Role of leukocyte cell-derived chemotaxin 2 as a biomarker in hepatocellular carcinoma

We sought to identify a secreted biomarker for β-catenin activation commonly seen in hepatocellular carcinoma (HCC). By examination of our previously published genearray of hepatocyte-specific β-catenin knockout (KO) livers, we identified secreted factors whose expression may be β-catenin-dependent. We verified expression and secretion of the leading factor in HCC cells transfected with mutated (Hep3BS33Y)-β- catenin. Serum levels of biomarker were next investigated in a mouse model of HCC with β-catenin gene (Ctnnb1) mutations and eventually in HCC patients. Leukocyte cell-derived chemotaxin-2 (LECT2) expression was decreased in KO livers. Hep3BS33Y expressed and secreted more LECT2 in media as compared to Hep3BWT. Mice developing HCC with Ctnnb1 mutations showed significantly higher serum LECT2 levels. However patients with CTNNB1 mutations showed LECT2 levels of 54.28±22.32 ng/mL (Mean ± SD; n = 8) that were insignificantly different from patients with non-neoplastic chronic liver disease (32.8±21.1 ng/mL; n = 15) or healthy volunteers (33.2±7.2 ng/mL; n = 11). Intriguingly, patients without β-catenin mutations showed significantly higher serum LECT2 levels (54.26 ± 22.25 ng/mL; n = 46). While β-catenin activation was evident in a subset of non-mutant β-catenin HCC group with high LECT2 expression, serum LECT2 was unequivocally similar between β-catenin-active and -normal group. Further analysis showed that LECT2 levels greater than 50 ng/ml diagnosed HCC in patients irrespective of β-catenin mutations with specificity of 96.1% and positive predictive value of 97.0%. Thus, LECT2 is regulated by β-catenin in HCC in both mice and men, but serum LECT2 reflects β-catenin activity only in mice. Serum LECT2 could be a potential biomarker of HCC in patients. © 2014 Okabe et al

A Cryptic Frizzled Module in Cell Surface Collagen 18 Inhibits Wnt/β−Catenin Signaling

Collagens contain cryptic polypeptide modules that regulate major cell functions, such as cell proliferation or death. Collagen XVIII (C18) exists as three amino terminal end variants with specific amino terminal polypeptide modules. We investigated the function of the variant 3 of C18 (V3C18) containing a frizzled module (FZC18), which carries structural identity with the extracellular cysteine-rich domain of the frizzled receptors. We show that V3C18 is a cell surface heparan sulfate proteoglycan, its topology being mediated by the FZC18 module. V3C18 mRNA was expressed at low levels in 21 normal adult human tissues. Its expression was up-regulated in fibrogenesis and in small well-differentiated liver tumors, but decreased in advanced human liver cancers. Low FZC18 immunostaining in liver cancer nodules correlated with markers of high Wnt/β−catenin activity. V3C18 (Mr = 170 kD) was proteolytically processed into a cell surface FZC18-containing 50 kD glycoprotein precursor that bound Wnt3a in vitro through FZC18 and suppressed Wnt3a-induced stabilization of β−catenin. Ectopic expression of either FZC18 (35 kD) or its 50 kD precursor inhibited Wnt/β−catenin signaling in colorectal and liver cancer cell lines, thus downregulating major cell cycle checkpoint gatekeepers cyclin D1 and c-myc and reducing tumor cell growth. By contrast, full-length V3C18 was unable to inhibit Wnt signaling. In summary, we identified a cell-surface signaling pathway whereby FZC18 inhibits Wnt/β−catenin signaling. The signal, encrypted within cell-surface C18, is released by enzymatic processing as an active frizzled cysteine-rich domain (CRD) that reduces cancer cell growth. Thus, extracellular matrix controls Wnt signaling through a collagen-embedded CRD behaving as a cell-surface sensor of proteolysis, conveying feedback cues to control cancer cell fate

