Ex Vivo Model of Neuroblastoma Plasticity

Simple Summary The complexity of tumor cell plasticity is still poorly understood. In particular, cellular changes during the metastatic process are difficult to monitor. This is a descriptive study of cell lines derived from primary tumors of xenografted LAN-1 cells and the corresponding three generations of bone metastases. Our results of ex vivo analysis of the cell lines depict the ability of tumor cells to adapt and survive in different microenvironments undergoing significant cellular alterations. The cell lines show strong phenotypical and biochemical changes and even an altered response to immune cells and chemotherapy. In conclusion, this mouse model allows to analyze the complex changes in tumor cell populations during metastasis and can be adapted to cell lines from different tumor origins. Abstract Tumor plasticity is essential for adaptation to changing environmental conditions, in particular during the process of metastasis. In this study, we compared morphological and biochemical differences between LAN-1 neuroblastoma (NB) cells recovered from a subcutaneous xenograft primary tumor (PT) and the corresponding three generations of bone metastasis (BM I–III). Moreover, growth behavior, as well as the response to chemotherapy and immune cells were assessed. For this purpose, F-actin was stained, mRNA and protein expression assessed, and lactate secretion analyzed. Further, we measured adhesion to collagen I, the growth rate of spheroids in the presence and absence of vincristine, and the production of IL-6 by peripheral blood mononuclear cells (PBMCs) co-incubated with PT or BM I–III. Analysis of PT and the three BM generations revealed that their growth rate decreased from PT to BM III, and accordingly, PT cells reacted most sensitively to vincristine. In addition, morphology, adaption to hypoxic conditions, as well as transcriptomes showed strong differences between the cell lines. Moreover, BM I and BM II cells exhibited a significantly different ability to stimulate human immune cells compared to PT and BM III cells. Interestingly, the differences in immune cell stimulation corresponded to the expression level of the cancer-testis antigen MAGE-A3. In conclusion, our ex vivo model allows to analyze the adaption of tumor populations to different microenvironments and clearly demonstrates the strong alteration of tumor cell populations during this process

Deep extragalactic visible legacy survey (DEVILS): the emergence of bulges and decline of disc growth since z = 1

We present a complete structural analysis of the ellipticals (E), diffuse bulges (dB), compact bulges (cB), and discs (D) within a redshift range 0 \u3c z \u3c 1, and stellar mass log10(M*/M⊙) ≥ 9.5 volume-limited sample drawn from the combined DEVILS and HST-COSMOS region. We use the PROFIT code to profile over ∼35 000 galaxies for which visual classification into single or double component was pre-defined in Paper-I. Over this redshift range, we see a growth in the total stellar mass density (SMD) of a factor of 1.5. At all epochs we find that the dominant structure, contributing to the total SMD, is the disc, and holds a fairly constant share of ∼60 per cent role= presentation style= box-sizing: border-box; margin: 0px; padding: 0px; border: 0px; font-variant: inherit; font-stretch: inherit; line-height: normal; font-family: inherit; vertical-align: baseline; display: inline; word-spacing: normal; overflow-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; position: relative; \u3e∼60 per cent∼60 per cent of the total SMD from z = 0.8 to z = 0.2, dropping to ∼30 per cent role= presentation style= box-sizing: border-box; margin: 0px; padding: 0px; border: 0px; font-variant: inherit; font-stretch: inherit; line-height: normal; font-family: inherit; vertical-align: baseline; display: inline; word-spacing: normal; overflow-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; position: relative; \u3e∼30 per cent∼30 per cent at z = 0.0 (representing ∼33 per cent role= presentation style= box-sizing: border-box; margin: 0px; padding: 0px; border: 0px; font-variant: inherit; font-stretch: inherit; line-height: normal; font-family: inherit; vertical-align: baseline; display: inline; word-spacing: normal; overflow-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; position: relative; \u3e∼33 per cent∼33 per cent decline in the total disc SMD). Other classes (E, dB, and cB) show steady growth in their numbers and integrated stellar mass densities. By number, the most dramatic change across the full mass range is in the growth of diffuse bulges. In terms of total SMD, the biggest gain is an increase in massive elliptical systems, rising from 20 per cent at z = 0.8 to equal that of discs at z = 0.0 (30 per cent) representing an absolute mass growth of a factor of 2.5. Overall, we see a clear picture of the emergence and growth of all three classes of spheroids over the past 8 Gyr, and infer that in the later half of the Universe’s timeline spheroid-forming processes and pathways (secular evolution, mass-accretion, and mergers) appear to dominate mass transformation over quiescent disc growth

