PYCARD

Gene Summary

Gene:PYCARD; PYD and CARD domain containing
Aliases: ASC, TMS, TMS1, CARD5, TMS-1
Location:16p11.2
Summary:This gene encodes an adaptor protein that is composed of two protein-protein interaction domains: a N-terminal PYRIN-PAAD-DAPIN domain (PYD) and a C-terminal caspase-recruitment domain (CARD). The PYD and CARD domains are members of the six-helix bundle death domain-fold superfamily that mediates assembly of large signaling complexes in the inflammatory and apoptotic signaling pathways via the activation of caspase. In normal cells, this protein is localized to the cytoplasm; however, in cells undergoing apoptosis, it forms ball-like aggregates near the nuclear periphery. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:apoptosis-associated speck-like protein containing a CARD
HPRD
Source:NCBIAccessed: 21 August, 2015

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 21 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 21 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: PYCARD (cancer-related)

Yang L, He Z, Huang XY, et al.
Prevalence of human papillomavirus and the correlation of HPV infection with cervical disease in Weihai, China.
Eur J Gynaecol Oncol. 2015; 36(1):73-7 [PubMed] Related Publications
OBJECTIVE: This study investigates the human papillomavirus (HPV) infection rate in female genital tracts, as well as the HPV genotype distribution and HPV correlation with cervical disease in Weihai, Shandong Province, China.
MATERIALS AND METHODS: A random sample of 9,460 volunteers was simultaneously screened using gene chips and examined by ThinPrep liquid-based cytology test (TCT). Cervical biopsy samples were collected from women with positive HPV-DNA and abnormal TCT for pathological diagnosis.
RESULTS: The overall HPV prevalence was 6.93% (656 of 9,460). A total of 753 subjects were infected with HPV subtypes (including multiple HPV infections). Of those with infections, 688 were infected with high-risk (HR) types (91.37%), and 65 were infected with low-risk subtypes (8.63%). The single-infection rate was 63.1%.The prevalence rates of HPV in women aged 20 to 39 years and 40 to 59 years were 7.29% and 6.71%, respectively. The most common genotype was HPV16. The HR genotypes were associated with cervical diseases such as atypical squamous cells of undetermined significance (ASCUS) (37.9%), atypical squamous cells high grade (ASC-H) (42.5%), low grade squamous intraepithelial lesion (LSIL) (50%), and high grade squamous intraepithelial lesion HSIL (66.7%). Cervical biopsy results show that the HPV detection rate increased in the following biopsy samples: cervical intraepithelial neoplasia (CIN) I (74.11%), CIN II (84.31%), CIN III (90.32%), and squamous-cell carcinoma (SCC) (100%).
CONCLUSIONS: The HPV infection rate with associated cervical disease in Weihai is equal to those in foreign countries but is lower than the average rate in China. The prevalence of HPV was higher in young people. The most common HPV genotype was 16, followed by 52 and 58. HR HPV is the most probable infection factor for cervical diseases.

Koo JS, Yoon JS
Expression of metabolism-related proteins in lacrimal gland adenoid cystic carcinoma.
Am J Clin Pathol. 2015; 143(4):584-92 [PubMed] Related Publications
OBJECTIVES: To investigate the expression and the clinical implications of metabolism-related proteins in lacrimal gland adenoid cystic carcinoma (ACC) in comparison with salivary gland ACC.
METHODS: Human tissue samples of lacrimal gland ACC (n = 11) and salivary gland ACC (n = 64) were analyzed. Immunochemistry was used to measure expression of proteins related to glycolysis (glucose transporter 1, hexokinase II, carbonic anhydrase IX, and monocarboxylate transporter 4 [MCT4]), glutaminolysis (glutaminase 1 [GLS1], glutamate dehydrogenase [GDH], and amino acid transporter 2 [ASCT2]), mitochondria (adenosine triphosphate [ATP] synthase, succinate dehydrogenase A [SDHA], and succinate dehydrogenase B), and glycolytic intermediate metabolism (phosphoserine phosphatase [PSPH], serine hydroxymethyl transferase 1 [SHMT1]).
RESULTS: GLS1 and ASCT2 were more highly expressed, and GDH, ATP synthase, and SDHA were expressed to a lesser degree in lacrimal gland ACC than in salivary gland ACC (P < .05). Lacrimal gland ACC showed less of a mitochondrial phenotype than did salivary gland ACC (P = .001). Positivity of MCT4 and PSPH was related to shorter disease-free survival, and SHMT1 was related to shorter overall survival (P < .05).
CONCLUSIONS: Lacrimal gland ACC exhibited higher expression of GLS1 and ASCT2, compared with salivary gland ACC. Overexpression of MCT4, PSPH, and SHMT1 was associated with poorer prognosis.

Hummel J, Kämmerer U, Müller N, et al.
Human endogenous retrovirus envelope proteins target dendritic cells to suppress T-cell activation.
Eur J Immunol. 2015; 45(6):1748-59 [PubMed] Related Publications
Though mostly defective, human endogenous retroviruses (HERV) can retain open reading frames, which are especially expressed in the placenta. There, the envelope (env) proteins of HERV-W (Syncytin-1), HERV-FRD (Syncytin-2), and HERV-K (HML-2) were implicated in tolerance against the semi-allogenic fetus. Here, we show that the known HERV env-binding receptors ASCT-1 and -2 and MFSD2 are expressed by DCs and T-cells. When used as effectors in coculture systems, CHO cells transfected to express Syncytin-1, -2, or HML-2 did not affect T-cell expansion or overall LPS-driven phenotypic DC maturation, however, promoted release of IL-12 and TNF-α rather than IL-10. In contrast, HERV env expressing choriocarcinoma cell lines suppressed T-cell proliferation and LPS-induced TNF-α and IL-12 release, however, promoted IL-10 accumulation, indicating that these effects might not rely on HERV env interactions. However, DCs conditioned by choriocarcinoma, but also transgenic CHO cells failed to promote allogenic T-cell expansion. This was associated with a loss of DC/T-cell conjugate frequencies, impaired Ca(2+) mobilization, and aberrant patterning of f-actin and tyrosine phosphorylated proteins in T-cells. Altogether, these findings suggest that HERV env proteins target T-cell activation indirectly by modulating the stimulatory activity of DCs.

