Gene Summary

Gene:CSF1; colony stimulating factor 1 (macrophage)
Aliases: MCSF, CSF-1
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, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:macrophage colony-stimulating factor 1
Source:NCBIAccessed: 25 June, 2015


What does this gene/protein do?
Show (41)
Pathways:What pathways are this gene/protein implicaed in?
Show (7)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 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.

  • Mice, Transgenic
  • CSF1R
  • Giant Cell Tumors
  • Oligonucleotide Array Sequence Analysis
  • Receptors, Growth Factor
  • Messenger RNA
  • Mutation
  • Breast Cancer
  • Translocation
  • fms-Like Tyrosine Kinase 3
  • Neoplastic Cell Transformation
  • Tumor Markers
  • siRNA
  • Adolescents
  • Chromosome 1
  • Immunohistochemistry
  • p53 Protein
  • Transcription Factors
  • Macrophages
  • Neoplasm Invasiveness
  • Base Sequence
  • Gene Expression Profiling
  • Chromosome 5
  • Gene Expression
  • RNA
  • Pancreatic Cancer
  • Fibroblasts
  • Disease Progression
  • Polymerase Chain Reaction
  • Cancer Gene Expression Regulation
  • Macrophage Colony-Stimulating Factor
  • Up-Regulation
  • Single Nucleotide Polymorphism
  • Stromal Cells
  • MicroRNAs
  • Molecular Sequence Data
  • Chromosome Aberrations
  • Transfection
Tag cloud generated 25 June, 2015 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)

Duan Y, Li Z, Cheng S, et al.
Nasopharyngeal carcinoma progression is mediated by EBER-triggered inflammation via the RIG-I pathway.
Cancer Lett. 2015; 361(1):67-74 [PubMed] Related Publications
EBERs (EBER1 and EBER2) are suggested to be involved in cellular transformation and tumor growth. Cytoplasmic pattern recognition receptor-RIG-I, which is characterized by the recognition of viral dsRNAs, could efficiently trigger the downstream pathways of innate immunity. Although some previous reports have shown that EBERs and RIG-I associate with hematological malignancies, the role of EBERs-RIG-I signaling in solid tumors remains to be clarified. Here we demonstrate that EBER mediation of the inflammatory response via RIG-I contributes to NPC development in vitro and in vivo. We first verified that the expression level of RIG-I was associated with EBER transcription in a dose-dependent manner in NPC cells and specimens from NPC patients. Furthermore, pro-inflammatory cytokine transcription and release were sharply reduced after RIG-I knockdown compared with the control shRNA group in the presence of EBERs, accompanied by an attenuation of the NF-κB and MAPK signaling pathways. Consequently, the tumor burden was greatly alleviated in the RIG-I knockdown group in a xenograft model. In addition, macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein (MCP-1), which promote the maturation and attraction of tumor-associated macrophages, were stimulated upon the introduction of EBERs, and this upregulation conceivably led to the tumor-promoting subset transition of the macrophages. Taken together, our results reveal that EBERs could promote NPC progression through RIG-I-mediated cancer-related inflammation.

Togami K, Kitaura J, Uchida T, et al.
A C-terminal mutant of CCAAT-enhancer-binding protein α (C/EBPα-Cm) downregulates Csf1r, a potent accelerator in the progression of acute myeloid leukemia with C/EBPα-Cm.
Exp Hematol. 2015; 43(4):300-8.e1 [PubMed] Related Publications
Two types of CCAAT-enhancer-binding protein α (C/EBPα) mutants are found in acute myeloid leukemia (AML) patients: N-terminal frame-shift mutants (C/EBPα-N(m)) generating p30 as a dominant form and C-terminal basic leucine zipper domain mutants (C/EBPα-C(m)). We have previously shown that C/EBPα-K304_R323dup belonging to C/EBPα-C(m), but not C/EBPα-T60fsX159 belonging to C/EBPα-N(m), alone induced AML in mouse bone marrow transplantation (BMT) models. Here we show that various C/EBPα-C(m) mutations have a similar, but not identical, potential in myeloid leukemogenesis. Notably, like C/EBPα-K304_R323dup, any type of C/EBPα-C(m) tested (C/EBPα-S299_K304dup, K313dup, or N321D) by itself induced AML, albeit with different latencies after BMT; C/EBPα-N321D induced AML with the shortest latency. By analyzing the gene expression profiles of C/EBPα-N321D- and mock-transduced c-kit(+)Sca-1(+)Lin(-) cells, we identified Csf1r as a gene downregulated by C/EBPα-N321D. In addition, leukemic cells expressing C/EBPα-C(m) exhibited low levels of colony stimulating factor 1 receptor in mice. On the other hand, transduction with C/EBPα-N(m) did not influence Csf1r expression in c-kit(+)Sca-1(+)Lin(-) cells, implying a unique role for C/EBPα-C(m) in downregulating Csf1r. Importantly, Csf1r overexpression collaborated with C/EBPα-N321D to induce fulminant AML with leukocytosis in mouse BMT models to a greater extent than did C/EBPα-N321D alone. Collectively, these results suggest that C/EBPα-C(m)-mediated downregulation of Csf1r has a negative, rather than a positive, impact on the progression of AML involving C/EBPα-C(m), which might possibly be accelerated by additional genetic and/or epigenetic alterations inducing Csf1r upregulation.

Garg M, Okamoto R, Nagata Y, et al.
Establishment and characterization of novel human primary and metastatic anaplastic thyroid cancer cell lines and their genomic evolution over a year as a primagraft.
J Clin Endocrinol Metab. 2015; 100(2):725-35 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
CONTEXT: Anaplastic thyroid cancer (ATC) has no effective treatment, resulting in a high rate of mortality. We established cell lines from a primary ATC and its lymph node metastasis, and investigated the molecular factors and genomic changes associated with tumor growth.
OBJECTIVE: The aim of the study was to understand the molecular and genomic changes of highly aggressive ATC and its clonal evolution to develop rational therapies.
DESIGN: We established unique cell lines from primary (OGK-P) and metastatic (OGK-M) ATC specimen, as well as primagraft from the metastatic ATC, which was serially xeno-transplanted for more than 1 year in NOD scid gamma mice were established. These cell lines and primagraft were used as tools to examine gene expression, copy number changes, and somatic mutations using RNA array, SNP Chip, and whole exome sequencing.
RESULTS: Mice carrying sc (OGK-P and OGK-M) tumors developed splenomegaly and neutrophilia with high expression of cytokines including CSF1, CSF2, CSF3, IL-1β, and IL-6. Levels of HIF-1α and its targeted genes were also elevated in these tumors. The treatment of tumor carrying mice with Bevacizumab effectively decreased tumor growth, macrophage infiltration, and peripheral WBCs. SNP chip analysis showed homozygous deletion of exons 3-22 of the PARD3 gene in the cells. Forced expression of PARD3 decreased cell proliferation, motility, and invasiveness, restores cell-cell contacts and enhanced cell adhesion. Next generation exome sequencing identified the somatic changes present in the primary, metastatic, and primagraft tumors demonstrating evolution of the mutational signature over the year of passage in vivo.
CONCLUSION: To our knowledge, we established the first paired human primary and metastatic ATC cell lines offering unique possibilities for comparative functional investigations in vitro and in vivo. Our exome sequencing also identified novel mutations, as well as clonal evolution in both the metastasis and primagraft.

