MARCO

Gene Summary

Gene:MARCO; macrophage receptor with collagenous structure
Aliases: SCARA2
Location:2q14.2
Summary:The protein encoded by this gene is a member of the class A scavenger receptor family and is part of the innate antimicrobial immune system. The protein may bind both Gram-negative and Gram-positive bacteria via an extracellular, C-terminal, scavenger receptor cysteine-rich (SRCR) domain. In addition to short cytoplasmic and transmembrane domains, there is an extracellular spacer domain and a long, extracellular collagenous domain. The protein may form a trimeric molecule by the association of the collagenous domains of three identical polypeptide chains. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:macrophage receptor MARCO
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
Show (9)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 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.

Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: MARCO (cancer-related)

Chipumuro E, Marco E, Christensen CL, et al.
CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer.
Cell. 2014; 159(5):1126-39 [PubMed] Article available free on PMC after 20/11/2015 Related Publications
The MYC oncoproteins are thought to stimulate tumor cell growth and proliferation through amplification of gene transcription, a mechanism that has thwarted most efforts to inhibit MYC function as potential cancer therapy. Using a covalent inhibitor of cyclin-dependent kinase 7 (CDK7) to disrupt the transcription of amplified MYCN in neuroblastoma cells, we demonstrate downregulation of the oncoprotein with consequent massive suppression of MYCN-driven global transcriptional amplification. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without the introduction of systemic toxicity. The striking treatment selectivity of MYCN-overexpressing cells correlated with preferential downregulation of super-enhancer-associated genes, including MYCN and other known oncogenic drivers in neuroblastoma. These results indicate that CDK7 inhibition, by selectively targeting the mechanisms that promote global transcriptional amplification in tumor cells, may be useful therapy for cancers that are driven by MYC family oncoproteins.

Rodrigues P, de Marco G, Furriol J, et al.
Oxidative stress in susceptibility to breast cancer: study in Spanish population.
BMC Cancer. 2014; 14:861 [PubMed] Article available free on PMC after 20/11/2015 Related Publications
BACKGROUND: Alterations in the redox balance are involved in the origin, promotion and progression of cancer. Inter-individual differences in the oxidative stress regulation can explain a part of the variability in cancer susceptibility.The aim of this study was to evaluate if polymorphisms in genes codifying for the different systems involved in oxidative stress levels can have a role in susceptibility to breast cancer.
METHODS: We have analyzed 76 single base polymorphisms located in 27 genes involved in oxidative stress regulation by SNPlex technology. First, we have tested all the selected SNPs in 493 breast cancer patients and 683 controls and we have replicated the significant results in a second independent set of samples (430 patients and 803 controls). Gene-gene interactions were performed by the multifactor dimensionality reduction approach.
RESULTS: Six polymorphisms rs1052133 (OGG1), rs406113 and rs974334 (GPX6), rs2284659 (SOD3), rs4135225 (TXN) and rs207454 (XDH) were significant in the global analysis. The gene-gene interactions demonstrated a significant four-variant interaction among rs406113 (GPX6), rs974334 (GPX6), rs105213 (OGG1) and rs2284659 (SOD3) (p-value = 0.0008) with high-risk genotype combination showing increased risk for breast cancer (OR = 1.75 [95% CI; 1.26-2.44]).
CONCLUSIONS: The results of this study indicate that different genotypes in genes of the oxidant/antioxidant pathway could affect the susceptibility to breast cancer. Furthermore, our study highlighted the importance of the analysis of the epistatic interactions to define with more accuracy the influence of genetic variants in susceptibility to breast cancer.

Lupino E, Ramondetti C, Buccinnà B, Piccinini M
Exposure of neuroblastoma cell lines to imatinib results in the upregulation of the CDK inhibitor p27(KIP1) as a consequence of c-Abl inhibition.
Biochem Pharmacol. 2014; 92(2):235-50 [PubMed] Related Publications
Imatinib mesylate is a tyrosine kinase inhibitor with selectivity for abelson tyrosine-protein kinase 1 (c-Abl), breakpoint cluster region (Bcr)-Abl fusion protein (Bcr-Abl), mast/stem cell growth factor receptor Kit (c-Kit), and platelet-derived growth factor receptor (PDGFR). Previous studies demonstrated that imatinib in the low micromolar range exerted antiproliferative effects on neuroblastoma cell lines. However, although neuroblastoma cells express c-Kit and PDGFR, the imatinib concentrations required to achieve significant growth inhibitory effects (≥ 10 μM) are substantially higher than those required for inhibition of ligand-induced phosphorylation of wild type c-Kit and PDGFR (≤ 1 μM), suggesting that additional mechanisms are responsible for the antitumor activity of imatinib on these cells. In this study, we show that treatment of neuroblastoma cell lines with 1-15 μM imatinib resulted in a dose dependent inhibition of 5-bromo-2'-deoxyuridine (BrdU) incorporation into newly synthesized DNA. The antiproliferative effect of imatinib was dependent on the upregulation of the cyclin-dependent kinase (CDK) inhibitor p27(KIP1) in the nuclear compartment as a result of increased p27(KIP1) protein stability. We demonstrate that the mechanism of p27(KIP1) stabilization relied on inhibition of p27(KIP1) phosphorylation on tyrosine residues by c-Abl. We provide evidence that in neuroblastoma cell lines a significant fraction of cellular c-Abl is phosphorylated on Tyr-245, consistent with an open and active conformation. Notably, exposure to imatinib did not affect Tyr-245 phosphorylation. Given the low affinity of active c-Abl for imatinib, these data provide a molecular explanation for the relatively high imatinib concentrations required to inhibit neuroblastoma cell proliferation.

