Chemotactic Cell Movement Research Articles

Tumor-derived Hsp70-CD14 interaction enhances the antitumor potential of cytotoxic T cells by activating tumor-associated macrophages to express CC chemokines and CD40 costimulatory molecules

Heat shock proteins are a widely distributed group of proteins. It is constitutively expressed in almost all organisms and shows little variation throughout evolution. Previously, HSPs, particularly Hsp70, were recognized as molecular chaperones that aid in the proper three-dimensional folding of newly synthesized polypeptides in cells. Recently, researchers have focused on the potential induction of immune cells, including macrophages, antigen-specific CD8+ cytotoxic T cells, and PBMCs. It induces the expression of CC chemokines such as MIP-1α and RANTES, which are responsible for the chemotactic movement and migration of immune cells at the site of infection to neutralize foreign particles in vivo and in vitro in several cell lines but their effect on tumor-associated macrophages is still not known. These cytokines are also known to influence the movement of several immune cells, including CD8+ cytotoxic T cells, toward inflammatory sites. Therefore, the effect of tumor-derived autologous Hsp70 on the expression of MIP-lα and RANTES in tumor-associated macrophages (TAMs) was investigated. Our results indicated that Hsp70 treatment-induced MIP-lα and RANTES expression was significantly greater in TAMs than in NMOs. According to the literature, the CC chemokine shares the same receptor, CCR5, as HIV does for their action, and therefore could provide better completion to the virus for ligand binding. Furthermore, Hsp70-preactivated TAMs induced increased IL-2 and IFN-γ expression in T cells during coculture for 48 h and upregulated the antitumor immune response of the host. Therefore, the outcome of our study could be useful for developing a better approach to restricting the growth and progression of tumors.

Derivatives of Differentiation-Inducing Factor 1 Differentially Control Chemotaxis and Stalk Cell Differentiation in Dictyostelium discoideum.

Differentiation-inducing factors 1 and 2 (DIF-1 and DIF-2) are small lipophilic signal molecules that induce stalk cell differentiation but differentially modulate chemotaxis toward cAMP in the cellular slime mold Dictyostelium discoideum; DIF-1 suppresses chemotactic cell movement in shallow cAMP gradients, whereas DIF-2 promotes it. The receptor(s) for DIF-1 and DIF-2 have not yet been identified. We examined the effects of nine derivatives of DIF-1 on chemotactic cell movement toward cAMP and compared their chemotaxis-modulating activity and stalk cell differentiation-inducing activity in wild-type and mutant strains. The DIF derivatives differentially affected chemotaxis and stalk cell differentiation; for example, TM-DIF-1 suppressed chemotaxis and showed poor stalk-inducing activity, DIF-1(3M) suppressed chemotaxis and showed strong stalk-inducing activity, and TH-DIF-1 promoted chemotaxis. These results suggest that DIF-1 and DIF-2 have at least three receptors: one for stalk cell induction and two for chemotaxis modulation. In addition, our results show that the DIF derivatives can be used to analyze the DIF-signaling pathways in D. discoideum.

Tailoring Escherichia coli Chemotactic Sensing towards Cadmium by Computational Redesign of Ribose-Binding Protein.