Zins K, Sioud M, Aharinejad S, et al.
Modulating the tumor microenvironment with RNA interference as a cancer treatment strategy.
Methods Mol Biol. 2015; 1218:143-61 [PubMed] Related Publications
The tumor microenvironment is composed of accessory cells and immune cells in addition to extracellular matrix (ECM) components. The stromal compartment interacts with cancer cells in a complex crosstalk to support tumor development. Growth factors and cytokines produced by stromal cells support the growth of tumor cells and promote interaction with the vasculature to enhance tumor progression and invasion. The activation of autocrine and paracrine oncogenic signaling pathways by growth factors, cytokines, and proteases derived from both tumor cells and the stromal compartment is thought to play a major role in assisting tumor cells during metastasis. Consequently, targeting tumor-stroma interactions by RNA interference (RNAi)-based approaches is a promising strategy in the search for novel treatment modalities in human cancer. Recent advances in packaging technology including the use of polymers, peptides, liposomes, and nanoparticles to deliver small interfering RNAs (siRNAs) into target cells may overcome limitations associated with potential RNAi-based therapeutics. Newly developed nonviral gene delivery approaches have shown improved anticancer efficacy suggesting that RNAi-based therapeutics provide novel opportunities to elicit significant gene silencing and induce regression of tumor growth. This chapter summarizes our current understanding of the tumor microenvironment and highlights some potential targets for therapeutic intervention with RNAi-based cancer therapeutics.

Kim M, Tan YS, Cheng WC, et al.
MIR144 and MIR451 regulate human erythropoiesis via RAB14.
Br J Haematol. 2015; 168(4):583-97 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Expression levels of MIR144 and MIR451 increase during erythropoiesis, a pattern that is conserved from zebrafish to humans. As these two miRs are expressed from the same polycistronic transcript, we manipulated MIR144 and MIR451 in human erythroid cells individually and together to investigate their effects on human erythropoiesis. Inhibition of endogenous human MIR451 resulted in decreased numbers of erythroid (CD71(hi) CD235a(hi) CD34(-) ) cells, consistent with prior studies in zebrafish and mice. In addition, inhibition of MIR144 impaired human erythroid differentiation, unlike in zebrafish and mouse studies where the functional effect of MIR144 on erythropoiesis was minimal. In this study, we found RAB14 is a direct target of both MIR144 and MIR451. As MIR144 and MIR451 expression increased during human erythropoiesis, RAB14 protein expression decreased. Enforced RAB14 expression phenocopied the effect of MIR144 and/or MIR451 depletion, whereas shRNA-mediated RAB14 knockdown protected cells from MIR144 and/or MIR451 depletion-mediated erythropoietic inhibition. RAB14 knockdown increased the frequency and number of erythroid cells, increased β-haemoglobin expression, and decreased CBFA2T3 expression during human erythropoiesis. In summary, we utilized MIR144 and MIR451 to identify RAB14 as a novel physiological inhibitor of human erythropoiesis.

Gutknecht MF, Bouton AH
Functional significance of mononuclear phagocyte populations generated through adult hematopoiesis.
J Leukoc Biol. 2014; 96(6):969-80 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Tissue homeostasis requires a complete repertoire of functional macrophages in peripheral tissues. Recent evidence indicates that many resident tissue macrophages are seeded during embryonic development and persist through adulthood as a consequence of localized proliferation. Mononuclear phagocytes are also produced during adult hematopoiesis; these cells are then recruited to sites throughout the body, where they function in tissue repair and remodeling, resolution of inflammation, maintenance of homeostasis, and disease progression. The focus of this review is on mononuclear phagocytes that comprise the nonresident monocyte/macrophage populations in the body. Key features of monocyte differentiation are presented, focusing primarily on the developmental hierarchy that is established through this process, the markers used to identify discrete cell populations, and novel, functional attributes of these cells. These features are then explored in the context of the tumor microenvironment, where mononuclear phagocytes exhibit extensive plasticity in phenotype and function.

Mathew E, Collins MA, Fernandez-Barrena MG, et al.
The transcription factor GLI1 modulates the inflammatory response during pancreatic tissue remodeling.
J Biol Chem. 2014; 289(40):27727-43 [PubMed] Article available free on PMC after 03/10/2015 Related Publications
Pancreatic cancer, one of the deadliest human malignancies, is almost uniformly associated with a mutant, constitutively active form of the oncogene Kras. Studies in genetically engineered mouse models have defined a requirement for oncogenic KRAS in both the formation of pancreatic intraepithelial neoplasias, the most common precursor lesions to pancreatic cancer, and in the maintenance and progression of these lesions. Previous work using an inducible model allowing tissue-specific and reversible expression of oncogenic Kras in the pancreas indicates that inactivation of this GTPase at the pancreatic intraepithelial neoplasia stage promotes pancreatic tissue repair. Here, we extend these findings to identify GLI1, a transcriptional effector of the Hedgehog pathway, as a central player in pancreatic tissue repair upon Kras inactivation. Deletion of a single allele of Gli1 results in improper stromal remodeling and perdurance of the inflammatory infiltrate characteristic of pancreatic tumorigenesis. Strikingly, this partial loss of Gli1 affects activated fibroblasts in the pancreas and the recruitment of immune cells that are vital for tissue recovery. Analysis of the mechanism using expression and chromatin immunoprecipitation assays identified a subset of cytokines, including IL-6, mIL-8, Mcp-1, and M-csf (Csf1), as direct GLI1 target genes potentially mediating this phenomenon. Finally, we demonstrate that canonical Hedgehog signaling, a known regulator of Gli1 activity, is required for pancreas recovery. Collectively, these data delineate a new pathway controlling tissue repair and highlight the importance of GLI1 in regulation of the pancreatic microenvironment during this cellular process.

