Gene Summary

Gene:APCS; amyloid P component, serum
Aliases: SAP, PTX2, HEL-S-92n
Summary:The protein encoded by this gene is a glycoprotein, belonging to the pentraxin family of proteins, which has a characteristic pentameric organization. These family members have considerable sequence homology which is thought to be the result of gene duplication. The binding of the encoded protein to proteins in the pathological amyloid cross-beta fold suggests its possible role as a chaperone. This protein is also thought to control the degradation of chromatin. It has been demonstrated that this protein binds to apoptotic cells at an early stage, which raises the possibility that it is involved in dealing with apoptotic cells in vivo. [provided by RefSeq, Sep 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:serum amyloid P-component
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (10)

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.

  • beta Catenin
  • Cancer Vaccines
  • Protein Binding
  • Lymphocyte Activation
  • Cell Proliferation
  • Dendritic Cells
  • Transfection
  • Cultured Cells
  • Oncogene Fusion Proteins
  • Immunohistochemistry
  • gp100 Melanoma Antigen
  • Cell Differentiation
  • Colorectal Cancer
  • Cancer Gene Expression Regulation
  • HLA-A2 Antigen
  • Phagocytosis
  • Brain Tumours
  • Cytokines
  • Antigen-Presenting Cells
  • Transcription Factors
  • Immunotherapy
  • Wnt Signaling Pathway
  • Epitopes, T-Lymphocyte
  • Disease Models, Animal
  • Brain Tumours
  • CD8-Positive T-Lymphocytes
  • Tumor Antigens
  • Antigen Presentation
  • Signal Transduction
  • Gene Expression
  • Molecular Sequence Data
  • Coculture Techniques
  • Biomarkers, Tumor
  • Knockout Mice
  • Chromosome 1
  • T-Lymphocytes, Cytotoxic
  • Mice, Transgenic
  • Brain Stem Glioma, Childhood
  • Cytotoxicity, Immunologic
  • T-Lymphocytes
  • Trisomy
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: APCS (cancer-related)

González-Castro TB, Juárez-Rojop IE, López-Narváez ML, et al.
Genetic Polymorphisms of CCDC26 rs891835, rs6470745, and rs55705857 in Glioma Risk: A Systematic Review and Meta-analysis.
Biochem Genet. 2019; 57(4):583-605 [PubMed] Related Publications
A genetic component is accepted in the etiology of the glioma. Evidence from candidate genes studies and GWAS reveal that CCDC26 gene could increase the risk of glioma. We performed a systematic review and up-to-date meta-analysis to explore if polymorphisms of CCDC26 gene (rs891835, rs6470745, and rs55705857) may be a susceptibility factor in developing glioma. An online search in PubMed, Web of Science, and SCOPUS up to September 2018 was performed. The pooled odds ratios were evaluated by fixed effects model and random effects model. Analyses of the overall sample and ethnic sub-groups were performed. In all the analyses, the allelic, additive, dominant, and recessive models were used. We found an association between all polymorphisms evaluated and an increased risk for glioma in the overall population in all the models studied. In sub-group analysis, we found that rs891835 and rs6470745 increased the risk of glioma in Europeans and Caucasians. On the other hand, the rs891835 polymorphism did not reveal any statistical association in Chinese population. Taken into consideration the limitations of this study, the present findings suggest a possible participation of rs891835, rs6470745, and rs55705857 as risk factors to develop glioma. Furthermore, it is possible that the involvement of CCDC26 variants depends on ethnicity. However, we recommend to perform further studies to have conclusive outcomes.

Jiang Q, Fu Q, Chang Y, et al.
Cancer Immunol Immunother. 2019; 68(1):45-56 [PubMed] Related Publications
EXPERIMENTAL DESIGN: We assessed TIB by immunohistochemical staining of CD19 in 246 MIBC patients from Zhongshan Hospital and Shanghai Cancer Center. We evaluated the survival benefit of platinum-based chemotherapy according to CD19

Haabeth OAW, Blake TR, McKinlay CJ, et al.
mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice.
Proc Natl Acad Sci U S A. 2018; 115(39):E9153-E9161 [PubMed] Free Access to Full Article Related Publications
In vivo delivery of antigen-encoding mRNA is a promising approach to personalized cancer treatment. The therapeutic efficacy of mRNA vaccines is contingent on safe and efficient gene delivery, biological stability of the mRNA, and the immunological properties of the vaccine. Here we describe the development and evaluation of a versatile and highly efficient mRNA vaccine-delivery system that employs charge-altering releasable transporters (CARTs) to deliver antigen-coding mRNA to antigen-presenting cells (APCs). We demonstrate in human peripheral blood mononuclear cells that CART vaccines can activate a robust antigen-specific immune response against mRNA-encoded viral epitopes. In an established mouse model, we demonstrate that CARTs preferentially target professional APCs in secondary lymphoid organs upon i.v. injections and target local APCs upon s.c. injection. Finally, we show that CARTs coformulated with mRNA and a Toll-like receptor ligand simultaneously transfect and activate target cells to generate an immune response that can treat and cure mice with large, established tumors.

