injection of human neuroblastoma cells and human monocytes into immunodeficient NOD/SCID mice had fewer human CD14

Cabrera RM, Mao SPH, Surve CR, et al.
A novel neuregulin - jagged1 paracrine loop in breast cancer transendothelial migration.
Breast Cancer Res. 2018; 20(1):24 [PubMed] Article available free on PMC after 15/09/2019 Related Publications
BACKGROUND: The interaction of breast cancer cells with other cells in the tumor microenvironment plays an important role in metastasis. Invasion and intravasation, two critical steps in the metastatic process, are influenced by these interactions. Macrophages are of particular interest when it comes to studying tumor cell invasiveness. Previous studies have shown that there is paracrine loop signaling between breast cancer cells and macrophages involving colony stimulating factor 1 (CSF-1) produced by tumor cells and epidermal growth factor (EGF) production by macrophages. In this paper, we identify a novel paracrine loop between tumor cells and macrophages involving neuregulin (NRG1) and notch signaling.
METHODS: The aim of this study was to determine the role of NRG1, a ligand of the ErbB3 receptor, in macrophage stimulation of tumor cell transendothelial migration and intravasation. We used fluorescence-activated cell sorting (FACS) and western blot to determine ErbB3 and NRG1 expression, respectively. An in vitro transendothelial migration (iTEM) assay was used to examine the effects of short hairpin (sh)RNA targeting NRG1 in tumor cells and clustered regularly interspaced short palindromic repeats (CRISPR) knockout of jagged 1 (JAG1) in macrophages. Orthotopic xenograft injections in mice were used to confirm results in vivo.
RESULTS: In our system, macrophages were the primary cells showing expression of ErbB3, and a blocking antibody against ErbB3 resulted in a significant decrease in macrophage-induced transendothelial migration of breast cancer cells. Stimulation of macrophages with NRG1 upregulated mRNA and protein expression of JAG1, a ligand of the Notch receptor, and JAG1 production by macrophages was important for transendothelial migration of tumor cells.
CONCLUSIONS: This study demonstrates that stimulation of macrophages by tumor cell NRG1 can enhance transendothelial migration and intravasation. We also demonstrate that this effect is due to induction of macrophage JAG1, an important ligand of the Notch signaling pathway.

Keklikoglou I, Kadioglu E, Bissinger S, et al.
Periostin Limits Tumor Response to VEGFA Inhibition.
Cell Rep. 2018; 22(10):2530-2540 [PubMed] Related Publications
Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs) under extended vascular-endothelial growth factor A (VEGFA) blockade are dependent on periostin (POSTN), a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and αSMA

Zhuo H, Zheng B, Liu J, et al.
Efficient targeted tumor imaging and secreted endostatin gene delivery by anti-CD105 immunoliposomes.
J Exp Clin Cancer Res. 2018; 37(1):42 [PubMed] Article available free on PMC after 15/09/2019 Related Publications
BACKGROUND: Anti-CD105 mAb-conjugated immunoliposomes, loaded with secreted mouse endostatin gene, were developed for targeted tumor imaging and antiangiogenic gene therapy.
METHODS: The liposomes were investigated for size, zeta-potential, lipid content, antibody binding ability, and pcDNA loading capacity. The ability of immunoliposomes to target tumor-derived endothelial cells and perform gene transfer in vitro was measured and their basic biocompatibility was evaluated. A nude mouse/breast cancer xenograft model was used to examine the tumor internalization of fluorescent-labeled liposomes and the clinical potential of immnuoliposomes loaded with pcDNA3.1-CSF1-endostatin.
RESULTS: Loaded immunoliposomes were homogenously distributed with a well-defined spherical shape and bilayer, diameter of 122 ± 11 nm, and zeta potential + 1.40 mV. No significant differences were observed in body weight, liver index, oxidative stress, or liver and kidney function in mice after liposomes exposure. The addition of CD105 mAb to liposomes conferred the ability to target tumor-derived endothelial cells in vitro and in vivo. Systemic intravenous administration of fluorescent immunoliposomes in the xenograft model resulted in selective and efficient internalization in tumor vasculature. Treatment of mice with pcDNA3.1-CSF1-endostatin-loaded immunoliposomes suppressed tumor growth by 71%.
CONCLUSIONS: These data demonstrate the advantages of using anti-CD105 mAb-conjugated immunoliposomes to enhance tumor targeting, imaging, and gene transfer applications.

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