Wang X, Docanto MM, Sasano H, et al.
Prostaglandin E2 inhibits p53 in human breast adipose stromal cells: a novel mechanism for the regulation of aromatase in obesity and breast cancer.
Cancer Res. 2015; 75(4):645-55 [PubMed] Related Publications
Obesity is a risk factor for postmenopausal breast cancer and the majority of these cancers are estrogen dependent. Aromatase converts androgens into estrogens and its increased expression in breast adipose stromal cells (ASC) is a major driver of estrogen receptor-positive breast cancer. In particular, obesity-associated and tumor-derived factors, such as prostaglandin E2 (PGE2), have been shown to drive the expression of aromatase by stimulating the activity of the proximal promoter II (PII). The tumor-suppressor p53 is a key regulator of cell-cycle arrest and apoptosis and is frequently mutated in breast cancer. Mutations in p53 are rare in tumor-associated ASCs. Therefore, it was hypothesized that p53 is regulated by PGE2 and involved in the PGE2-mediated regulation of aromatase. Results demonstrate that PGE2 causes a significant decrease in p53 transcript and nuclear protein expression, as well as phosphorylation at Ser15 in primary human breast ASCs. Stabilization of p53 with RITA leads to a significant decrease in the PGE2-stimulated aromatase mRNA expression and activity, and PII activity. Interaction of p53 with PII was demonstrated and this interaction is decreased in the presence of PGE2. Moreover, mutation of the identified p53 response element leads to an increase in the basal activity of the promoter. Immunofluorescence on clinical samples demonstrates that p53 is decreased in tumor-associated ASCs compared with ASCs from normal breast tissue, and that there is a positive association between perinuclear (inactive) p53 and aromatase expression in these cells. Furthermore, aromatase expression is increased in breast ASCs from Li-Fraumeni patients (germline TP53 mutations) compared with non-Li-Fraumeni breast tissue. Overall, our results demonstrate that p53 is a negative regulator of aromatase in the breast and its inhibition by PGE2 provides a novel mechanism for aromatase regulation in obesity and breast cancer.

Mersakova S, Visnovsky J, Holubekova V, et al.
Detection of methylation of the promoter region of the MAL and CADM1 genes by pyrosequencing in cervical carcinoma.
Neuro Endocrinol Lett. 2014; 35(7):619-23 [PubMed] Related Publications
OBJECTIVE: Cervical cancer is the second most common cancer disease affecting the female population. A key factor in development of the disease is the human papillomavirus infection (HPV). The disease is also impacted by epigenetic changes such as DNA methylation, which causes activation or exclusion of certain genes, and simultaneously the hypermethylation of cytosines in the promoters and turn-off of previously active genes occur. In this study, we focused on the introduction of pyrosequencing for the detection of DNA methylation of the selected CADM1 and MAL genes.
METHODS: DNA was isolated from cytological cervical smear of patients with different types of dysplasia [L-SIL (n=14), ASC-US (n=15), H-SIL (n=1)] and four control samples from healthy women. Prepared samples were further analyzed by bisulfite conversion and subsequent pyrosequencing (Pyromark Q96 ID, Qiagen, Germany). We examined the extent of methylation of CpG islands and as control samples of this method we used a fully methylated and unmethylated DNA. Methylation level (Met level) from each sample was quantified as the mean value [sum of all methylated CpG islands in %/total number of CpG islands (MAL n=4; CADM1 n=3)].
RESULTS: In total, 30 clinical samples and 4 control samples from healthy women were analyzed. By means of the analysis of the CADM1promoter region, the values of the Met level were obtained [fully methylated DNA (94.83 and 88); completely unmethylated DNA (0 and 0); and control samples from healthy patients (6.825 and 0.825), L-SIL (2.107 and 2.778), ASC-US (7.313 and 3.626), H-SIL (0 and 0)]. By means of the analysis of the MAL promoter region, the values of Met level were obtained [fully methylated DNA (53.25); completely unmethylated DNA (0.875); and control samples from healthy patients (2.925), L-SIL (1.517), ASC-US (2.833), and H-SIL (4)].
CONCLUSION: We introduced a pyrosequencing method for quantification of methylation of CADM1, MAL promoter regions, and detected methylations in clinical samples and also some basal methylation in healthy women.

Logsdon BA, Gentles AJ, Miller CP, et al.
Sparse expression bases in cancer reveal tumor drivers.
Nucleic Acids Res. 2015; 43(3):1332-44 [PubMed] Free Access to Full Article Related Publications
We define a new category of candidate tumor drivers in cancer genome evolution: 'selected expression regulators' (SERs)-genes driving dysregulated transcriptional programs in cancer evolution. The SERs are identified from genome-wide tumor expression data with a novel method, namely SPARROW ( SPAR: se selected exp R: essi O: n regulators identified W: ith penalized regression). SPARROW uncovers a previously unknown connection between cancer expression variation and driver events, by using a novel sparse regression technique. Our results indicate that SPARROW is a powerful complementary approach to identify candidate genes containing driver events that are hard to detect from sequence data, due to a large number of passenger mutations and lack of comprehensive sequence information from a sufficiently large number of samples. SERs identified by SPARROW reveal known driver mutations in multiple human cancers, along with known cancer-associated processes and survival-associated genes, better than popular methods for inferring gene expression networks. We demonstrate that when applied to acute myeloid leukemia expression data, SPARROW identifies an apoptotic biomarker (PYCARD) for an investigational drug obatoclax. The PYCARD and obatoclax association is validated in 30 AML patient samples.

Ren P, Yue M, Xiao D, et al.
ATF4 and N-Myc coordinate glutamine metabolism in MYCN-amplified neuroblastoma cells through ASCT2 activation.
J Pathol. 2015; 235(1):90-100 [PubMed] Related Publications
Amplification of the MYCN gene in human neuroblastoma predicts poor prognosis and resistance to therapy. We previously showed that MYCN-amplified neuroblastoma cells constantly require large amounts of glutamine to support their unabated growth. However, the identity and regulation of the transporter(s) that capture glutamine in MYCN-amplified neuroblastoma cells and the clinical significance of the transporter(s) in neuroblastoma diagnosis remain largely unknown. Here, we performed a systemic glutamine influx analysis and identified that MYCN-amplified neuroblastoma cells predominantly rely on activation of ASCT2 (solute carrier family 1 member 5, SLC1A5) to maintain sufficient levels of glutamine essential for the TCA cycle anaplerosis. Consequently, ASCT2 depletion profoundly inhibited glutaminolysis, concomitant with a substantial decrease in cell proliferation and viability in vitro and inhibition of tumourigenesis in vivo. Mechanistically, we identified ATF4 as a novel regulator which coordinates with N-Myc to directly activate ASCT2 expression. Of note, ASCT2 expression, which correlates with that of N-Myc and ATF4, is markedly elevated in high-stage neuroblastoma tumour samples compared with low-stage ones. More importantly, high ASCT2 expression is significantly associated with poor prognosis and survival of neuroblastoma patients. In aggregate, these findings elucidate a novel mechanism depicting how cell autonomous insults (MYCN amplification) and microenvironmental stresses (ATF4 induction) in concert coordinate ASCT2 activation to promote aggressive neuroblastoma progression, and establish ASCT2 as a novel biomarker in patient prognosis and stratification.

