ADAMTS1

Gene Summary

Gene:ADAMTS1; ADAM metallopeptidase with thrombospondin type 1 motif, 1
Aliases: C3-C5, METH1
Location:21q21.2
Summary:This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The protein encoded by this gene contains two disintegrin loops and three C-terminal TS motifs and has anti-angiogenic activity. The expression of this gene may be associated with various inflammatory processes as well as development of cancer cachexia. This gene is likely to be necessary for normal growth, fertility, and organ morphology and function. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:A disintegrin and metalloproteinase with thrombospondin motifs 1
HPRD
Source:NCBIAccessed: 20 August, 2015

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 20 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 20 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: ADAMTS1 (cancer-related)

Kara M, Yumrutas O, Ozcan O, et al.
Differential expressions of cancer-associated genes and their regulatory miRNAs in colorectal carcinoma.
Gene. 2015; 567(1):81-6 [PubMed] Related Publications
Colorectal cancer is one of the frequently seen malignancies in the world. To date, several oncogenes and tumor suppressor genes have been identified and linked to colorectal cancer pathogenesis. Although recent advances in the diagnosis and therapy of colorectal cancer are promising, identifying novel genetic contributors is still high priority. In the present study, expression profile of some cancer-related genes and their regulatory miRNA molecules were evaluated by using a high-throughput real-time PCR method. For the study, a total of 54 patients diagnosed with CRC and normal colon tissue samples of 42 healthy controls were included. For the expression analysis, total RNA was extracted from FFPE tissue samples and converted to cDNA. All expression analyses were assessed by using Fluidigm Microfluidic Dynamic Array chips for 96 samples and the reactions were held in Fluidigm BioMark™ HD System Real-Time PCR. As a result of the study, expression of the ADAMTS1, FHIT, RUNX1, RUNX3 and WWOX genes was shown to be significantly altered in CRC tissues in contrast to normal tissue samples. Moreover, miR-378a-3p, miR-155-5p, miR-193b-3p, miR-96-5p, miR-17-5p, miR-27a-3p, miR-133b, miR-203a, miR-205-5p, miR-34c-5p, miR-130a-3p, miR-301a-3p, miR-132-3p, miR-222-3p, miR-34a-5p, miR-21-5p, miR-29a-3p and miR-29b-3p were found to be significantly deregulated in CRC. Consequently, results of the current study strongly suggest the involvement of novel cancer-related genes and their regulatory miRNAs in CRC physiopathology.

Junes-Gill KS, Lawrence CE, Wheeler CJ, et al.
Human Hematopoietic Signal peptide-containing Secreted 1 (hHSS1) modulates genes and pathways in glioma: implications for the regulation of tumorigenicity and angiogenesis.
BMC Cancer. 2014; 14:920 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Human Hematopoietic Signal peptide-containing Secreted 1 (hHSS1) is a truly novel protein, defining a new class of secreted factors. We have previously reported that ectopic overexpression of hHSS1 has a negative modulatory effect on cell proliferation and tumorigenesis in glioblastoma model systems. Here we have used microarray analysis, screened glioblastoma samples in The Cancer Genome Atlas (TCGA), and studied the effects of hHSS1 on glioma-derived cells and endothelial cells to elucidate the molecular mechanisms underlying the anti-tumorigenic effects of hHSS1.
METHODS: Gene expression profiling of human glioma U87 and A172 cells overexpressing hHSS1 was performed. Ingenuity® iReport™ and Ingenuity Pathway Analysis (IPA) were used to analyze the gene expression in the glioma cells. DNA content and cell cycle analysis were performed by FACS, while cell migration, cell invasion, and effects of hHSS1 on HUVEC tube formation were determined by transwell and matrigel assays. Correlation was made between hHSS1 expression and specific genes in glioblastoma samples in the TCGA database.
RESULTS: We have clarified the signaling and metabolic pathways (i.e. role of BRCA1 in DNA damage response), networks (i.e. cell cycle) and biological processes (i.e. cell division process of chromosomes) that result from hHSS1effects upon glioblastoma growth. U87-overexpressing hHSS1 significantly decreased the number of cells in the G0/G1 cell cycle phase, and significantly increased cells in the S and G2/M phases (P < 0.05). U87-overexpressing hHSS1 significantly lost their ability to migrate (P < 0.001) and to invade (P < 0.01) through matrigel matrix. hHSS1-overexpression significantly decreased migration of A172 cells (P < 0.001), inhibited A172 tumor-induced migration and invasion of HUVECs (P < 0.001), and significantly inhibited U87 tumor-induced invasion of HUVECs (P < 0.001). Purified hHSS1 protein inhibited HUVEC tube formation. TCGA database revealed significant correlation between hHSS1 and BRCA2 (r = -0.224, P < 0.0005), ADAMTS1 (r = -0.132, P <0.01) and endostatin (r = 0.141, P < 0.005).
CONCLUSIONS: hHSS1-overexpression modulates signaling pathways involved in tumorigenesis. hHSS1 inhibits glioma-induced cell cycle progression, cell migration, invasion and angiogenesis. Our data suggest that hHSS1 is a potential therapeutic for malignant glioblastoma possessing significant antitumor and anti-angiogenic activity.

Le Bras GF, Taylor C, Koumangoye RB, et al.
TGFβ loss activates ADAMTS-1-mediated EGF-dependent invasion in a model of esophageal cell invasion.
Exp Cell Res. 2015; 330(1):29-42 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
The TGFβ signaling pathway is essential to epithelial homeostasis and is often inhibited during progression of esophageal squamous cell carcinoma. Recently, an important role for TGFβ signaling has been described in the crosstalk between epithelial and stromal cells regulating squamous tumor cell invasion in mouse models of head-and-neck squamous cell carcinoma (HNSCC). Loss of TGFβ signaling, in either compartment, leads to HNSCC however, the mechanisms involved are not well understood. Using organotypic reconstruct cultures (OTC) to model the interaction between epithelial and stromal cells that occur in dysplastic lesions, we show that loss of TGFβ signaling promotes an invasive phenotype in both fibroblast and epithelial compartments. Employing immortalized esophageal keratinocytes established to reproduce common mutations of esophageal squamous cell carcinoma, we show that treatment of OTC with inhibitors of TGFβ signaling (A83-01 or SB431542) enhances invasion of epithelial cells into a fibroblast-embedded Matrigel/collagen I matrix. Invasion induced by A83-01 is independent of proliferation but relies on protease activity and expression of ADAMTS-1 and can be altered by matrix density. This invasion was associated with increased expression of pro-inflammatory cytokines, IL1 and EGFR ligands HB-EGF and TGFα. Altering EGF signaling prevented or induced epithelial cell invasion in this model. Loss of expression of the TGFβ target gene ROBO1 suggested that chemorepulsion may regulate keratinocyte invasion. Taken together, our data show increased invasion through inhibition of TGFβ signaling altered epithelial-fibroblasts interactions, repressing markers of activated fibroblasts, and altering integrin-fibronectin interactions. These results suggest that inhibition of TGFβ signaling modulates an array of pathways that combined promote multiple aspects of tumor invasion.

