Chromosome 19 encodes several well described tumor suppressor genes whose downregulation is associated with progression in various cancers. We identiﬁed ﬁve of these tumor suppressor genes to be downregulated in relapse DTCs. BBC3/PUMA is a critical apoptosis inducer whose expression ablation is oncogenic and can lead to therapeutic resistance. 39 A recent study demonstrated that BBC3/PUMA is the critical determinant of the therapeutic response to p53 activation and subsequent apoptosis induced by Nutlin3a, a cancer therapeutics that is in clinical trial. 40 A screening study with ﬂubendazole, another compound that exerts anti- cancer activity, identiﬁed neuroblastoma as a potential ﬂubendazole-sensitive cancer entity. The ﬂubendazole efﬁcacy was increased by nutlin-3, but the ﬂubendazole-induced anti- neuroblastoma effect was signiﬁcantly impaired upon BBC3/ PUMA depletion in the analyzed neuroblastoma cell lines. 41 SIRT6 is another tumor suppressor that we found to be downregulated in relapse DTCs and whose loss was associ- ated with poor outcome in several cancers. 42 Analysis of data from the Cancer Genome Atlas database revealed that SIRT6 was deleted in 20% of analyzed cancers. 43 The loss and/or downregulation of the remaining three suppressor genes in DTCs of relapse samples, namely STK11, CADM4 and GLTSCR2, was also reported to be associated with tumorprogression in various cancers. Thus, we assume that the downregulation of the ﬁve tumor suppressor genes encoded by chromosome 19 in relapse DTCs represents a possible survival advantage for DTCs.
To gain more detailed insight on the underlying mechanisms of neutrophils in tumorprogression, we also employed several other in vitro experiments such as a cell proliferation assay or a cell migration assay. The MTT cell proliferation assay is a commonly used method to investigate the number of viable cells, based on the transformation of yellow MTT((3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) into blue formazan via mitochondrial enzymes (Sylvester, 2011). Thus, we were able to examine the influence of different stimuli and specific molecular factors on cell proliferation. In order to explore cell migration we employed a scratch assay. By creating a scratch in the monolayer of confluent cells, and comparing the cell migration rate into this scratch, the effect of different stimuli could be observed. However, it should be noted that in vitro experiments display isolated events as there is no environmental influence. Hence, it is best to combine these with other in vivo approaches. For instance, a possible approach might be to target the molecular factors found in these experiments, in tumor- bearing mice and measure tumorprogression.
Stat3 is considered to be a oncogene since overexpression of constitutively active Stat3 in 3T3 cells induces cellular transformation and tumor formation in nude mice (Bromberg et al., 1999). Moreover, activated Stat3 is present in many tumors of mice and humans including CRC (Hodge et al., 2005). Recently, the requirement for IL- 6/gp130-mediated Stat3 activation in CRC has been directly addressed in IL-6 -/- mice and mice with conditional inactivation of Stat3 in intestinal epithelial cells (Stat3 IEC ). Both animal models displayed reduced tumor size and tumor multiplicity after treatment with azoxymethane/dextransulfate (AOM/DSS) which was due to impaired tumor initiation (Bollrath et al., 2009) (Grivennikov et al., 2009). Consistently, we have observed that Stat3 is required for tumor initiation and formation of early microadenomas in APC min/+ mice. However, at later stages, Stat3-deficient tumors in APC min/+ mice grew to a bigger size than Stat3-proficient tumors and displayed histopathological characteristics of invasive carcinomas . Similarly, tumorprogression was slightly enhanced in colorectal tumors of male Stat3 IEC mice that have been treated with AOM/DSS indicating that Stat3 negatively regulates CRC progression. However, we did not observe any difference in tumor initiation upon Stat3 ablation in the AOM/DSS induced colorectal cancer model. This finding is in contrast with recently published manuscripts. A possible explanation can be the use of different mouse models. While we use a mouse with floxed Stat3 DNA binding domain (floxed exons 12 to 14) (Alonzi et al., 2001) Bollrath et al. and Grivennikov et al. use a mouse with floxed Tyr705 phosphorylation site (floxed exon 21) (Takeda et al., 1998). Deletion of exon 21 results in the generation of a Stat3 protein lacking the phosphorylation site. Recently the role of unphosphorylated Stat3 protein in signal transduction has been described (Yang and Stark, 2008).