Liu C, Karam R, Zhou Y, et al.
The UPF1 RNA surveillance gene is commonly mutated in pancreatic adenosquamous carcinoma.
Nat Med. 2014; 20(6):596-8 [PubMed] Free Access to Full Article Related Publications
Pancreatic adenosquamous carcinoma (ASC) is an enigmatic and aggressive tumor that has a worse prognosis and higher metastatic potential than its adenocarcinoma counterpart. Here we report that ASC tumors frequently harbor somatically acquired mutations in the UPF1 gene, which encodes the core component of the nonsense-mediated RNA decay (NMD) pathway. These tumor-specific mutations alter UPF1 RNA splicing and perturb NMD, leading to upregulated levels of NMD substrate mRNAs. UPF1 mutations are, to our knowledge, the first known unique molecular signatures of pancreatic ASC.

Lee JM, Hays JL, Annunziata CM, et al.
Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses.
J Natl Cancer Inst. 2014; 106(6):dju089 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Olaparib has single-agent activity against breast/ovarian cancer (BrCa/OvCa) in germline BRCA1 or BRCA2 mutation carriers (gBRCAm). We hypothesized addition of olaparib to carboplatin can be administered safely and yield preliminary clinical activity.
METHODS: Eligible patients had measurable or evaluable disease, gBRCAm, and good end-organ function. A 3 + 3 dose escalation tested daily oral capsule olaparib (100 or 200mg every 12 hours; dose level1 or 2) with carboplatin area under the curve (AUC) on day 8 (AUC3 day 8), then every 21 days. For dose levels 3 to 6, patients were given olaparib days 1 to 7 at 200 and 400 mg every 12 hours, with carboplatin AUC3 to 5 on day 1 or 2 every 21 days; a maximum of eight combination cycles were permitted, after which daily maintenance of olaparib 400mg every12 hours continued until progression. Dose-limiting toxicity was defined in the first two cycles. Peripheral blood mononuclear cells were collected for polymorphism analysis and polyADP-ribose incorporation. Paired tumor biopsies (before/after cycle 1) were obtained for biomarker proteomics and apoptosis endpoints.
RESULTS: Forty-five women (37 OvCa/8 BrCa) were treated. Dose-limiting toxicity was not reached on the intermittent schedule. Expansion proceeded with olaparib 400mg every 12 hours on days 1 to 7/carboplatin AUC5. Grade 3/4 adverse events included neutropenia (42.2%), thrombocytopenia (20.0%), and anemia (15.6%). Responses included 1 complete response (1 BrCa; 23 months) and 21 partial responses (50.0%; 15 OvCa; 6 BrCa; median = 16 [4 to >45] in OvCa and 10 [6 to >40] months in BrCa). Proteomic analysis suggests high pretreatment pS209-eIF4E and FOXO3a correlated with duration of response (two-sided P < .001; Pearson's R (2) = 0.94).
CONCLUSIONS: Olaparib capsules 400mg every 12 hours on days 1 to 7/carboplatin AUC5 is safe and has activity in gBRCAm BrCa/OvCa patients. Exploratory translational studies indicate pretreatment tissue FOXO3a expression may be predictive for response to therapy, requiring prospective validation.

Vargas A, Zhou S, Éthier-Chiasson M, et al.
Syncytin proteins incorporated in placenta exosomes are important for cell uptake and show variation in abundance in serum exosomes from patients with preeclampsia.
FASEB J. 2014; 28(8):3703-19 [PubMed] Related Publications
Exosomes are extracellular vesicles that mediate intercellular communication and are involved in several biological processes. The objective of our study was to determine whether endogenous retrovirus group WE, member l (ERVWE1)/syncytin-1 and endogenous retrovirus group FRD, member 1 (ERVFRDE1)/syncytin-2, encoded by human endogenous retrovirus (HERV) envelope (env) genes, are present at the surface of exosomes produced by placenta-derived villous cytotrophoblasts and whether they play a role in cellular uptake of exosomes. In addition, we sought to determine whether these proteins are present in various abundances in serum-derived exosomes from normal pregnant women vs. women with preeclampsia (PE). Isolated exosomes were analyzed for their content by Western blot, a bead-associated flow cytometry approach, and a syncytin-2 ELISA. Binding and uptake were tested through confocal and electron microscopy using the BeWo choriocarcinoma cell line. Quality control of exosome preparations consisted of detection of exosomal and nonexosomal markers. Exosome-cell interactions were compared between cells incubated in the presence of control exosomes, syncytin-1 or syncytin-2-deprived exosomes, or exosomes solely bearing the uncleaved forms of these HERV env proteins. From our data, we conclude that villous cytotrophoblast exosomes are positive for both env proteins and are rapidly taken up by BeWo cells in a syncytin-1- and syncytin-2-dependent manner and that syncytin-2 is reduced in serum-derived exosomes from women with PE when compared to exosomes from normal pregnant women.

Shimizu K, Kaira K, Tomizawa Y, et al.
ASC amino-acid transporter 2 (ASCT2) as a novel prognostic marker in non-small cell lung cancer.
Br J Cancer. 2014; 110(8):2030-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: ASC amino-acid transporter 2 (ASCT2) is a major glutamine transporter that has an essential role in tumour growth and progression. Although ASCT2 is highly expressed in various cancer cells, the clinicopathological significance of its expression in non-small cell lung cancer (NSCLC) remains unclear.
METHODS: One hundred and four patients with surgically resected NSCLC were evaluated as one institutional cohort. Tumour sections were stained by immunohistochemistry (IHC) for ASCT2, Ki-67, phospho-mTOR (mammalian target of rapamycin), and CD34 to assess the microvessel density. Two hundred and four patients with NSCLC were also validated by IHC from an independent cohort.
RESULTS: ASC amino-acid transporter 2 was expressed in 66% of patients, and was closely correlated with disease stage, lymphatic permeation, vascular invasion, CD98, cell proliferation, angiogenesis, and mTOR phosphorylation, particularly in patients with adenocarcinoma (AC). Moreover, two independent cohorts confirmed that ASCT2 was an independent marker for poor outcome in AC patients.
CONCLUSIONS: ASC amino-acid transporter 2 expression has a crucial role in the metastasis of pulmonary AC, and is a potential molecular marker for predicting poor prognosis after surgery.