Rösner T, Lohse S, Peipp M, et al.
Epidermal growth factor receptor targeting IgG3 triggers complement-mediated lysis of decay-accelerating factor expressing tumor cells through the alternative pathway amplification loop.
J Immunol. 2014; 193(3):1485-95 [PubMed] Related Publications
Binding of C1q to target-bound IgG initiates complement-mediated lysis (CML) of pathogens, as well as of malignant or apoptotic cells, and thus constitutes an integral part of the innate immune system. Despite its prominent molecular flexibility and higher C1q binding affinity compared with human IgG1, IgG3 does not consistently promote superior CML. Hence the aim of this study was to investigate underlying molecular mechanisms of IgG1- and IgG3-driven complement activation using isotype variants of the therapeutic epidermal growth factor receptor (EGFR) Ab cetuximab. Both IgG1 and IgG3 Abs demonstrated similar EGFR binding and similar efficiency in Fab-mediated effector mechanisms. Whereas anti-EGFR-IgG1 did not promote CML of investigated target cells, anti-EGFR-IgG3 triggered significant CML of some, but not all tested cell lines. CML triggered by anti-EGFR-IgG3 negatively correlated with expression levels of the membrane-bound complement regulatory proteins CD55 and CD59, but not CD46. Notably, anti-EGFR-IgG3 promoted strong C1q and C3b, but relatively low C4b and C5b-9 deposition on analyzed cell lines. Furthermore, anti-EGFR-IgG3 triggered C4a release on all cells but failed to induce C3a and C5a release on CD55/CD59 highly expressing cells. RNA interference-induced knockdown or overexpression of membrane-bound complement regulatory proteins revealed CD55 expression to be a pivotal determinant of anti-EGFR-IgG3-triggered CML and to force a switch from classical complement pathway activation to C1q-dependent alternative pathway amplification. Together, these data suggest human anti-EGFR-IgG3, although highly reactive with C1q, to weakly promote assembly of the classical C3 convertase that is further suppressed in the presence of CD55, forcing human IgG3 to act mainly through the alternative pathway.

Martino-Echarri E, Fernández-Rodríguez R, Bech-Serra JJ, et al.
Relevance of IGFBP2 proteolysis in glioma and contribution of the extracellular protease ADAMTS1.
Oncotarget. 2014; 5(12):4295-304 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Expression of IGFBP2 (Insulin-like Growth Factor Binding Protein 2) has been positively correlated with glioma progression. Although the proteolysis of IGFBP2 has been widely recognized, with consequences as a major modulator of IGFII signaling, the relevance of this post-translational modification has not been well studied in tumors. Using an in vivo proteomic approach by Isotope-Coded Protein Label (ICPL), we identified IGFBP2 as a target of the extracellular protease ADAMTS1 (A Disintegrin And Metalloproteinase with ThromboSpondin motifs 1). Notably, the proteolytic pattern of IGFBP2 was also detected in human glioma culture cells and, more importantly, in all glioma samples evaluated. In addition, high expression of ADAMTS1 correlates with higher levels of cleaved IGFBP2 in glioblastoma multiforme cases. Using gene expression public databases, we confirmed that IGFBP2 is a poor prognosis marker for gliomas, and we also observed an important contribution of ADAMTS1.Finally, we showed the impact of ADAMTS1 on IGFII-mediated IGF1R phosphorylation and cellular migration. Our results support a functional interaction between IGFBP2 and ADAMTS1 and suggest the need to evaluate post-translational modifications of IGFBP2 in glioma, in order to approach new therapies.

Hollern DP, Honeysett J, Cardiff RD, Andrechek ER
The E2F transcription factors regulate tumor development and metastasis in a mouse model of metastatic breast cancer.
Mol Cell Biol. 2014; 34(17):3229-43 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
While the E2F transcription factors (E2Fs) have a clearly defined role in cell cycle control, recent work has uncovered new functions. Using genomic signature methods, we predicted a role for the activator E2F transcription factors in the mouse mammary tumor virus (MMTV)-polyomavirus middle T oncoprotein (PyMT) mouse model of metastatic breast cancer. To genetically test the hypothesis that the E2Fs function to regulate tumor development and metastasis, we interbred MMTV-PyMT mice with E2F1, E2F2, or E2F3 knockout mice. With the ablation of individual E2Fs, we noted alterations of tumor latency, histology, and vasculature. Interestingly, we noted striking reductions in metastatic capacity and in the number of circulating tumor cells in both the E2F1 and E2F2 knockout backgrounds. Investigating E2F target genes that mediate metastasis, we found that E2F loss led to decreased levels of vascular endothelial growth factor (Vegfa), Bmp4, Cyr61, Nupr1, Plod 2, P4ha1, Adamts1, Lgals3, and Angpt2. These gene expression changes indicate that the E2Fs control the expression of genes critical to angiogenesis, the remodeling of the extracellular matrix, tumor cell survival, and tumor cell interactions with vascular endothelial cells that facilitate metastasis to the lungs. Taken together, these results reveal that the E2F transcription factors play key roles in mediating tumor development and metastasis in addition to their well-characterized roles in cell cycle control.

Lee SY, Lee HS, Gil M, et al.
Differential expression patterns of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) -1, -4, -5, and -14 in human placenta and gestational trophoblastic diseases.
Arch Pathol Lab Med. 2014; 138(5):643-50 [PubMed] Related Publications
CONTEXT: The ability of intermediate trophoblasts to invade maternal tissue during placentation depends on how well they can degrade the extracellular matrix. Invasion into the extracellular matrix requires many complex proteases. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is a novel family of secreted metalloproteinases. The ADAMTS-1, -4, -5, and -14 subtypes are known to be expressed in human placenta, but little is understood about their expression patterns.
OBJECTIVE: To examine the expression patterns of ADAMTS-1, -4, -5, and -14 in specific human placenta cell types during gestation and in gestational trophoblastic diseases.
DESIGN: Placental tissues were obtained from 25 pregnant women and 21 cases of gestational trophoblastic diseases (10 early complete moles, 3 placental site trophoblastic tumors, 4 invasive moles, and 4 choriocarcinomas). The expression of the 4 ADAMTS was analyzed by immunohistochemistry.
RESULTS: ADAMTS-1, -4, -5, and -14 were differentially expressed by the human placenta throughout gestation in a time-specific and cell type-specific manner, as well as in gestational trophoblastic diseases. ADAMTS-1 showed gradually strong staining intensity in gestational trophoblastic diseases according to the invasive potential but showed consistent strong intensity throughout normal placenta. ADAMTS-4 and ADAMTS-5 exhibited higher and restricted expression in first-trimester intermediate trophoblasts. They also exhibited comparably strong expression in gestational trophoblastic diseases. However, ADAMTS-14 expression remained unchanged throughout gestation.
CONCLUSIONS: The restricted expression pattern of ADAMTS-4 and ADAMTS-5 and their increased expression in gestational trophoblastic diseases suggest that these 2 ADAMTS subtypes are associated with a biological phenotype of trophoblasts involved in human placentation and the development of gestational trophoblastic diseases.