ABSTRACTPeriplasmic binding proteins such as ribose-binding proteins (RBPs) are involved in the bacterial chemotaxis two-component system. RBP selectively identifies and interacts with ribose to induce a conformational change that leads to chemotaxis. Here, we report the development of an engineered Escherichia coli (E. coli) strain expressing a redesigned RBP that can effectively sense cadmium ions and regulate chemotactic movement of cells toward a cadmium ion gradient. RBP was computationally redesigned to bind cadmium ions and produce the conformational change required for chemoreceptor binding. The successful design, CdRBP1, binds to cadmium ions with a dissociation constant of 268 nM. When CdRBP1 was expressed in the periplasmic space of E. coli, the bacteria became live cadmium ion hunters with high selectivity over other divalent metal ions. This work presents an example of making cadmium ions, which are toxic for most organisms, as an attractant to regulate cells movement. Our approach also demonstrates that RBP can be precisely designed to develop metal-detecting living systems for potential applications in synthetic biology and environmental studies.IMPORTANCE Cadmium pollution is one of the major environmental problems due to excessive release and accumulation. New technologies that can auto-detect cadmium ions with good biocompatibility are in urgent need. In this study, we engineered the bacterial chemotaxis system to positively sense cadmium ions by redesigning ribose-binding protein (RBP) to tightly bind cadmium ion and produce the right conformational change for receptor binding and signaling. Our engineered E. coli cells can auto-detect and chase cadmium ions with divalent metal ion selectivity. Many attempts have been carried out to redesign RBP at the ribose binding site with little success. Instead of the ribose binding site, we introduced the cadmium binding site in the opening of the ribose binding pocket by a specially developed computational algorithm. Our design strategy can be applied to engineer live bacteria with autonomous detection and remediation abilities for metal ions or other chemicals in the future.

Abstract PS17-54: Hepatocyte growth factor regulates the expression of chemokine family in vascular endothelial cells; potential implications in clinical breast cancer

Abstract Background. Hepatocyte growth factor (HGF) is a powerful cellular migration stimulating cytokine (a motogen) of both epithelial and endothelial cells. The induced cell motility is mainly in the form of chemokinesis, namely undirectional movement of the cells in response to exogenous stimuli. HGF is a key angiogenic and lymphangiogenic factor, partially through its effects on endothelial cellular migration, adhesiveness and morphogenesis, which in turn contribute to the growth and spread of cancer cells including breast cancer cells. It has been suggested that HGF might directly or indirectly mediate chemotactic cell movement, namely chemotaxis. Here, we investigated the impact of HGF on the expression of the chemokine family, including the CCL (C-C Motif Chemokine Ligands) family and the CXCL (C-X-C Motif Chemokine Ligands) family and the subsequent consequence of these chemokines on endothelial and cancer cells. Method. Human recombinant hepatocyte growth factor and human recombinant CCLs were used in the study. Human vascular endothelial cells were challenged with HGF and their gene expression was profiled using gene microarray technology. The effects of the responsive chemokines were further tested on endothelial cells and the expression of the respective CCLs was knocked down in endothelial cells by way of siRNA. The impact on the paracellular permeability was assessed by PCP (paracellular permeability) assay using a fluorescence tracer and by transendothelial electrical resistance (TER). TER and cellular migration were also evaluated using automated electric cell substrate impedance sensing (ECIS) methods. Results. Within the concentrations known to induce biological functions in endothelial cells, HGF had a profound upregulatory effect on the expression of multiple chemokines, including CCL14, CCL20, CCL21, CCL28. CXCL family members also responded to HGF, including CXCL8 (p<0.001), CXCL3 (p<0.01), CXCL2 (p=0.01) and CXCL17 (p<0.05). We chose to further investigate the effects of a panel of CCLs which have significant clinical connections in breast cancer, notably CCL20 (otherwise known as LARC, Liver And Activation-Regulated Chemokine). High level CCL20 expression in breast cancer is correlated with a favourable relapse free survival (p=0.0021) of the patients (TCGA database, kmplot.com). CCL20 had a marginal inhibitory effect on the permeability of paracellular space, however, it had profound effects on the migration of cancer cells, seen by a marked increase in cellular migration. A similar stimulatory effect on cancer cells was seen in conditioned media from HGF activated endothelial cells, and partially abolished by siRNA to CCL20. Discussion. HGF exerts an upregulatory effect on the expression of certain chemokines from endothelial cells, which in turn acted on cancer cells by inducing chemotaxic effects. HGF, via regulation of chemokines, may regulate both directional and unidirectional migration of cancer cells, and impact the disease progression in breast cancer. Citation Format: Wenjing Gong, Andrew James Sanders, Tracey Amanda Martin, Yanan Gu, Ping Sun, Wen Guo Jiang. Hepatocyte growth factor regulates the expression of chemokine family in vascular endothelial cells; potential implications in clinical breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-54.