De Marco P, Romeo E, Vivacqua A, et al.
GPER1 is regulated by insulin in cancer cells and cancer-associated fibroblasts.
Endocr Relat Cancer. 2014; 21(5):739-53 [PubMed] Related Publications
Elevated insulin levels have been associated with an increased cancer risk as well as with aggressive and metastatic cancer phenotypes characterized by a poor prognosis. Insulin stimulates the proliferation, migration, and invasiveness of cancer cells through diverse transduction pathways, including estrogen signaling. As G protein estrogen receptor 1 (GPER1) mediates rapid cell responses to estrogens, we evaluated the potential of insulin to regulate GPER1 expression and function in leiomyosarcoma cancer cells (SKUT-1) and breast cancer-associated fibroblasts (CAFs), which were used as a model system. We found that insulin transactivates the GPER1 promoter sequence and increases the mRNA and protein expression of GPER1 through the activation of the PRKCD/MAPK1/c-Fos/AP1 transduction pathway, as ascertained by means of specific pharmacological inhibitors and gene-silencing experiments. Moreover, cell migration triggered by insulin occurred through GPER1 and its main target gene CTGF, whereas the insulin-induced expression of GPER1 boosted cell-cycle progression and the glucose uptake stimulated by estrogens. Notably, a positive correlation between insulin serum levels and GPER1 expression was found in cancer fibroblasts obtained from breast cancer patients. Altogether, our data indicate that GPER1 may be included among the complex network of transduction signaling triggered by insulin that drives cells toward cancer progression.

Guglielmi A, Ruzzenente A, Conci S, et al.
Hepatocellular carcinoma: surgical perspectives beyond the barcelona clinic liver cancer recommendations.
World J Gastroenterol. 2014; 20(24):7525-33 [PubMed] Article available free on PMC after 20/11/2015 Related Publications
The barcelona clinic liver cancer (BCLC) staging system has been approved as guidance for hepatocellular carcinoma (HCC) treatment guidelines by the main Western clinical liver associations. According to the BCLC classification, only patients with a small single HCC nodule without signs of portal hypertension or hyperbilirubinemia should undergo liver resection. In contrast, patients with intermediate-advanced HCC should be scheduled for palliative therapies, even if the lesion is resectable. Recent studies report good short-term and long-term outcomes in patients with intermediate-advanced HCC treated by liver resection. Therefore, this classification has been criticised because it excludes many patients who could benefit from curative resection. The aim of this review was to evaluate the role of surgery beyond the BCLC recommendations. Safe liver resection can be performed in patients with portal hypertension and well-compensated liver function with a 5-year survival rate of 50%. Surgery also offers good long-term result in selected patients with multiple or large HCCs with a reported 5-year survival rate of over 50% and 40%, respectively. Although macrovascular invasion is associated with a poor prognosis, liver resection provides better long-term results than palliative therapies or best supportive care. Recently, researchers have identified several genes whose altered expression influences the prognosis of patients with HCC. These genes may be useful for classifying the biological behaviour of different tumours. A revision of the BCLC classification should be introduced to provide the best treatment strategy and to ensure the best prognosis in patients with HCC.

Santambrogio F, Gandellini P, Cimino-Reale G, et al.
MicroRNA-dependent regulation of telomere maintenance mechanisms: a field as much unexplored as potentially promising.
Curr Pharm Des. 2014; 20(41):6404-21 [PubMed] Related Publications
The activation of telomere maintenance mechanisms, which rely on telomerase reactivation or on a recombination-based process known as alternative lengthening of telomeres, guarantees a limitless proliferative potential to human tumor cells. To date, the molecular underpinnings that drive the activation of telomere maintenance mechanisms during tumorigenesis are poorly understood, but there are indications that complex signaling networks might be involved. Since telomerase activity has been mainly detected in tumors of epithelial origin and the alternative lengthening of telomere mechanisms is more frequently expressed in mesenchymal and neuroepithelial cancers, it could be hypothesized that cell-type specific mechanisms can favor their activation during tumor development. In this context, microRNAs - small non coding RNAs that regulate gene expression at post-transcriptional level - have emerged as key players in the development and progression of human cancers, being involved in the control of all the typical features of cancer cells, including the limitless replicative potential. In the present review, we will summarize the recent findings concerning the identification and biological validation of microRNAs which may play a role in the regulation of telomere biology as well as of the mechanisms that govern telomere maintenance.

Tucci M, Stucci S, Savonarola A, et al.
An imbalance between Beclin-1 and p62 expression promotes the proliferation of myeloma cells through autophagy regulation.
Exp Hematol. 2014; 42(10):897-908.e1 [PubMed] Related Publications
Autophagy occurs in tumor cells acquiring cytotoxic drug resistance and its activation may impair their susceptibility to apoptosis in response to apoptogen agents. We investigated the pro-apoptotic effect of dexamethasone (Dex) on MM cell lines (U266, INA-6, LR5-8226, LIG, and MCC2) and primary malignant plasma cells from naïve and refractory/relapsed patients. We evaluated the transcriptional and ultrastructural events leading to autophagy by measuring Beclin-1 and p62 levels and transmission electronic microscopy. Autophagy was inhibited by hydroxychloroquine (HCQ), whereas the ability of Dex-resistant MM cells to recover the susceptibility to apoptosis was measured. A direct relationship between autophagy and Beclin-1 or LC3/Atg8 levels was observed, whereas their mRNAs were inversely correlated to p62 expression. Starvation strongly activated autophagy by inducing cellular, transcriptional, and ultrastructural modifications that were reversed by HCQ. Taken together, these data suggest that autophagy is a potential mechanism leading to drug resistance in MM, and suggest Beclin-1 and p62 as early markers of cell susceptibility to apoptosis. The combination of HCQ with novel agents may thus be considered to improve the therapeutic response in relapsed/resistant MM patients.