In this study, it was shown that KRAS is a predicted target of miR-200c and that the protein expression of KRAS inversely correlates with the miR-200c expression in a panel of human breast cancer cell lines. KRAS was experimentally validated as a target of miR-200c by Western blot analyses and luciferase reporter assays. Interestingly, upon molecular evolution, an assay for acquired chemoresistance in which cancer cells were sequentially treated with doxorubicin, BT-474 cells displayed a significantly reduced miR-200c and a remarkably enhanced K-ras protein expression. Even though BT-474 cells express wild-type K-ras (121), the up- regulation of K-ras is a reasonable way to overcome the chemotherapeutic treatment as those cells have an amplification of the pro-survival gene encoding for the receptor tyrosine kinase HER2 (143), which signals downstream among others via the RAS/MAPK signaling pathway. This suggests that not only the presence of mutated but also the expression levels of wild-type K-ras are important for tumorprogression and may serve as predictive marker for therapy efficacy, especially when occurring in combination with other genetic alterations such as EGFR mutations or HER2 amplifications.
although CHOP and thereby ER stress dependent apoptosis were not induced (Figure 1C). Indeed, it has been described before that intrahepatic cholestasis due to accumulation of bile acids in the liver was associated with ER stress . However, the cellular pathways that regulate the hepatic UPR and ER stress in cholestasis remain undefined . The unfolded protein response (UPR) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance . On the other hand, it has been demonstrated that induction of ER-stress is essential for hepatocarcinogenesis . A mouse model describing bile duct ligation combined with alpha-1 antitrypsin mutation PiZZ causing an ER storage disease has been published previously . The authors concluded, that patients with α1-AT deficiency might be more susceptible to the development of severe liver disease when suffering from concomitant cholestatic liver injury and vice versa . Our study confirms the conclusion that ER storage disease exacerbates cholestasis.
autocrine and paracrine manner. IL6 is a double-edged sword in the tumor microenvironment. Several studies demonstrated the role of IL6-mediated pro-proliferative, anti-apoptotic, angiogenic, metastatic, and immunosuppressive responses in tumor development and progression. While other studies demonstrated the role of IL6 in promoting anti-tumor immunity through the stimulation of proliferation, survival and trafficking of T cells to lymph nodes and tumor sites, where T cells effectively shift tumor-suppressive state to responsive state to inhibit tumor growth and progression ( 89 , 90 ). An increased level of IL6 correlates with the poor prognosis and survival of lung cancer patients ( 54 , 60 ). TAM-derived IL6 plays a role in progression, invasion, angiogenesis, EMT, immune cell infiltration, and cancer stem cell (CSC) development and maintenance, through multiple unexplored molecular mechanisms ( 91 – 93 ). The activation of signal transducer and activator of transcription (STAT) 3 by TAM-derived IL6 in the lung TME considered as the prime mechanism responsible for the development of mouse lung tumor model and crosstalk with small cell lung cancer (SCLC) cell lines ( 94 , 95 ). Phosphatidylinositol-4,5-Bisphosphate 3- Kinase/AKT Serine/Threonine Kinase 1 (PI3K/AKT) signaling is another pathway engaged by TAM-derived IL6 to influence growth of lung cancer cell line, A549 ( 96 ). TAM-derived IL6- mediated STAT3 signaling pathway also found to increase the proliferation of human cancer stem cells ( 97 ). In different phases of lung cancer development and its therapeutic management, IL6 drives multiple molecular mechanisms responsible for the epithelial-mesenchymal transition (EMT) ( 98 , 99 ) and therapy resistance, such as infiltration of pro-tumor macrophages after irradiation through the upregulation of CCL2/CCL5 in vitro human and in vivo mouse lung tumor models ( 100 ). Therefore, the blockade of IL6 reprograms the TME to restrict lung