G-CSF Inhibits Pulmonary Fibrosis by Promoting BMSC Homing to the Lungs via SDF-1/CXCR4 Chemotaxis

Bone marrow mesenchymal stem cells (BMSCs) have multi-lineage differentiation potential and play an important role in tissue repair. Studies have shown that BMSCs gather at the injured tissue site after granulocyte-colony stimulating factor (G-CSF) administration. In this study, we first investigated whether G-CSF could promote BMSC homing to damaged lung tissue induced by bleomycin (BLM) and then investigated whether SDF-1/CXCR4 chemotaxis might be involved in this process. Next, we further studied the potential inhibitory effect of G-CSF administration in mice with lung fibrosis induced by bleomycin. We examined both the antifibrotic effects of G-CSF in mice with bleomycin-induced pulmonary fibrosis in vivo and its effects on the proliferation, differentiation and chemotactic movement of cells in vitro. Flow cytometry, real-time PCR, transwell and Cell Counting Kit-8 (CCK-8) assays were used in this study. The results showed that both preventative and therapeutic G-CSF administration could significantly inhibit bleomycin-induced pulmonary fibrosis. G-CSF enhanced BMSC migration to lung tissues, but this effect could be alleviated by AMD3100, which blocked the SDF-1/CXCR4 axis. We also found that BMSCs could inhibit fibroblast proliferation and transdifferentiation into myofibroblasts through paracrine actions. In conclusion, G-CSF exerted antifibrotic effects in bleomycin-induced lung fibrosis, in part by promoting BMSC homing to injured lung tissues via SDF-1/CXCR4 chemotaxis.

A device for investigation of natural cell mobility and deformability.

A microfluidic device made of polydimethylsiloxane was developed for continuous evaluation of natural migration mobility of many eukaryotic cells in relaxed and deformed state. The device was fabricated by standard photolithography and soft lithography techniques using the SU-8 3010 negative photoresist on a glass wafer as the master mold. The simple flow-free device exploits the chemotactic movement of cells through a set of mechanical barriers in the direction of concentration gradients of attractants. The barriers are formed by arrays of circular cross-section pillars with decreasing spacing 7, 5, and 3μm. To pass through the obstacles, the cells are deformed and change their cytoskeletal architecture. The instantaneous migration velocities of cells are monitored in a time-lapse setup of the scanning confocal microscope. Thus, the cellular deformability and migratory activity can easily be evaluated. The functionality of the device was tested with model HeLa cells stably transfected with fluorescent Premo FUCCI Cell Cycle Sensor. The designed device has the potential to be implemented for testing the tendency of patients' tumors to metastasis.

Glutathione S-transferase 4 is a putative DIF-binding protein that regulates the size of fruiting bodies in Dictyostelium discoideum

In the development of the cellular slime mold Dictyostelium discoideum, two chlorinated compounds, the differentiation-inducing factors DIF-1 and DIF-2, play important roles in the regulation of both cell differentiation and chemotactic cell movement. However, the receptors of DIFs and the components of DIF signaling systems have not previously been elucidated. To identify the receptors for DIF-1 and DIF-2, we here performed DIF-conjugated affinity gel chromatography and liquid chromatography–tandem mass spectrometry and identified the glutathione S-transferase GST4 as a major DIF-binding protein. Knockout and overexpression mutants of gst4 (gst4– and gst4OE, respectively) formed fruiting bodies, but the fruiting bodies of gst4– cells were smaller than those of wild-type Ax2 cells, and those of gst4OE cells were larger than those of Ax2 cells. Both chemotaxis regulation and in vitro stalk cell formation by DIFs in the gst4 mutants were similar to those of Ax2 cells. These results suggest that GST4 is a DIF-binding protein that regulates the sizes of cell aggregates and fruiting bodies in D. discoideum.