Scarpa M, Castagliuolo I, Castoro C, et al.
Inflammatory colonic carcinogenesis: a review on pathogenesis and immunosurveillance mechanisms in ulcerative colitis.
World J Gastroenterol. 2014; 20(22):6774-85 [PubMed] Article available free on PMC after 20/11/2015 Related Publications
Ulcerative colitis (UC) is characterized by repeated flare-ups of inflammation that can lead to oncogenic insults to the colonic epithelial. UC-associated carcinogenesis presents a different sequence of tumorigenic events compared to those that contribute to the development of sporadic colorectal cancer. In fact, in UC, the early events are represented by oxidative DNA damage and DNA methylation that can produce an inhibition of oncosuppressor genes, mutation of p53, aneuploidy, and microsatellite instability. Hypermethylation of tumor suppressor and DNA mismatch repair gene promoter regions is an epigenetic mechanism of gene silencing that contribute to tumorigenesis and may represent the first step in inflammatory carcinogenesis. Moreover, p53 is frequently mutated in the early stages of UC-associated cancer. Aneuploidy is an independent risk factor for forthcoming carcinogenesis in UC. Epithelial cell-T-cell cross-talk mediated by CD80 is a key factor in controlling the progression from low to high grade dysplasia in UC-associated carcinogenesis.

Duregon E, Rapa I, Votta A, et al.
MicroRNA expression patterns in adrenocortical carcinoma variants and clinical pathologic correlations.
Hum Pathol. 2014; 45(8):1555-62 [PubMed] Related Publications
Several microRNAs (miRNAs) were shown to be deregulated in adrenocortical carcinoma (ACC) as compared with adenoma, but a detailed assessment of their expression in its histologic variants and correlation with clinicopathologic characteristics has not been performed, so far. Our aim was to assess the expression of 5 selected miRNAs (IGF2 gene-related miR-483-3p and 5p and hypoxia-induced miR-210, miR-195, and miR-1974) in a series of 51 ACCs (35 classical, 6 myxoid, and 10 oncocytic) as compared with clinical and pathologic features and immunohistochemical expression of prognostic markers, including steroidogenic factor 1, p53, β-catenin, and glucose transporter 1. Oncocytic carcinomas had a reduced expression of miR-483-3p (P = .0325), miR-483-5p (P = .0175), and miR-210 (P = .0366), as compared with other histotypes. Overexpression of miR-210 was associated with the presence of necrosis (P = .0035), high Ki-67 index (P = .0013), and high glucose transporter 1 expression (P = .0043), whereas an inverse correlation with mitotic rate was observed in cases with high miR-493-3p (P = .0191) and miR-1974 (P = .0017) expression. High miR-1974 was also associated with low Ki-67 (P = .0312) and European Network for the Study of Adrenal Tumors stage (P = .0082) and negative p53 (P = .0013). At univariate analysis myxoid/classic histotype (P = .026), high miR-210 (P = .0465), high steroidogenic factor 1 protein (P = .0017), high Ki-67 (P = .0066), and high mitotic index (P = .0006) were significantly associated the shorter overall survival, the latter being the sole independent prognostic factor at multivariate analysis (P = .017). In conclusion, (a) miR-483-3p, miR-483-5p, and miR-210 are differentially expressed in ACC variants, and (b) high miR-210 is associated with clinicopathologic parameters of aggressiveness and a poor prognosis.

Couto P, Miranda D, Vieira R, et al.
Association between CLOCK, PER3 and CCRN4L with non‑small cell lung cancer in Brazilian patients.
Mol Med Rep. 2014; 10(1):435-40 [PubMed] Related Publications
Circadian rhythms comprise of daily oscillations in a variety of biological processes and are regulated by an endogenous clock. Disruption of these rhythms has been associated with cancer progression, and understanding natural oscillations in cellular growth control, tumor suppression and cancer treatment, may reveal how clock and clock‑controlled genes are regulated in normal physiological functioning. To investigate the association between clock genes and non‑small cell lung cancer (NSCLC), we genotyped three tag SNPs (rs938836, rs17050680, rs3805213) in the Nocturnin gene (CCRN4L), five SNPs (rs228727, rs228644, rs228729, rs707467, rs104620202) in the period 3 (PER3) gene and one SNP (rs6855837) in the CLOCK gene, in 78 Brazilian patients with NSCLC. One tag SNP in CCRN4L (rs3805213) and another tag SNP from PER3 (rs228729) demonstrated a significant correlation with genotype and allele frequency in lung cancer (P=4.4x10‑3 and P=5.7x10‑2; P=0.004 and P=0.02, respectively). The results of our study suggest these polymorphisms in the CCRN4L and PER3 genes may represent a risk factor in the occurrence and development of NSCLC in Brazilian patients.

Zuccotti P, Colombrita C, Moncini S, et al.
hnRNPA2/B1 and nELAV proteins bind to a specific U-rich element in CDK5R1 3'-UTR and oppositely regulate its expression.
Biochim Biophys Acta. 2014; 1839(6):506-16 [PubMed] Related Publications
Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) encodes p35, a specific activator of cyclin-dependent kinase 5 (CDK5). CDK5 and p35 have a fundamental role in neuronal migration and differentiation during CNS development. Both the CDK5R1 3'-UTR's remarkable size and its conservation during evolution strongly indicate an important role in post-transcriptional regulation. We previously validated different regulatory elements in the 3'-UTR of CDK5R1, which affect transcript stability, p35 levels and cellular migration through the binding with nELAV proteins and miR-103/7 miRNAs. Interestingly, a 138 bp-long region, named C2.1, was identified as the most mRNA destabilizing portion within CDK5R1 3'-UTR. This feature was maintained by a shorter region of 73 bp, characterized by two poly-U stretches. UV-CL experiments showed that this region interacts with protein factors. UV-CLIP assays and pull-down experiments followed by mass spectrometry analysis demonstrated that nELAV and hnRNPA2/B1 proteins bind to the same U-rich element. These RNA-binding proteins (RBPs) were shown to oppositely control CDK5R1 mRNA stability and p35 protein content at post-trascriptional level. While nELAV proteins have a positive regulatory effect, hnRNPA2/B1 has a negative action that is responsible for the mRNA destabilizing activity both of the C2.1 region and of the full-length 3'-UTR. In co-expression experiments of hnRNPA2/B1 and nELAV RBPs we observed an overall decrease of p35 content. We also demonstrated that hnRNPA2/B1 can downregulate nELAV protein content but not vice versa. This study, by providing new insights on the combined action of different regulatory factors, contributes to clarify the complex post-transcriptional control of CDK5R1 gene expression.