Rowan BG, Gimble JM, Sheng M, et al.
Human adipose tissue-derived stromal/stem cells promote migration and early metastasis of triple negative breast cancer xenografts.
PLoS One. 2014; 9(2):e89595 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Fat grafting is used to restore breast defects after surgical resection of breast tumors. Supplementing fat grafts with adipose tissue-derived stromal/stem cells (ASCs) is proposed to improve the regenerative/restorative ability of the graft and retention. However, long term safety for ASC grafting in proximity of residual breast cancer cells is unknown. The objective of this study was to determine the impact of human ASCs derived from abdominal lipoaspirates of three donors, on a human breast cancer model that exhibits early metastasis.
METHODOLOGY/PRINCIPAL FINDINGS: Human MDA-MB-231 breast cancer cells represents "triple negative" breast cancer that exhibits early micrometastasis to multiple mouse organs [1]. Human ASCs were derived from abdominal adipose tissue from three healthy female donors. Indirect co-culture of MDA-MB-231 cells with ASCs, as well as direct co-culture demonstrated that ASCs had no effect on MDA-MB-231 growth. Indirect co-culture, and ASC conditioned medium (CM) stimulated migration of MDA-MB-231 cells. ASC/RFP cells from two donors co-injected with MDA-MB-231/GFP cells exhibited a donor effect for stimulation of primary tumor xenografts. Both ASC donors stimulated metastasis. ASC/RFP cells were viable, and integrated with MDA-MB-231/GFP cells in the tumor. Tumors from the co-injection group of one ASC donor exhibited elevated vimentin, matrix metalloproteinase-9 (MMP-9), IL-8, VEGF and microvessel density. The co-injection group exhibited visible metastases to the lung/liver and enlarged spleen not evident in mice injected with MDA-MB-231/GFP alone. Quantitation of the total area of GFP fluorescence and human chromosome 17 DNA in mouse organs, H&E stained paraffin sections and fluorescent microscopy confirmed multi-focal metastases to lung/liver/spleen in the co-injection group without evidence of ASC/RFP cells.
CONCLUSIONS: Human ASCs derived from abdominal lipoaspirates of two donors stimulated metastasis of MDA-MB-231 breast tumor xenografts to multiple mouse organs. MDA-MB-231 tumors co-injected with ASCs from one donor exhibited partial EMT, expression of MMP-9, and increased angiogenesis.

Wang ZM
PAX1 methylation analysis by MS-HRM is useful in triage of high-grade squamous intraepithelial lesions.
Asian Pac J Cancer Prev. 2014; 15(2):891-4 [PubMed] Related Publications
This study is aimed to investigate the role of paired boxed gene 1 (PAX1) methylation analysis by methylation- sensitive high-resolution melting (MS-HRM) in the detection of high grade lesions in atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (ASC-H) and compared its performance with the Hybrid Capture 2 (HC2) human papillomavirus (HPV) test. In our study, 130 cases with a diagnosis of ASC-H from the cervical cytological screening by Thinprep cytologic test (TCT) technique were selected for triage. Their cervical scrapings were collected and evaluated by using PAX1 methylation analysis (MS-HRM) and high-risk HPV DNA test (HC2), followed by colposcopy and cervical biopsy. Chi-square test were used to test the differences of PAX1 methylation or HPV infection between groups. In the detection of CIN2+, the sensitivity, specificity, the PPV, NPV and the accuracy of PAX1 MS-HRM assay and high-risk HPV (HR-HPV) tests were respectively 80.6% vs 67.7%, 94.9% vs 54.5%, 83.3%, vs 31.8%, 94.0% vs 84.4%, and 91.5% vs 57.7%. The PAX1 MS-HRM assay proved superior to HR-HPV testing in the detection of high grade lesions (CIN2+) in ASC-H. This approach could screen out the majority of high grade lesion cases of ASC-H, and thus could reduce the referral rate to colposcopy.

Rankeillor KL, Cairns DA, Loughrey C, et al.
Methylation-specific multiplex ligation-dependent probe amplification identifies promoter methylation events associated with survival in glioblastoma.
J Neurooncol. 2014; 117(2):243-51 [PubMed] Related Publications
DNA methylation plays an important role in cancer biology and methylation events are important prognostic and predictive markers in many tumor types. We have used methylation-specific multiplex ligation-dependent probe amplification to survey the methylation status of MGMT and 25 tumor suppressor genes in 73 glioblastoma cases. The data obtained was correlated with overall survival and response to treatment. The study revealed that methylation of promoter regions in TP73 (seven patients), THBS1 (eight patients) and PYCARD (nine patients) was associated with improved outcome, whereas GATA5 (21 patients) and WT1 (24 patients) promoter methylation were associated with poor outcome. In patients treated with temozolomide and radiation MGMT and PYCARD promoter methylation events remained associated with improved survival whereas GATA5 was associated with a poor outcome. The identification of GATA5 promoter methylation in glioblastoma has not previously been reported. Furthermore, a cumulative methylation score separated patients into survival groups better than any single methylation event. In conclusion, we have identified specific methylation events associated with patient outcome and treatment response in glioblastoma, and these may be of functional and predictive/prognostic significance. This study therefore provides novel candidates and approaches for future prospective validation.

Wang Q, Beaumont KA, Otte NJ, et al.
Targeting glutamine transport to suppress melanoma cell growth.
Int J Cancer. 2014; 135(5):1060-71 [PubMed] Related Publications
Amino acids, especially leucine and glutamine, are important for tumor cell growth, survival and metabolism. A range of different transporters deliver each specific amino acid into cells, some of which are increased in cancer. These amino acids consequently activate the mTORC1 pathway and drive cell cycle progression. The leucine transporter LAT1/4F2hc heterodimer assembles as part of a large complex with the glutamine transporter ASCT2 to transport amino acids. In this study, we show that the expression of LAT1 and ASCT2 is significantly increased in human melanoma samples and is present in both BRAF(WT) (C8161 and WM852) and BRAF(V600E) mutant (1205Lu and 451Lu) melanoma cell lines. While inhibition of LAT1 by BCH did not suppress melanoma cell growth, the ASCT2 inhibitor BenSer significantly reduced both leucine and glutamine transport in melanoma cells, leading to inhibition of mTORC1 signaling. Cell proliferation and cell cycle progression were significantly reduced in the presence of BenSer in melanoma cells in 2D and 3D cell culture. This included reduced expression of the cell cycle regulators CDK1 and UBE2C. The importance of ASCT2 expression in melanoma was confirmed by shRNA knockdown, which inhibited glutamine uptake, mTORC1 signaling and cell proliferation. Taken together, our study demonstrates that ASCT2-mediated glutamine transport is a potential therapeutic target for both BRAF(WT) and BRAF(V600E) melanoma.