Differentiation-inducing factor 2 modulates chemotaxis via the histidine kinase DhkC-dependent pathway in Dictyostelium discoideum.

Differentiation-inducing factor 1(DIF-1) and DIF-2 are signaling molecules that control chemotaxis in Dictyostelium discoideum. Whereas DIF-1 suppresses chemotaxis in shallow cAMP gradients, DIF-2 enhances chemotaxis under the same conditions via a phosphodiesterase, response regulator A (RegA), which is a part of the DhkC-RdeA-RegA two-component signaling system. In this study, to investigate the mechanism of the chemotaxis regulation by DIF-2, we examined the effects of DIF-2 (and DIF-1) on chemotaxis in rdeA(-) and dhkC(-) mutant strains. In the parental wild-type strains, chemotactic cell movement was suppressed with DIF-1 and enhanced with DIF-2 in shallow cAMP gradients. In contrast, in both rdeA(-) and dhkC(-) strains, chemotaxis was suppressed with DIF-1 but unaffected by DIF-2. The results suggest that DIF-2 modulates chemotaxis via the DhkC-RdeA-RegA signaling system.

HDAC6 deacetylates alpha tubulin in sperm and modulates sperm motility in Holtzman rat.

Histone deacetylase 6 (HDAC6) is an alpha (α)-tubulin deacetylase and its over-expression has been demonstrated to promote chemotactic cell movement. Motility in sperm is driven by the flagella, the cytoskeletal structure comprising the microtubules, which are heterodimers of α- and β-tubulins. We have hypothesized that HDAC6, by virtue of being an α-tubulin deacetylase, might modulate sperm motility. However, the presence of HDAC6 on sperm has hitherto not been reported. In this study, we have demonstrated, for the first time, the presence of HDAC6 transcript and protein in the testicular and caudal sperm of rat. We have observed a significantly overlapping expression of HDAC6 with acetyl α-tubulin (Ac α-tubulin) in the mid-piece and principal piece of sperm flagella, and the co-precipitation of α-tubulin and Ac α-tubulin together with HDAC6 and vice versa in sperm lysates. This indicates that HDAC6 interacts with α-tubulin. The HDAC6 activity of sperm, sperm motility and status of Ac α-tubulin investigated in the presence of HDAC inhibitors Trichostatin A, Tubastatin A and sodium butyrate demonstrate that HDAC6 in sperm is catalytically active and that inhibitors of HDAC6 increase acetylation and restrict sperm motility. Thus, we show that (1) active HDAC6 enzyme is present in sperm, (2) HDAC6 in sperm is able to deacetylate α-tubulin, (3) inhibition of HDAC6 results in increased Ac α-tubulin expression and (4) HDAC6 inhibition affects sperm motility. This evidence suggests that HDAC6 is involved in modulating sperm movement.

Reduction of critical mass in a chemotaxis system by external application of chemoattractant

In this paper we study non-negative radially symmetric solutions of a parabolic-elliptic Keller-Segel system. The system describes the chemotactic movement of cells under the additional circumstance that an external application of a chemo attractant at a distinguished point is introduced.

Loss of the Histidine Kinase DhkD Results in Mobile Mounds during Development of Dictyostelium discoideum