GAMA/DEVILS: Cosmic star formation and AGN activity over 12.5 billion years

We use the Galaxy and Mass Assembly (GAMA) and the Deep Extragalactic Visible Legacy Survey (DEVILS) observational data sets to calculate the cosmic star formation rate (SFR) and active galactic nuclei (AGN) bolometric luminosity history (CSFH/CAGNH) over the last 12.5 billion years. SFRs and AGN bolometric luminosities were derived using the spectral energy distribution fitting code ProSpect, which includes an AGN prescription to self consistently model the contribution from both AGN and stellar emission to the observed rest-frame ultra-violet to far-infrared photometry. We find that both the CSFH and CAGNH evolve similarly, rising in the early Universe up to a peak at look-back time $\approx 10$~Gyr ($z \approx 2$), before declining toward the present day. The key result of this work is that we find the ratio of CAGNH to CSFH has been flat ($\approx 10^{42.5}\mathrm{erg \, s^{-1}M_{\odot}^{-1}yr}$) for $11$~Gyr up to the present day, indicating that star formation and AGN activity have been coeval over this time period. We find that the stellar masses of the galaxies that contribute most to the CSFH and CAGNH are similar, implying a common cause, which is likely gas inflow. The depletion of the gas supply suppresses cosmic star formation and AGN activity equivalently to ensure that they have experienced similar declines over the last 10 Gyr. These results are an important milestone for reconciling the role of star formation and AGN activity in the life cycle of galaxies.Comment: 16 pages, 10 figures. Figures 9 and 10 are the main results. Accepted for publication in Monthly Notices of the Royal Astronomical Societ

Malignant H1299 tumour cells preferentially internalize iron-bound inositol hexakisphosphate

In colon enterocytes and in well-differentiated colon cancer CaCo-2 cells, InsP6 (inositol hexakisphosphate) inhibits iron uptake by forming extracellular insoluble iron/InsP6 complexes. In this study, we confirmed that CaCo-2 cells are not able to take up iron/InsP6 but, interestingly, found that the cells are able to internalize metal-free and Cr3+-bound InsP6. Thus, the inability of CaCo-2 cells to take up iron/InsP6 complexes seems to be due to the iron-bound state of InsP6. Since recently we demonstrated that the highly malignant bronchial carcinoma H1299 cells internalize and process InsP6, we examined whether these cells may be able to take up iron/InsP6 complexes. Indeed, we found that InsP6 dose-dependently increased uptake of iron and demonstrated that in the iron-bound state InsP6 is more effectively internalized than in the metal-free or Cr3+-bound state, indicating that H1299 cells preferentially take up iron/InsP6 complexes. Electron microscope and cell fraction assays indicate that after uptake H1299 cells mainly stored InsP6/iron in lysosomes as large aggregates, of which about 10% have been released to the cytosol. However, this InsP6-mediated iron transport had no significant effects on cell viability. This result together with our finding that the well-differentiated CaCo-2 cells did not, but the malignant H1299 cells preferentially took up iron/InsP6, may offer the possibility to selectively transport cytotoxic substances into tumour cells

Tight Junction Proteins Claudin-1 and Occludin Are Important for Cutaneous Wound Healing

Tight junction (TJ) proteins are known to be involved in proliferation and differentiation. These processes are essential for normal skin wound healing. Here, we investigated the TJ proteins claudin-1 and occludin in ex vivo skin wound healing models and tissue samples of acute and chronic human wounds and observed major differences in localization/expression of these proteins, with chronic wounds often showing a loss of the proteins at the wound margins and/or in the regenerating epidermis. Knockdown experiments in primary human keratinocytes showed that decreased claudin-1 expression resulted in significantly impaired scratch wound healing, with delayed migration and reduced proliferation. Activation of AKT pathway was significantly attenuated after claudin-1 knockdown, and protein levels of extracellular signal-related kinase 1/2 were reduced. For occludin, down-regulation had no impact on wound healing in normal scratch assays, but after subjecting the cells to mechanical stress, which is normally present in wounds, wound healing was impaired. For both proteins we show that most of these actions are independent from the formation of barrier-forming TJ structures, thus demonstrating nonbarrier-related functions of TJ proteins in the skin. However, for claudin-1 effects on scratch wound healing were more pronounced when TJs could form. Together, our findings provide evidence for a role of claudin-1 and occludin in epidermal regeneration with potential clinical importance