insensitive to senescence-inducing signals, demonstrating functional redundancy between pocket proteins. Still, the relative impact of pRB on tumor prevention may be more significant than that of the other pocket proteins as mutations of p130 and p107 occur rarely, if ever in human cancer, whereas pRB mutations are common (Classon and Harlow, 2002). Consistently, acute ablation of Rb in senescent cells is sufficient for reversal of the cellular senescence program (Sage et al., 2003). The role of pRB in the control of senescence turned out to be more complex than simply antagonizing E2F-driven transition from G1 to S phase of cell cycle. Recently, onset of senescence has been shown to correlate with the establishment of a specific form of heterochromatin present in discrete nuclear foci, known as senescence-associated heterochromatic foci (SAHF), the formation of which is directed in part by hypophosphorylated pRB (Narita et al., 2003). These data suggest that senescence results from the stable repression of promoters associated with growth control genes. Inactivation of cell-cycle check-points by the expression of viral oncoproteins, such as SV40 large T antigen or HPV E7, or by targeted disruption of p21 gene in primary human fibroblasts abrogates the onset of typical replicative senescence (Figure 1a). However, cell growth eventually reaches a plateau designated as crisis (mortality stage 2, M2). In contrast to the senescent phenotype, such cells display ongoing replication (e.g. high index of BrdU incorporation), but also a high rate of apoptosis, presumably initiated due to eroded telomeres in the absence of telomerase activity. The fact, that human fibroblasts never become immortal spontaneously, underlines a very tight control of proliferation by the telomere-length check-point.
In our recent study, we showed that apoptotic breast cancer cell-derived miR-375 is shuttled to macrophages via LDL and induced macrophage migration and infiltration [ 38 ]. In breast cancer, TAMs are the predominant immune cell subtype and most of them originate from blood-derived monocytes [ 145 , 146 ]. Currently, it is unclear how the tumor microenvironment achieves this massive influx of monocytes and macrophages and how it initiates genetic reprogramming of TAMs. While tumor-derived miRs that alter the macrophage phenotype have been reported in this review and elsewhere [ 123 ], our study provides evidence that miR-375 provokes monocyte/macrophage migration and infiltration without affecting cell polarization [ 38 ]. To identify miR-375 targets in macrophages, we overexpressed miR-375 using a synthetic miR-mimic and subsequently performed AGO-RIP-Seq. On the basis of the results we obtained from sequencing, we identified paxillin (PXN) and tensin 3 (TNS3) as targets of miR-375 in macrophages, which was verified in vitro and in vivo. Paxillin and tensin 3 mRNA and protein levels were reduced in macrophages upon coculture with breast cancer cells, as well as after treatment with miR-375 containing supernatants from apoptotic MCF-7 cells. Paxillin is a focal adhesion adapter protein that, depending on its subcellular localization, can positively or negatively regulate cell migration [ 147 – 149 ]. Similarly, tensin 3 acts as a link between the extracellular matrix and the cytoskeleton and functionally contributes to the switch between adhesive and non-adhesive states in cancer cells, including breast cancer [ 150 , 151 ]. In tissue microarrays of mammary carcinoma patients, miR-375 was elevated in breast cancer tissue as compared to normal breast tissue, and positively correlated with the number of infiltrated macrophages. These findings highlight the important role of tumor-derived miR-375 in the early stages of tumorigenesis, specifically in the recruitment of circulating monocytes to sites of tumorprogression, which makes miR-375 a promising new therapeutic target at the onset of breast cancer.