BackgroundHistidine kinases are receptors for sensing cellular and environmental signals, and in response to the appropriate cue they initiate phosphorelays that regulate the activity of response regulators. The Dictyostelium discoideum genome encodes 15 histidine kinases that function to regulate several processes during the multicellular developmental program, including the slug to culmination transition, osmoregulation, and spore differentiation. While there are many histidine kinases, there is only a single response regulator, RegA. Not surprisingly given the ubiquitous involvement of cAMP in numerous processes of development in Dictyostelium , RegA is a cAMP phosphodiesterase that is activated upon receiving phosphates through a phosphorelay. Hence, all of the histidine kinases characterized to date regulate developmental processes through modulating cAMP production. Here we investigate the function of the histidine kinase DhkD.Principal FindingsThe dhkD gene was disrupted, and the resulting cells when developed gave a novel phenotype. Upon aggregation, which occurred without streaming, the mounds were motile, a phenotype termed the pollywog stage. The pollywog phenotype was dependent on a functional RegA. After a period of random migration, the pollywogs attempted to form fingers but mostly generated aberrant structures with no tips. While prestalk and prespore cell differentiation occurred with normal timing, proper patterning did not occur. In contrast, wild type mounds are not motile, and the cAMP chemotactic movement of cells within the mound facilitates proper prestalk and prespore patterning, tip formation, and the vertical elongation of the mound into a finger.ConclusionsWe postulate that DhkD functions to ensure the proper cAMP distribution within mounds that in turn results in patterning, tip formation and the transition of mounds to fingers. In the absence of DhkD, aberrant cell movements in response to an altered cAMP distribution result in mound migration, a lack of proper patterning, and an inability to generate normal finger morphology.

Chemotactic cell movement a key mechanism of tissue dynamics and morphogenesis

We investigate the molecular mechanisms by which cells produce and detect chemotactic signals and translate this information in directed movement up or down chemical gradients in the social amoebae Dictyostelium discoideum, and during gastrulation in the chick embryo. Investigation of Dictyostelium mutants with changes in cAMP cell-cell signalling dynamics and chemotaxis, show how cellular heterogeneity in signalling dynamics and polarised activation of the actin-myosin cytoskeleton drive aggregation, cell sorting, slug formation and migration. Our experiments furthermore show that chemotactic cell movement plays a critical role during gastrulation in the chick embryo. We suggest that epiblast cell movement during the formation of the primitive streak as well as the movement of the mesoderm cells after their ingression through the streak is controlled by a combination of attractive and repulsive guidance cues. We have identified FGF4 and VEGFA as attractive cues for mesoderm cells, while FGF8 and Wnt's act as repulsive signals. We are currently establishing how signalling and movement interact and use models to design experimentally testable hypotheses.

A free boundary problem modeling the cell cycle and cell movement in multicellular tumor spheroids

This paper deals with a mathematical model describing the cell cycle dynamics and chemotactic driven cell movement in a multicellular tumor spheroid. Tumor cells consist of two types of cells: proliferating cells and quiescent cells, which have different chemotactic responses to an extracellular nutrient supply. The model is a free boundary problem for a nonlinear system of reaction–diffusion–advection equations, where the free boundary is the outer boundary of the spheroid. The free boundary condition is quite novel due to different velocity of two types of cells. The global existence and uniqueness of solutions to the model is proved. The proof is based on a fixed point argument, together with the L p -theory for parabolic equations with the third boundary condition.

Coordinated integrin and growth factor regulation of primary keratinocyte migration mediated through extracellular signal regulated kinase and phosphoinositide 3-kinase