Bodoor K, Haddad Y, Alkhateeb A, et al.
DNA hypermethylation of cell cycle (p15 and p16) and apoptotic (p14, p53, DAPK and TMS1) genes in peripheral blood of leukemia patients.
Asian Pac J Cancer Prev. 2014; 15(1):75-84 [PubMed] Related Publications
Aberrant DNA methylation of tumor suppressor genes has been reported in all major types of leukemia with potential involvement in the inactivation of regulatory cell cycle and apoptosis genes. However, most of the previous reports did not show the extent of concurrent methylation of multiple genes in the four leukemia types. Here, we analyzed six key genes (p14, p15, p16, p53, DAPK and TMS1) for DNA methylation using methylation specific PCR to analyze peripheral blood of 78 leukemia patients (24 CML, 25 CLL, 12 AML, and 17 ALL) and 24 healthy volunteers. In CML, methylation was detected for p15 (11%), p16 (9%), p53 (23%) and DAPK (23%), in CLL, p14 (25%), p15 (19%), p16 (12%), p53 (17%) and DAPK (36%), in AML, p14 (8%), p15 (45%), p53 (9%) and DAPK (17%) and in ALL, p15 (14%), p16 (8%), and p53 (8%). This study highlighted an essential role of DAPK methylation in chronic leukemia in contrast to p15 methylation in the acute cases, whereas TMS1 hypermethylation was absent in all cases. Furthermore, hypermethylation of multiple genes per patient was observed, with obvious selectiveness in the 9p21 chromosomal region genes (p14, p15 and p16). Interestingly, methylation of p15 increased the risk of methylation in p53, and vice versa, by five folds (p=0.03) indicating possible synergistic epigenetic disruption of different phases of the cell cycle or between the cell cycle and apoptosis. The investigation of multiple relationships between methylated genes might shed light on tumor specific inactivation of the cell cycle and apoptotic pathways.

Earley A, Lamont JL, Dahabreh IJ, et al.
Fluorescence in situ hybridization testing for the diagnosis of high-grade cervical abnormalities: a systematic review.
J Low Genit Tract Dis. 2014; 18(3):218-27 [PubMed] Related Publications
OBJECTIVE: We examined the diagnostic performance of fluorescence in situ hybridization (FISH) tests on cervical cytology for precancerous lesions or cancer on cervical histology.
MATERIALS AND METHODS: A search was conducted in MEDLINE, the Cochrane Central Register of Controlled Trials, and Scopus through September 3, 2013. Eleven studies examined FISH tests for telomerase RNA component gene (TERC), myelocytomatosis oncogene (MYC), or human papillomavirus (HPV) type 16 or 18 in samples exhibiting atypical squamous cells of unknown significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). None examined HPV-positive, cytologically normal samples. We extracted data on the sensitivity and specificity for high-grade cervical intraepithelial neoplasia (CIN 2+ or CIN 3+).
RESULTS: Fluorescence in situ hybridization test probes and thresholds varied across studies. Included populations were convenience samples. Only 1 study testing for TERC specified HPV status. In meta-analysis, FISH for TERC in LSIL (9 studies, 1,082 cases) had a summary sensitivity of 0.76 (95% confidence interval = 0.63-0.85) and a summary specificity of 0.78 (95% confidence interval = 0.57-0.91) for CIN 2+. Fluorescence in situ hybridization for TERC in ASC-US (3 studies, 839 cases) showed sensitivities ranging from 0.75 to 1.00 and specificities from 0.87 to 0.93 for CIN 2+. For CIN 3+, sensitivity and specificity appeared similar, although a small number of studies preclude firm conclusions. For FISH tests for HPV, we found only few studies with small sample sizes.
CONCLUSIONS: The evidence on FISH testing is limited given the small number of studies for each cytology subgroup and the lack of studies in well-defined screening contexts stratifying participants by HPV status.

Knight ER, Patel EY, Flowers CA, et al.
ASC deficiency suppresses proliferation and prevents medulloblastoma incidence.
Oncogene. 2015; 34(3):394-402 [PubMed] Free Access to Full Article Related Publications
Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is silenced by promoter methylation in many types of tumors, yet ASC's role in most cancers remains unknown. Here, we show that ASC is highly expressed in a model of medulloblastoma, the most common malignant pediatric brain cancer; ASC is also expressed in human medulloblastomas. Importantly, while ASC deficiency did not affect normal cerebellar development, ASC knockout mice on the Smoothened (ND2:SmoA1) transgenic model of medulloblastoma exhibited a profound reduction in medulloblastoma incidence and a delayed tumor onset. A similar decrease in tumorigenesis with ASC deficiency was also seen in the hGFAP-Cre:SmoM2 mouse model of medulloblastoma. Interestingly, hyperproliferation of the external granule layer (EGL) was comparable at P20 in both wild-type and ASC-deficient SmoA1 mice. However, while the apoptosis and differentiation markers remained unchanged at this age, proliferation makers were decreased, and the EGL was reduced in thickness and area by P60. This reduction in proliferation with ASC deficiency was also seen in isolated SmoA1 cerebellar granule precursor cells in vitro, indicating that the effect of ASC deletion on proliferation was cell autonomous. Interestingly, ASC-deficient SmoA1 cerebella exhibited disrupted expression of genes in the transforming growth factor-β pathway and increased level of nuclear Smad3. Taken together, these results demonstrate an unexpected role for ASC in Sonic hedgehog-driven medulloblastoma tumorigenesis, thus identifying ASC as a promising novel target for antitumor therapy.

Zolochevska O, Shearer J, Ellis J, et al.
Human adipose-derived mesenchymal stromal cell pigment epithelium-derived factor cytotherapy modifies genetic and epigenetic profiles of prostate cancer cells.
Cytotherapy. 2014; 16(3):346-56 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AIMS: Adipose-derived mesenchymal stromal cells (ASCs) are promising tools for delivery of cytotherapy against cancer. However, ASCs can exert profound effects on biological behavior of tumor cells. Our study aimed to examine the influence of ASCs on gene expression and epigenetic methylation profiles of prostate cancer cells as well as the impact of expressing a therapeutic gene on modifying the interaction between ASCs and prostate cancer cells.
METHODS: ASCs were modified by lentiviral transduction to express either green fluorescent protein as a control or pigment epithelium-derived factor (PEDF) as a therapeutic molecule. PC3 prostate cancer cells were cultured in the presence of ASC culture-conditioned media (CCM), and effects on PC3 or DU145. Ras cells were examined by means of real-time quantitative polymerase chain reaction, EpiTect methyl prostate cancer-focused real-time quantitative polymerase chain reaction arrays, and luciferase reporter assays.
RESULTS: ASCs transduced with lentiviral vectors were able to mediate expression of several tumor-inhibitory genes, some of which correlated with epigenetic methylation changes on cocultured PC3 prostate cancer cells. When PC3 cells were cultured with ASC-PEDF CCM, we observed a shift in the balance of gene expression toward tumor inhibition, which suggests that PEDF reduces the potential tumor-promoting activity of unmodified ASCs.
CONCLUSIONS: These results suggest that ASC-PEDF CCM can promote reprogramming of tumor cells in a paracrine manner. An improved understanding of genetic and epigenetic events in prostate cancer growth in response to PEDF paracrine therapy would enable a more effective use of ASC-PEDF, with the goal of achieving safer yet more potent anti-tumor effects.