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] Free Access to Full Article 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 (

Ahn J, Xia T, Rabasa Capote A, et al.
Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells.
Cancer Cell. 2018; 33(5):862-873.e5 [PubMed] Free Access to Full Article Related Publications
The ability of dying cells to activate antigen-presenting cells (APCs) is carefully controlled to avoid unwarranted inflammatory responses. Here, we show that engulfed cells containing cytosolic double-stranded DNA species (viral or synthetic) or cyclic di-nucleotides (CDNs) are able to stimulate APCs via extrinsic STING (stimulator of interferon genes) signaling, to promote antigen cross-presentation. In the absence of STING agonists, dying cells were ineffectual in the stimulation of APCs in trans. Cytosolic STING activators, including CDNs, constitute cellular danger-associated molecular patterns (DAMPs) only generated by viral infection or following DNA damage events that rendered tumor cells highly immunogenic. Our data shed insight into the molecular mechanisms that drive appropriate anti-tumor adaptive immune responses, while averting harmful autoinflammatory disease, and provide a therapeutic strategy for cancer treatment.

Duan S, Li J, Zhao N, Xu FJ
Multifunctional hybrids with versatile types of nanoparticles via self-assembly for complementary tumor therapy.
Nanoscale. 2018; 10(16):7649-7657 [PubMed] Related Publications
Self-assembly is a promising method for the construction of multifunctional nanohybrids for biomedical application. In this work, self-assembled multifunctional nanohybrids with a controllable disassembly property have been successfully fabricated. By modification with cyclodextrin (CD)-decorated ethylenediamine-functionalized poly(glycidyl methacrylate) (PGED), CD groups and polycations were conjugated onto Au nanorods (Au NRs) or Fe3O4 nanoparticles (denoted as Au-PGED-CD or Fe3O4-PGED-CD), and different SiO2@Fe3O4-PGED (SFP) or SiO2@Au-PGED (SAP) nanohybrids were readily fabricated by the host-guest interaction between Au-PGED-CD or Fe3O4-PGED-CD and adamantyl (Ad)-functionalized chiral silica NRs under mild conditions. The DNA condensation ability of the polycation, the photothermal effects of Au NRs or Fe3O4 nanoparticles, as well as the unique structure of chiral silica NRs were integrated into one nanohybrid. Such nanohybrids have high gene transfection efficiency and low cytotoxicity. The photothermal effects of the nanohybrids could be utilized for photothermal therapy, and also could induce the disassembly of the nanohybrids, which is beneficial for DNA release. The nanohybrids with good transfection performance and excellent photothermal effects were further applied for multimodal therapy. This work presents a flexible strategy for the fabrication of multifunctional nanoplatforms with integration of the advantages of various types of nanoparticles.

Thomas SK, Cha SC, Smith DL, et al.
Phase I study of an active immunotherapy for asymptomatic phase Lymphoplasmacytic lymphoma with DNA vaccines encoding antigen-chemokine fusion: study protocol.
BMC Cancer. 2018; 18(1):187 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There is now a renewed interest in cancer vaccines. Patients responding to immune checkpoint blockade usually bear tumors that are heavily infiltrated by T cells and express a high load of neoantigens, indicating that the immune system is involved in the therapeutic effect of these agents; this finding strongly supports the use of cancer vaccine strategies. Lymphoplasmacytic lymphoma (LPL) is a low grade, incurable disease featuring an abnormal proliferation of Immunoglobulin (Ig)-producing malignant cells. Asymptomatic patients are currently managed by a "watchful waiting" approach, as available therapies provide no survival advantage if started before symptoms develop. Idiotypic determinants of a lymphoma surface Ig, formed by the interaction of the variable regions of heavy and light chains, can be used as a tumor-specific marker and effective vaccination using idiotypes was demonstrated in a positive controlled phase III trial.
METHODS: These variable region genes can be cloned and used as a DNA vaccine, a delivery system holding tremendous potential for streamlining vaccine production. To increase vaccination potency, we are targeting antigen-presenting cells (APCs) by fusing the antigen with a sequence encoding a chemokine (MIP-3α), which binds an endocytic surface receptor on APCs. Asymptomatic phase LPL is an excellent model to test our vaccine since patients have not received chemotherapeutics that interfere with innate immune function and have low tumor burden. We are evaluating the safety of this next-generation DNA vaccine in a first-in-human clinical trial currently enrolling asymptomatic LPL patients. To elucidate the mode of action of this vaccine, we will assess its ability to generate tumor-specific immune responses and examine changes in the immune profile of both the peripheral blood and bone marrow.
DISCUSSION: This vaccine could shift the current paradigm of clinical management for patients with asymptomatic LPL and inform development of other personalized approaches.
TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01209871; registered on September 24, 2010.

Wu H, Gong J, Liu Y
Indoleamine 2, 3-dioxygenase regulation of immune response (Review).
Mol Med Rep. 2018; 17(4):4867-4873 [PubMed] Related Publications
Indoleamine 2, 3-dioxygenase (IDO) catalyzes the initial and rate‑limiting step in the degradation pathway of the essential amino acid tryptophan and is expressed by professional antigen presenting cells (APCs), epithelial cells, vascular endothelium and tumor cells. IDO‑mediated catabolic products, which are additionally termed 'kynurenines', exerts important immunosuppressive functions primarily via regulating T effector cell anergy and inducing the proliferation of T regulatory cells. This endogenous tolerogenic pathway has a critical effect on mediating the magnitude of immune responses under various stress conditions, including tumor, infection and transplantation. The present review evaluates the recent progress in elucidating how catabolism of tryptophan regulated by IDO modulates the immune response to inflammatory and immunological signals. Blocking this pathway may be a novel adjuvant therapeutic strategy for clinical application in immunotherapy.