We have examined coordinated integrin and growth factor regulation of primary keratinocyte migration mediated by phosphoinositide 3-kinase (PI3K) and mitogen-activated extracellular-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK). On collagen I and fibronectin substrates, both epidermal growth factor (EGF) and hepatocyte growth factor (HGF) stimulated chemokinetic (random) and chemotactic (directional) migration. On provisional matrix, a combination of fibronectin and fibrin found in the early phase of wound healing, EGF and HGF-stimulated significant chemotactic but little or no chemokinetic cell movement. Blocking mAbs to integrin alpha2beta1 and alpha5beta1 effectively inhibited EGF- and HGF-stimulated chemokinetic and chemotactic cell movement on collagen I and fibronectin, respectively; however, HGF-stimulated chemotactic migration on collagen I was only partially inhibited by alpha2beta1 blocking mAb. Differentiated keratinocytes underwent reduced chemokinetic and chemotactic migration compared with undifferentiated keratinocytes; however, EGF-stimulated migration was reduced more than HGF-stimulated migration. When the migratory response on collagen I and fibronectin was assessed in the presence of the MEK-specific inhibitor PD98059, EGF- and HGF-stimulated chemotaxis was significantly reduced, whereas PD98059 had little effect on the stimulated chemokinesis. PI3K-specific inhibitor LY294002 reduced EGF- and HGF-stimulated chemokinesis and chemotaxis on collagen I and fibronectin. Thus beta1 integrins acted in concert with EGF and HGF to regulate migration of primary keratinocytes on extracellular matrix components via PI3K and MEK/ERK.

Valproic acid reduces the ability of neutrophils to fight infection in epileptic patients

Valproic acid (VPA) is well established as a first-line and widely used antiepileptic agent. It is well tolerated in most patients and the main issues of concern of VPA are hematological toxicity, tertogenicity and idiosyncratic hepatotoxicity. Recently, researches have showed that VPA monotherapy could cause immunological function disorder, characterized that VPA monotherapy induced imbalance of oxidative/antioxidative status. Measures of oxidative stress were elevated while the antioxidative agent like Reduced glutathione (GSH) was degraded. Besides, antioxidants vitamin C and vitamin E can protect hepatocyte from VPA toxicity. In addition, in a eukaryon, social amoeba dictyostelium discoideum, VPA inhibit the chemotactic cell movement and endocytosis/exocytosis by attenuating its phospholipid signaling. Neutrophil is an important composition of innate immunity, it works mainly through phagocytosis and oxidization. The phagocytosis and oxidization activity are the basic and primitive function of neutrophils which are mimic to that of a eukaryon. Herein, we hypothesize that VPA, may have unexpected effects on the endocytic and oxidative function of neutrophil. The potential unfavorable subsequent events in the individuals with VPA treatment would be in the increased episodes of infection. Any agent to boost neutrophlic endocytic and antioxidative function may be helpful to the epileptic patients.

The Mechanisms Underlying Primitive Streak Formation in the Chick Embryo

Formation of the primitive streak is one of the key events in the early development of amniote embryos. The streak is the site where during gastrulation the mesendoderm cells ingress to take up their correct topographical positions in the embryo. The process of streak formation can be conveniently observed in the chick embryo, where the streak forms as an accumulation of cells in the epiblast in the posterior pole of the embryo and extends subsequently in anterior direction until it covers 80% of the epiblast. A prerequisite for streak formation is the differentiation of mesoderm, which is induced in the epiblast at the interface between the posterior Area Opaca and Area Pellucida in a sickle shaped domain overlying Koller's sickle. Current views on the molecular mechanisms of mesoderm induction by inducing signals from the Area Opaca and inhibitory signals from the hypoblast are briefly discussed. During streak formation the sickle of mesoderm cells transforms into an elongated structure in the central midline of the embryo. We discuss possible cellular mechanisms underlying this process, such as oriented cell division, cell-cell intercalation, chemotactic cell movement in response to attractive and repulsive signals and a combination of chemotaxis and contact following. We review current experimental evidence in favor and against these different hypotheses and outline some the outstanding questions. Since many of the interactions between cells signaling and moving are dynamic and nonlinear in nature they will require detailed modeling and computer simulations to be understood in detail.

Derivation and analysis of a system modeling the chemotactic movement of hematopoietic stem cells

It has been shown that hematopoietic stem cells migrate in vitro and in vivo following the gradient of a chemotactic factor produced by stroma cells. In this paper, a quantitative model for this process is presented. The model consists of chemotaxis equations coupled with an ordinary differential equation on the boundary of the domain and subjected to nonlinear boundary conditions. The existence and uniqueness of a local solution is proved and the model is simulated numerically. It turns out that for adequate parameter ranges, the qualitative behavior of the stem cells observed in the experiment is in good agreement with the numerical results. Our investigations represent a first step in the process of elucidating the mechanism underlying the homing of hematopoietic stem cells quantitatively.