Veronese A, Pepe F, Chiacchia J, et al.
Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia.
Leukemia. 2015; 29(1):86-95 [PubMed] Article available free on PMC after 20/11/2015 Related Publications
Deregulation of the miR-15a/16-1 cluster has a key role in the pathogenesis of chronic lymphocytic leukemia (CLL), a clinically heterogeneous disease with indolent and aggressive forms. The miR-15a/16-1 locus is located at 13q14, the most frequently deleted region in CLL. Starting from functional investigations of a rare SNP upstream the miR cluster, we identified a novel allele-specific mechanism that exploits a cryptic activator region to recruit the RNA polymerase III for miR-15a/16-1 transcription. This regulation of the miR-15a/16- locus is independent of the DLEU2 host gene, which is often transcribed monoallellically by RPII. We found that normally one allele of miR-15a/16-1 is transcribed by RNAPII, the other one by RNAPIII. In our subset of CLL patients harboring 13q14 deletions, exclusive RNA polymerase III (RPIII)-driven transcription of the miR-15a/16-1 was the consequence of loss of the RPII-regulated allele and correlated with high expression of the poor prognostic marker ZAP70 (P=0.019). Thus, our findings point to a novel biological process, characterized by double allele-specific transcriptional regulation of the miR-15a/16-1 locus by alternative mechanisms. Differential usage of these mechanisms may distinguish at onset aggressive from indolent forms of CLL. This provides a basis for the clinical heterogeneity of the CLL patients carrying 13q14 deletions.

Carneiro JG, Couto PG, Bastos-Rodrigues L, et al.
Spectrum of somatic EGFR, KRAS, BRAF, PTEN mutations and TTF-1 expression in Brazilian lung cancer patients.
Genet Res (Camb). 2014; 96:e002 [PubMed] Related Publications
Lung cancer is the leading global cause of cancer-related mortality. Inter-individual variability in treatment response and prognosis has been associated with genetic polymorphisms in specific genes: EGFR, KRAS, BRAF, PTEN and TTF-1. Somatic mutations in EGFR and KRAS genes are reported at rates of 15-40% in non-small cell lung cancer (NSCLC) in ethnically diverse populations. BRAF and PTEN are commonly mutated genes in various cancer types, including NSCLC, with PTEN mutations exerting an effect on the therapeutic response of EGFR/AKT/PI3K pathway inhibitors. TTF-1 is expressed in approximately 80% of lung adenocarcinomas and its positivity correlates with higher prevalence of EGFR mutation in this cancer type. To determine molecular markers for lung cancer in Brazilian patients, the rate of the predominant EGFR, KRAS, BRAF and PTEN mutations, as well as TTF-1 expression, was assessed in 88 Brazilian NSCLC patients. EGFR exon 19 deletions (del746-750) were detected in 3/88 (3·4%) patients. Activating KRAS mutations in codons 12 and 61 were noted in five (5·7%) and two (2·3%) patients, respectively. None of the common somatic mutations were detected in either the BRAF or PTEN genes. TTF-1 was overexpressed in 40·7% of squamous-cell carcinoma (SCC). Our findings add to a growing body of data that highlights the genetic heterogeneity of the abnormal EGFR pathway in lung cancer among ethnically diverse populations.

Fiano V, Trevisan M, Trevisan E, et al.
MGMT promoter methylation in plasma of glioma patients receiving temozolomide.
J Neurooncol. 2014; 117(2):347-57 [PubMed] Related Publications
Promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene plays a role in cellular response to alkylating agents. In the present study aimed to: (i) evaluate the concordance between MGMT promoter methylation status in tumor tissue and plasma; (ii) monitor MGMT promoter methylation status in plasma taken before and during temozolomide treatment; (iii) explore the value of MGMT promoter methylation status in plasma as a prognostic/predictive biomarker in glioma patients. We enrolled 58 patients with histologically confirmed glioma at different grades of malignancy. All patients underwent surgical resection and temozolomide treatment. Paraffin-embedded tumor tissue was available for 48 patients. Blood samples were collected from all patients before temozolomide treatment (baseline) and at each MRI examination for a 12-month period. MGMT promoter methylation status was assessed in both sample types by real time PCR with a specific probe. The frequency of MGMT promoter methylation was 60.4 % in tumor tissue and 41.38 % in plasma. MGMT promoter methylation status was concordant in the two sample types (Kappa = 0.75, 95 % confidence interval (CI) 0.57-0.93; p value <0.001). Overall and progression-free survival were longer in patients with methylated MGMT promoter. Mortality was higher in patients with unmethylated MGMT promoter, whether in tumor tissue [hazard ratio (HR) 2.21; 95 % CI 0.99-4.95] or plasma (HR 2.19; 95 % CI 1.02-4.68). Progression-free survival was shorter in patients with unmethylated MGMT promoter, whether in tissue (HR 2.30; 95 % CI 1.19-4.45) or plasma (HR 1.77; 95 % CI 0.95-3.30). The cumulative incidence of unmethylated MGMT promoter in plasma at baseline was 58 %, and reached virtually 100 % at 12 months. In conclusion MGMT promoter methylation status in tumor tissue and plasma was highly concordant, and both were associated with longer survival, supporting the role of the detection of methylated MGMT promoter in predicting treatment response. However we suggest caution in using plasma as a surrogate of tumor tissue due to possible false-negative results.