Fujisawa M, Chiba S, Sakata-Yanagimoto M
Recent Progress in the Understanding of Angioimmunoblastic T-cell Lymphoma.
J Clin Exp Hematop. 2017; 57(3):109-119 [PubMed] Free Access to Full Article Related Publications
Angioimmunoblastic T-cell lymphoma (AITL) has been classified as a subtype of mature T-cell neoplasms. The recent revision of the WHO classification proposed a new category of nodal T-cell lymphoma with follicular helper T (TFH)-cell phenotype, which was classified into three diseases: AITL, follicular T-cell lymphoma, and nodal peripheral T-cell lymphoma with TFH phenotype. These lymphomas are defined by the expression of TFH-related antigens, CD279/PD-1, CD10, BCL6, CXCL13, ICOS, SAP, and CXCR5. Although recurrent mutations in TET2, IDH2, DNMT3A, RHOA, and CD28, as well as gene fusions, such as ITK-SYK and CTLA4-CD28, were not diagnostic criteria, they may be considered as novel criteria in the near future. Notably, premalignant mutations, tumor-specific mutations, and mutations specific to tumor-infiltrating B cells were identified in AITL. Thus, multi-step and multi-lineage genetic events may lead to the development of AITL.

Chen W, Pilling D, Gomer RH
C-reactive protein (CRP) but not the related pentraxins serum amyloid P and PTX3 inhibits the proliferation and induces apoptosis of the leukemia cell line Mono Mac 6.
BMC Immunol. 2017; 18(1):47 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pentraxins are a family of highly conserved secreted proteins that regulate the innate immune system, including monocytes and macrophages. C-reactive protein (CRP) is a plasma protein whose levels can rise to 1000 μg/ml from the normal <3 μg/ ml during inflammation.
RESULTS: We find that CRP inhibits proliferation of the human myeloid leukemia cell line Mono Mac 6 with an IC50 of 75 μg/ ml by inducing apoptosis of these cells. The related proteins serum amyloid P (SAP) and pentraxin 3 (PTX3) do not inhibit Mono Mac 6 proliferation. CRP has no significant effect on the proliferation of other leukemia cell lines such as HL-60, Mono Mac 1, K562, U937, or THP-1, or the survival of normal peripheral blood cells. The effect of CRP appears to be dependent on the CRP receptor FcγRI, and is negatively regulated by a phosphatidylinositol -3-kinase pathway.
CONCLUSION: These data reveal differential signaling by pentraxins on immune cells, and suggest that CRP can regulate the proliferation of some myeloid leukemia cells.

Fucikova J, Kasikova L, Truxova I, et al.
Relevance of the chaperone-like protein calreticulin for the biological behavior and clinical outcome of cancer.
Immunol Lett. 2018; 193:25-34 [PubMed] Related Publications
The death of cancer cells can be categorized as either immunogenic (ICD) or nonimmunogenic, depending on the initiating stimulus. The immunogenic processes of immunogenic cell death are mainly mediated by damage-associated molecular patterns (DAMPs), which include surface exposure of calreticulin (CRT), secretion of adenosine triphosphate (ATP), release of non-histone chromatin protein high-mobility group box 1 (HMGB1) and the production of type I interferons (IFNs). DAMPs are recognized by various receptors that are expressed by antigen-presenting cells (APCs) and potentiate the presentation of tumor antigens to T lymphocytes. Accumulating evidence indicates that CRT exposure constitutes one of the major checkpoints, that determines the immunogenicity of cell death both in vitro and in vivo in mouse models. Moreover, recent studies have identified CRT expression on tumor cells not only as a marker of ICD and active anti-tumor immune reactions but also as a major predictor of a better prognosis in various cancers. Here, we discuss the recent information on the CRT capacity to activate anticancer immune response as well as its prognostic and predictive role for the clinical outcome in cancer patients.

Mittal VK, McDonald JF
De novo assembly and characterization of breast cancer transcriptomes identifies large numbers of novel fusion-gene transcripts of potential functional significance.
BMC Med Genomics. 2017; 10(1):53 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gene-fusion or chimeric transcripts have been implicated in the onset and progression of a variety of cancers. Massively parallel RNA sequencing (RNA-Seq) of the cellular transcriptome is a promising approach for the identification of chimeric transcripts of potential functional significance. We report here the development and use of an integrated computational pipeline for the de novo assembly and characterization of chimeric transcripts in 55 primary breast cancer and normal tissue samples.
METHODS: An integrated computational pipeline was employed to screen the transcriptome of breast cancer and control tissues for high-quality RNA-sequencing reads. Reads were de novo assembled into contigs followed by reference genome mapping. Chimeric transcripts were detected, filtered and characterized using our R-SAP algorithm. The relative abundance of reads was used to estimate levels of gene expression.
RESULTS: De novo assembly allowed for the accurate detection of 1959 chimeric transcripts to nucleotide level resolution and facilitated detailed molecular characterization and quantitative analysis. A number of the chimeric transcripts are of potential functional significance including 79 novel fusion-protein transcripts and many chimeric transcripts with alterations in their un-translated leader regions. A number of chimeric transcripts in the cancer samples mapped to genomic regions devoid of any known genes. Several 'pro-neoplastic' fusions comprised of genes previously implicated in cancer are expressed at low levels in normal tissues but at high levels in cancer tissues.
CONCLUSIONS: Collectively, our results underscore the utility of deep sequencing technologies and improved bioinformatics workflows to uncover novel and potentially significant chimeric transcripts in cancer and normal somatic tissues.