Der Abbau der so genannten kalten Progression gehört mit vorhersehbarer Regelmäßigkeit zu den prominentesten finanzpolitischen Forderungen. Dabei geht es darum, dass die Steuerpflichtigen inflationsbedingt in eine höhere Progressionszone hineinwachsen, ohne dass ihr Realeinkommen entsprechend gestiegen wäre. Eine reale Höherbelastung ist die Folge. Befürworter eines Abbaus, oder gar einer kompletten Abschaffung der kalten Progression durch einen inflationsindexierten Einkommensteuertarif („Tarif“ auf Rädern) können sich dabei der Unterstützung einflussreicher wirtschaftswissenschaftlicher Beratungsgremien sicher sein: Die Gemeinschaftsdiagnose empfiehlt regelmäßig ihren Abbau (vgl. Projektgruppe Gemeinschaftsdiagnose 2015, S. 64 u. 70), und schon seit 2013 fordert auch der Sachverständigenrat zur Begutachtung der gesamtwirtschaftlichen Entwicklung (SVR) in seiner Mehrheit entsprechende Korrekturen des Einkommensteuertarifs (SVR 2013, S. 368). Obwohl es in den letzten Jahren wiederholt Tarifanpassungen gegeben hat, kommt der SVR (2017, S. 24) in seinem jüngsten Gutachten sogar zu dem Ergebnis, die seit 2010 aufgelaufene Belastung durch die
Kalte Progression – 3 Abschwung versta rkt wird. Erst im seltenen Fall einer Deflation wu rde sie stabilisierend wirken, da die Durchschnittssteuerbelastung der Haushalte sinken wu rde.
Daneben kann Kalte Progression auch aus anderen Gru nden makroo konomisch problematisch sein. So argumentiert Immervoll (2000), dass die vorherigen U berlegungen lediglich auf die Nachfrageseite abstellen, die Angebotsseite aber ausblenden. So kann der durch die Kalte Progression ausgelo ste Anstieg des Durchschnittssteuersatzes in zusa tzliche Lohnforderungen mu nden und die Inflation weiter anheizen. Das gilt insbesondere im Fall einer importierten Inflation (z.B. Anstieg von Preisen importierter Rohstoffe, wie Erdo l). Der Anstieg der Lohnkosten fu hrt zu einem Verlust der internationalen Wettbewerbsfa higkeit und damit zu einer Schwa chung der Volkswirtschaft. Auf diesen Punkt hat bereits Dernburg (1976) wa hrend des ersten Erdo lpreisschocks hingewiesen. Des Weiteren geht die Argumentation der automatischen Stabilisierung davon aus, dass die o ffentliche Hand die zusa tzlichen Einnahmen aus der Lohn- und Einkommensteuer nicht fu r zusa tzliche o ffentliche Ausgaben verwendet. Ist dies jedoch der Fall, dann wa re auch nicht von einer Stabilisierung der inla ndischen gesamtwirtschaftlichen Nachfrage auszugehen.
The DPT model with the least significant meta-/gene profiles was discarded. Samples from the metagene DPT model were sorted by pseudotime in increasing order, forming a matrix, where each line then would show the expression behaviour over time. Samples, assigned to neither ’branch 1’ or ’branch 2’ were discarded as too unspecific. This way, the metagene profiles contain only expression values from samples most clearly associated to certain parts of CAP progression. Remaining metagenes, that passed the p-value threshold were correlated with pseudotime and those with an absolute Pearson correlation below 0.7 removed. Metagenes with a variance below 0.02 were assumed genetically inactive and removed as well. Remaining neighboured metagenes were grouped into respective/separate spots (see Figure A.5). To provide comparability of these results to other studies, the steps from Section 2.7 were repeated with the genes contained in the metagenes of all identified spots. The remaining genes again were correlated with pseudotime and filtered by variance. Those with an absolute Pearson correlation below 0.7 and a variance below 0.02 were removed. Identified spots within the SOM were checked for potential specific functions by a general geneset analysis with all genesets contained in the ’oposSOM’ pipeline. The pipeline internal description of all significant genesets with a p-value below 0.05 were checked for keywords. After- wards, geneset analysis only with Chaussabel’s genesets was conducted, taking only those genests into account that were proven significant regarding the enrichment with a p-value below 0.05.