McCready J, Arendt LM, Glover E, et al.
Pregnancy-associated breast cancers are driven by differences in adipose stromal cells present during lactation.
Breast Cancer Res. 2014; 16(1):R2 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: The prognosis of breast cancer is strongly influenced by the developmental stage of the breast when the tumor is diagnosed. Pregnancy-associated breast cancers (PABCs), cancers diagnosed during pregnancy, lactation, or in the first postpartum year, are typically found at an advanced stage, are more aggressive and have a poorer prognosis. Although the systemic and microenvironmental changes that occur during post-partum involution have been best recognized for their role in the pathogenesis of PABCs, epidemiological data indicate that PABCs diagnosed during lactation have an overall poorer prognosis than those diagnosed during involution. Thus, the physiologic and/or biological events during lactation may have a significant and unrecognized role in the pathobiology of PABCs.
METHODS: Syngeneic in vivo mouse models of PABC were used to examine the effects of system and stromal factors during pregnancy, lactation and involution on mammary tumorigenesis. Mammary adipose stromal cell (ASC) populations were isolated from mammary glands and examined by using a combination of in vitro and in vivo functional assays, gene expression analysis, and molecular and cellular assays. Specific findings were further investigated by immunohistochemistry in mammary glands of mice as well as in functional studies using ASCs from lactating mammary glands. Additional findings were further investigated using human clinical samples, human stromal cells and using in vivo xenograft assays.
RESULTS: ASCs present during lactation (ASC-Ls), but not during other mammary developmental stages, promote the growth of carcinoma cells and angiogenesis. ASCs-Ls are distinguished by their elevated expression of cellular retinoic acid binding protein-1 (crabp1), which regulates their ability to retain lipid. Human breast carcinoma-associated fibroblasts (CAFs) exhibit traits of ASC-Ls and express crabp1. Inhibition of crabp1in CAFs or in ASC-Ls abolished their tumor-promoting activity and also restored their ability to accumulate lipid.
CONCLUSIONS: These findings imply that (1) PABC is a complex disease, which likely has different etiologies when diagnosed during different stages of pregnancy; (2) both systemic and local factors are important for the pathobiology of PABCs; and (3) the stromal changes during lactation play a distinct and important role in the etiology and pathogenesis of PABCs that differ from those during post-lactational involution.

Mather JP, Roberts PE, Pan Z, et al.
Isolation of cancer stem like cells from human adenosquamous carcinoma of the lung supports a monoclonal origin from a multipotential tissue stem cell.
PLoS One. 2013; 8(12):e79456 [PubMed] Free Access to Full Article Related Publications
There is increasing evidence that many solid tumors are hierarchically organized with the bulk tumor cells having limited replication potential, but are sustained by a stem-like cell that perpetuates the tumor. These cancer stem cells have been hypothesized to originate from transformation of adult tissue stem cells, or through re-acquisition of stem-like properties by progenitor cells. Adenosquamous carcinoma (ASC) is an aggressive type of lung cancer that contains a mixture of cells with squamous (cytokeratin 5+) and adenocarcinoma (cytokeratin 7+) phenotypes. The origin of these mixtures is unclear as squamous carcinomas are thought to arise from basal cells in the upper respiratory tract while adenocarcinomas are believed to form from stem cells in the bronchial alveolar junction. We have isolated and characterized cancer stem-like populations from ASC through application of selective defined culture medium initially used to grow human lung stem cells. Homogeneous cells selected from ASC tumor specimens were stably expanded in vitro. Primary xenografts and metastatic lesions derived from these cells in NSG mice fully recapitulate both the adenocarcinoma and squamous features of the patient tumor. Interestingly, while the CSLC all co-expressed cytokeratins 5 and 7, most xenograft cells expressed either one, or neither, with <10% remaining double positive. We also demonstrated the potential of the CSLC to differentiate to multi-lineage structures with branching lung morphology expressing bronchial, alveolar and neuroendocrine markers in vitro. Taken together the properties of these ASC-derived CSLC suggests that ASC may arise from a primitive lung stem cell distinct from the bronchial-alveolar or basal stem cells.

Sugiyama R, Agematsu K, Migita K, et al.
Defect of suppression of inflammasome-independent interleukin-8 secretion from SW982 synovial sarcoma cells by familial Mediterranean fever-derived pyrin mutations.
Mol Biol Rep. 2014; 41(1):545-53 [PubMed] Related Publications
Familial Mediterranean fever (FMF) is a recessive inherited autoinflammatory syndrome. Patients with FMF have symptoms such as recurrent fever and abdominal pain, sometimes accompanied by arthralgia. Biopsy specimens have revealed substantial neutrophil infiltration into synovia. FMF patients have a mutation in the Mediterranean fever gene, encoding pyrin, which is known to regulate the inflammasome, a platform for processing interleukin (IL)-1β. FMF patients heterozygous for E148Q mutation, heterozygous for M694I mutation, or combined heterozygous for E148Q and M694I mutations, which were found to be major mutations in an FMF study group in Japan, suffer from arthritis, the severity of which is likely to be lower than in FMF patients with M694V mutations. Expression plasmids of wild-type (WT) pyrin and mutated pyrin, such as E148Q, M694I, M694V, and E148Q+M694I, were constructed, and SW982 synovial sarcoma cells were transfected with these expression plasmids. IL-8 and IL-6 were spontaneously secreted from the culture supernatant of SW982 cells without any stimulation, whereas IL-1β and TNF-α could not be detected even when stimulated with lipopolysaccharide. Notably, two inflammasome components, ASC and caspase-1, could not be detected in SW982 cells by Western blotting. IL-8 but not IL-6 secretion from SW982 cells was largely suppressed by WT pyrin, but less suppressed by mutated pyrin, which appeared to become weaker in the order of E148Q, M694I, E148Q+M694I, and M694V mutations. As for IL-8 and IL-6, similar results were obtained using stable THP-1 cells expressing the WT pyrin or mutated pyrins, such as M694V or E148Q, when stimulated by LPS. In addition, IL-8 secretion from mononuclear cells of FMF patients was significantly higher than that of healthy volunteers when incubated on a culture plate. Thus, our results suggest that IL-8 secretion from SW982 synovial sarcoma cells suppressed by pyrin independently of inflammasome is affected by pyrin mutations, which may reflect the activity in FMF arthritis.