Fu Z, Han X, Du J, et al.
Euphorbia lunulata extract acts on multidrug resistant gastric cancer cells to inhibit cell proliferation, migration and invasion, arrest cell cycle progression, and induce apoptosis.
J Ethnopharmacol. 2018; 212:8-17 [PubMed] Related Publications
ETHNOPHARMACOLOGICAL RELEVANCE: The milky sap or the aboveground part of the plant Euphorbia lunulata has long been used by Chinese people to treat noncancerous growths and cancerous ailments but the specific mode of action and the action mechanism remain to be elucidated.
AIM OF THE STUDY: To investigate the effects of Euphorbia lunulata extract on cell proliferation, migration, invasion, cell cycle progression, and apoptosis of multidrug resistant human gastric cancer cells; To study the mechanism of apoptosis induction by Euphorbia lunulata extract in multidrug resistant human gastric cancer cells.
MATERIALS AND METHODS: The aboveground part of fresh Euphorbia lunulata plant was extracted first with ethanol and then with n-hexane. The aseptic extract at varying concentrations was used to treat the multidrug resistant human gastric cancer SGC7901/ADR cells. After treatment, the inhibition of cell proliferation was examined by MTT assay. The inhibitions of cell migration and invasion were detected by Transwell method. The alteration of cell cycle progression was studied by flow cytometry. The morphological changes of cell nuclei were observed with fluorescence microscopy following Hoechst 33258 staining and the apoptotic indexes were calculated. The activation of caspase enzymes was analyzed by spectrophotometry. The sub-cellular distribution of cytochrome complex and the expression of Bax and Bcl-2 proteins were determined by Western blot.
RESULTS: The proliferation, migration, and invasion of SGC7901/ADR cells were significantly inhibited by Euphorbia lunulata extract, which showed time- and dose-dependent manners. Cell cycle was arrested in G2/M phase. Significant apoptotic morphological changes were observed in the nuclei of the treated cells, and apoptotic indexes were increased significantly; these changes were diminished when Z-VAD-FMK, a caspase inhibitor, was also presented. The activities of caspase-3, caspase-8, and caspase-9 were increased. The sub-cellular distribution of cytochrome complex was altered----reduced in the mitochondria and increased in the cytoplasm. The expression of Bax was upregulated, while that of Bcl-2 was downregulated.
CONCLUSION: Euphorbia lunulata extract inhibited the proliferation, migration, and invasion of SGC7901/ADR cells, arrested cell cycle progression, and induced cell apoptosis; the mechanism of apoptosis induction involved both the extrinsic and the intrinsic pathways.

Bujko M, Kober P, Statkiewicz M, et al.
Downregulation of PTPRH (Sap-1) in colorectal tumors.
Int J Oncol. 2017; 51(3):841-850 [PubMed] Related Publications
Tyrosine phosphorylation is one of the basic mechanisms for signal transduction in the cell. Receptors exhibiting tyrosine kinase activity are widely involved in carcinogenesis and are negatively regulated by receptor protein tyrosine phosphatases (RPTP). Genes encoding different RPTPs are affected by aberrant epigenetic regulation in cancer. PTPRH (SAP-1) has been previously described to be overexpressed in colorectal cancer (CRC) and classified as an oncogenic factor. Previous microarray-based mRNA expression comparison of colorectal adenomas (AD), CRC and normal mucosa samples (NM) demonstrated that PTPRH tumor expression is the most reduced of all RPTP genes. qRT-PCR validation revealed gene downregulation for CRC (7.6-fold-change; P<0.0001) and AD (3.4-fold-change; P<0.0001) compared to NM. This was confirmed by immunohistochemical staining of tumor and NM sections as pronounced decrease of protein expression was observed in CRCs compared to the corresponding normal tissue. DNA methylation of two PTPRH promoter fragments was analyzed by pyrosequencing in a group of CRC, and AD patients as well as NM samples and CRC cell lines. The mean DNA methylation levels of these two regions were significantly higher in CRC than in NM. Both regions were highly methylated in SW480 and HCT116 cell lines contrary to unmethylated HT29 and COLO205. Cell lines with highly methylated promoters notably showed lower PTPRH expression levels, lower RNA II polymerase concentrations and higher levels of H3K27 trimethylation in the promoter and gene body, measured by chromatin immunoprecipitation. Cells were cultured with 5-aza-deoxycitidine and an increase in PTPRH expression was observed in SW480 and HCT116, whereas this was unchanged in the unmethylated cell lines. The results indicate that PTPRH is downregulated in colorectal tumors and its expression is epigenetically regulated via DNA methylation and chromatin modifications.