Dallaglio K, Bruno A, Cantelmo AR, et al.
Paradoxic effects of metformin on endothelial cells and angiogenesis.
Carcinogenesis. 2014; 35(5):1055-66 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
The biguanide metformin is used in type 2 diabetes management and has gained significant attention as a potential cancer preventive agent. Angioprevention represents a mechanism of chemoprevention, yet conflicting data concerning the antiangiogenic action of metformin have emerged. Here, we clarify some of the contradictory effects of metformin on endothelial cells and angiogenesis, using in vitro and in vivo assays combined with transcriptomic and protein array approaches. Metformin inhibits formation of capillary-like networks by endothelial cells; this effect is partially dependent on the energy sensor adenosine-monophosphate-activated protein kinase (AMPK) as shown by small interfering RNA knockdown. Gene expression profiling of human umbilical vein endothelial cells revealed a paradoxical modulation of several angiogenesis-associated genes and proteins by metformin, with short-term induction of vascular endothelial growth factor (VEGF), cyclooxygenase 2 and CXC chemokine receptor 4 at the messenger RNA level and downregulation of ADAMTS1. Antibody array analysis shows an essentially opposite regulation of numerous angiogenesis-associated proteins in endothelial and breast cancer cells including interleukin-8, angiogenin and TIMP-1, as well as selective regulation of angiopioetin-1, -2, endoglin and others. Endothelial cell production of the cytochrome P450 member CYP1B1 is upregulated by tumor cell supernatants in an AMPK-dependent manner, metformin blocks this effect. Metformin inhibits VEGF-dependent activation of extracellular signal-regulated kinase 1/2, and the inhibition of AMPK activity abrogates this event. Metformin hinders angiogenesis in matrigel pellets in vivo, prevents the microvessel density increase observed in obese mice on a high-fat diet, downregulating the number of white adipose tissue endothelial precursor cells. Our data show that metformin has an antiangiogenic activity in vitro and in vivo associated with a contradictory short-term enhancement of pro-angiogenic mediators, as well as with a differential regulation in endothelial and breast cancer cells.

Prasad NB, Fischer AC, Chuang AY, et al.
Differential expression of degradome components in cutaneous squamous cell carcinomas.
Mod Pathol. 2014; 27(7):945-57 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Although the cure rate for cutaneous squamous cell carcinoma is high, the diverse spectrum of squamous cell carcinoma has made it difficult for early diagnosis, particularly the aggressive tumors that are highly associated with mortality. Therefore, molecular markers are needed as an adjunct to current staging methods for diagnosing high-risk lesions, and stratifying those patients with aggressive tumors. To identify such biomarkers, we have examined a comprehensive set of 200 histologically defined squamous cell carcinoma and normal skin samples by using a combination of microarray, QRT-PCR and immunohistochemistry analyses. A characteristic and distinguishable profile including matrix metalloproteinase (MMP) as well as other degradome components was differentially expressed in squamous cell carcinoma compared with normal skin samples. The expression levels of some of these genes including matrix metallopeptidase 1 (MMP1), matrix metallopeptidase 10 (MMP10), parathyroid hormone-like hormone (PTHLH), cyclin-dependent kinase inhibitor 2A (CDKN2A), A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1), FBJ osteosarcoma oncogene (FOS), interleukin 6 (IL6) and reversion-inducing-cysteine-rich protein with kazal motifs (RECK) were significantly differentially expressed (P≤0.02) in squamous cell carcinoma compared with normal skin. Furthermore, based on receiver operating characteristic analyses, the mRNA and protein levels of MMP1 are significantly higher in aggressive tumors compared with non-aggressive tumors. Given that MMPs represent the most prominent family of proteinases associated with tumorigenesis, we believe that they may have an important role in modulating the tumor microenvironment of squamous cell carcinoma.

Yi JM, Guzzetta AA, Bailey VJ, et al.
Novel methylation biomarker panel for the early detection of pancreatic cancer.
Clin Cancer Res. 2013; 19(23):6544-55 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
PURPOSE: Pancreatic cancer is the fourth leading cause of cancer deaths and there currently is no reliable modality for the early detection of this disease. Here, we identify cancer-specific promoter DNA methylation of BNC1 and ADAMTS1 as a promising biomarker detection strategy meriting investigation in pancreatic cancer.
EXPERIMENTAL DESIGN: We used a genome-wide pharmacologic transcriptome approach to identify novel cancer-specific DNA methylation alterations in pancreatic cancer cell lines. Of eight promising genes, we focused our studies on BNC1 and ADAMTS1 for further downstream analysis, including methylation and expression. We used a nanoparticle-enabled methylation on beads (MOB) technology to detect early-stage pancreatic cancers by analyzing DNA methylation in patient serum.
RESULTS: We identified two novel genes, BNC1 (92%) and ADAMTS1 (68%), that showed a high frequency of methylation in pancreatic cancers (n = 143), up to 100% in PanIN-3 and 97% in stage I invasive cancers. Using the nanoparticle-enabled MOB technology, these alterations could be detected in serum samples (n = 42) from patients with pancreatic cancer, with a sensitivity for BNC1 of 79% [95% confidence interval (CI), 66%-91%] and for ADAMTS1 of 48% (95% CI, 33%-63%), whereas specificity was 89% for BNC1 (95% CI, 76%-100%) and 92% for ADAMTS1 (95% CI, 82%-100%). Overall sensitivity using both markers is 81% (95% CI, 69%-93%) and specificity is 85% (95% CI, 71%-99%).
CONCLUSIONS: Promoter DNA methylation of BNC1 and ADAMTS1 is a potential biomarker to detect early-stage pancreatic cancers. Assaying the promoter methylation status of these genes in circulating DNA from serum is a promising strategy for early detection of pancreatic cancer and has the potential to improve mortality from this disease.