Garattini E, Bolis M, Garattini SK, et al.
Retinoids and breast cancer: from basic studies to the clinic and back again.
Cancer Treat Rev. 2014; 40(6):739-49 [PubMed] Related Publications
All-trans retinoic acid (ATRA) is the most important active metabolite of vitamin A controlling segmentation in the developing organism and the homeostasis of various tissues in the adult. ATRA as well as natural and synthetic derivatives, collectively known as retinoids, are also promising agents in the treatment and chemoprevention of different types of neoplasia including breast cancer. The major aim of the present article is to review the basic knowledge acquired on the anti-tumor activity of classic retinoids, like ATRA, in mammary tumors, focusing on the underlying cellular and molecular mechanisms and the determinants of retinoid sensitivity/resistance. In the first part, an analysis of the large number of pre-clinical studies available is provided, stressing the point that this has resulted in a limited number of clinical trials. This is followed by an overview of the knowledge acquired on the role played by the retinoid nuclear receptors in the anti-tumor responses triggered by retinoids. The body of the article emphasizes the potential of ATRA and derivatives in modulating and in being influenced by some of the most relevant cellular pathways involved in the growth and progression of breast cancer. We review the studies centering on the cross-talk between retinoids and some of the growth-factor pathways which control the homeostasis of the mammary tumor cell. In addition, we consider the cross-talk with relevant intra-cellular second messenger pathways. The information provided lays the foundation for the development of rational and retinoid-based therapeutic strategies to be used for the management of breast cancer.

Brandi G, Tavolari S, Guarnieri T, et al.
Antiprotease strategy in pancreatic cancer treatment: emergence from a preclinical study.
Pancreas. 2014; 43(1):53-63 [PubMed] Related Publications
OBJECTIVES: Resistance to gemcitabine is one of the main causes of treatment failure in pancreatic cancer. Compelling evidences have shown the involvement of nuclear factor κB (NF-κB) activation in such phenomenon. The protease inhibitor gabexate mesilate has been shown to inhibit NF-κB. We here investigated if combined treatment with this drug could improve gemcitabine antitumoral efficacy in pancreatic cancer cells.
METHODS: The effect of gabexate mesilate and gemcitabine, both used at concentrations achievable in human plasma, was assessed on in vitro pancreatic cancer cell growth, invasion, and tumor angiogenesis. The molecular mechanism at the basis of these effects was also investigated.
RESULTS: Gabexate mesilate significantly increased gemcitabine anti-invasive and antiangiogenic efficacy. This effect was related to inhibition of gemcitabine-induced NF-κB activation by gabexate mesilate, which prevented RelA/p65 nuclear translocation and resulted in metalloproteinase 2, metalloproteinase 9, vascular endothelial growth factor, and interleukin 8 down-regulation. Combined treatment with gabexate mesilate also inhibited gemcitabine-induced extracellular-regulated kinase 1/2 and AKT activation by increased expression of Raf kinase inhibitor protein and phosphatase and tensin homolog.
CONCLUSIONS: Combined treatment with gabexate mesilate sensitizes pancreatic cancer cells to gemcitabine by inhibition of the NF-κB pathway. The efficacy of this therapeutic strategy in pancreatic cancer patients remains to be established and deserves future clinical investigation.

Ronca R, Di Salle E, Giacomini A, et al.
Long pentraxin-3 inhibits epithelial-mesenchymal transition in melanoma cells.
Mol Cancer Ther. 2013; 12(12):2760-71 [PubMed] Related Publications
During melanoma progression, malignant melanocytes are reprogrammed into mesenchymal-like cells through to an epithelial-mesenchymal transition (EMT) process associated with the acquisition of an invasive, prometastatic phenotype. The fibroblast growth factor-2 (FGF2)/FGF receptor (FGFR) system plays a pivotal role in melanoma, leading to autocrine/paracrine induction of tumor cell proliferation and angiogenesis. Long pentraxin-3 (PTX3) interacts with FGF2, and other FGF family members, inhibiting FGF-dependent neovascularization and tumor growth. Here, PTX3 protein and the PTX3-derived acetylated pentapeptide Ac-ARPCA-NH2 inhibit FGF2-driven proliferation and downstream FGFR signaling in murine melanoma B16-F10 cells. Moreover, human PTX3-overexpressing hPTX_B16-F10 cells are characterized by the reversed transition from a mesenchymal to an epithelial-like appearance, inhibition of cell proliferation, loss of clonogenic potential, reduced motility and invasive capacity, downregulation of various mesenchymal markers, and upregulation of the epithelial marker E-cadherin. Accordingly, PTX3 affects cell proliferation and EMT transition in human A375 and A2058 melanoma cells. Also, hPTX_B16-F10 cells showed a reduced tumorigenic and metastatic activity in syngeneic C57BL/6 mice. In conclusion, PTX3 inhibits FGF/FGFR-driven EMT in melanoma cells, hampering their tumorigenic and metastatic potential. These data represent the first experimental evidence about a nonredundant role of the FGF/FGFR system in the modulation of the EMT process in melanoma and indicate that PTX3 or its derivatives may represent the basis for the design of novel therapeutic approaches in FGF/FGFR-dependent tumors, including melanoma.

Bidzinska J, Cimino-Reale G, Zaffaroni N, Folini M
G-quadruplex structures in the human genome as novel therapeutic targets.
Molecules. 2013; 18(10):12368-95 [PubMed] Related Publications
G-quadruplexes are secondary structures that may form within guanine-rich nucleic acid sequences. Telomeres have received much attention in this regard since they can fold into several distinct intramolecular G-quadruplexes, leading to the rational design and development of G-quadruplex‑stabilizing molecules. These ligands were shown to selectively exert an antiproliferative and chemosensitizing activity in in vitro and in vivo tumor models, without appreciably affecting normal cells. Such findings point to them as possible drug candidates for clinical applications. Other than in telomeres, G-quadruplexes may form at additional locations in the human genome, including gene promoters and untranslated regions. For instance, stabilization of G-quadruplex structures within the promoter of MYC, KIT, or KRAS resulted in the down-regulation of the corresponding oncogene either in gene reporter assays or in selected experimental models. In addition, the alternative splicing of a number of genes may be affected for a therapeutic benefit through the stabilization of G-quadruplexes located within pre-mRNAs. It is now emerging that G-quadruplex structures may act as key regulators of several biological processes. Consequently, they are considered as attractive targets for broad-spectrum anticancer therapies, and much effort is being made to develop a variety of ligands with improved G-quadruplex recognition properties. Quarfloxin, a fluoroquinolone derivative designed to target a G-quadruplex within ribosomal DNA and disrupt protein-DNA interactions, has entered clinical trials for different malignancies. This review will provide some hints on the role of G-quadruplex structures in biological processes and will evaluate their implications as novel therapeutic targets.