Salem DA, Korde N, Venzon DJ, et al.
Expression of the IL-6 receptor alpha-chain (CD126) in normal and abnormal plasma cells in monoclonal gammopathy of undetermined significance and smoldering myeloma.
Leuk Lymphoma. 2018; 59(1):178-186 [PubMed] Free Access to Full Article Related Publications
IL-6 activity in normal plasma cells (nPCs) and abnormal plasma cells (aPCs) is CD126 (subunit of IL-6 receptor) dependent. We quantified CD126 expression on nPCs and aPCs in monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM), and multiple myeloma (MM). CD126 was detected on all nPCs and aPCs indicating that CD126 does not have diagnostic utility. CD126 expression was higher in aPCs than in nPCs in 85% SMM but only 41% MGUS and there was evidence that CD126 was higher in aPCs than nPCs in the SMM (p = .048) but not MGUS (p = .96) patients. There is also a greater association between nPC and aPC CD126 expression in low risk MGUS than observed in high risk MGUS and SMM, suggesting normal regulation of CD126 decreases with disease progression. Future studies need to elucidate the role of bone marrow milieu versus escape from normal CD126 regulation in malignant transformation of clonal plasma cells.

Cerullo V, Capasso C, Vaha-Koskela M, et al.
Cancer-Targeted Oncolytic Adenoviruses for Modulation of the Immune System.
Curr Cancer Drug Targets. 2018; 18(2):124-138 [PubMed] Related Publications
Adenovirus is one of the most commonly used vectors for gene therapy and it is the first approved virus-derived drug for treatment of cancer. As an oncolytic agent, it can induce lysis of infected cells, but it can also engage the immune system, promoting activation and maturation of antigen- presenting cells (APCs). In essence, oncolysis combined with the associated immunostimulatory actions result in a "personalized in situ vaccine" for each patient. In order to take full advantage of these features, we should try to understand how adenovirus interacts with the immune system, what are the receptors involved in triggering subsequent signals and which kind of responses they elicit. Tackling these questions will give us further insight in how to manipulate adenovirus-mediated immune responses for enhancement of anti-tumor efficacy. In this review, we first highlight how oncolytic adenovirus interacts with the innate immune system and its receptors such as Toll-like receptors, nucleotide-binding and oligomerization domain (NOD)- like receptors and other immune sensors. Then we describe the effect of these interactions on the adaptive immune system and its cells, especially B and T lymphocytes. Finally, we summarize the most significant preclinical and clinical results in the field of gene therapy where researchers have engineered adenovirus to manipulate the host immune system by expressing cytokines and signalingmediators.

Tanaka N, Mashima T, Mizutani A, et al.
Mol Cancer Ther. 2017; 16(4):752-762 [PubMed] Related Publications
In most colorectal cancers, Wnt/β-catenin signaling is activated by loss-of-function mutations in the

Smith AJ, Smith LA
Viral Carcinogenesis.
Prog Mol Biol Transl Sci. 2016; 144:121-168 [PubMed] Related Publications
Cancer has been recognized for thousands of years. Egyptians believed that cancer occurred at the will of the gods. Hippocrates believed human disease resulted from an imbalance of the four humors: blood, phlegm, yellow bile, and black bile with cancer being caused by excess black bile. The lymph theory of cancer replaced the humoral theory and the blastema theory replaced the lymph theory. Rudolph Virchow was the first to recognize that cancer cells like all cells came from other cells and believed chronic irritation caused cancer. At the same time there was a belief that trauma caused cancer, though it never evolved after many experiments inducing trauma. The birth of virology occurred in 1892 when Dimitri Ivanofsky demonstrated that diseased tobacco plants remained infective after filtering their sap through a filter that trapped bacteria. Martinus Beijerinck would call the tiny infective agent a virus and both Dimitri Ivanofsky and Marinus Beijerinck would become the fathers of virology. Not to long thereafter, Payton Rous founded the field of tumor virology in 1911 with his discovery of a transmittable sarcoma of chickens by what would come to be called Rous sarcoma virus or RSV for short. The first identified human tumor virus was the Epstein-Barr virus (EBV), named after Tony Epstein and Yvonne Barr who visualized the virus particles in Burkitt's lymphoma cells by electron microscopy in 1965. Since that time, many viruses have been associated with carcinogenesis including the most studied, human papilloma virus associated with cervical carcinoma, many other anogenital carcinomas, and oropharyngeal carcinoma. The World Health Organization currently estimates that approximately 22% of worldwide cancers are attributable to infectious etiologies, of which viral etiologies is estimated at 15-20%. The field of tumor virology/viral carcinogenesis has not only identified viruses as etiologic agents of human cancers, but has also given molecular insights to all human cancers including the oncogene activation and tumor suppressor gene inactivation.