Martino-Echarri E, Fernández-Rodríguez R, Rodríguez-Baena FJ, et al.
Contribution of ADAMTS1 as a tumor suppressor gene in human breast carcinoma. Linking its tumor inhibitory properties to its proteolytic activity on nidogen-1 and nidogen-2.
Int J Cancer. 2013; 133(10):2315-24 [PubMed] Related Publications
The extracellular protease ADAMTS1 (A disintegrin and metalloprotease with thrombospondin repeats 1) has been described as an anti-angiogenic molecule and its role as a putative tumor protective molecule has also been suggested. Here, we have used a tumor xenograft model to determine the role of ADAMTS1 in tumor growth and angiogenesis. Increasing levels of the protease led to the complete inhibition of tumor growth. In an attempt to elucidate the mechanism of action of this protease, we focused our attention on its proteolytic activity on nidogens, one of the main components of the vascular basement membrane. The increased expression of ADAMTS1 was accompanied by increased proteolysis of nidogen-1 and -2 and their almost complete removal from vascular structures, together with major morphological alterations of tumor blood vessels and a decreased vessel density. The clinical relevance of this work is supported by our observations that ADAMTS1 expression is decreased in breast tumor specimens when compared with healthy tissue. Our studies also reveal that the cleavage of nidogen-1 and -2 is partially inhibited in human tumor samples. Moreover, the deposition of both nidogens surrounding vascular structures is drastically altered, implying a possible reduction in the maintenance of vessel integrity. Our studies reflect the requirement to explore the functional interactions between proteases and specific substrates in cancer biology.

Aravindan S, Natarajan M, Herman TS, Aravindan N
Radiation-induced TNFα cross signaling-dependent nuclear import of NFκB favors metastasis in neuroblastoma.
Clin Exp Metastasis. 2013; 30(6):807-17 [PubMed] Related Publications
Ascertaining function-specific orchestration of NFκB in response to radiation may reveal a molecular blue-print that dictates induced relapse and metastasis of the neuroblastoma. We recently demonstrated that sustained activation of NFκB caused by ionizing radiation (IR)-initiated TNFα-NFκB feedback signaling leads to radioresistance and recurrence of neuroblastoma. We investigated whether muting IR-triggered or TNFα-dependent second-signaling feedback-dependent NFκB nuclear import results in limiting IR-altered invasion and metastasis. Neuroblastoma cells were exposed to 2 Gy and incubated for 1 h or 24 h. The cells were then treated with an NFκB-targeting peptide blocker, SN50. Upon confirming the blockade in DNA-binding activity, transcription driven transactivation of NFκB and secretion of soluble TNFα, transcriptional alterations of 93 tumor invasion/metastasis genes were assessed by using QPCR profiling and then were selectively validated at the protein level. Exposure to 2 Gy induced 63, 42 and 71 genes in surviving SH-SY5Y, IMR-32 and SK-N-MC cells, respectively. Blocking post-translational nuclear import of NFκB comprehensively inhibited both initial activation of genes (62/63, 34/42 and 65/71) triggered by IR and also TNFα-mediated second signaling-dependent sustained (59/63, 32/42 and 71/71) activation of tumor invasion and metastasis signaling molecules. Furthermore, alterations in the proteins MMP9, MMP2, PYK-2, SPA-1, Dnmt3b, Ask-1, CTGF, MMP10, MTA-2, NF-2, E-Cadherin, TIMP-2 and ADAMTS1 and the results of our scratch-wound assay validate the role of post-translational NFκB in IR-regulated invasion/metastasis. These data demonstrate that IR-induced second-phase (post-translational) NFκB activation mediates TNFα-dependent second signaling and further implies that IR induced NFκB in cells that survive after treatment regulates tumor invasion/metastasis signaling.

Freitas VM, do Amaral JB, Silva TA, et al.
Decreased expression of ADAMTS-1 in human breast tumors stimulates migration and invasion.
Mol Cancer. 2013; 12:2 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
BACKGROUND: ADAMTS-1 (a disintegrin and metalloprotease with thrombospondin motifs) is a member of the ADAMTS family of metalloproteases. Here, we investigated mRNA and protein levels of ADAMTS-1 in normal and neoplastic tissues using qPCR, immunohistochemistry and immunoblot analyses, and we addressed the role of ADAMTS-1 in regulating migration, invasion and invadopodia formation in breast tumor cell lines.
RESULTS: In a series of primary breast tumors, we observed variable levels of ADAMTS-1 mRNA expression but lower levels of ADAMTS-1 protein expression in human breast cancers as compared to normal tissue, with a striking decrease observed in high-malignancy cases (triple-negative for estrogen, progesterone and Her-2). This result prompted us to analyze the effect of ADAMTS-1 knockdown in breast cancer cells in vitro. MDA-MB-231 cells with depleted ADAMTS-1 expression demonstrated increased migration, invasion and invadopodia formation. The regulatory mechanisms underlying the effects of ADAMTS-1 may be related to VEGF, a growth factor involved in migration and invasion. MDA-MB-231 cells with depleted ADAMTS-1 showed increased VEGF concentrations in conditioned medium capable of inducing human endothelial cells (HUVEC) tubulogenesis. Furthermore, expression of the VEGF receptor (VEGFR2) was increased in MDA-MB-231 cells as compared to MCF7 cells. To further determine the relationship between ADAMTS-1 and VEGF regulating breast cancer cells, MDA-MB-231 cells with reduced expression of ADAMTS-1 were pretreated with a function-blocking antibody against VEGF and then tested in migration and invasion assays; both were partially rescued to control levels.
CONCLUSIONS: ADAMTS-1 expression was decreased in human breast tumors, and ADAMTS-1 knockdown stimulated migration, invasion and invadopodia formation in breast cancer cells in vitro. Therefore, this series of experiments suggests that VEGF is involved in the effects mediated by ADAMTS-1 in breast cancer cells.

Filou S, Stylianou M, Triantaphyllidou IE, et al.
Expression and distribution of aggrecanases in human larynx: ADAMTS-5/aggrecanase-2 is the main aggrecanase in laryngeal carcinoma.
Biochimie. 2013; 95(4):725-34 [PubMed] Related Publications
Members of the ADAMTS family of proteases degrade proteoglycans and thereby have the potential to alter tissue architecture and regulate cellular functions. Aggrecanases are the main enzymes responsible for aggrecan degradation, due to their specific cleavage pattern. In this study, the expression status, the macromolecular organization and localization of ADAMTS-1, ADAMTS-4/aggrecanase-1 and ADAMTS-5/aggrecanase-2 in human normal larynx and laryngeal squamous cell carcinoma (LSCC) were investigated. On mRNA level, the results showed that ADAMTS-4 was the highest expressed enzyme in normal larynx, whereas ADAMTS-5 was the main aggrecanase in LSCC presenting a stage-related increase up to stage III (8-fold higher expression compared to normal), and thereafter decreased in stage IV. Accordingly, immunohistochemical analysis showed that ADAMTS-5, but not ADAMTS-4, was highly expressed by carcinoma cells. Sequential extraction revealed an altered distribution and organization of multiple molecular forms (latent, activated and fragmented forms) of the enzymes within the cancerous and their corresponding macroscopically normal laryngeal tissues, compared to the normal ones. Importantly, these analyses indicated that critical macromolecular changes occurred from the earliest LSCC stages not only in malignant parts of the tissue but also in areas that were not in proximity to carcinoma cells and appeared otherwise normal. Overall, the results of the present study show that ADAMTS-5/aggrecanase-2 is the main aggrecanase present in laryngeal carcinoma suggesting a critical role for the enzyme in aggrecan degradation and laryngeal tissue destruction during tumor progression.