Sakashita K, Kato I, Daifu T, et al.
In vitro expansion of CD34(+)CD38(-) cells under stimulation with hematopoietic growth factors on AGM-S3 cells in juvenile myelomonocytic leukemia.
Leukemia. 2015; 29(3):606-14 [PubMed] Related Publications
Using serum-containing culture, we examined whether AGM-S3 stromal cells, alone or in combination with hematopoietic growth factor(s), stimulated the proliferation of CD34(+) cells from patients with juvenile myelomonocytic leukemia (JMML). AGM-S3 cells in concert with stem cell factor plus thrombopoietin increased the numbers of peripheral blood CD34(+) cells to approximately 20-fold of the input value after 2 weeks in nine JMML patients with either PTPN11 mutations or RAS mutations, who received allogeneic hematopoietic transplantation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) also augmented the proliferation of JMML CD34(+) cells on AGM-S3 cells. The expansion potential of CD34(+) cells was markedly low in four patients who achieved spontaneous hematological improvement. A large proportion of day-14-cultured CD34(+) cells were negative for CD38 and cryopreservable. Cultured JMML CD34(+)CD38(-) cells expressed CD117, CD116, c-mpl, CD123, CD90, but not CXCR4, and formed GM and erythroid colonies. Day-7-cultured CD34(+) cells from two of three JMML patients injected intrafemorally into immunodeficient mice stimulated with human GM-CSF after transplantation displayed significant hematopoietic reconstitution. The abilities of OP9 cells and MS-5 cells were one-third and one-tenth, respectively, of the value obtained with AGM-S3 cells. Our culture system may provide a useful tool for elucidating leukemogenesis and for therapeutic approaches in JMML.

Riccardo F, Arigoni M, Buson G, et al.
Characterization of a genetic mouse model of lung cancer: a promise to identify Non-Small Cell Lung Cancer therapeutic targets and biomarkers.
BMC Genomics. 2014; 15 Suppl 3:S1 [PubMed] Article available free on PMC after 03/10/2015 Related Publications
BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for 81% of all cases of lung cancer and they are often fatal because 60% of the patients are diagnosed at an advanced stage. Besides the need for earlier diagnosis, there is a high need for additional effective therapies. In this work, we investigated the feasibility of a lung cancer progression mouse model, mimicking features of human aggressive NSCLC, as biological reservoir for potential therapeutic targets and biomarkers.
RESULTS: We performed RNA-seq profiling on total RNA extracted from lungs of a 30 week-old K-ras(LA1)/p53(R172HΔg) and wild type (WT) mice to detect fusion genes and gene/exon-level differential expression associated to the increase of tumor mass. Fusion events were not detected in K-ras(LA1)/p53(R172HΔg) tumors. Differential expression at exon-level detected 33 genes with differential exon usage. Among them nine, i.e. those secreted or expressed on the plasma membrane, were used for a meta-analysis of more than 500 NSCLC RNA-seq transcriptomes. None of the genes showed a significant correlation between exon-level expression and disease prognosis. Differential expression at gene-level allowed the identification of 1513 genes with a significant increase in expression associated to tumor mass increase. 74 genes, i.e. those secreted or expressed on the plasma membrane, were used for a meta-analysis of two transcriptomics datasets of human NSCLC samples, encompassing more than 900 samples. SPP1 was the only molecule whose over-expression resulted statistically related to poor outcome regarding both survival and metastasis formation. Two other molecules showed over-expression associated to poor outcome due to metastasis formation: GM-CSF and ADORA3. GM-CSF is a secreted protein, and we confirmed its expression in the supernatant of a cell line derived by a K-ras(LA1)/p53(R172HΔg) mouse tumor. ADORA3 is instead involved in the induction of p53-mediated apoptosis in lung cancer cell lines. Since in our model p53 is inactivated, ADORA3 does not negatively affect tumor growth but remains expressed on tumor cells. Thus, it could represent an interesting target for the development of antibody-targeted therapy on a subset of NSCLC, which are p53 null and ADORA3 positive.
CONCLUSIONS: Our study provided a complete transcription overview of the K-ras(LA1)/p53(R172HΔg) mouse NSCLC model. This approach allowed the detection of ADORA3 as a potential target for antibody-based therapy in p53 mutated tumors.

Jehs T, Faber C, Juel HB, et al.
Inflammation-induced chemokine expression in uveal melanoma cell lines stimulates monocyte chemotaxis.
Invest Ophthalmol Vis Sci. 2014; 55(8):5169-75 [PubMed] Related Publications
PURPOSE: Uveal melanoma (UM) is the most common primary intraocular tumor in adults and the presence of infiltrating leucocytes is associated with a poor prognosis. Little is known how infiltrating leucocytes influence the tumor cells. The purpose of this study was to investigate the effect of activated T cells on the expression of chemotactic cytokines in UM cells. Furthermore, we examined the ability of stimulated UM cells to attract monocytes.
METHODS: We used an in vitro coculture system in which UM cell lines and T cells were cultured together, but separated by a membrane. Uveal melanoma gene expression was quantified using a microarray. Protein expression in the supernatant was quantified with ELISA or cytometric bead array. For the monocyte migration assay, a transwell plate was used.
RESULTS: Gene-expression analysis of UM cell lines showed that coculture with activated T cells resulted in an upregulation of chemokines such as CXCL8, CXCL9, CXCL10, CXCL11, CCL2, CCL5, VEGF, intracellular adhesion molecule 1 (ICAM1), and granulocyte-macrophage colony-stimulating factor (GM-CSF). The upregulation of these molecules was confirmed at the protein level. This increase of chemokines coincided with an increased chemotactic capacity of the supernatant toward monocytes.
CONCLUSIONS: Cytokines derived from activated T cells shifted the UM cell transcriptome toward a more inflammatory state, including upregulation of several chemokines, which led to an increased migration of monocytes. Therefore, UM cells might actively participate in generating a tumor-promoting inflammatory microenvironment.