Metastasis is a leading cause of death of cancer patients (Gupta and Massague 2006). Although major advances have been made in the treatment of cancer, it is still urgent to disclose mechanisms of cancer cell mobilization from primary tumors to distant organs in order to generate new therapeutic strategies. Many research groups have pointed out that the epithelial-to-mesenchymal transition (EMT) is critical during the cancer metastatic cascade. Down-regulation of cell-cell adhesion proteins is a frequent event. Due to this reason, tumor cells lose contact to their neighboring cells and become motile. Furthermore, the proteins of the cytoskeleton, for example vimentin, might also be affected in parallel. EpCAM is illustrated by many studies as a typical epithelial marker, and is frequently overexpressed in most carcinomas. In vitro, down-regulation of EpCAM facilitates the migration of tumor cells. Since the intracellular portion EpICD accelerates proliferation of tumor cells, it is rational to imagine that EpCAM is dispensable for circulating tumor cells, but required again at later stages of the metastatic process.
That mitochondrial content has a different role and function in ERG positive and ERG negative cancers is further supported by our ERG-stratified analysis of disease outcome. Mitochondrial content had a prognos- tic role in ERG negative but not in ERG positive cancers. This striking difference may be caused by the substantial increase of cellular mitochondrial content by ERG rearrangements, which by themselves do not have any prognostic impact on prostate cancers. The magnitude of ERG-induced molecular and cellular changes, at least most of which are unrelated to cancer progression, may lead to an increased mitochondrial content in “fusion- type” prostate cancers, that masks demand for higher mitochondria content caused by specific molecular “pro- gression events” requiring more mitochondrial function. The strong prognostic impact of mitochondria content in ERG negative prostate cancers fits well with models suggesting, that in a surrounding with low mitochondria content, “progression events” requiring more mitochon- drial function would rather lead to a detectable increase of the mitochondria count, than in an environment with high mitochondria content.
The exact molecular and cellular mechanisms which build up to the initiation and progression of atherosclerosis and ultimately to dangerous disease-associated events, including myocardial infarction and stroke, remain elusive and are, to date, subject to various medical and biochemical research. This thesis will elaborate on the functional role of the growth factor Progranulin and its role in the progression of atherosclerosis. This was investigated in vivo by means of two different mouse models. Crossbreeding ApoE-deficient mice, used frequently as mouse model of early-stage atherosclerosis, with mice lacking PGRN, we generated mice double deficient of the ApoE - and PGRN - gene. Building on this model, we were able to elucidate the influence of Progranulin on atherogenesis. We were able to show, that deficiency of Progranulin exhibits a strong influence on atheroprogression. PGRN -/- ApoE -/- - mice, in contrast to PGRN +/+ ApoE -/- - mice, showed a severely accelerated and aggravated version of atherosclerosis. PGRN -/- ApoE -/- - mice presented with significantly higher tight leukocyte adhesion at the atherosclerotic predilection sites of the carotid artery vessel endothelium as well as greater predisposition to diffuse and extended atherosclerotic vascular alterations.
symptomatisch und nur 3 % der Männer versterben an ihrer Tumorerkrankung 3 . Ein bestehendes Problem bei der Diagnostik und Therapie des Prostatakarzinoms ist allerdings die Einschätzung des Progressionsrisikos der Tumoren. Insbesondere in der großen Gruppe der Karzinome mit einem Gleason-Score von 3+4 und 4+3 ist eine sichere Einschätzung der Aggressivität der Tumoren nicht möglich 9 . Aus diesem Grund entscheiden sich viele Männer mit einem eigentlich nicht therapiebedürftigen Karzinom für eine Ektomie, um das Risiko einer Progression sicher auszuschließen. Hieraus erschließt sich, von welcher Bedeutung es ist, Prostatakarzinome frühzeitig in aggressive, akut behandlungsbedürftige Tumoren und in indolente, nicht akut behandlungsbedürftige Karzinome einteilen zu können. Große Hoffnung wird daher in die Etablierung von molekularen Prognosemarkern gesetzt, welche die vorhandenen Prognoseparameter, wie zum Beispiel den Gleason-Score, bei der Einschätzung der Aggressivität der Tumoren unterstützen. Daher ist es essentiell die Genetik und Biologie der Prostatakarzinome besser zu verstehen.