Sandoval J, Mendez-Gonzalez J, Nadal E, et al.
A prognostic DNA methylation signature for stage I non-small-cell lung cancer.
J Clin Oncol. 2013; 31(32):4140-7 [PubMed] Related Publications
PURPOSE: Non-small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard.
PATIENTS AND METHODS: A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC.
RESULTS: Unsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio [HR], 2.35; 95% CI, 1.29 to 4.28; P = .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high- and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P = .001).
CONCLUSION: The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging.

Civenni G, Malek A, Albino D, et al.
RNAi-mediated silencing of Myc transcription inhibits stem-like cell maintenance and tumorigenicity in prostate cancer.
Cancer Res. 2013; 73(22):6816-27 [PubMed] Related Publications
Several studies link disease progression, recurrence, and treatment failures to the cancer stem-like cell (CSC) subpopulation within the heterogeneous tumor cell population. Myc is a transcription factor having a central function in stem cell biology and in human cancers. Hence, Myc represents an attractive target to develop CSC-specific therapies. Recent findings suggest that Myc transcription can be silenced using an RNA interference (RNAi)-based strategy that targets noncoding promoter-associated RNA (paRNA) overlapping the transcription start site. In this study, we investigated the effects of silencing Myc transcription on prostate CSC in cell culture and xenograft models of human prostate cancer. Treatment with an effective promoter-targeting siRNA reduced the fraction of CSCs, leading to reduced self-renewal, tumor-initiating, and metastatic capability. Combined analysis of stem-like cells and senescence markers indicated that Myc silencing triggered a phenotypic shift and senescence in the CSC subpopulation. Notably, systemic delivery of the promoter-targeting siRNA in the xenograft model produced a striking suppression in the development of prostate tumors. Our results support a pivotal role for Myc in CSC maintenance and show that Myc targeting via RNAi-based transcriptional silencing can trigger CSC senescence and loss of their tumor-initiating capability. More generally, our findings demonstrate the efficacy of RNAi-based transcriptional strategies and the potential to target regulatory noncoding paRNAs for therapeutic applications.

Guo G, Luc S, Marco E, et al.
Mapping cellular hierarchy by single-cell analysis of the cell surface repertoire.
Cell Stem Cell. 2013; 13(4):492-505 [PubMed] Article available free on PMC after 20/11/2015 Related Publications
Stem cell differentiation pathways are most often studied at the population level, whereas critical decisions are executed at the level of single cells. We have established a highly multiplexed, quantitative PCR assay to profile in an unbiased manner a panel of all commonly used cell surface markers (280 genes) from individual cells. With this method, we analyzed over 1,500 single cells throughout the mouse hematopoietic system and illustrate its utility for revealing important biological insights. The comprehensive single cell data set permits mapping of the mouse hematopoietic stem cell differentiation hierarchy by computational lineage progression analysis. Further profiling of 180 intracellular regulators enabled construction of a genetic network to assign the earliest differentiation event during hematopoietic lineage specification. Analysis of acute myeloid leukemia elicited by MLL-AF9 uncovered a distinct cellular hierarchy containing two independent self-renewing lineages with different clonal activities. The strategy has broad applicability in other cellular systems.

Gessi M, Zur Mühlen A, Hammes J, et al.
Genome-wide DNA copy number analysis of desmoplastic infantile astrocytomas and desmoplastic infantile gangliogliomas.
J Neuropathol Exp Neurol. 2013; 72(9):807-15 [PubMed] Related Publications
Little is known about the molecular features of desmoplastic infantile ganglioglioma (DIG) and desmoplastic infantile astrocytoma (DIA). We performed a genome-wide DNA copy number analysis in combination with a multiplex ligation-dependent probe amplification-based analysis of copy number changes of candidate genes in 4 DIAs and 10 DIGs. Molecular inversion probe (MIP) assay showed that large chromosomal alterations were rare among DIG and DIA. Focal recurrent genomic losses were observed in chromosome regions such as 5q13.3, 21q22.11, and 10q21.3 in both DIA and DIG. Principal component analysis did not show any significant differences between the molecular profiles of DIG and DIA, and a hierarchical cluster analysis did not clearly separate the 2 tumor groups according to their molecular profiles. In 6 cases, gain of genomic material at 7q31 (corresponding to MET gene) was found in multiplex ligation-dependent probe amplification (MLPA) analysis. Furthermore, two cases showed gain at 4q12, and a single case showed BRAF mutation. In agreement with previous analyses, this study demonstrates the absence of consistent recurrent chromosomal alterations in DIA and DIG and overall rarity of the BRAF mutation in these tumors. Notably, these results suggest that DIA and DIG represent a histologic spectrum of the same tumor rather than 2 separate entities.

Ranzani M, Annunziato S, Adams DJ, Montini E
Cancer gene discovery: exploiting insertional mutagenesis.
Mol Cancer Res. 2013; 11(10):1141-58 [PubMed] Article available free on PMC after 20/11/2015 Related Publications
Insertional mutagenesis has been used as a functional forward genetics screen for the identification of novel genes involved in the pathogenesis of human cancers. Different insertional mutagens have been successfully used to reveal new cancer genes. For example, retroviruses are integrating viruses with the capacity to induce the deregulation of genes in the neighborhood of the insertion site. Retroviruses have been used for more than 30 years to identify cancer genes in the hematopoietic system and mammary gland. Similarly, another tool that has revolutionized cancer gene discovery is the cut-and-paste transposons. These DNA elements have been engineered to contain strong promoters and stop cassettes that may function to perturb gene expression upon integration proximal to genes. In addition, complex mouse models characterized by tissue-restricted activity of transposons have been developed to identify oncogenes and tumor suppressor genes that control the development of a wide range of solid tumor types, extending beyond those tissues accessible using retrovirus-based approaches. Most recently, lentiviral vectors have appeared on the scene for use in cancer gene screens. Lentiviral vectors are replication-defective integrating vectors that have the advantage of being able to infect nondividing cells, in a wide range of cell types and tissues. In this review, we describe the various insertional mutagens focusing on their advantages/limitations, and we discuss the new and promising tools that will improve the insertional mutagenesis screens of the future.