Chen J, Zhi Y, Chang X, et al.
Expression of ADAMTS1 and its correlation with angiogenesis in primary gastric cancer and lymph node metastasis.
Dig Dis Sci. 2013; 58(2):405-13 [PubMed] Related Publications
BACKGROUND: A disintegrin and metallopeptidase with thrombospondin motif type 1 (ADAMTS1) is a recently discovered metalloproteinase with antiangiogenic activity. The function of ADAMTS1 in gastric cancer remains unknown. Therefore, we were interested in examining ADAMTS1 expression in human gastric cancer, as well as its possible correlation with angiogenesis.
METHODS: The mRNA and protein expression of ADAMTS1, thrombospondin type I (TSP1), and vascular endothelial growth factor (VEGF) was evaluated by RT-PCR and immunohistochemistry, respectively, in 56 paired tumor and normal tissue samples, and corresponding metastatic lymph nodes (n = 42). Microvessel density (MVD) was also evaluated by immunohistochemistry.
RESULTS: ADAMTS1 mRNA and protein levels were significantly lower in primary tumors than in corresponding normal tissues, and were significantly higher in metastatic lymph nodes compared to their matched primary tumors. High ADAMTS1 mRNA and protein expression was found to be significantly associated with lymph node metastasis in primary tumors. There was a negative correlation between ADAMTS1 and VEGF mRNA and protein expression in primary gastric tumors and normal tissues. A negative correlation was also found between ADAMTS1 protein expression and MVD in primary gastric tumors. In contrast, no correlation was detected between ADAMTS1 and TSP1 mRNA and protein expression in primary gastric tumors, normal tissues, and metastatic lymph nodes.
CONCLUSIONS: These findings suggest that ADAMTS1 expression is altered in primary gastric cancer and paired lymph node metastasis. In addition, ADAMTS1 has angioinhibitory effects in primary gastric cancer due to its low expression and negative correlation with VEGF and MVD. However, it appears to lose its anti-angiogenic activity in metastatic lymph nodes in gastric cancer.

Guzman L, Adriaenssens T, Ortega-Hrepich C, et al.
Human antral follicles <6 mm: a comparison between in vivo maturation and in vitro maturation in non-hCG primed cycles using cumulus cell gene expression.
Mol Hum Reprod. 2013; 19(1):7-16 [PubMed] Related Publications
Within the context of an oocyte in vitro maturation (IVM) program for reproductive treatment, oocyte cumulus complexes (COCs) derived from follicles <6 mm in patients with PCOS were matured in vitro. Key transcripts related to meiotic maturation (FSHR, LHCGR, EGFR, PGR) and oocyte competence (AREG, ADAMTS, HAS2, PTGS2) were quantified in cumulus cells (CCs) before and after maturation. Control CC samples were collected from PCOS and normo-ovulatory patients who had undergone conventional gonadotrophin stimulation for IVF/ICSI. Additional control samples from a non-stimulated condition were obtained ex vivo from patients undergoing ovariectomy for fertility preservation. Expression data from CCs from follicles with a diameter of <6 mm before (IVM-CCs) and after in vitro maturation (IVM-CCs) were obtained after pooling CCs into four groups in relation to the percentage of matured (MII) oocytes obtained after 40 h of IVM (0; 40-60; 61-80; 100% MII) and values were compared with in vivo matured controls (IVO-CCs). Genes encoding key receptors mediating meiotic resumption are expressed in human antral follicles of <6 mm before and after IVM. The expression levels of FSHR, EGFR and PGR in CCs were significantly down-regulated in the IVO-CCs groups and in the 100% MII IVM group compared with the BM groups; all the receptors studied in the 100% MII IVM group reached an expression profile similar to that of IVO-CCs. However, after maturation in a conventional IVF/ICSI cycle, IVO-CCs from large follicles contained significantly increased levels of ADAMTS1, AREG, HAS2 and PTGS2 compared with IVM-CCs and IVM-CCs; the expression patterns for these genes in all IVM-CCs were unchanged compared with IVM-CCs. In conclusion, genes encoding receptors involved in oocyte meiotic resumption appeared to be expressed in CCs of small human antral follicles. Expression levels of genes-encoding factors reflecting oocyte competence were significantly altered in IVM-CCs compared with in vivo matured oocytes from large follicles. Observed differences might be explained by the different stimulation protocols, doses of gonadotrophin or by the intrinsic differences between in vivo and in vitro maturation.

Obaya AJ, Rua S, Moncada-Pazos A, Cal S
The dual role of fibulins in tumorigenesis.
Cancer Lett. 2012; 325(2):132-8 [PubMed] Related Publications
The human fibulin family consists of seven complex extracellular glycoproteins originally characterized as components of elastic fibers in connective tissue. However, beyond its structural role, fibulins are involved in complex biological processes such as cell adhesion, migration or proliferation. Indeed, they have proved to be essential elements in normal physiology, as shown by mouse models lacking these proteins, that evidence several developmental abnormalities and pathological features. Their relevance is also apparent in tumorigenesis, an aspect that has started to be intensely studied. Distinct fibulins are expressed in both tumor and stromal cells and are subjected to multiple expression regulations with either anti or pro-tumor effects. The mechanistic insights that underlie these observations are now commencing to emerge, portraying these proteins as very versatile and active constituents of connective tissue. The aim of this review is to highlight the most relevant connections between fibulins and cancer.

Obika M, Ogawa H, Takahashi K, et al.
Tumor growth inhibitory effect of ADAMTS1 is accompanied by the inhibition of tumor angiogenesis.
Cancer Sci. 2012; 103(10):1889-97 [PubMed] Related Publications
Angiogenesis plays an important role in tumor progression. Several reports have demonstrated that a disintegrin and metalloproteinase with thrombospondin motifs1 (ADAMTS1) inhibited angiogenesis via multiple mechanisms. The aim of this study was to investigate the effect of ADAMTS1 on endothelial cells in vitro and on tumor growth with regard to angiogenesis in vivo. We examined the effects of the transfection of ADAMTS1 using two constructs, full-length ADAMTS1 (full ADAMTS1) and catalytic domain-deleted ADAMTS1 (delta ADAMTS1). Transfection of both the full ADAMTS1 and delta ADAMTS1 gene constructs demonstrated the secretion of tagged-ADAMTS1 protein into the conditioned medium, so we examined the effects of ADAMTS1-containing conditioned medium on endothelial cells. Both types of conditioned media inhibited endothelial tube formation, and this effect was completely abolished after immunoprecipitation of the secreted protein from the medium. Both types of conditioned media also inhibited endothelial cell migration and proliferation. We then examined the impact of ADAMTS1 on endothelial cell apoptosis. Both conditioned media increased the number of Annexin V-positive endothelial cells and caspase-3 activity and this effect was attenuated when z-vad was added. These results indicated that ADAMTS1 induced endothelial cell apoptosis. We next examined the effects of ADAMTS1 gene transfer into tumor-bearing mice. Both full ADAMTS1 and delta ADAMTS1 significantly inhibited the subcutaneous tumor growth. Collectively, our results demonstrated that ADAMTS1 gene transfer inhibited angiogenesis in vitro and in vivo, likely as a result of the induction of endothelial cell apoptosis by ADAMTS1 that occurs independent of the protease activity.