Kalte Progression –
Gefahr für die Stabilität der Schuldenbremse
Martin Altemeyer-Bartscher, Götz Zeddies
Geringfügige Steuermehrbelastungen, die auf die kalte Progression bei der Einkommensteuer zurückzuführen sind, werden vom Steuerzahler kaum wahrgenommen und bieten dem deutschen Staat daher die Möglichkeit für schleichende Steuererhöhungen. Überschreiten die kumulierten Mehrbelastungen allerdings nach einigen Jahren eine kritische Schwelle, entsteht gewöhnlich ein politischer Druck für die Korrektur der kalten Progression. Wie im Beitrag gezeigt wird, kann die kalte Progression somit Auslöser eines Einnahmezyklus sein. Im Unterschied zu konjunkturbedingten Einnahmeschwankungen findet dieser Einnahmezyklus in den Regelungen zur Schul- denbremse keine Berücksichtigung. Ob die Regierungen eigenverantwortlich einen ausreichenden Sicherheits- abstand zur maximal zulässigen Nettokreditaufnahme einhalten, um diesen Schwankungen vorzubeugen, ist fraglich. Eine Indexierung des Steuertarifs, die eine automatische Korrektur der kalten Progression vorsieht, könnte derartige Schwankungen verhindern und für ein weniger volatiles Einkommensteueraufkommen sorgen.
This study investigates whether and when during the life cycle women fall behind in terms of career progression because of children. We use 1987-1997 Norwegian panel data that contain information on individuals’ position in their career hierarchy as well as a direct measure of their promotions. We measure overall promotions as increases in rank within the same establishment as well as in combination with an establishment change. Women with children are 1.6 percentage points less likely promoted than women without children; this is what we refer to as the family gap in climbing the career. We find that mothers tend to enter on lower ranks than non-mothers. 37 percent of the gap can be explained by rank fixed effects and human capital characteristics. A large part remains unexplained. Graphical analyses show that part of the difference already evolves during the early career. Part of this seems related to the relatively low starting ranks.
In Figure 4, the stabilization ratio for the less than high school group averages 0.41 in the pre-tax reform period of 1995-97, whereas the average rises to 0.62 over the post-tax reform period 1998-2006, representing a 50 percent increase in the ratio, which is by far the largest increase among the education groups. In contrast, the ratio for university educated heads of households rises by only seven percent between the pre- and post-tax reform periods. Furthermore, the average, across all years, of the ratio of variances for the university educated group is about 1.68 times higher than for the less than high school group, indicating that the system contributes much more to stabilizing the incomes at the lower end of the income distribution. In the case of college educated families, the level and changes in the stabilization ratio broadly resemble the group with less than high school. For the families with just high school education the intertemporal pattern is less in synchrony with the other groups, and the ratio of transitory variances lies above the curve for the college educated group in many of the years. Nevertheless, the ratio for the high school group also rises between the post- and pre-tax reform periods. Thus the tax reforms around 2000 and changes to SA program benefits reduced family protection against market income instability. The fact that, in Figure 4, there are relatively small differences in the average levels of the stabilization ratio across the lowest three educational categories is also interesting. It may reflect the fact that the Canadian federal personal income tax system has few tax brackets and a comparatively small progression of tax rates.
4 Koalitionsvertrag zwischen CDU, CSU und FDP: Wachstum. Bildung. Zusammenhalt., http://www.cdu.de/doc/pdfc/091026-koalitionsver- trag-cducsu-fdp.pdf, Oktober 2009.
Der Gesetzentwurf der Bundesregierung vom 7. Dezem- ber 2011 zum Abbau der kalten Progression durch eine inﬂ ationsbedingte Anpassung des Einkommensteuer- tarifs wurde Anfang Februar dieses Jahres mit Verweis auf die prekäre Haushaltssituation vieler Länder und Ge- meinden vom Bundesrat abgelehnt. Zentrales Ziel des Reformvorschlags ist es, die durch die kalte Progression entstehenden ungewollten Mehreinnahmen des Staates an die Steuerzahler zurückzugeben. 1 Diese Steuermehr-