Gao X, Han D, Fan W
Down-regulation of RBP-J mediated by microRNA-133a suppresses dendritic cells and functions as a potential tumor suppressor in osteosarcoma.
Exp Cell Res. 2016; 349(2):264-272 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: In recent years, immunotherapy for the treatment of tumors have been established. Dendritic cells (DCs) are extremely efficient and professional antigen presenting cells (APCs), which are an important target for immune therapeutic interventions in cancer. In present study, we investigated whether RBP-J signaling regulated by miR-133a was involved in the DCs mediated tumor suppressor in osteosarcoma.
METHODS: DCs were isolated from 30 osteosarcoma patients and 30 healthy subjects. Mouse macrophage-like cell line RAW264.7 were cultured and osteosarcoma mouse model with injection of murine osteosarcoma cell line S180 were established.
RESULTS: In osteosarcoma patients, miR-133a expression level of DCs was increased, and RBP-J expression in mRNA and protein levels were decreased. MiR-133a inhibitor promoted maturation and activation of DCs in osteosarcoma patients. In osteosarcoma mouse model, miR-133a mimic suppressed the maturation and activation of spleen DCs, while miR-133a inhibitor promoted them. Overexpression of miR-133a decreased therapeutic effect of DCs on osteosarcoma mice. In RAW264.7 cells, miR-133a was observed to target RBP-J and regulate its expression. MiR-133a mimic inhibited the maturation of DCs in cells exposed to LPS, the effect of which was reversed by overexpression of RBP-J.
CONCLUSION: RBP-J mediated by miR-133a probably contributed to the regulation of DCs maturation and activation in osteosarcoma, which functioned as a therapeutic target for the immunotherapy in cancers.

Behzadi E, Halabian R, Hosseini HM, Fooladi AAI
Bacterial toxin's DNA vaccine serves as a strategy for the treatment of cancer, infectious and autoimmune diseases.
Microb Pathog. 2016; 100:184-194 [PubMed] Related Publications
DNA vaccination -a third generation vaccine-is a modern approach to stimulate humoral and cellular responses against different diseases such as infectious diseases, cancer and autoimmunity. These vaccines are composed of a gene that encodes sequences of a desired protein under control of a proper (eukaryotic or viral) promoter. Immune response following DNA vaccination is influenced by the route and the dose of injection. In addition, antigen presentation following DNA administration has three different mechanisms including antigen presentation by transfected myocytes, transfection of professional antigen presenting cells (APCs) and cross priming. Recently, it has been shown that bacterial toxins and their components can stimulate and enhance immune responses in experimental models. A study demonstrated that DNA fusion vaccine encoding the first domain (DOM) of the Fragment C (FrC) of tetanus neurotoxin (CTN) coupled with tumor antigen sequences is highly immunogenic against colon carcinoma. DNA toxin vaccines against infectious and autoimmune diseases are less studied until now. All in all, this novel approach has shown encouraging results in animal models, but it has to go through adequate clinical trials to ensure its effectiveness in human. However, it has been proven that these vaccines are safe, multifaceted and simple and can be used widely in organisms which may be of advantage to public health in the near future. This paper outlines the mechanism of the action of DNA vaccines and their possible application for targeting infectious diseases, cancer and autoimmunity.

Meng Y, Hu J, Chen Y, et al.
Silencing MARCH1 suppresses proliferation, migration and invasion of ovarian cancer SKOV3 cells via downregulation of NF-κB and Wnt/β-catenin pathways.
Oncol Rep. 2016; 36(5):2463-2470 [PubMed] Free Access to Full Article Related Publications
Membrane-associated RING-CH (MARCH) belongs to the family of RING-CH type E3 ubiquitin ligases. MARCH1 ubiquitinates and downregulates MHC class II expression in APCs and targets major players of the immune system. However, the role of MARCH1 in ovarian cancer has not been elucidated. The present study investigated the function of MARCH1 in ovarian cancer and the potential mechanisms involved. MARCH1 expression was examined in human ovarian cancer tissue specimens by immunohistochemistry. The role of MARCH1 in ovarian cancer cells was assessed by cell proliferation, migration and invasion assays with MARCH1 gene silencing. To investigate the mechanism by which MARCH1 functions, correlation between MARCH1 and the cell signaling pathways were analyzed using a luciferase reporter assay, real-time RT-PCR, western blot assay and immunofluorescence. MARCH1 was found to be overexpressed in ovarian cancer tissues when compared to adjacent non-tumor and normal ovarian tissues. Silencing MARCH1 inhibited SKOV3 cell proliferation, invasion and migration, as well as inhibiting the NF-κB and the Wnt/β‑catenin pathways. MARCH1 functions as a tumor promoter by upregulating the NF-κB and the Wnt/β-catenin pathways, indicating that MARCH1 may be a therapeutic target for patients with ovarian cancer.

Garin-Muga A, Corrales FJ, Segura V
Proteogenomic Analysis of Single Amino Acid Polymorphisms in Cancer Research.
Adv Exp Med Biol. 2016; 926:93-113 [PubMed] Related Publications
The integration of genomics and proteomics has led to the emergence of proteogenomics, a field of research successfully applied to the characterization of cancer samples. The diagnosis, prognosis and response to therapy of cancer patients will largely benefit from the identification of mutations present in their genome. The current state of the art of high throughput experiments for genome-wide detection of somatic mutations in cancer samples has allowed the development of projects such as the TCGA, in which hundreds of cancer genomes have been sequenced. This huge amount of data can be used to generate protein sequence databases in which each entry corresponds to a mutated peptide associated with certain cancer types. In this chapter, we describe a bioinformatics workflow for creating these databases and detecting mutated peptides in cancer samples from proteomic shotgun experiments. The performance of the proposed method has been evaluated using publicly available datasets from four cancer cell lines.

