72 research outputs found
Podoplanin in Inflammation and Cancer.
Podoplanin is a small cell-surface mucin-like glycoprotein that plays a crucial role in the
development of the alveoli, heart, and lymphatic vascular system. Emerging evidence indicates that
it is also involved in the control of mammary stem-cell activity and biogenesis of platelets in the
bone marrow, and exerts an important function in the immune response. Podoplanin expression is
upregulated in different cell types, including fibroblasts, macrophages, T helper cells, and epithelial
cells, during inflammation and cancer, where it plays important roles. Podoplanin is implicated
in chronic inflammatory diseases, such as psoriasis, multiple sclerosis, and rheumatoid arthritis,
promotes inflammation-driven and cancer-associated thrombosis, and stimulates cancer cell invasion
and metastasis through a variety of strategies. To accomplish its biological functions, podoplanin must
interact with other proteins located in the same cell or in neighbor cells. The binding of podoplanin
to its ligands leads to modulation of signaling pathways that regulate proliferation, contractility,
migration, epithelial–mesenchymal transition, and remodeling of the extracellular matrix. In this
review, we describe the diverse roles of podoplanin in inflammation and cancer, depict the protein
ligands of podoplanin identified so far, and discuss the mechanistic basis for the involvement of
podoplanin in all these processes.post-print1279 K
Sensory integration dynamics in a hierarchical network explains choice probabilities in cortical area MT
Neuronal variability in sensory cortex predicts perceptual decisions. This relationship, termed choice probability (CP), can arise from sensory variability biasing behaviour and from top-down signals reflecting behaviour. To investigate the interaction of these mechanisms during the decision-making process, we use a hierarchical network model composed of reciprocally connected sensory and integration circuits. Consistent with monkey behaviour in a fixed-duration motion discrimination task, the model integrates sensory evidence transiently, giving rise to a decaying bottom-up CP component. However, the dynamics of the hierarchical loop recruits a concurrently rising top-down component, resulting in sustained CP. We compute the CP time-course of neurons in the medial temporal area (MT) and find an early transient component and a separate late contribution reflecting decision build-up. The stability of individual CPs and the dynamics of noise correlations further support this decomposition. Our model provides a unified understanding of the circuit dynamics linking neural and behavioural variability
Greater diversity than previously thought of chromaffin cell Ca2+ channels, derived from mRNA identification studies
AbstractUsing reverse transcription followed by PCR amplification (RT-PCR), we have identified multiple messenger RNAs encoding for the neuronal pore-forming Ca2+ channel subunits α1A (P/Q channel), α1B (N channel), α1D (neuronal/endocrine L channel), α1E (R channel), α1G-H (T channel) and α1S (skeletal muscle L channel) in bovine chromaffin cells. mRNAs for the auxiliary β2, β3, β4, α2/δ and γ2 subunits were also identified. In agreement with these molecular data, perforated patch-clamp recordings of whole-cell Ca2+ currents reveal the existence of functional R-type Ca2+ channels in these cells that were previously undetected with other techniques. Our results provide a molecular frame for a much wider functional diversity of Ca2+ channels in chromaffin cells than that previously established using pharmacological and electrophysiological approaches
Interplay between Podoplanin, CD44s and CD44v in Squamous Carcinoma Cells.