Custodio A, López-Farré AJ, Zamorano-León JJ, et al.
Changes in the expression of plasma proteins associated with thrombosis in BRCA1 mutation carriers.
J Cancer Res Clin Oncol. 2012; 138(5):867-75 [PubMed] Related Publications
PURPOSE: Although BRCA1 gene mutations have been associated with breast cancer, BRCA1 mutations have been also involved in other functions. Thrombosis and coagulation are novel mechanisms recently associated with cancer. The aims of the present study were (a) to evaluate, using proteomics, if BRCA1 mutation carriers have a different plasma proteins expression related to thrombosis and coagulation profile than non-mutant BRCA1 women and (b) to analyze if the expression of these proteins may be different among BRCA1 mutation carriers with and without breast cancer.
METHODS: Proteomic study was based on 2-dimensional electrophoresis and mass spectrometry. The study was performed in 10 BRCA1 non-mutant controls and 21 women with BRCA1 mutations (with breast cancer (n = 8) and breast cancer-free (n = 13)), all of them free of family history or diagnosis of ovarian cancer.
RESULTS: Proteomic study showed that fibrinogen gamma chain isotypes 2 and 3, serotransferrin isotype 4, and convertase C3/C5 isotypes 1-5 were significantly increased in plasma from BRCA1 mutation carriers with respect to BRCA1 non-mutant controls. Plasma levels of alpha-1 antitrypsin isotypes 2-5, apolipoprotein A-IV, and vitamin D-binding protein isotypes 1 and 2 were significantly reduced in BRCA1 mutation carriers with respect to non-mutant controls. Only apolipoprotein A-IV plasma levels were significantly higher in cancer-free BRCA1 mutations carriers compared with BRCA1 mutations carriers who developed breast cancer.
CONCLUSION: It is suggested that independently of breast cancer generation, BRCA1-encoded gene alterations are associated with changes in the expression of circulating proteins associated with thrombosis and coagulation.

Casimiro S, Luis I, Fernandes A, et al.
Analysis of a bone metastasis gene expression signature in patients with bone metastasis from solid tumors.
Clin Exp Metastasis. 2012; 29(2):155-64 [PubMed] Related Publications
Bone is a major target for metastases in the most frequent solid tumors, which result in severe complications and are a major cause of pain. A bone metastasis gene expression signature was identified using human breast cancer cells in a mouse model. The bone metastasis-related genes encode secretory and cell surface proteins implicated in bone-homing (CXCR4), angiogenesis (CTGF and FGF5), invasion (MMP-1 and ADAMTS1), and osteoclast recruitment (IL11). This signature superimposes on the 70-gene poor prognosis gene expression signature for breast cancer, and only ADAMTS1, CTGF and IL11 were found to be overexpressed in human primary breast cancers with bone relapse. We analyzed the expression of the six bone metastasis-related genes in bone metastases from patients with different types of solid tumors, to assess its relevance in human clinical samples. MMP-1, CXCR4, FGF5 and CTGF were found to be overexpressed in tumor cells of human bone metastases when compared to a human normal epithelial cell line. All the analyzed genes were overexpressed in the tumor cells of breast cancer bone metastases when compared to normal breast tissue. We did not detect any differences between the expression of these genes in bone metastases from breast cancer or from other types of solid tumors. Importantly, there was a significant correlation between the expressions of IL11/CTGF, IL11/ADAMTS1, CTGF/CXCR4, CTGF/ADAMTS1, and MMP-1/ADAMTS1, supporting the cooperative function of these proteins in the bone microenvironment, and the potential functional role of these genes in the establishment of bone metastases in vivo.

Yegnasubramanian S, Wu Z, Haffner MC, et al.
Chromosome-wide mapping of DNA methylation patterns in normal and malignant prostate cells reveals pervasive methylation of gene-associated and conserved intergenic sequences.
BMC Genomics. 2011; 12:313 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
BACKGROUND: DNA methylation has been linked to genome regulation and dysregulation in health and disease respectively, and methods for characterizing genomic DNA methylation patterns are rapidly emerging. We have developed/refined methods for enrichment of methylated genomic fragments using the methyl-binding domain of the human MBD2 protein (MBD2-MBD) followed by analysis with high-density tiling microarrays. This MBD-chip approach was used to characterize DNA methylation patterns across all non-repetitive sequences of human chromosomes 21 and 22 at high-resolution in normal and malignant prostate cells.
RESULTS: Examining this data using computational methods that were designed specifically for DNA methylation tiling array data revealed widespread methylation of both gene promoter and non-promoter regions in cancer and normal cells. In addition to identifying several novel cancer hypermethylated 5' gene upstream regions that mediated epigenetic gene silencing, we also found several hypermethylated 3' gene downstream, intragenic and intergenic regions. The hypermethylated intragenic regions were highly enriched for overlap with intron-exon boundaries, suggesting a possible role in regulation of alternative transcriptional start sites, exon usage and/or splicing. The hypermethylated intergenic regions showed significant enrichment for conservation across vertebrate species. A sampling of these newly identified promoter (ADAMTS1 and SCARF2 genes) and non-promoter (downstream or within DSCR9, C21orf57 and HLCS genes) hypermethylated regions were effective in distinguishing malignant from normal prostate tissues and/or cell lines.
CONCLUSIONS: Comparison of chromosome-wide DNA methylation patterns in normal and malignant prostate cells revealed significant methylation of gene-proximal and conserved intergenic sequences. Such analyses can be easily extended for genome-wide methylation analysis in health and disease.