Komine H, Kuhn L, Matsushita N, et al.
Examination of MARCO activity on dendritic cell phenotype and function using a gene knockout mouse.
PLoS One. 2013; 8(7):e67795 [PubMed] Article available free on PMC after 20/11/2015 Related Publications
We have reported the upregulation of MARCO, a member of the class A scavenger receptor family, on the surface of murine and human dendritic cells (DCs) pulsed with tumor lysates. Exposure of murine tumor lysate-pulsed DCs to an anti-MARCO antibody led to loss of dendritic-like processes and enhanced migratory capacity. In this study, we have further examined the biological and therapeutic implications of MARCO expression by DCs. DCs generated from the bone marrow (bm) of MARCO knockout (MARCO⁻/⁻) mice were phenotypically similar to DCs generated from the bm of wild-type mice and produced normal levels of IL-12 and TNF-α when exposed to LPS. MARCO⁻/⁻ DCs demonstrated enhanced migratory capacity in response to CCL-21 in vitro. After subcutaneous injection into mice, MARCO⁻/⁻ TP-DCs migrated more efficiently to the draining lymph node leading to enhanced generation of tumor-specific IFN-γ producing T cells and improved tumor regression and survival in B16 melanoma-bearing mice. These results support targeting MARCO on the surface of DCs to improve trafficking and induction of anti-tumor immunity.

Gismondi A, Canuti L, Impei S, et al.
Antioxidant extracts of African medicinal plants induce cell cycle arrest and differentiation in B16F10 melanoma cells.
Int J Oncol. 2013; 43(3):956-64 [PubMed] Related Publications
African ethnomedicine is essentially based on the traditional use of vegetal extracts. Since these natural drugs have shown health giving properties, in the present study we increased further the scientific basis supporting these data. We investigated the effects, on murine B16F10 melanoma cells, of plant extracts that were directly obtained by a Cameroon 'traditional healer'. After a preliminary study on the antioxidant functions of these compounds, already abundant in literature, Moringa oleifera Lam., Eremomastax speciosa (Hochst.) Cufod and Aframomum melegueta K. Schum extracts were individually analyzed. We performed laboratory assessments on these medicinal preparations in order to clearly demonstrate their antineoplastic features. All the treatments caused in tumor cells a great reduction in growth and proliferation rate, cell cycle arrest, increase of p53, p21WAF1/Cip1 and p27Kip1 protein levels and induction of differentiation. These results, on the bioactivity and the biochemical characteristics of African plant extracts, may increase the comprehension of indigenous therapeutic practices and represent the first step for the individuation of new inexpensive and natural drugs able to prevent and contrast cancer onset.

Massa PE, Paniccia A, Monegal A, et al.
Salmonella engineered to express CD20-targeting antibodies and a drug-converting enzyme can eradicate human lymphomas.
Blood. 2013; 122(5):705-14 [PubMed] Related Publications
Escape from immune detection favors both tumor survival and progression, and new approaches to circumvent this are essential to combat cancers. Nonvirulent, tumor-tropic bacteria, such as Salmonella typhimurium, can unmask a tumor by transforming it into a site of inflammation; however, the nonspecific invasiveness of Salmonella leads to off-target effects diluting its therapeutic efficacy and making its use in human patients inherently risky. Here, we demonstrate that Salmonella tumor specificity can be significantly improved via a surface-expressed single-domain antibody directed to a tumor-associated antigen (CD20). Antibody-dependent bacterial targeting specifies the infection of CD20+ lymphoma cells in vitro and in vivo, while significantly diminishing nonspecific cell invasion. Indeed, CD20-targeted Salmonella was less generally invasive, even in organs that normally serve as physiological reservoirs. Furthermore, tumor-specific Salmonella engineered to carry the herpes simplex virus thymidine kinase prodrug-converting enzyme effectively treats human lymphoma xenografts when coadministered intratumorally or intravenously with ganciclovir in mice lacking a functional adaptive immune system. Therefore, tumor-targeted Salmonella could prove effective even in those patients displaying a debilitated immune system, which is often the case with late-stage cancers. Altogether, antibody-displaying Salmonella vectors can mediate a tumor-specific response and rejection with few detectable adverse effects while specifically delivering cytotoxic payloads.

Ríos-Marco P, Martín-Fernández M, Soria-Bretones I, et al.
Alkylphospholipids deregulate cholesterol metabolism and induce cell-cycle arrest and autophagy in U-87 MG glioblastoma cells.
Biochim Biophys Acta. 2013; 1831(8):1322-34 [PubMed] Related Publications
Glioblastoma is the most common malignant primary brain tumour in adults and one of the most lethal of all cancers. Growing evidence suggests that human tumours undergo abnormal lipid metabolism, characterised by an alteration in the mechanisms that regulate cholesterol homeostasis. We have investigated the effect that different antitumoural alkylphospholipids (APLs) exert upon cholesterol metabolism in the U-87 MG glioblastoma cell line. APLs altered cholesterol homeostasis by interfering with its transport from the plasma membrane to the endoplasmic reticulum (ER), thus hindering its esterification. At the same time they stimulated the synthesis of cholesterol from radiolabelled acetate and its internalisation from low-density lipoproteins (LDLs), inducing both 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and LDL receptor (LDLR) genes. Fluorescent microscopy revealed that these effects promoted the accumulation of intracellular cholesterol. Filipin staining demonstrated that this accumulation was not confined to the late endosome/lysosome (LE/LY) compartment since it did not colocalise with LAMP2 lysosomal marker. Furthermore, APLs inhibited cell growth, producing arrest at the G2/M phase. We also used transmission electron microscopy (TEM) to investigate ultrastructural alterations induced by APLs and found an abundant presence of autophagic vesicles and autolysosomes in treated cells, indicating the induction of autophagy. Thus our findings clearly demonstrate that antitumoural APLs interfere with the proliferation of the glioblastoma cell line via a complex mechanism involving cholesterol metabolism, cell-cycle arrest or autophagy. Knowledge of the interrelationship between these processes is fundamental to our understanding of tumoural response and may facilitate the development of novel therapeutics to improve treatment of glioblastoma and other types of cancer.