Molecular Dissection of the Interaction between hBLT2 and the G Protein Alpha Subunits

Leukotriene B4 (LTB4) is a potent chemoattractant for leukocytes and considered to be an inflammatory mediator. Human BLT2 (hBLT2) is a low-affinity G-protein coupled receptor for LTB4 and mediates pertussis toxin-sensitive chemotactic cell movement. Here, we dissected the interaction between hBLT2 and G-protein alpha subunits using GST fusion proteins containing intracellular regions of hBLT2 and various Gα protein including Gα i1, Gα i2, Gα i3, Gα s1, Gα o1, and Gα z. Among the tested Gα subunits, Gα i3 showed the highest binding to the third intracellular loop region of hBLT2 with a dissociation constant (KD) of 5.0 × 10?6 M. These results suggest that Gα i3 has the highest affinity to hBLT2, and the third intracellular loop region of hBLT2 is the major component for the interaction with Gα i3.

Attenuation of phospholipid signaling provides a novel mechanism for the action of valproic acid.

Valproic acid (VPA) is used to treat epilepsy and bipolar disorder and to prevent migraine. It is also undergoing trials for cancer therapy. However, the biochemical and molecular biological actions of VPA are poorly understood. Using the social amoeba Dictyostelium discoideum, we show that an acute effect of VPA is the inhibition of chemotactic cell movement, a process partially dependent upon phospholipid signaling. Analysis of this process shows that VPA attenuates the signal-induced translocation of PH(Crac)-green fluorescent protein from cytosol to membrane, suggesting the inhibition of phosphatidylinositol-(3,4,5)-trisphosphate (PIP(3)) production. Direct labeling of lipids in vivo also shows a reduction in PIP and PIP(2) phosphorylation following VPA treatment. We further show that VPA acutely reduces endocytosis and exocytosis-processes previously shown to be dependent upon PIP(3) production. These results suggest that in Dictyostelium, VPA rapidly attenuates phospholipid signaling to reduce endocytic trafficking. To examine this effect in a mammalian model, we also tested depolarization-dependent neurotransmitter release in rat nerve terminals, and we show that this process is also suppressed upon application of VPA and an inhibitor of phosphatidylinositol 3-kinase. Although a more comprehensive analysis of the effect of VPA on lipid signaling will be necessary in mammalian systems, these results suggest that VPA may function to reduce phospholipid signaling processes and thus may provide a novel therapeutic effect for this drug.

Modelling the Cell Cycle and Cell Movement in Multicellular Tumour Spheroids

This paper analyses a recent mathematical model of avascular tumour spheroid growth which accounts for both cell cycle dynamics and chemotactic driven cell movement. The model considers cells to exist in one of two compartments: proliferating and quiescent, as well as accounting for necrosis and apoptosis. One particular focus of this paper is the behaviour created when proliferating and quiescent cells have different chemotactic responses to an extracellular nutrient supply. Two very different steady-state behaviours are identified corresponding to those cases where proliferating cells move either more quickly or more slowly than quiescent cells in response to a gradient in the extracellular nutrient supply. The case where proliferating cells move more rapidly leads to the commonly accepted spheroid structure of a thin layer of proliferating cells surrounding an inner quiescent core. In the case where proliferating cells move more slowly than quiescent cells the model predicts an interesting structure of a thin layer of quiescent cells surrounding an inner core of proliferating and quiescent cells. The sensitivity of this tumour structure to the cell cycle model parameters is also discussed. In particular variations in the steady-state size of the tumour and the types of transient behaviour are explored. The model reveals interesting transient behaviour with sharply delineated regions of proliferating and quiescent cells.