225 research outputs found
Stem-like and highly invasive prostate cancer cells expressing CD44v8-10 marker originate from CD44-negative cells
In human prostate cancer (PCa), the neuroendocrine cells, expressing the prostate cancer stem cell (CSC) marker CD44, may be resistant to androgen ablation and promote tumor recurrence. During the study of heterogeneity of the highly aggressive neuroendocrine PCa cell lines PC3 and DU-145, we isolated and expanded in vitro a minor subpopulation of very small cells lacking CD44 (CD44neg). Unexpectedly, these sorted CD44neg cells rapidly and spontaneously converted to a stable CD44high phenotype specifically expressing the CD44v8-10 isoform which the sorted CD44high subpopulation failed to express. Surprisingly and potentially interesting, in these cells expression of CD44v8-10 was found to be induced in stem cell medium. CD44 variant isoforms are known to be more expressed in CSC and metastatic cells than CD44 standard isoform. In agreement, functional analysis of the two sorted and cultured subpopulations has shown that the CD44v8-10pos PC3 cells, resulting from the conversion of the CD44neg subpopulation, were more invasive in vitro and had a higher clonogenic potential than the sorted CD44high cells, in that they produced mainly holoclones, known to be enriched in stem-like cells. Of interest, the CD44v8-10 is more expressed in human PCa biopsies than in normal gland. The discovery of CD44v8-10pos cells with stem-like and invasive features, derived from a minoritarian CD44neg cell population in PCa, alerts on the high plasticity of stem-like markers and urges for prudency on the approaches to targeting the putative CSC
Toll-iike receptor-3 activation enhances malignant traits in human breast cancer cells through hypoxia-inducible factor-1α
Background/Aim: Hypoxia-inducible factor 1 (HIF1) inhibitors have been proposed as therapeutic agents for several tumor types. HIF1α is induced by hypoxia and by pathogens in normoxia through toll-like receptors (TLRs). The TLR3 activator polyinosinic:polycytidylic acid [poly(I:C)] induces apoptosis in various types of cancer but not in the most aggressive breast cancer cell lines. We hypothesized that the failure of TLR3 stimulation to induce apoptosis in these cells might be due to an elevated HIF1α level and this link might be exploited. Materials and Methods: Poly(I:C)-induced signaling pathway and expression of HIF1α and HIF1α targets were studied in MDA MB-231 and MCF-7 breast cancer cell lines by western blot. Flow cytometry was used for apoptotic responses and vasculogenic mimicry as bioassay. Results: Poly(I:C) increased expression of HIF1α and its targets BCL2 apoptosis regulator and c-MYC. Moreover, using pharmacological or genetic HIF1 inhibition, reduction of poly(I:C)-induced expression of HIF1α was paralleled by lowering of c-MYC and increased sensitivity to poly(I:C)-induced apoptosis, demonstrating the crucial role of this factor. We provide the first evidence in breast cancer cells that TLR3 stimulation induces HIF1αdependent vasculogenic mimicry. By using specific inhibitors, we identified a signaling cascade upstream of HIF1α induction. Conclusion: Combined treatment with poly(I:C) and HIF1 inhibitors deserves consideration as an effective strategy in breast cancer therapy
c-FLIP regulates autophagy by interacting with Beclin-1 and influencing its stability
c-FLIP (cellular FLICE-like inhibitory protein) protein is mostly known as an apoptosis modulator. However, increasing data underline that c-FLIP plays multiple roles in cellular homoeostasis, influencing differently the same pathways depending on its expression level and isoform predominance. Few and controversial data are available regarding c-FLIP function in autophagy. Here we show that autophagic flux is less effective in c-FLIP−/− than in WT MEFs (mouse embryonic fibroblasts). Indeed, we show that the absence of c-FLIP compromises the expression levels of pivotal factors in the generation of autophagosomes. In line with the role of c-FLIP as a scaffold protein, we found that c-FLIPL interacts with Beclin-1 (BECN1: coiled-coil, moesin-like BCL2-interacting protein), which is required for autophagosome nucleation. By a combination of bioinformatics tools and biochemistry assays, we demonstrate that c-FLIPL interaction with Beclin-1 is important to prevent Beclin-1 ubiquitination and degradation through the proteasomal pathway. Taken together, our data describe a novel molecular mechanism through which c-FLIPL positively regulates autophagy, by enhancing Beclin-1 protein stability