Zhang X, Akech J, Browne G, et al.
Runx2-Smad signaling impacts the progression of tumor-induced bone disease.
Int J Cancer. 2015; 136(6):1321-32 [PubMed] Article available free on PMC after 15/03/2016 Related Publications
Runx2, a master regulator of osteogenesis, is abnormally expressed in advanced prostate cancer. Here, we addressed Runx2 contribution to formation of prostate cancer-related osteolytic and osteoblastic bone lesions by mediating TGFβ/BMP signaling through direct interaction with Smads. Further, we examined involvement of the Runx2-Smad complex in mediating tumor growth and distal metastasis. To identify Runx2-Smad-specific mechanisms of prostate tumor activity in bone, we generated PC3 prostate cancer cell lines expressing Runx2-WT or one of two mutant proteins (Runx2-HTY and Runx2-ΔC) that each disrupt the Runx2-Smad interaction, either directly through a point mutation or by deletion of the functional C-terminus, respectively. Intratibial tumors generated from these cells revealed that Runx2-WT-expressing cells resulted in predominantly osteolytic disease, whereas cells expressing mutant proteins exhibited tumors with mixed osteolytic/osteoblastic lesions. Extent of bone loss and woven bone formation was assessed by radiography and micro-computed tomography. Bioluminescent imaging showed the presence of labeled prostate cancer cells in the lung at the latest time point examined, with Runx2-WT group exhibiting increased incidence of tumor cells in lung. Notably, disruption of the Runx2-Smad interaction significantly reduced incidence and size of lung tumors. Altered expression of Runx2 target genes involved in invasion, growth, adhesion and metastasis supported our findings. Thus, our studies demonstrate that Runx2 in prostate cancer cells plays a significant role in intratibial prostate cancer-related tumor growth and bone loss through mechanisms mediated by the Runx2-Smad signaling pathway. This work expands upon the potential importance of Runx2 as a therapeutic target in cancer.

Parviainen S, Ahonen M, Diaconu I, et al.
GMCSF-armed vaccinia virus induces an antitumor immune response.
Int J Cancer. 2015; 136(5):1065-72 [PubMed] Related Publications
Oncolytic Western Reserve strain vaccinia virus selective for epidermal growth factor receptor pathway mutations and tumor-associated hypermetabolism was armed with human granulocyte-macrophage colony-stimulating factor (GMCSF) and a tdTomato fluorophore. As the assessment of immunological responses to human transgenes is challenging in the most commonly used animal models, we used immunocompetent Syrian golden hamsters, known to be sensitive to human GMCSF and semipermissive to vaccinia virus. Efficacy was initially tested in vitro on various human and hamster cell lines and oncolytic potency of transgene-carrying viruses was similar to unarmed virus. The hGMCSF-encoding virus was able to completely eradicate subcutaneous pancreatic tumors in hamsters, and to fully protect the animals from subsequent rechallenge with the same tumor. Induction of specific antitumor immunity was also shown by ex vivo co-culture experiments with hamster splenocytes. In addition, histological examination revealed increased infiltration of neutrophils and macrophages in GMCSF-virus-treated tumors. These findings help clarify the mechanism of action of GMCSF-armed vaccinia viruses undergoing clinical trials.

Du T, Shi G, Li YM, et al.
Tumor-specific oncolytic adenoviruses expressing granulocyte macrophage colony-stimulating factor or anti-CTLA4 antibody for the treatment of cancers.
Cancer Gene Ther. 2014; 21(8):340-8 [PubMed] Related Publications
The purpose of this study was to examine the tumor specificity, cytotoxicity and the antitumor activity of two conditionally replicating oncolytic adenoviruses, SKL001 and SKL002, which expressed granulocyte macrophage colony-stimulating factor (GM-CSF) or anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA4) antibody, respectively, and determine their antitumor efficacy in A549 lung tumor model, B16F10 mouse melanoma tumor model and CMT-64 mouse small lung carcinoma tumor model. Virus yield and cytotoxicity were used to determine tumor specificity and virus replication-mediated cytotoxicity of SKL001 and SKL002 in a panel of human tumor cell lines and primary cells in vitro. Two subcutaneous (s.c.) tumor nexograft tumor models were used to assess their antitumor activity. Under the control of the E2F promoter, the expression of E1a genes appeared only in tumor cells, whereas the wild-type Ad5 expressed its E1a genes in both tumor cells and normal cells. GM-CSF and anti-CTLA4 production were significantly higher in tumor cells than normal cells. SKL001 and SKL002 replicated in Rb-defective cell lines as efficiently as wild-type adenovirus but produced 100-fold less virus in normal human cells. SKL001 and SKL002 was up to 1000-fold more cytotoxic in Rb pathway-defective human tumor cells in comparison with normal human cells. Antitumor activity of SKL001 and SKL002 following intravenous administration was shown in a human lung A549 s.c. xenograft tumor model and mouse B16F10 melanoma tumor model when compared with phosphate-buffered saline treatment. In immune-competent mice, the addition of GM-CSF produced a stronger antitumor activity and induced a higher number of mature dendritic cells and macrophages, whereas additive antitumor activity was observed in the group when SKL001 and SKL002 were combined. In vitro and in vivo studies showed the selective replication, cytotoxicity, gene production and antitumor efficacy of SKL001 and SKL002 in human tumor model, suggesting a potential utility of this oncolytic agent for the treatment of human cancer. Further studies are warranted to show the role of human GM-CSF and anti-CTLA4 antibody in the antitumor efficacy of these two oncolytic viruses.

La Piana R, Webber A, Guiot MC, et al.
A novel mutation in the CSF1R gene causes a variable leukoencephalopathy with spheroids.
Neurogenetics. 2014; 15(4):289-94 [PubMed] Related Publications
Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids is a neurodegenerative disease associated with mutations in the colony-stimulating factor 1 receptor gene (CSF1R). A 44-year-old woman with a 7-year history of depression presented with neurological signs and a recent cognitive decline. The diagnosis of hereditary diffuse leukoencephalopathy with neuroaxonal spheroids was suspected based on the findings of a predominant frontal leukoencephalopathy and neuroaxonal spheroids on brain biopsy. She shares with her mother a novel CSF1R exon 18 missense mutation (c.2350G > A; p.V784M). The mother has a long-standing bipolar disorder and mild multifocal white matter abnormalities in her 70s. This is the first report of hereditary diffuse leukoencephalopathy with neuroaxonal spheroids due to this novel CSF1R missense mutation. Our report suggests that either marked intrafamilial variability or incomplete penetrance can be associated with CSF1R mutations. The observation of a small bone cyst in our patient supports the hypothesis that hereditary diffuse leukoencephalopathy with neuroaxonal spheroids and polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy may belong to a spectrum of overlapping phenotypes.