Podoplanin and CD44 are transmembrane glycoproteins involved in inflammation and
cancer. In this paper, we report that podoplanin is coordinately expressed with the CD44 standard
(CD44s) and variant (CD44v) isoforms in vivo—in hyperplastic skin after a pro-inflammatory
stimulus with 12-O-tetradecanoylphorbol-13-acetate (TPA)—and in vitro—in cell lines representative
of di erent stages of mouse-skin chemical carcinogenesis, as well as in human squamous carcinoma
cell (SCC) lines. Moreover, we identify CD44v10 in the mouse-skin carcinogenesis model as the only
CD44 variant isoform expressed in highly aggressive spindle carcinoma cell lines together with CD44s
and podoplanin. We also characterized CD44v3-10, CD44v6-10 and CD44v8-10 as the major variant
isoforms co-expressed with CD44s and podoplanin in human SCC cell lines. Immunofluorescence
confocal microscopy experiments show that these CD44v isoforms colocalize with podoplanin
at plasma membrane protrusions and cell–cell contacts of SCC cells, as previously reported for
CD44s. Furthermore, CD44v isoforms colocalize with podoplanin in chemically induced mouse-skin
SCCs in vivo. Co-immunoprecipitation experiments indicate that podoplanin physically binds to
CD44v3-10, CD44v6-10 and CD44v8-10 isoforms, as well as to CD44s. Podoplanin–CD44 interaction is
mediated by the transmembrane and cytosolic regions and is negatively modulated by glycosylation of
the extracellular domain. These results point to a functional interplay of podoplanin with both CD44v
and CD44s isoforms in SCCs and give insight into the regulation of the podoplanin–CD44 associationpost-print4.258 K
Response of Spiking Neurons to Correlated Inputs
The effect of a temporally correlated afferent current on the firing rate of
a leaky integrate-and-fire (LIF) neuron is studied. This current is
characterized in terms of rates, auto and cross-correlations, and correlation
time scale of excitatory and inhibitory inputs. The output rate
is calculated in the Fokker-Planck (FP) formalism in the limit of
both small and large compared to the membrane time constant of
the neuron. By simulations we check the analytical results, provide an
interpolation valid for all and study the neuron's response to rapid
changes in the correlation magnitude.Comment: 4 pages, 3 figure
Soluble endoglin antagonizes Met signaling in spindle carcinoma cells
Increased levels of soluble endoglin (Sol-Eng) correlate with poor outcome in human cancer. We have previously shown that shedding of membrane endoglin, and concomitant release of Sol-Eng is a late event in chemical mouse skin carcinogenesis associated with the development of undifferentiated spindle cell carcinomas (SpCCs). In this report, we show that mouse skin SpCCs exhibit a high expression of hepatocyte growth factor (HGF) and an elevated ratio of its active tyrosine kinase receptor Met versus total Met levels. We have evaluated the effect of Sol-Eng in spindle carcinoma cells by transfection of a cDNA encoding most of the endoglin ectodomain or by using purified recombinant Sol-Eng. We found that Sol-Eng inhibited both mitogen-activated protein kinase (MAPK) activity and cell growth in vitro and in vivo. Sol-Eng also blocked MAPK activation by transforming growth factor-β1 (TGF-β1) and impaired both basal and HGF-induced activation of Met and downstream MAPK. Moreover, Sol-Eng strongly reduced basal and HGF-stimulated spindle cell migration and invasion. Both Sol-Eng and full-length endoglin were shown to interact with Met by coimmunoprecipitation experiments. However, full-length endoglin expressed at the plasma membrane of spindle carcinoma cells had no effect on Met signaling activity, and was unable to inhibit HGF-induced cell migration/invasion. These results point to a paradoxical suppressor role for Sol-Eng in carcinogenesis.Ministerio de Economía y Competitividad (SAF2010-19152, SAF2013-46183-R to M.Q., and SAF2010-19222, SAF2013-43421-R to C.B.), Comunidad Autónoma de Madrid (S2010/BMD-2359, SkinModel, to M.Q.). GdC was the recipient of a Juan de la Cierva postdoctoral research contract. EP-G and EM-V are the recipients of a postdoctoral research contract from the scientific foundation of Asociación Española Contra el Cáncer (AECC).Peer reviewe
Plasma levels of mitochondrial and nuclear DNA in patients with massive pulmonary embolism in the emergency department: A prospective cohort study
Introduction: Cell-free plasma mitochondrial DNA (mt-DNA) and nuclear DNA (n-DNA) are biomarkers with
prognostic utility in conditions associated with a high rate of cell death. This exploratory study aimed to determine
the plasma levels of both nucleic acids in patients with massive and submassive pulmonary embolism (PE) and to
compare them with other biomarkers, such as heart-type fatty acid-binding protein (H-FABP) and troponin I (Tn-I)
Methods: This was a prospective observational study of 37 consecutive patients with massive PE, 37 patients with
submassive PE, and 37 healthy subjects. Quantifications of plasma mt-DNA and n-DNA with real-time quantitative
polymerase chain reaction (PCR), and plasma H-FABP and Tn-I by commercial assays, were done on blood samples
drawn within 4 hours after presentation at the emergency department.