Chang HH, McGeachie M, Alterovitz G, Ramoni MF
Mapping transcription mechanisms from multimodal genomic data.
BMC Bioinformatics. 2010; 11 Suppl 9:S2 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
BACKGROUND: Identification of expression quantitative trait loci (eQTLs) is an emerging area in genomic study. The task requires an integrated analysis of genome-wide single nucleotide polymorphism (SNP) data and gene expression data, raising a new computational challenge due to the tremendous size of data.
RESULTS: We develop a method to identify eQTLs. The method represents eQTLs as information flux between genetic variants and transcripts. We use information theory to simultaneously interrogate SNP and gene expression data, resulting in a Transcriptional Information Map (TIM) which captures the network of transcriptional information that links genetic variations, gene expression and regulatory mechanisms. These maps are able to identify both cis- and trans- regulating eQTLs. The application on a dataset of leukemia patients identifies eQTLs in the regions of the GART, PCP4, DSCAM, and RIPK4 genes that regulate ADAMTS1, a known leukemia correlate.
CONCLUSIONS: The information theory approach presented in this paper is able to infer the dependence networks between SNPs and transcripts, which in turn can identify cis- and trans-eQTLs. The application of our method to the leukemia study explains how genetic variants and gene expression are linked to leukemia.

Reynolds LE, Watson AR, Baker M, et al.
Tumour angiogenesis is reduced in the Tc1 mouse model of Down's syndrome.
Nature. 2010; 465(7299):813-7 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Down's syndrome (DS) is a genetic disorder caused by full or partial trisomy of human chromosome 21 and presents with many clinical phenotypes including a reduced incidence of solid tumours. Recent work with the Ts65Dn model of DS, which has orthologues of about 50% of the genes on chromosome 21 (Hsa21), has indicated that three copies of the ETS2 (ref. 3) or DS candidate region 1 (DSCR1) genes (a previously known suppressor of angiogenesis) is sufficient to inhibit tumour growth. Here we use the Tc1 transchromosomic mouse model of DS to dissect the contribution of extra copies of genes on Hsa21 to tumour angiogenesis. This mouse expresses roughly 81% of Hsa21 genes but not the human DSCR1 region. We transplanted B16F0 and Lewis lung carcinoma tumour cells into Tc1 mice and showed that growth of these tumours was substantially reduced compared with wild-type littermate controls. Furthermore, tumour angiogenesis was significantly repressed in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative anti-angiogenic genes (ADAMTS1and ERG) and novel endothelial cell-specific genes, never previously shown to be involved in angiogenesis (JAM-B and PTTG1IP), that, when overexpressed, are responsible for inhibiting angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumour angiogenesis, explaining the reduced tumour growth in DS. Furthermore, we expect that, in addition to the candidate genes that we show to be involved in the repression of angiogenesis, the Tc1 mouse model of DS will permit the identification of other endothelium-specific anti-angiogenic targets relevant to a broad spectrum of cancer patients.

Casal C, Torres-Collado AX, Plaza-Calonge Mdel C, et al.
ADAMTS1 contributes to the acquisition of an endothelial-like phenotype in plastic tumor cells.
Cancer Res. 2010; 70(11):4676-86 [PubMed] Related Publications
Cancer stem cells have been hypothesized to explain tumor plasticity, including the capability to adopt distinct differentiation commitments. Among the mechanisms of tumor neovascularization, the ability of some malignant cells to mimic an endothelial phenotype has been recognized by a capacity to form matrix-enriched pseudovascular structures. In addition to the expression of genes associated with an endothelial nature, the molecular dynamism of specific microenvironments may also be critical. Here, we report the identification of the extracellular protease ADAMTS1 as a critical molecule for tumor cells to acquire endothelial-like properties. In a fibrosarcoma model, ADAMTS1 increased tumor growth rate in an angiogenesis-independent manner, influencing the tumor cells to display an exclusive endothelial-like gene signature. We documented the relevant expression of ADAMTS1 in aggressive and highly plastic melanoma and Ewing sarcoma cells. Notably, inhibiting ADAMTS1 action compromised the endothelial mimetic attributes observed in this setting. Our findings provide insights into how the tumor microenvironment can elicit endothelial mimicry by tumor cells.

Stokes A, Joutsa J, Ala-Aho R, et al.
Expression profiles and clinical correlations of degradome components in the tumor microenvironment of head and neck squamous cell carcinoma.
Clin Cancer Res. 2010; 16(7):2022-35 [PubMed] Related Publications
PURPOSE: Head and neck squamous cell carcinomas (HNSCC) are characterized by high morbidity and mortality, largely due to the high invasive and metastatic potential of these tumors, high recurrence rates, and low treatment responses. Proteinases have been implicated in several aspects of tumor growth and metastasis in a broad range of tumors including HNSCC.
EXPERIMENTAL DESIGN: Comprehensive expression profiling of proteinases [matrix metalloproteinases (MMPs), A disintegrin and metalloproteinase (ADAMs), and ADAMs with thrombospondin motif (ADAMTSs)] and their inhibitors [tissue inhibitor of metalloproteinases (TIMPs)] was done using quantitative real-time reverse transcription-PCR analysis of a large cohort of tissue samples representing the tumor (n = 83), the invasive margin (n = 41), and the adjacent tissue (n = 41) from 83 HNSCC patients, along with normal tissue controls (n = 13), as well as cell lines established from tumors of 34 HNSCC patients.
RESULTS: The results show specifically elevated gene expression of several proteinases, including MMP1, MMP3, MMP10, and MMP13 within tumor tissue and peritumoral adjacent tissue. In addition, the results identify several novel HNSCC-associated proteinases, including ADAM8, ADAM9, ADAM17, ADAM28, ADAMTS1, ADAMTS8, and ADAMTS15. There were also significant differences in proteinase expression based on clinical parameters, i.e., tumor location, grade, and local invasion. MMP13 expression was significantly higher in large (>4 cm) locally invasive tumors (P < 0.05). MMP9 expression was significantly decreased in tumors with regional metastasis, whereas increased expression of ADAM8 was noted in the metastatic tumors (P < 0.001 for both).
CONCLUSIONS: These findings suggest the HNSCC degradome as a valuable source of diagnostic, predictive, and prognostic molecular markers for these malignant tumors.

Koo BH, Coe DM, Dixon LJ, et al.
ADAMTS9 is a cell-autonomously acting, anti-angiogenic metalloprotease expressed by microvascular endothelial cells.
Am J Pathol. 2010; 176(3):1494-504 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
The metalloprotease ADAMTS9 participates in melanoblast development and is a tumor suppressor in esophageal and nasopharyngeal cancer. ADAMTS9 null mice die before gastrulation, but, ADAMTS9+/- mice were initially thought to be normal. However, when congenic with the C57Bl/6 strain, 80% of ADAMTS9+/- mice developed spontaneous corneal neovascularization. beta-Galactosidase staining enabled by a lacZ cassette targeted to the ADAMTS9 locus showed that capillary endothelial cells (ECs) in embryonic and adult tissues and in capillaries growing into heterotopic tumors expressed ADAMTS9. Heterotopic B.16-F10 melanomas elicited greater vascular induction in ADAMTS9+/- mice than in wild-type littermates, suggesting a potential inhibitory role in tumor angiogenesis. Treatment of cultured human microvascular ECs with ADAMTS9 small-interfering RNA resulted in enhanced filopodial extension, decreased cell adhesion, increased cell migration, and enhanced formation of tube-like structures on Matrigel. Conversely, overexpression of catalytically active, but not inactive, ADAMTS9 in ECs led to fewer tube-like structures, demonstrating that the proteolytic activity of ADAMTS9 was essential. However, unlike the related metalloprotease ADAMTS1, which exerts anti-angiogenic effects by cleavage of thrombospondins and sequestration of vascular endothelial growth factor165, ADAMTS9 neither cleaved thrombospondins 1 and 2, nor bound vascular endothelial growth factor165. Taken together, these data identify ADAMTS9 as a novel, constitutive, endogenous angiogenesis inhibitor that operates cell-autonomously in ECs via molecular mechanisms that are distinct from those used by ADAMTS1.