The evolution of galaxy star formation activity in massive halos
There is now a large consensus that the current epoch of the Cosmic Star
Formation History (CSFH) is dominated by low mass galaxies while the most
active phase at 1<z<2 is dominated by more massive galaxies, which undergo a
faster evolution. Massive galaxies tend to inhabit very massive halos such as
galaxy groups and clusters. We aim to understand whether the observed "galaxy
downsizing" could be interpreted as a "halo downsizing", whereas the most
massive halos, and their galaxy populations, evolve more rapidly than the halos
of lower mass. Thus, we study the contribution to the CSFH of galaxies
inhabiting group-sized halos. This is done through the study of the evolution
of the Infra-Red (IR) luminosity function of group galaxies from redshift 0 to
~1.6. We use a sample of 39 X-ray selected groups in the Extended Chandra Deep
Field South (ECDFS), the Chandra Deep Field North (CDFN), and the COSMOS field,
where the deepest available mid- and far-IR surveys have been conducted with
Spitzer MIPS and Hersche PACS. Groups at low redshift lack the brightest,
rarest, and most star forming IR-emitting galaxies observed in the field. Their
IR-emitting galaxies contribute <10% of the comoving volume density of the
whole IR galaxy population in the local Universe. At redshift >~1, the most
IR-luminous galaxies (LIRGs and ULIRGs) are preferentially located in groups,
and this is consistent with a reversal of the star-formation rate vs .density
anti-correlation observed in the nearby Universe. At these redshifts, group
galaxies contribute 60-80% of the CSFH, i.e. much more than at lower redshifts.
Below z~1, the comoving number and SFR densities of IR-emitting galaxies in
groups decline significantly faster than those of all IR-emitting galaxies. Our
results are consistent with a "halo downsizing" scenario and highlight the
significant role of "environment" quenching in shaping the CSFH.Comment: 14 pages, 10 figures, accepted for publication by A&
The impact of protocluster environments at z = 1.6
We investigate the effects of dense environments on galaxy evolution by examining how the properties of galaxies in the z = 1.6 protocluster Cl 0218.3−0510 depend on their location. We determine galaxy properties using spectral energy distribution fitting to 14-band photometry, including data at three wavelengths that tightly bracket the Balmer and 4000 Å breaks of the protocluster galaxies. We find that two-thirds of the protocluster galaxies, which lie between several compact groups, are indistinguishable from field galaxies. The other third, which reside within the groups, differ significantly from the intergroup galaxies in both colour and specific star formation rate. We find that the fraction of red galaxies within the massive protocluster groups is twice that of the intergroup region. These excess red galaxies are due to enhanced fractions of both passive galaxies (1.7 times that of the intergroup region) and dusty star-forming galaxies (3 times that of the intergroup region). We infer that some protocluster galaxies are processed in the groups before the cluster collapses. These processes act to suppress star formation and change the mode of star formation from unobscured to obscured
The role of massive halos in the Star Formation History of the Universe
The most striking feature of the Cosmic Star Formation History (CSFH) of the
Universe is a dramatic drop of the star formation (SF) activity, since z~1. In
this work we investigate if the very same process of assembly and growth of
structures is one of the major drivers of the observed decline. We study the
contribution to the CSFH of galaxies in halos of different masses. This is done
by studying the total SFR-halo mass-redshift plane from redshift 0 to redshift
z~1.6 in a sample of 57 groups and clusters by using the deepest available mid-
and far-infrared surveys conducted with Spitzer MIPS and Herschel PACS and
SPIRE. Our results show that low mass groups provide a 60-80% contribution to
the CSFH at z~1. Such contribution declines faster than the CSFH in the last 8
billion years to less than 10% at z<0.3, where the overall SF activity is
sustained by lower mass halos. More massive systems provide only a marginal
contribution (<10%) at any epoch. A simplified abundance matching method shows
that the large contribution of low mass groups at z~1 is due to a large
fraction (>50%) of very massive, highly star forming Main Sequence galaxies.