Nowicka A, Marini FC, Solley TN, et al.
Human omental-derived adipose stem cells increase ovarian cancer proliferation, migration, and chemoresistance.
PLoS One. 2013; 8(12):e81859 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: Adipose tissue contains a population of multipotent adipose stem cells (ASCs) that form tumor stroma and can promote tumor progression. Given the high rate of ovarian cancer metastasis to the omental adipose, we hypothesized that omental-derived ASC may contribute to ovarian cancer growth and dissemination.
MATERIALS AND METHODS: We isolated ASCs from the omentum of three patients with ovarian cancer, with (O-ASC4, O-ASC5) and without (O-ASC1) omental metastasis. BM-MSCs, SQ-ASCs, O-ASCs were characterized with gene expression arrays and metabolic analysis. Stromal cells effects on ovarian cancer cells proliferation, chemoresistance and radiation resistance was evaluated using co-culture assays with luciferase-labeled human ovarian cancer cell lines. Transwell migration assays were performed with conditioned media from O-ASCs and control cell lines. SKOV3 cells were intraperitionally injected with or without O-ASC1 to track in-vivo engraftment.
RESULTS: O-ASCs significantly promoted in vitro proliferation, migration chemotherapy and radiation response of ovarian cancer cell lines. O-ASC4 had more marked effects on migration and chemotherapy response on OVCA 429 and OVCA 433 cells than O-ASC1. Analysis of microarray data revealed that O-ASC4 and O-ASC5 have similar gene expression profiles, in contrast to O-ASC1, which was more similar to BM-MSCs and subcutaneous ASCs in hierarchical clustering. Human O-ASCs were detected in the stroma of human ovarian cancer murine xenografts but not uninvolved ovaries.
CONCLUSIONS: ASCs derived from the human omentum can promote ovarian cancer proliferation, migration, chemoresistance and radiation resistance in-vitro. Furthermore, clinical O-ASCs isolates demonstrate heterogenous effects on ovarian cancer in-vitro.

Melson J, Li Y, Cassinotti E, et al.
Commonality and differences of methylation signatures in the plasma of patients with pancreatic cancer and colorectal cancer.
Int J Cancer. 2014; 134(11):2656-62 [PubMed] Related Publications
Profiling of DNA methylation status of specific genes is a way to screen for colorectal cancer (CRC) and pancreatic cancer (PC) in blood. The commonality of methylation status of cancer-related tumor suppressor genes between CRC and PC is largely unknown. Methylation status of 56 cancer-related genes was compared in plasma of patients in the following cohorts: CRC, PC and healthy controls. Cross validation determined the best model by area under ROC curve (AUC) to differentiate cancer methylation profiles from controls. Optimal preferential gene methylation signatures were derived to differentiate either cancer (CRC or PC) from controls. For CRC alone, a three gene signature (CYCD2, HIC and VHL) had an AUC 0.9310, sensitivity (Sens) = 0.826, specificity (Spec) = 0.9383. For PC alone, an optimal signature consisted of five genes (VHL, MYF3, TMS, GPC3 and SRBC), AUC 0.848; Sens = 0.807, Spec = 0.666. Combined PC and CRC signature or "combined cancer signature" was derived to differentiate either CRC and PC from controls (MDR1, SRBC, VHL, MUC2, RB1, SYK and GPC3) AUC = 0.8177, Sens = 0.6316 Spec = 0.840. In a validation cohort, N = 10 CRC patients, the optimal CRC signature (CYCD2, HIC and VHL) had AUC 0.900. In all derived signatures (CRC, PC and combined cancer signature) the optimal panel used preferential VHL methylation. In conclusion, CRC and PC differ in specific genes methylated in plasma other than VHL. Preferential methylation of VHL is shared in the optimal signature for CRC alone, PC alone and combined PC and CRC. Future investigations may identify additional methylation markers informative for the presence of both CRC and PC.

Leclerc D, Lévesque N, Cao Y, et al.
Genes with aberrant expression in murine preneoplastic intestine show epigenetic and expression changes in normal mucosa of colon cancer patients.
Cancer Prev Res (Phila). 2013; 6(11):1171-81 [PubMed] Related Publications
An understanding of early genetic/epigenetic changes in colorectal cancer would aid in diagnosis and prognosis. To identify these changes in human preneoplastic tissue, we first studied our mouse model in which Mthfr⁺/⁻ BALB/c mice fed folate-deficient diets develop intestinal tumors in contrast to Mthfr⁺/⁺ BALB/c mice fed control diets. Transcriptome profiling was performed in normal intestine from mice with low or high tumor susceptibility. We identified 12 upregulated and 51 downregulated genes in tumor-prone mice. Affected pathways included retinoid acid synthesis, lipid and glucose metabolism, apoptosis and inflammation. We compared murine candidates from this microarray analysis, and murine candidates from an earlier strain-based comparison, with a set of human genes that we had identified in previous methylome profiling of normal human colonic mucosa, from colorectal cancer patients and controls. From the extensive list of human methylome candidates, our approach uncovered five orthologous genes that had shown changes in murine expression profiles (PDK4, SPRR1A, SPRR2A, NR1H4, and PYCARD). The human orthologs were assayed by bisulfite-pyrosequencing for methylation at 14 CpGs. All CpGs exhibited significant methylation differences in normal mucosa between colorectal cancer patients and controls; expression differences for these genes were also observed. PYCARD and NR1H4 methylation differences showed promise as markers for presence of polyps in controls. We conclude that common pathways are disturbed in preneoplastic intestine in our animal model and morphologically normal mucosa of patients with colorectal cancer, and present an initial version of a DNA methylation-based signature for human preneoplastic colon.

Yang ZL, Yang L, Zou Q, et al.
Positive ALDH1A3 and negative GPX3 expressions are biomarkers for poor prognosis of gallbladder cancer.
Dis Markers. 2013; 35(3):163-72 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gallbladder cancers (GBCs) are highly aggressive cancers with high mortality. However, biological markers for the progression and prognosis of GBC are currently unavailable in the clinic.
OBJECTIVE: To identify biomarkers for predicting GBC metastasis and prognosis.
METHODS: We examined ALDH1A3 and GPX3 expressions in 46 squamous cell/adenosquamous carcinomas (SC/ASC) and 80 adenocarcinomas (AC) by using immunohistochemistry.
RESULTS: Positive ALDH1A3 and negative GPX3 expressions were significantly associated with lymph node metastasis and invasion of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that either positive ALDH1A3 (P < 0.001) or negative GPX3 (P < 0.001) expression significantly correlated with decreased overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive ALDH1A3 expression or negative GPX3 expression was an independent poor-prognostic predictor in both SC/ASC and AC patients.
CONCLUSIONS: Our study suggested that positive ALDH1A3 and negative GPX3 expressions are closely associated with clinical pathological behaviors and poor prognosis of gallbladder cancer.