Vigneshwaran V, Thirusangu P, Madhusudana S, et al.
The latex sap of the 'Old World Plant' Lagenaria siceraria with potent lectin activity mitigates neoplastic malignancy targeting neovasculature and cell death.
Int Immunopharmacol. 2016; 39:158-171 [PubMed] Related Publications
Lifestyle and dietary modifications have contributed much to somatic genetic alteration which has concomitantly led to increase in malignant diseases. Henceforth, plant based and dietary interventions to mitigate and impede oncogenic transformation are in great demand. We investigated the latex sap (LSL) of the dietary Lagenaria siceraria vegetable, the first domesticated plant species with the potent lectin activity for its functional role against the tumor progression and its mechanism. LSL has markedly stimulated proliferation of lymphocytes and displayed strong cytotoxic activity against cancer both in-vitro and in-vivo. The tumor regression was paralleled with drastic reduction in tumoral neovasculature as evidenced from angiogenic parameters and abrogated related gene expressions. LSL has also triggered apoptotic signaling cascade in cancer cells through activation of caspase-3 mediated activation of endonuclease and inducing apoptotic cellular events. Collectively our study provides tangible evidences that latex sap from L. siceraria with immunopotentiating ability significantly regresses the tumor progression by targeting angiogenesis and inducing cell death.

Liu L, Li D, Chen S, et al.
B7-H4 expression in human infiltrating ductal carcinoma‑associated macrophages.
Mol Med Rep. 2016; 14(3):2135-42 [PubMed] Related Publications
B7-H4 is a co‑inhibitory molecule of the B7 family, which is expressed on antigen‑presenting cells (APCs) and is able to limit the T‑cell immune response. Macrophages act as professional APCs and are important for immunoregulation of the tumor microenvironment in breast cancer. In order to identify the association between the presence of B7‑H4 on macrophages and infiltrating ductal carcinoma (IDC), the present study investigated the expression of B7‑H4 on macrophages with different polarizations. The expression levels of B7‑H4 in IDC tissues were determined using immunohistochemistry, and the expression of B7‑H4 on macrophages in the breast IDC microenvironment were determined using western blot analysis and reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The expression levels of interleukin (IL)‑6 and IL‑10 were detected in IDC tissues and the supernatants of polarized macrophages using an enzyme‑linked immunosorbent assay and RT‑qPCR. The present study demonstrated that B7‑H4 was overexpressed in IDC tissues and macrophages. In vitro, M1 and M2 macrophages exhibited different expression levels of B7‑H4. IL‑6 and ‑10 exhibited higher expression in the IDC tissues compared with in distal pericarcinomatous tissues. In conclusion, B7‑H4 exhibited overexpression in IDC tissues and cultured macrophage cells. Furthermore, M2 macrophages exhibited higher expression levels of B7‑H4 compared with the M1 subtype. In addition, IL‑6 and ‑10 may be associated with B7‑H4 expression on macrophages of different polarizations in the IDC microenvironment.

Roth M, Wang Z, Chen WY
SIRT1 and LSD1 competitively regulate KU70 functions in DNA repair and mutation acquisition in cancer cells.
Oncotarget. 2016; 7(31):50195-50214 [PubMed] Free Access to Full Article Related Publications
Acquisition of BCR-ABL mutations underlies drug resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors, but the molecular mechanisms of mutation acquisition are poorly understood. We previously showed that lysine deacetylase sirtuin 1, SIRT1, promotes acquisition of BCR-ABL mutations in association with enhancing KU70 mediated non-homologous end joining DNA repair. In this study, we demonstrate that lysine specific demethylase 1 (LSD1) plays an opposite role to SIRT1 in regulating DNA repair and mutation acquisition. In response to therapeutic stress and DNA damage, LSD1 and SIRT1 compete for binding to KU70 on DNA damage foci globally and on the ABL locus. The recruitment of SIRT1 or LSD1 to KU70 impacts chromatin structure but does not correlate well with their direct histone modification functions, and SIRT1 helps maintain histone H4K16 acetylation and open chromatin for repair. The competitive KU70 binding by these proteins affects cancer cells' ability to repair broken DNA and acquire resistant genetic mutations in CML and prostate cancer cells. We identify that the core domain of KU70 binds both LSD1 and SIRT1, forming a molecular basis for the competition. The C-terminal SAP motif of KU70 mediates LSD1/SIRT1 competitive interaction by suppressing LSD1 binding to KU70 and ectopic expression of SAP-deleted KU70 to CML cells compromises their ability to acquire BCR-ABL mutations. Our study reveals a novel cellular stress response mechanism in cancer cells and a key role of LSD1/SIRT1/KU70 dynamic interaction in regulating DNA repair and mutation acquisition.