EOS. Entwicklungs-Offensive Solar

Das Ministerium fuer Wissenschaft und Forschung des Landes Nordrhein-Westfalen hat die beiden Gesellschaften AMO GmbH (Aachen) und NEA Neue Energie GmbH (Herzogenrath) beauftragt, die Aussichten fuer eine Grossserienfertigung von Photovoltaik-Modulen in NRW zu untersuchen. In der hiermit vorgelegten EOS-Studie werden die technologischen, oekonomischen, oekologischen und politischen Rahmenbedingungen fuer den Aufbau einer Photovoltaik-Fabrik umfassend dargestellt. Der Uebersichtlichkeit halber wurde die Studie in vier Teile gegliedert, die jeweils in sich weitgehend abgeschlossen sind. Teil A gibt einen Ueberblick ueber das Gesamtprojekt und fasst die wichtigsten Ergebnisse und Empfehlungen zusammen. Teil B geht auf die zentrale Frage der Zellen- und Modulfertigung ein und soll in der aktuellen Diskussion ueber den Aufbau einer Solarfabrik in NRW vor allem einen Beitrag zur Technologieauswahl und zu den anzustrebenden Kostenzielen leisten. Teil C befasst sich mit photovoltaischer Systemtechnik (Montageverfahren, Elektrik) und analysiert die Gesamtkosten, die bei der Errichtung und im Betrieb einer Photovoltaik-Anlage entstehen. Dabei ist eine Vielzahl von Einsatzbereichen zu unterscheiden. Teil D untersucht die Marktsituation und die sonstigen Rahmenbedingungen der Photovoltaik. Es werden Begleitmassnahmen vorgeschlagen, mit denen die nordrhein-westfaelische Landesregierung den Aufbau einer Solar-Industrie unterstuetzen kann. Die Photovoltaik besitzt das Potential, sich in 21. Jahrhundert zu einer tragenden Saeule der Energieversorgung zu entwickeln. Hierin liegt eine industriepolitische Herausforderung - aber auch eine grosse Chance - fuer das Energieland Nordrhein-Westfalen. (orig.)The Ministry of Science and Technology of the Land Northrhine-Westphalia (NRW) has instructed the two companies AMO GmbH (Aachen) and NEA New Energy GmbH (Herzogenrath) to examine the prospect for large scale manufacture of photo-electric modules in NRW. The EOS study submitted here shows the technical, economical, ecological, and political boundary conditions for building up a photo-electric factory comprehensively. To make it easier to understand, the study was divided into four parts, which are largely self-contained. Part A gives a survey of the whole project and summarises the most important results and recommendations. Part B deals with the central question of cell and module manufacture and should make a contribution to the current discussion of the construction of a solar factory in NRW, above all a contribution to selecting the technique and the cost targets to be aimed at. Part C is concerned with photo-electric system technique (assembly process, electrics) and analyses the total costs which occur in the erection and operation of a photo-electric plant. One must distinguish between many areas of use here. Part D examines the situation of the market and the other boundary conditions of photo-electrics. Accompanying measures are proposed, by which the Government of the Land Nordrhine-Westphalia can support the build-up of a solar industry. Photo-electrics has the potential to develop into a pillar of the energy supplies in the 21st century. There is an industrial policy challenge here, but also a great chance for the energy Land of Northrhine-Westphalia. (orig.)Available from FIZ Karlsruhe / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEMinisterium fuer Wissenschaft und Forschung des Landes Nordrhein-Westfalen, Duesseldorf (Germany)DEGerman

Activating CAR and β-catenin induces uncontrolled liver growth and tumorigenesis

Aberrant β-catenin activation contributes to a third or more of human hepatocellular carcinoma (HCC), but β-catenin activation alone is not sufficient to induce liver cancer in mice. Differentiated hepatocytes proliferate upon acute activation of either β-catenin or the nuclear xenobiotic receptor CAR. These responses are strictly limited and are tightly linked, since β-catenin is activated in nearly all of the CAR-dependent tumors generated by the tumor promoter phenobarbital. Here we show that full activation of β-catenin in the liver induces senescence and growth arrest, which is overcome by combined CAR activation, resulting in uncontrolled hepatocyte proliferation, hepatomegaly, and rapid lethality despite maintenance of normal liver function. Combining CAR activation with limited β-catenin activation induces tumorigenesis, and the tumors share a conserved gene expression signature with β-catenin positive human HCC. These results reveal an unexpected route for hepatocyte proliferation and define a murine model of hepatocarcinogenesis with direct relevance to human HCC

A Preliminary Operational Classification System for Nonmutagenic Modes of Action for Carcinogenesis

This article proposes a system of categories for nonmutagenic modes of action for carcinogenesis. The classification is of modes of action rather than individual carcinogens, because the same compound can affect carcinogenesis in more than one way. Basically, we categorize modes of action as: (1) co-initiation (facilitating the original mutagenic changes in stem and progenitor cells that start the cancer process) (e.g. induction of activating enzymes for other carcinogens); (2) promotion (enhancing the relative growth vs differentiation/death of initiated clones (e.g. inhibition of growth-suppressing cell-cell communication); (3) progression (enhancing the growth, malignancy, or spread of already developed tumors) (e.g. suppression of immune surveillance, hormonally mediated growth stimulation for tumors with appropriate receptors by estrogens); and (4) multiphase (e.g., epigenetic silencing of tumor suppressor genes). A priori, agents that act at relatively early stages in the process are expected to manifest greater relative susceptibility in early life, whereas agents that act via later stage modes will tend to show greater susceptibility for exposures later in life. Copyright © 2008 Informa UK Ltd