Feierabend D, Walter J, Grube S, et al.
Methylation-specific multiplex ligation-dependent probe amplification and its impact on clinical findings in medulloblastoma.
J Neurooncol. 2014; 116(2):213-20 [PubMed] Related Publications
Gain of (proto-)oncogenes and loss or promoter hypermethylation of tumor suppressor genes (TSGs) play essential roles in tumorigenesis. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) allows simultaneous detection of both these alterations. MS-MLPA was performed on 20 medulloblastoma samples (n = 12 cryoconserved; n = 8 formalin-fixed paraffin-embedded, FFPE) in order to screen for copy number changes in 77 unselected TSGs and (proto-)oncogenes as well as for promoter hypermethylation in a subset of 33 TSGs. In all specimens, determination of promoter methylation status was possible, whereas robust data concerning copy number changes could be obtained on cryopreserved material only. We found a median of 1.5 deletions and 6.5 amplifications in the 12 cryopreserved medulloblastoma and a median of 5 promoter hypermethylation per tumor. Frequent copy number changes included amplification of ASC on 16p12 (5/12) and amplification of several adjacent genes on 17q (3/12) including IGFBP4. Hypermethylation of MSH6 on 2p16 was found in 16 samples. MS-MLPA findings were also correlated with clinical and histological characteristics. The number of promoter hypermethylation was significantly associated with presence of necrosis (p = 0.004). Tumors which recurred within 1 year were more likely to show amplification of the GATA5 gene (p = 0.038), while hypermethylation of CASP8 was associated with a lower tumor recurrence rate (p = 0.036). There was also a trend towards a correlation between total number of aberrations and CSF dissemination (p = 0.055). Our findings confirm frequent presence of certain aberrations and reveal novel candidates for improving prognosis based on genetic and epigenetic tumor features. A medulloblastoma-specific MS-MLPA probe set seems a potentially valuable tool for further investigations on larger sample series.

Mainberger F, Jung NH, Zenker M, et al.
Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1.
BMC Neurol. 2013; 13:131 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders causing learning disabilities by mutations in the neurofibromin gene, an important inhibitor of the RAS pathway. In a mouse model of NF1, a loss of function mutation of the neurofibromin gene resulted in increased gamma aminobutyric acid (GABA)-mediated inhibition which led to decreased synaptic plasticity and deficits in attentional performance. Most importantly, these defictis were normalized by lovastatin. This placebo-controlled, double blind, randomized study aimed to investigate synaptic plasticity and cognition in humans with NF1 and tried to answer the question whether potential deficits may be rescued by lovastatin.
METHODS: In NF1 patients (n = 11; 19-44 years) and healthy controls (HC; n = 11; 19-31 years) paired pulse transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (paired pulse) and synaptic plasticity (paired associative stimulation). On behavioural level the Test of Attentional Performance (TAP) was used. To study the effect of 200 mg lovastatin for 4 days on all these parameters, a placebo-controlled, double blind, randomized trial was performed.
RESULTS: In patients with NF1, lovastatin revealed significant decrease of intracortical inhibition, significant increase of synaptic plasticity as well as significant increase of phasic alertness. Compared to HC, patients with NF1 exposed increased intracortical inhibition, impaired synaptic plasticity and deficits in phasic alertness.
CONCLUSIONS: This study demonstrates, for the first time, a link between a pathological RAS pathway activity, intracortical inhibition and impaired synaptic plasticity and its rescue by lovastatin in humans. Our findings revealed mechanisms of attention disorders in humans with NF1 and support the idea of a potential clinical benefit of lovastatin as a therapeutic option.

Orecchioni S, Gregato G, Martin-Padura I, et al.
Complementary populations of human adipose CD34+ progenitor cells promote growth, angiogenesis, and metastasis of breast cancer.
Cancer Res. 2013; 73(19):5880-91 [PubMed] Related Publications
Obesity is associated with an increased frequency, morbidity, and mortality of several types of neoplastic diseases, including postmenopausal breast cancer. We found that human adipose tissue contains two populations of progenitors with cooperative roles in breast cancer. CD45(-)CD34(+)CD31(+)CD13(-)CCRL2(+) endothelial cells can generate mature endothelial cells and capillaries. Their cancer-promoting effect in the breast was limited in the absence of CD45(-)CD34(+)CD31(-)CD13(+)CD140b(+) mesenchymal progenitors/adipose stromal cells (ASC), which generated pericytes and were more efficient than endothelial cells in promoting local tumor growth. Both endothelial cells and ASCs induced epithelial-to-mesenchymal transition (EMT) gene expression in luminal breast cancer cells. Endothelial cells (but not ASCs) migrated to lymph nodes and to contralateral nascent breast cancer lesions where they generated new vessels. In vitro and in vivo, endothelial cells were more efficient than ASCs in promoting tumor migration and in inducing metastases. Granulocyte colony-stimulating factor (G-CSF) effectively mobilized endothelial cells (but not ASCs), and the addition of chemotherapy and/or of CXCR4 inhibitors did not increase endothelial cell or ASC blood mobilization. Our findings suggest that adipose tissue progenitor cells cooperate in driving progression and metastatic spread of breast cancer.

Ponomareva L, Liu H, Duan X, et al.
AIM2, an IFN-inducible cytosolic DNA sensor, in the development of benign prostate hyperplasia and prostate cancer.
Mol Cancer Res. 2013; 11(10):1193-202 [PubMed] Related Publications
UNLABELLED: Close links have been noted between chronic inflammation of the prostate and the development of human prostatic diseases such as benign prostate hyperplasia (BPH) and prostate cancer. However, the molecular mechanisms that contribute to prostatic inflammation remain largely unexplored. Recent studies have indicated that the IFN-inducible AIM2 protein is a cytosolic DNA sensor in macrophages and keratinocytes. Upon sensing DNA, AIM2 recruits the adaptor ASC and pro-CASP1 to assemble the AIM2 inflammasome. Activation of the AIM2 inflammasome cleaves pro-interleukin (IL)-1β and pro-IL-18 and promotes the secretion of IL-1β and IL-18 proinflammatory cytokines. Given that human prostatic infections are associated with chronic inflammation, the development of BPH is associated with an accumulation of senescent cells with a proinflammatory phenotype, and the development of prostate cancer is associated with the loss of IFN signaling, the role of AIM2 in mediating the formation of prostatic diseases was investigated. It was determined that IFNs (α, β, or γ) induced AIM2 expression in human prostate epithelial cells and cytosolic DNA activated the AIM2 inflammasome. Steady-state levels of the AIM2 mRNA were higher in BPH than in normal prostate tissue. However, the levels of AIM2 mRNA were significantly lower in clinical tumor specimens. Accordingly, constitutive levels of AIM2 mRNA and protein were lower in a subset of prostate cancer cells as compared with BPH cells. Further, the cytosolic DNA activated the AIM2 inflammasome in the androgen receptor-negative PC3 prostate cancer cell line, suggesting that AIM2-mediated events are independent of androgen receptor status.
IMPLICATIONS: The AIM2 inflammasome has a fundamental role in the generation of human prostatic diseases.

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