Zhang X, Blaskovich MA, Forinash KD, Sebti SM
Withacnistin inhibits recruitment of STAT3 and STAT5 to growth factor and cytokine receptors and induces regression of breast tumours.
Br J Cancer. 2014; 111(5):894-902 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
BACKGROUND: The binding of STAT3 and STAT5 to growth factor and cytokine receptors such as EGFR and IL-6 receptor gp130 is critical to their activation and ability to contribute to malignant transformation. Therefore, interfering with these biochemical processes could lead to the discovery of novel anticancer agents.
METHODS: Co-immunoprecipitation, western blotting, microscopy, DNA binding, invasion, and soft agar assays as well as a mouse model were used to investigate the mechanism by which the natural product Withacnistin (Wit) inhibits STAT 3/5 tyrosine phosphoryaltion and activation.
RESULTS: Wit blocks EGF- and IL-6-stimulated binding of STAT3 and STAT5 to EGFR and gp130. Wit inhibits EGF-, PDGF-, IL-6-, IFNβ-, and GM-CSF-stimulation of tyrosine phosphorylation of STAT3 and STAT5 but not of EGFR or PDGFR. The inhibition of P-STAT3 and P-STAT5 occurred rapidly, within minutes of Wit treatment and growth factor stimulation. Wit also inhibits STAT3 nuclear translocation, DNA binding, promoter transcriptional activation, and it suppresses the expression levels of STAT3 target genes such as Bcl-xL and Mcl-1. Finally, Wit induces apoptosis, inhibits anchorage-dependent and -independent growth and invasion, and causes breast tumour regression in an ErbB2-driven transgenic mouse model.
CONCLUSIONS: These data warrant further development of Wit as a novel anticancer drug for targeting tumours that harbour hyperactivated STAT3 and STAT5.

Van Overmeire E, Laoui D, Keirsse J, et al.
STAT of the union: dynamics of distinct tumor-associated macrophage subsets governed by STAT1.
Eur J Immunol. 2014; 44(8):2238-42 [PubMed] Related Publications
The tumor stroma has long been ignored as therapeutic target, but it has become clear that several stromal cell types play a nonredundant role during tumor progression. In particular, macrophages possess the capacity to stimulate tumor growth and metastasis via multiple mechanisms. In this issue of the European Journal of Immunology, a study by Tymoszuk et al. Eur. J. Immunol. 2014. 44: 2247-2262 demonstrates that both monocyte recruitment and local macrophage proliferation determines the tumor-associated macrophage (TAM) pool size in HER2/Neu-driven mammary carcinomas. These tumors contain two main TAM subsets--MHC class II (MHC-II)(lo) F4/80(hi) and MHC-II(hi) F4/80(lo)--similar to what was observed in other tumor models. Interestingly, only the MHC-II(lo) F4/80(hi) subset is largely absent in a STAT1-deficient background. STAT1 induces the expression of CSF-1, which in turn drives TAM proliferation and possibly also the M2 gene signature of MHC-II(lo) F4/80(hi) TAM. Conversely, STAT1 deficiency upregulates M2 gene expression in MHC-II(hi) F4/80(lo) TAM, demonstrating that both TAM subsets are differentially regulated, probably as a consequence of their distinct intratumoral localization. In this Commentary, we place these findings in the context of current knowledge and propose new avenues for future research.

Villaverde MS, Combe K, Duchene AG, et al.
Suicide plus immune gene therapy prevents post-surgical local relapse and increases overall survival in an aggressive mouse melanoma setting.
Int Immunopharmacol. 2014; 22(1):167-75 [PubMed] Related Publications
In an aggressive B16-F10 murine melanoma model, we evaluated the effectiveness and antitumor mechanisms triggered by a surgery adjuvant treatment that combined a local suicide gene therapy (SG) with a subcutaneous genetic vaccine (Vx) composed of B16-F10 cell extracts and lipoplexes carrying the genes of human interleukin-2 and murine granulocyte and macrophage colony stimulating factor. Pre-surgical SG treatment, neither alone nor combined with Vx was able to slow down the fast evolution of this tumor. After surgery, both SG and SG + Vx treatments, significantly prevented (in 50% of mice) or delayed (in the remaining 50%) post-surgical recurrence, as well as significantly prolonged recurrence-free (SG and SG + Vx) and overall median survival (SG + Vx). The treatment induced the generation of a pseudocapsule wrapping and separating the tumor from surrounding host tissue. Both, SG and the subcutaneous Vx, induced this envelope that was absent in the control group. On the other hand, PET scan imaging of the SG + Vx group suggested the development of an effective systemic immunostimulation that enhanced (18)FDG accrual in the thymus, spleen and vertebral column. When combined with surgery, direct intralesional injection of suicide gene plus distal subcutaneous genetic vaccine displayed efficacy and systemic antitumor immune response without host toxicity. This suggests the potential value of the assayed approach for clinical purposes.

Nemunaitis J, Barve M, Orr D, et al.
Summary of bi-shRNA/GM-CSF augmented autologous tumor cell immunotherapy (FANG™) in advanced cancer of the liver.
Oncology. 2014; 87(1):21-9 [PubMed] Related Publications
Therapies for advanced hepatocellular carcinoma (HCC) are limited. We carried out a phase I trial of a novel autologous whole-cell tumor cell immunotherapy (FANG™), which incorporates a dual granulocyte macrophage colony-stimulating factor (GM-CSF) expressive/bifunctional small hairpin RNA interference (bi-shRNAi) vector. The bi-shRNAi DNA targets furin, which is a proconvertase of transforming growth factors beta (TGFβ) 1 and 2. Safety, mechanism, immunoeffectiveness, and suggested benefit were previously shown [Senzer et al.: Mol Ther 2012;20:679-689; Senzer et al.: J Vaccines Vaccin 2013;4:209]. We now provide further follow-up of a subset of 8 HCC patients. FANG manufacturing was successful in 7 of 8 attempts (one failure due to insufficient cell yield). Median GM-CSF expression was 144 pg/10(6) cells, TGFβ1 knockdown was 100%, and TGFβ2 knockdown was 93% of the vector-transported cells. Five patients were vaccinated (1 or 2.5×10(7) cells/intradermal injection, 6-11 vaccinations). No FANG toxicity was observed. Three of these patients demonstrated evidence of an immune response to the autologous tumor cell sample. Long-term follow-up demonstrated survival of 319, 729, 784, 931+, and 1,043+ days of the FANG-treated patients. In conclusion, evidence supports further assessment of the FANG immunotherapy in HCC.

