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 $2\times10^{-16}$ ergs s$^{-1}$ cm$^{-2}$. We present the search for the extended emission on spatial scales of 32$^{\prime\prime}$ 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$\Omega$ test reveals that a redshift range of $0.2<z<0.5$ 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