Results: Plasma mt-DNA and n-DNA concentrations were much higher in patients with massive PE (median, 2,970
GE/ml; interquartile range (IQR), 1,050 to 5,485; and 3,325 GE/ml, IQR: 1,080 to 5,790, respectively) than in patients
with submassive PE (870 GE/ml and 1,245 GE/ml, respectively; P < 0.01) or controls (185 GE/ml and 520 GE/ml,
respectively). Eighteen patients with massive PE died of a PE-related cause by day 15 of observation. Plasma mt-
DNA and n-DNA values were 2.3-fold and 1.9-fold higher in the subgroup of nonsurviving patients than in
survivors. H-FABP and Tn-I values were also higher in patients with massive PE who died (7.3 ng/ml and 0.023 ng/ml,
respectively) than in those who survived (6.4 ng/ml, and 0.016 ng/ml, respectively). By receiver operating curve (ROC)
analysis, the best cutoff values for predicting 15-day mortality were 3,380 GE/ml for mt-DNA, 6.8 ng/ml for H-FABP,
3,625 GE/ml for n-DNA, and 0.020 ng/ml for Tn-I, based on the calculated areas under the curve (AUCs) of 0.89
(95% confidence interval (CI), 0.78 to 0.99), 0.76 (95% CI, 0.69 to 093), 0.73 (95% CI, 0.58 to 0.91), and 0.59 (95% CI,
0.41 to 0.79), respectively. By stepwise logistic regression, a plasma mt-DNA concentration greater than 3,380 GE/ml
(adjusted odds ratio (OR), 8.22; 95% CI, 1.72 to 39.18; P 6.8 ng/ml (OR, 5.36;
95% CI, 1.06 to 27.08; P < 0.01) were the only independent predictors of mortality.
Conclusions: mt-DNA and H-FBAP might be promising markers for predicting 15-day mortality in massive PE, with
mt-DNA having better prognostic accuracy.This work
was supported partially by grants from Plan Nacional I+D+I (SAF 2008-05347
and SAF2011-23575) and from Fundación Mutua Madrileña de Investigación
Biomédica (2008 and 2011) to Francisco Arnalich and Carmen Montie
Reduced expression of the murine HLA-G homolog Qa-2 is associated with malignancy, epithelialmesenchymal transition and stemness in breast cancer cells.
Qa-2 is believed to mediate a protective immune response against cancer; however, little is known
about the role of Qa-2 in tumorigenesis. Here, we used 4T1 breast cancer cells to study the involvement
of Qa-2 in tumor progression in a syngeneic host. Qa-2 expression was reduced during in vivo tumor
growth and in cell lines derived from 4T1-induced tumors. Tumor-derived cells elicited an epithelialmesenchymal
transition associated with upregulation of Zeb1 and Twist1/2 and enhanced tumor
initiating and invasive capacities. Furthermore, these cells showed increased stem characteristics, as
demonstrated by upregulation of Hes1, Sox2 and Oct3/4, and enrichment of CD44high/CD24median/low
cells. Remarkably, Qa-2 cell-surface expression was excluded from the CD44high/CD24median/low
subpopulation. Tumor-derived cells showed increased Src activity, and treatment of these cells with the
Src kinase inhibitor PP2 enhanced Qa-2 but reduced Sox2 and CD44high/CD24median/low expression levels,
suggesting that Src signaling, while positively associated with stemness, negatively regulates Qa-2
expression in breast cancer. Finally, overexpression of the Qa-2 family member Q7 on the cell surface
slowed down in vivo tumor growth and reduced the metastatic potential of 4T1 cells. These results
suggest an anti-malignant role for Qa-2 in breast cancer development, which appears to be absent from
cancer stem cells.post-print2122 K
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