Liverani C, Mercatali L, Spadazzi C, et al.
CSF-1 blockade impairs breast cancer osteoclastogenic potential in co-culture systems.
Bone. 2014; 66:214-22 [PubMed] Related Publications
Metastatic bone disease has a major impact on the morbidity and mortality of breast cancer patients, and studies on bone metastasis biology have led to the development of the most widely used drugs for bone metastases treatment: zoledronate (Zol) and denosumab (Den). The aim of the present study was to assess the effect of soluble mediators produced by breast cancer cells on human osteoclast maturation in a co-culture model. We also tested the ability of zoledronate, denosumab and 5H4, an antibody directed against CSF-1, to interfere with the osteoclastogenic potential of breast cancer. The study was performed on the triple negative cell line MDA-MB-231 and on human osteoclasts obtained from the differentiation of peripheral blood monocytes of a healthy volunteer. Osteoclastogenesis was evaluated by TRAP assay after 14days of differentiation with 10% MDA-MB-231-conditioned media or with CSF-1 and RANKL. Den, Zol and 5H4 were administered after 7days of differentiation. MDA-MB-231-conditioned media doubled the differentiation of monocytes into osteoclasts. MDA-MB-231 secreted CSF-1, especially when cells were cultured to confluence. Induced osteoclasts were sensitive to bone-targeted drugs: Den and 5H4 blocked osteoclast differentiation and survival, while Zol induced osteoclast apoptosis. Osteoclasts differentiated by breast cancer cells were less sensitive to Zol than those induced by differentiation factors, whereas sensitivity to Den was similar. Conversely, breast cancer-induced osteoclast activation resulted in a higher sensitivity to 5H4. A significant increase in CSF-1 secretion was observed in osteoclast precursors after treatment with the highest concentration of Den. Further research is ongoing to evaluate the efficacy of 5H4 combination with Den.

Yano M, Imamura T, Asai D, et al.
An overall characterization of pediatric acute lymphoblastic leukemia with CRLF2 overexpression.
Genes Chromosomes Cancer. 2014; 53(10):815-23 [PubMed] Related Publications
For an overall characterization of pediatric B-cell precursor acute lymphoblastic leukemia (BCPALL) with CRLF2 overexpression (OE), we conducted genetic analysis of CRLF2 in 167 pediatric BCPALL patients. CRLF2 OE was detected in 30 (18%) of 167 patients, the P2RY8-CRLF2 fusion was identified in only 3 (1.8%) of 167 patients, all of which demonstrated CRLF2 OE. Moreover, CRLF2 gain was identified in 18 (11%) of 167 patients. Messenger RNA sequencing revealed a novel fusion transcript, CSF2RA-CRLF2, in a case with CRLF2 OE, suggesting that this fusion is associated with CRLF2 OE. In survival analysis, no significant differences in 5-year event-free survival (EFS) and overall survival were observed between patients with and without CRLF2 OE (70.7 vs. 75.4%, log rank P = 0.68 and 96.4 vs. 82.1%, log rank P = 0.11, respectively). However, a significant difference in 5-year EFS between CRLF2 OE patients with and without IKZF1 deletion was observed (44.4 vs. 83.1%, log rank P = 0.02). In multivariate analysis, only IKZF1 deletion was a significant predictor of inferior OS (hazard ratio: 2.427, P = 0.04).These findings suggest that CRLF2 OE is not an independent prognostic factor in pediatric BCPALL.

Staff C, Mozaffari F, Frödin JE, et al.
Telomerase (GV1001) vaccination together with gemcitabine in advanced pancreatic cancer patients.
Int J Oncol. 2014; 45(3):1293-303 [PubMed] Related Publications
Telomerase is expressed in 85-90 % of pancreatic adenocarcinomas and might be a target for active cancer immunotherapy. A study was conducted to investigate safety and immunogenicity in non-resectable pancreatic carcinoma patients using a 16-amino acid telomerase peptide (GV1001) for vaccination in combination with GM-CSF and gemcitabine as first line treatment. Three different vaccine treatment schedules were used; [A (n=6), B (n=6) and C (n=5)]. Groups A/B received GV1001, GM-CSF and gemcitabine concurrently. Group C received initially GV1001 and GM-CSF while gemcitabine was added at disease progression. Group D (n=4) was treated with gemcitabine alone. Adverse events (AE) related to vaccination were mild (grades I-II). Grade III AEs were few and transient. An induced GV 1001‑specific immune response was defined as an increase ≥2 above the baseline value in one of the assays (DTH, proliferation, ELISPOT and cytokine secretion assays, respectively). A telomerase‑specific immune response was noted in 4/6 patients in group A, 4/6 patients in group B and 2/5 patients in group C. An induced ras‑specific immune response (antigenic spreading) was seen in 5 of the 17 patients. The cytokine pattern was that of a Th1-like profile. A treatment induced telomerase or ras response was also noted in group D. All responses were weak and transient. A significant decrease in regulatory T-cells over time was noted in patients in groups A and B (p<0.05). Telomerase vaccination (GV1001) in combination with chemotherapy appeared to be safe but the immune responses were weak and transient. Measures have to be taken to optimize immune responses of GV1001 for it to be considered of clinical interest.