Singhal S, Bhojnagarwala PS, O'Brien S, et al.
Origin and Role of a Subset of Tumor-Associated Neutrophils with Antigen-Presenting Cell Features in Early-Stage Human Lung Cancer.
Cancer Cell. 2016; 30(1):120-135 [PubMed] Free Access to Full Article Related Publications
Based on studies in mouse tumor models, granulocytes appear to play a tumor-promoting role. However, there are limited data about the phenotype and function of tumor-associated neutrophils (TANs) in humans. Here, we identify a subset of TANs that exhibited characteristics of both neutrophils and antigen-presenting cells (APCs) in early-stage human lung cancer. These APC-like "hybrid neutrophils," which originate from CD11b(+)CD15(hi)CD10(-)CD16(low) immature progenitors, are able to cross-present antigens, as well as trigger and augment anti-tumor T cell responses. Interferon-γ and granulocyte-macrophage colony-stimulating factor are requisite factors in the tumor that, working through the Ikaros transcription factor, synergistically exert their APC-promoting effects on the progenitors. Overall, these data demonstrate the existence of a specialized TAN subset with anti-tumor capabilities in human cancer.

Wang L, Heng X, Lu Y, et al.
Could B7-H4 serve as a target to activate anti-cancer immunity?
Int Immunopharmacol. 2016; 38:97-103 [PubMed] Related Publications
It has been over 13years since the identification of B7-H4, the co-stimulatory molecule of B7 family members. While B7-H4 mRNA is widely distributed protein expression seems to be limited on tissues. Various cytokines and inflammatory mediators induce the expression of B7-H4. However, the specific regulatory mechanisms of B7-H4 remain to be defined. Recently, it has been shown that B7-H4 executes an inhibitory function in the T-cell response via reduced expansion, cell cycle arrest, decreased cytokine secretion and induced apoptosis of activated T-cells. Furthermore, B7-H4 suppresses the function of antigen presenting cells (APCs) and promotes the proliferation and development of regulatory T-cells (Treg). Moreover, a growing body of literature demonstrates that various cancers express B7-H4 and that the expression levels of B7-H4 correlate with cancer size, histological type, pathologic stage, grade, infiltration, lymph node metastasis, cancer progression, recurrence and death. The over-expression of B7-H4 in cancer may be related to an increased resistance to immune responses. The aim of this review is to supply an overview of the advances in the regulation and function of B7-H4. Additionally, many studies have suggested that B7-H4 is a molecular target for therapeutic intervention in cancer and that targeting B7-H4 may have promising potential for improving the efficacy of immunotherapy for cancer patients.

Magrini E, Mantovani A, Garlanda C
The Dual Complexity of PTX3 in Health and Disease: A Balancing Act?
Trends Mol Med. 2016; 22(6):497-510 [PubMed] Free Access to Full Article Related Publications
The humoral arm of innate immunity is complex and includes various molecules that serve as markers of inflammation with complementary characteristics, such as the short pentraxins C-reactive protein (CRP) and serum amyloid P (SAP) and the long pentraxin PTX3. There is a growing amount of evidence - including mouse and human genetics - that suggests that PTX3 is essential in conferring host resistance against selected pathogens and, moreover, that it plays a dual antagonistic role in the regulation of inflammation. Dissection of such a yin-and-yang role of pentraxins in immunity and inflammation is timely and significant as it may pave the way for better clinical exploitation against various diseases.

Zizzari IG, Napoletano C, Battisti F, et al.
MGL Receptor and Immunity: When the Ligand Can Make the Difference.
J Immunol Res. 2015; 2015:450695 [PubMed] Free Access to Full Article Related Publications
C-type lectin receptors (CLRs) on antigen-presenting cells (APCs) facilitate uptake of carbohydrate antigens for antigen presentation, modulating the immune response in infection, homeostasis, autoimmunity, allergy, and cancer. In this review, we focus on the role of the macrophage galactose type C-type lectin (MGL) in the immune response against self-antigens, pathogens, and tumor associated antigens (TAA). MGL is a CLR exclusively expressed by dendritic cells (DCs) and activated macrophages (MØs), able to recognize terminal GalNAc residues, including the sialylated and nonsialylated Tn antigens. We discuss the effects on DC function induced throughout the engagement of MGL, highlighting the importance of the antigen structure in the modulation of immune response. Indeed modifying Tn-density, the length, and steric structure of the Tn-antigens can result in generating immunogens that can efficiently bind to MGL, strongly activate DCs, mimic the effects of a danger signal, and achieve an efficient presentation in HLA classes I and II compartments.

Wu N, Veillette A
SLAM family receptors in normal immunity and immune pathologies.
Curr Opin Immunol. 2016; 38:45-51 [PubMed] Related Publications
The signaling lymphocytic activation molecule (SLAM) family is a group of six receptors restricted to hematopoietic cells. Most of these receptors are self-ligands, and thus are triggered in the context of interactions between hematopoietic cells. By way of their cytoplasmic domain, SLAM-related receptors associate with the SLAM-associated protein (SAP) family of adaptors, which control the signals and functions of SLAM family receptors. Recent findings have provided new insights into the key roles of SLAM family receptors in normal immunity, their involvement in human diseases and their usefulness as drug targets to treat human malignancies. These data are reviewed herein.

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