Tucci M, Stucci S, Savonarola A, et al.
Immature dendritic cells in multiple myeloma are prone to osteoclast-like differentiation through interleukin-17A stimulation.
Br J Haematol. 2013; 161(6):821-31 [PubMed] Related Publications
Interleukin 17A (IL17A), a cytokine involved in allergy, inflammation and osteoclastogenesis, was investigated in multiple myeloma (MM) to assess its role in the osteoclast (OC)-like activity of marrow immature dendritic cells (iDCs). Comparing nine MM patients with control subjects affected by monoclonal gammopathy of undetermined significance, we found high IL17A expression in the marrow plasma of MM patients in parallel with its deposits within the stromal matrix. Increased expression of the IL17A receptor (IL17RA) was also found in primary myeloma iDCs, which underwent OC-like transdifferentiation after IL17A stimulation. To assess the role of IL17A, we measured the activity of the IL17/IL17RA pathway in IL17A-transdifferentiated iDCs and the expression of functional OC genes by Western blotting and real-time polymerase chain reaction. These cells showed increased RNA transcription of genes enrolled in the maturation of OCs, while NFATC1 and FOS were induced by IL17A, independently of NFKB1 phosphorylation. Moreover, the concurrent phosphorylation of the Lip isoform of CEBPB and the down-regulation of MAFB supported the activation of IL17RA pathway in OC-like transdifferentiated iDCs that was apparently unrelated to TNFRSF11A signalling. These data emphasize the involvement of iDCs in MM hyperactive osteoclastogenesis and suggest that their bone resorption activity is also regulated, at least in vitro, by IL17RA.

de Mesquita Netto AC, Gomez RS, Diniz MG, et al.
Assessing the contribution of HRPT2 to the pathogenesis of jaw fibrous dysplasia, ossifying fibroma, and osteosarcoma.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2013; 115(3):359-67 [PubMed] Related Publications
OBJECTIVE: To investigate HRPT2 in jaw ossifying fibroma (OF), fibrous dysplasia (FD), and osteosarcoma (OS).
STUDY DESIGN: We combined microsatellite loss of heterozygosity (LOH), HRPT2 sequence alterations at the mRNA level by reverse-transcription polymerase chain reaction (PCR), cDNA sequencing, and quantitative PCR (qPCR) and immunohistochemistry (IHC) in a total of 19 OF, 15 FD, and 9 OS. Because HRPT2 (parafibromin) interacts with cyclin D1, we investigated cyclin D1 expression with the use of qPCR and IHC.
RESULTS: LOH was detected in 3/5 FD, 6/9 OF, and 2/2 OS heterozygous samples. LOH was not associated with decreased mRNA levels or HRPT2 protein expression except for 1 OF which harbored an inactivating mutation. However, this tumor did not display altered transcription or protein levels of HRPT2 nor cyclin compared with the other OF.
CONCLUSIONS: The contribution of HRPT2 inactivation to the pathogenesis of OF, FD, and OS is marginal at best and may be limited to progression rather than tumor initiation.

De Marco C, Rinaldo N, Bruni P, et al.
Multiple genetic alterations within the PI3K pathway are responsible for AKT activation in patients with ovarian carcinoma.
PLoS One. 2013; 8(2):e55362 [PubMed] Article available free on PMC after 20/11/2015 Related Publications
The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is activated in multiple cancers including ovarian carcinoma (OC). However, the relative contribution of the single components within the PI3K pathway to AKT activation in OC is still unclear. We examined 98 tumor samples from Italian OC patients for alterations in the members of the PI3K pathway. We report that AKT is significantly hyperactive in OC compared to normal tissue (n = 93; p<0.0001) and that AKT activation is preferentially observed in the elderly (>58 years old; n = 93; p<0.05). The most frequent alteration is the overexpression of the p110α catalytic subunit of PI3K (63/93, ∼68%); less frequent alterations comprise the loss of PTEN (24/89, 27%) and the overexpression of AKT1 (18/96, 19%) or AKT2 (11/88,12.5%). Mutations in the PIK3CA or KRAS genes were detected at lower frequency (12% and 10%, respectively) whereas mutations in AKT1 or AKT2 genes were absent. Although many tumors presented a single lesion (28/93, of which 23 overexpressed PIK3CA, 1 overexpressed AKT and 4 had lost PTEN), many OC (35/93) presented multiple alterations within the PI3K pathway. Apparently, aberrant PI3K signalling was mediated by activation of the canonical downstream AKT-dependent mTOR/S6K1/4EBP1 pathway and by regulation of expression of oncogenic transcription factors that include HMGA1, JUN-B, FOS and MYC but not by AKT-independent activation of SGK3. FISH analysis indicated that gene amplification of PIK3CA, AKT1 and AKT2 (but not of PI3KR1) and the loss of PTEN are common and may account for changes in the expression of the corresponding proteins. In conclusion, our results indicate that p110α overexpression represents the most frequent alteration within the PI3K/AKT pathway in OC. However, p110α overexpression may not be sufficient to activate AKT signalling and drive ovarian tumorigenesis since many tumors overexpressing PI3K presented at least one additional alteration.

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