Below z~1 a quenching process must take place in massive halos to cause the
observed faster suppression of their SF activity. Such process must be a slow
one though, as most of the models implementing a rapid quenching of the SF
activity in accreting satellites significantly underpredicts the observed SF
level in massive halos at any redshift. Starvation or the transition from cold
to hot accretion would provide a quenching timescale of 1 Gyrs more consistent
with the observations. Our results suggest a scenario in which, due to the
structure formation process, more and more galaxies experience the group
environment and, thus, the associated quenching process. This leads to the
progressive suppression of their SF activity shaping the CSFH below z~1.Comment: 18 pages, 21 figures, accepted for publication by A&
Ultra-deep catalog of X-ray groups in the Extended Chandra Deep Field South
Ultra-deep observations of ECDF-S with Chandra and XMM-Newton enable a search
for extended X-ray emission down to an unprecedented flux of
ergs s cm. We present the search for the extended emission on
spatial scales of 32 in both Chandra and XMM data, covering
0.3 square degrees and model the extended emission on scales of arcminutes. We
present a catalog of 46 spectroscopically identified groups, reaching a
redshift of 1.6. We show that the statistical properties of ECDF-S, such as
logN-logS and X-ray luminosity function are broadly consistent with LCDM, with
the exception that dn/dz/d test reveals that a redshift range of
in ECDF-S is sparsely populated. The lack of nearby structure,
however, makes studies of high-redshift groups particularly easier both in
X-rays and lensing, due to a lower level of clustered foreground. We present
one and two point statistics of the galaxy groups as well as weak-lensing
analysis to show that the detected low-luminosity systems are indeed low-mass
systems. We verify the applicability of the scaling relations between the X-ray
luminosity and the total mass of the group, derived for the COSMOS survey to
lower masses and higher redshifts probed by ECDF-S by means of stacked weak
lensing and clustering analysis, constraining any possible departures to be
within 30% in mass. Abridged.Comment: 20 pages, 21 figures, 3 tables, to match the journal versio
Reversal or no reversal: the evolution of the star formation rate-density relation up to z~1.6
We investigate the evolution of the star formation rate (SFR)-density
relation in the Extended Chandra Deep Field South (ECDFS) and the Great
Observatories Origin Deep Survey (GOODS) fields up to z~1.6. In addition to the
"traditional method", in which the environment is defined according to a
statistical measurement of the local galaxy density, we use a "dynamical"
approach, where galaxies are classified according to three different
environment regimes: group, "filament-like", and field. Both methods show no
evidence of a SFR-density reversal. Moreover, group galaxies show a mean SFR
lower than other environments up to z~1, while at earlier epochs group and
field galaxies exhibit consistent levels of star formation (SF) activity. We
find that processes related to a massive dark matter halo must be dominant in
the suppression of the SF below z~1, with respect to purely density-related
processes. We confirm this finding by studying the distribution of galaxies in
different environments with respect to the so-called Main Sequence (MS) of
star-forming galaxies. Galaxies in both group and "filament-like" environments
preferentially lie below the MS up to z~1, with group galaxies exhibiting lower
levels of star-forming activity at a given mass. At z>1, the star-forming
galaxies in groups reside on the MS. Groups exhibit the highest fraction of
quiescent galaxies up to z~1, after which group, "filament-like", and field
environments have a similar mix of galaxy types. We conclude that groups are
the most efficient locus for star-formation quenching. Thus, a fundamental
difference exists between bound and unbound objects, or between dark matter
haloes of different masses.Comment: Accepted for publication in MNRA
The endogenous caspase-8 inhibitor c-FLIPL regulates ER morphology and crosstalk with mitochondria
Components of the death receptors-mediated pathways like caspase-8 have been identified in complexes at intracellular membranes to spatially restrict the processing of local targets. In this study, we report that the long isoform of the cellular FLICE-inhibitory protein (c-FLIPL), a well- known inhibitor of the extrinsic cell death initiator caspase-8, localizes at the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs). ER morphology was disrupted and ER Ca2+-release as well as ER-mitochondria tethering were decreased in c-FLIP-/- mouse embryonic fibroblasts (MEFs). Mechanistically, c-FLIP ablation resulted in enhanced basal caspase-8 activation and in caspase-mediated processing of the ER-shaping protein reticulon-4 (RTN4) that was corrected by re-introduction of c-FLIPL and caspase inhibition, resulting in the recovery of a normal ER morphology and ER-mitochondria juxtaposition. Thus, the caspase-8 inhibitor c-FLIPL emerges as a component of the MAMs signaling platforms, where caspases appear to regulate ER morphology and ER-mitochondria crosstalk by impinging on ER-shaping proteins like the RTN4
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