Li P, Harris D, Liu Z, et al.
STAT3-activated GM-CSFRα translocates to the nucleus and protects CLL cells from apoptosis.
Mol Cancer Res. 2014; 12(9):1267-82 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
UNLABELLED: Here, it was determined that chronic lymphocytic leukemia (CLL) cells express the α subunit, but not the β subunit, of the granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR/CSF2R). GM-CSFRα was detected on the surface, in the cytosol, and in the nucleus of CLL cells via confocal microscopy, cell fractionation, and GM-CSFRα antibody epitope mapping. Because STAT3 is frequently activated in CLL and the GM-CSFRα promoter harbors putative STAT3 consensus binding sites, MM1 cells were transfected with truncated forms of the GM-CSFRα promoter, then stimulated with IL6 to activate STAT3 and to identify STAT3-binding sites. Chromatin immunoprecipitation (ChIP) and an electoromobility shift assay (EMSA) confirmed STAT3 occupancy to those promoter regions in both IL6-stimulated MM1 and CLL cells. Transfection of MM1 cells with STAT3-siRNA or CLL cells with STAT3-shRNA significantly downregulated GM-CSFRα mRNA and protein levels. RNA transcripts, involved in regulating cell survival pathways, and the proteins KAP1 (TRIM28) and ISG15 coimmunoprecipitated with GM-CSFRα. GM-CSFRα-bound KAP1 enhanced the transcriptional activity of STAT3, whereas GM-CSFRα-bound ISG15 inhibited the NF-κB pathway. Nevertheless, overexpression of GM-CSFRα protected MM1 cells from dexamethasone-induced apoptosis, and GM-CSFRα knockdown induced apoptosis in CLL cells, suggesting that GM-CSFRα provides a ligand-independent survival advantage.
IMPLICATIONS: Constitutively, activation of STAT3 induces the expression of GM-CSFRα that protects CLL cells from apoptosis, suggesting that inhibition of STAT3 or GM-CSFRα may benefit patients with CLL.

Su S, Liu Q, Chen J, et al.
A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis.
Cancer Cell. 2014; 25(5):605-20 [PubMed] Related Publications
The close vicinity of cancer cells undergoing epithelial-mesenchymal transition (EMT) and tumor-associated macrophages (TAMs) at the invasive front of tumors suggests that these two cell type may mutually interact. We show that mesenchymal-like breast cancer cells activate macrophages to a TAM-like phenotype by GM-CSF. Reciprocally, CCL18 from TAMs induces cancer cell EMT, forming a positive feedback loop, in coculture systems and humanized mice. Inhibition of GM-CSF or CCL18 breaks this loop and reduces cancer metastasis. High GM-CSF expression in breast cancer samples is associated with more CCL18(+) macrophages, cancer cell EMT, enhanced metastasis, and reduced patient survival. These findings suggest that a positive feedback loop between GM-CSF and CCL18 is important in breast cancer metastasis.

Chaturvedi P, Gilkes DM, Takano N, Semenza GL
Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment.
Proc Natl Acad Sci U S A. 2014; 111(20):E2120-9 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Intratumoral hypoxia induces the recruitment of stromal cells, such as macrophages and mesenchymal stem cells (MSCs), which stimulate invasion and metastasis by breast cancer cells (BCCs). Production of macrophage colony-stimulating factor 1 (CSF1) by BCCs is required for macrophage recruitment, but the mechanisms underlying CSF1 expression have not been delineated. Triple-negative breast cancers have increased expression of genes regulated by hypoxia-inducible factors (HIFs). In this study, we delineate two feed-forward signaling loops between human MDA-MB-231 triple-negative BCCs and human MSCs that drive stromal cell recruitment to primary breast tumors. The first loop, in which BCCs secrete chemokine (C-X-C motif) ligand 16 (CXCL16) that binds to C-X-C chemokine receptor type 6 (CXCR6) on MSCs and MSCs secrete chemokine CXCL10 that binds to receptor CXCR3 on BCCs, drives recruitment of MSCs. The second loop, in which MSCs secrete chemokine (C-C motif) ligand 5 that binds to C-C chemokine receptor type 5 on BCCs and BCCs secrete cytokine CSF1 that binds to the CSF1 receptor on MSCs, drives recruitment of tumor-associated macrophages and myeloid-derived suppressor cells. These two signaling loops operate independent of each other, but both are dependent on the transcriptional activity of HIFs, with hypoxia serving as a pathophysiological signal that synergizes with chemokine signals from MSCs to trigger CSF1 gene transcription in triple-negative BCCs.

Tymoszuk P, Evens H, Marzola V, et al.
In situ proliferation contributes to accumulation of tumor-associated macrophages in spontaneous mammary tumors.
Eur J Immunol. 2014; 44(8):2247-62 [PubMed] Related Publications
Infiltration of a neoplasm with tumor-associated macrophages (TAMs) is considered an important negative prognostic factor and is functionally associated with tumor vascularization, accelerated growth, and dissemination. However, the ontogeny and differentiation pathways of TAMs are only incompletely characterized. Here, we report that intense local proliferation of fully differentiated macrophages rather than low-pace recruitment of blood-borne precursors drives TAM accumulation in a mouse model of spontaneous mammary carcinogenesis, the MMTVneu strain. TAM differentiation and expansion is regulated by CSF1, whose expression is directly controlled by STAT1 at the gene promoter level. These findings appear to be also relevant for human breast cancer, in which an interrelationship between STAT1, CSF1, and macrophage marker expression was identified. We propose that, akin to various MU subtypes in nonmalignant tissues, local proliferation and CSF1 play a vital role in the homeostasis of TAMs.

Cioce M, Canino C, Goparaju C, et al.
Autocrine CSF-1R signaling drives mesothelioma chemoresistance via AKT activation.
Cell Death Dis. 2014; 5:e1167 [PubMed] Related Publications
Clinical management of malignant pleural mesothelioma (MPM) is very challenging because of the uncommon resistance of this tumor to chemotherapy. We report here increased expression of macrophage colony-stimulating-factor-1-receptor (M-CSF/CSF-1R) mRNA in mesothelioma versus normal tissue specimens and demonstrate that CSF-1R expression identifies chemoresistant cells of mesothelial nature in both primary cultures and mesothelioma cell lines. By using RNAi or ligand trapping, we demonstrate that the chemoresistance properties of those cells depend on autocrine CSF-1R signaling. At the single-cell level, the isolated CSF-1R(pos) cells exhibit a complex repertoire of pluripotency, epithelial-mesenchymal transition and detoxifying factors, which define a clonogenic, chemoresistant, precursor-like cell sub-population. The simple activation of CSF-1R in untransformed mesothelial cells is sufficient to confer clonogenicity and resistance to pemetrexed, hallmarks of mesothelioma. In addition, this induced a gene expression profile highly mimicking that observed in the MPM cells endogenously expressing the receptor and the ligands, suggesting that CSF-1R expression is mainly responsible for the phenotype of the identified cell sub-populations. The survival of CSF1R(pos) cells requires active AKT (v-akt murine thymoma viral oncogene homolog 1) signaling, which contributed to increased levels of nuclear, transcriptionally competent β-catenin. Inhibition of AKT reduced the transcriptional activity of β-catenin-dependent reporters and sensitized the cells to senescence-induced clonogenic death after pemetrexed treatment. This work expands what is known on the non-macrophage functions of CSF-1R and its role in solid tumors, and suggests that CSF-1R signaling may have a critical pathogenic role in a prototypical, inflammation-related cancer such as MPM and therefore may represent a promising target for therapeutic intervention.