Kohno T, Otsuka A, Girard L, et al.
A catalog of genes homozygously deleted in human lung cancer and the candidacy of PTPRD as a tumor suppressor gene.
Genes Chromosomes Cancer. 2010; 49(4):342-52 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
A total of 176 genes homozygously deleted in human lung cancer were identified by DNA array-based whole genome scanning of 52 lung cancer cell lines and subsequent genomic PCR in 74 cell lines, including the 52 cell lines scanned. One or more exons of these genes were homozygously deleted in one (1%) to 20 (27%) cell lines. These genes included known tumor suppressor genes, e.g., CDKN2A/p16, RB1, and SMAD4, and candidate tumor suppressor genes whose hemizygous or homozygous deletions were reported in several types of human cancers, such as FHIT, KEAP1, and LRP1B/LRP-DIP. CDKN2A/p16 and p14ARF located in 9p21 were most frequently deleted (20/74, 27%). The PTPRD gene was most frequently deleted (8/74, 11%) among genes mapping to regions other than 9p21. Somatic mutations, including a nonsense mutation, of the PTPRD gene were detected in 8/74 (11%) of cell lines and 4/95 (4%) of surgical specimens of lung cancer. Reduced PTPRD expression was observed in the majority (>80%) of cell lines and surgical specimens of lung cancer. Therefore, PTPRD is a candidate tumor suppressor gene in lung cancer. Microarray-based expression profiling of 19 lung cancer cell lines also indicated that some of the 176 genes, such as KANK and ADAMTS1, are preferentially inactivated by epigenetic alterations. Genetic/epigenetic as well as functional studies of these 176 genes will increase our understanding of molecular mechanisms behind lung carcinogenesis.

Wang L, Sun Y, Jiang M, et al.
FOS proliferating network construction in early colorectal cancer (CRC) based on integrative significant function cluster and inferring analysis.
Cancer Invest. 2009; 27(8):816-24 [PubMed] Related Publications
The aim is to setup single distinguished molecular network. We constructed FOS proliferating network from 22 colorectal samples of the same GEO dataset by GRNInfer tool and DAVID based on linear programming and a decomposition procedure with integrated Kappa statistics and fuzzy heuristic clustering. In the control, we found no proliferating subnetwork. In CRC, we identified one FOS proliferating module (SFRP2, ADAMTS1, SYNPO2, VIP, ADAM33 inhibition to FOS and MGP, FOSB activation to FOS. FOS activation to IGFBP5, LGI1, GAS1 and FOS inhibition to VIP). These results may be useful for developing novel prognostic markers and therapeutic targets in CRC.

Braconi C, Meng F, Swenson E, et al.
Candidate therapeutic agents for hepatocellular cancer can be identified from phenotype-associated gene expression signatures.
Cancer. 2009; 115(16):3738-48 [PubMed] Related Publications
BACKGROUND: The presence of vascular invasion in hepatocellular cancer (HCC) correlates with prognosis, and is a critical determinant of both the therapeutic approach and the recurrence or intrahepatic metastases. The authors sought to identify candidate therapeutic agents capable of targeting the invasive phenotype in HCC.
METHODS: A gene expression signature associated with vascular invasion derived from 81 human cases of HCC was used to screen a database of 453 genomic profiles associated with 164 bioactive molecules using the connectivity map. Candidate agents were identified by their inverse correlation to the query gene signature. The efficacy of the candidate agents to target invasion was experimentally verified in PLC/PRF-5 and HepG2 HCC cells.
RESULTS: The gene signature associated with vascular invasion in HCC comprised of 47 up-regulated and 26 down-regulated genes. Computational bioinformatics analysis revealed several putative candidates, including resveratrol and 17-allylamino-geldanamycin (17-AAG). Both of these agents reduced HCC cell invasion at noncytotoxic concentrations. 17-AAG, a heat shock protein 90 (HSP-90) inhibitor, was shown to modulate the expression of several diverse cancer-associated genes, including ADAMTS1, part of the query signature, and maspin, an HSP-90-associated protein with a tumor suppressor role in HCC.
CONCLUSIONS: Candidates for further evaluation as therapies to limit invasion in HCC have been identified using a computational bioinformatics analysis of phenotype-associated gene expression. Phenotype targeting using genomic profiling is a rational approach for drug discovery. Therapeutic strategies targeting a defined cancer-associated phenotype can be identified without a detailed knowledge of individual downstream targets.

Viloria CG, Obaya AJ, Moncada-Pazos A, et al.
Genetic inactivation of ADAMTS15 metalloprotease in human colorectal cancer.
Cancer Res. 2009; 69(11):4926-34 [PubMed] Related Publications
Matrix metalloproteinases have been traditionally linked to cancer dissemination through their ability to degrade most extracellular matrix components, thus facilitating invasion and metastasis of tumor cells. However, recent functional studies have revealed that some metalloproteases, including several members of the ADAMTS family, also exhibit tumor suppressor properties. In particular, ADAMTS1, ADAMTS9, and ADAMTS18 have been found to be epigenetically silenced in malignant tumors of different sources, suggesting that they may function as tumor suppressor genes. Herein, we show that ADAMTS15 is genetically inactivated in colon cancer. We have performed a mutational analysis of the ADAMTS15 gene in human colorectal carcinomas, with the finding of four mutations in 50 primary tumors and 6 colorectal cancer cell lines. Moreover, functional in vitro and in vivo studies using HCT-116 and SW-620 colorectal cancer cells and severe combined immunodeficient mice have revealed that ADAMTS15 restrains tumor growth and invasion. Furthermore, the presence of ADAMTS15 in human colorectal cancer samples showed a negative correlation with the histopathologic differentiation grade of the corresponding tumors. Collectively, these results provide evidence that extracellular proteases, including ADAMTS15, may be targets of inactivating mutations in human cancer and further validate the concept that secreted metalloproteases may show tumor suppressor properties.

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