Cao Z, Ding BS, Guo P, et al.
Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance.
Cancer Cell. 2014; 25(3):350-65 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is unknown how vascular niche-derived paracrine factors, defined as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B cell lymphoma cells (LCs) through activating FGFR1 upregulates the Notch ligand Jagged1 (Jag1) on neighboring ECs. In turn, upregulation of Jag1 on ECs reciprocally induces Notch2-Hey1 in LCs. This crosstalk enforces aggressive CD44(+)IGF1R(+)CSF1R(+) LC phenotypes, including extranodal invasion and chemoresistance. Inducible EC-selective deletion of Fgfr1 or Jag1 in the Eμ-Myc lymphoma model or impairing Notch2 signaling in mouse and human LCs diminished lymphoma aggressiveness and prolonged mouse survival. Thus, targeting the angiocrine FGF4-FGFR1/Jag1-Notch2 loop inhibits LC aggressiveness and enhances chemosensitivity.

Panagopoulos I, Brandal P, Gorunova L, et al.
Novel CSF1-S100A10 fusion gene and CSF1 transcript identified by RNA sequencing in tenosynovial giant cell tumors.
Int J Oncol. 2014; 44(5):1425-32 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
RNA-sequencing was performed on three tenosynovial giant cell tumors (TSGCT) in an attempt to elicit more information on the mechanisms of CSF1 expression in this tumor type. A novel CSF1-S100A10 fusion gene was found in a TSGCT that carried the translocation t(1;1)(q21;p11) as the sole karyotypic abnormality. In this fusion gene, the part of CSF1 coding for the CSF1 protein (exons 1-8 in sequences with accession nos. NM_000757 and NM_172212) is fused to the 3'-part of S100A10. Since the stop codon TAG of CSF1 is present in it, the CSF1-S100A10 fusion gene's predominant consequence seems to be the replacement of the 3'-untranslated region (UTR) of CSF1 (exon 9; nt 2092-4234 in sequence with accession no. NM_000757 or nt 2092-2772 in NM_172212) by the 3'-end of S100A10 (exon 3; nt 641-1055 in sequence with accession no. NM_002966). In the other two TSGCT, a novel CSF1 transcript was detected, the same in both tumors. Similar to the occurrence in the CSF1-S100A10 fusion gene, the novel CSF1 transcript 3'-UTR is replaced by a new exon located ~48 kb downstream of CSF1 and 11 kb upstream of AHCYL1. Although only 3 TSGCT were available for study, the finding in all of them of a novel CSF1-S100A10 fusion gene or CSF1 transcript indicates the existence of a common pathogenetic theme in this tumor type: the replacement of the 3'-UTR of CSF1 with other sequences.

Jeffery JJ, Lux K, Vogel JS, et al.
Autocrine inhibition of the c-fms proto-oncogene reduces breast cancer bone metastasis assessed with in vivo dual-modality imaging.
Exp Biol Med (Maywood). 2014; 239(4):404-13 [PubMed] Related Publications
Breast cancer cells preferentially home to the bone microenvironment, which provides a unique niche with a network of multiple bidirectional communications between host and tumor, promoting survival and growth of bone metastases. In the bone microenvironment, the c-fms proto-oncogene that encodes for the CSF-1 receptor, along with CSF-1, serves as one critical cytokine/receptor pair, functioning in paracrine and autocrine fashion. Previous studies concentrated on the effect of inhibition of host (mouse) c-fms on bone metastasis, with resulting decrease in osteolysis and bone metastases as a paracrine effect. In this report, we assessed the role of c-fms inhibition within the tumor cells (autocrine effect) in the early establishment of breast cancer cells in bone and the effects of this early c-fms inhibition on subsequent bone metastases and destruction. This study exploited a multidisciplinary approach by employing two non-invasive, in vivo imaging methods to assess the progression of bone metastases and bone destruction, in addition to ex vivo analyses using RT-PCR and histopathology. Using a mouse model of bone homing human breast cancer cells, we showed that an early one-time application of anti-human c-fms antibody delayed growth of bone metastases and bone destruction for at least 31 days as quantitatively measured by bioluminescence imaging and computed tomography, compared to controls. Thus, neutralizing human c-fms in the breast cancer cell alone decreases extent of subsequent bone metastasis formation and osteolysis. Furthermore, we are the first to show that anti-c-fms antibodies can impact early establishment of breast cancer cells in bone.

Gupta RK, Qureshi A, Choi JK
Histologic findings in skin biopsy in a JMML rash: a case report and review of literature.
Pediatr Dev Pathol. 2014 Mar-Apr; 17(2):130-3 [PubMed] Related Publications
Juvenile myelomonocytic leukemia (JMML), belonging to the category of myeloproliferative/myelodysplastic syndromes, is a rare pediatric hematologic malignancy with frequent skin manifestations commonly in the form of rashes. However, these rashes are not always biopsied and their immunophenotype studied in details. We report one such case in a 2-year-old boy who presented with a 1-month history of nonresolving fever, fatigue, and pallor along with a generalized maculopapular skin rash. The child also had mild hepatomegaly. A complete blood count with differential revealed a hemoglobin value of 8.6 g/L, leukocytosis (white blood cell count of 55.3 × 109/L), absolute monocytosis (27 × 109/L), immature granulocytes, and a platelet count of 126 × 109/L. The bone marrow aspirate showed a hypercellular marrow with trilineage hematopoiesis, 10% blasts (including promonocytes), increased monocytes (46%), and dysplastic changes in the erythroid and myeloid cell lines. These findings along with absence of a BCR-ABL1 fusion gene and a hemoglobin F level of 3.4% were consistent with the diagnosis of JMML, which was confirmed by subsequent positive granulocyte macrophage-colony stimulating factor hypersensitivity and NRAS mutation studies. A skin biopsy of the rash revealed a dermal infiltrate composed predominantly of atypical monocytic cells that were positive for CD68, myeloperoxidase, and lysozyme and negative for CD117, CD1a, and S100, consistent with JMML.

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