It is widely accepted that macrophages and other inflammatory cells support tumor progression and metastasis. During early stages of neoplastic development, tumor-infiltrating macrophages (TAMs) mount an immune response against transformed cells. Frequently, however, cancer cells escape the immune surveillance, an event that is accompanied by macrophage transition from an anti-tumor to a pro-tumorigenic type. The latter is characterized by high expression of factors that activate endothelial cells, suppress immune response, degrade extracellular matrix, and promote tumor growth. Cumulatively, these products of TAMs promote tumor expansion and growth of both blood and lymphatic vessels that facilitate metastatic spread. Breast cancers and other epithelial malignancies induce the formation of new lymphatic vessels ( i.e ., lymphangiogenesis) that leads to lymphatic and subsequently, to distant metastasis. Both experimental and clinical studies have shown that TAMs significantly promote tumor lymphangiogenesis through paracrine and cell autonomous modes. The paracrine effect consists of the expression of a variety of pro-lymphangiogenic factors that activate the preexisting lymphatic vessels. The evidence for cell-autonomous contribution is based on the observed tumor mobilization of macrophage-derived lymphatic endothelial cell progenitors (M-LECP) that integrate into lymphatic vessels prior to sprouting. This review will summarize the current knowledge of macrophage-dependent growth of new lymphatic vessels with specific emphasis on an emerging role of macrophages as lymphatic endothelial cell progenitors (M-LECP).
Radioligand binding studies have shown that AMPA receptors exist in two variants that differ about twenty-fold in their binding affinities, with brain receptors being mainly of the low-affinity type and recombinantly expressed receptors having almost exclusively high affinity. However, the physiological correlate of high- and low-affinity binding is not yet known. In this study we examined if physiological experiments similarly reveal evidence for two distinct receptor variants. We therefore measured equilibrium desensitization by glutamate and determined IC(50) values for neuronal receptors and for the homomeric receptors GluR1-4 expressed in HEK293 cells. Contrary to the prediction that these IC(50) values exhibit large differences commensurate with those of high- and low-affinity binding, values for homomeric receptors (1-18 microM) were on an average not different from those of neuronal receptors (3-10 microM). Moreover, simulations with kinetic receptor models suggest that the IC(50) values for neuronal and recombinant receptors correspond to the binding affinity of the low-affinity receptor variant. These findings indicate that the high-affinity binding measured in heterologous expression systems represents an immature receptor variant that does not contribute to the currents recorded from these cells, and that the functional low-affinity receptors are present in such small number that they are effectively masked in binding assays by the high-affinity receptors. Thus, in order to compare experimentally determined saturation binding profiles with those predicted by kinetic receptor models and with dose-response curves from physiological studies, it will be imperative to develop methods for isolating first the low-affinity receptors.
Ampakines are cognitive enhancers that potentiate ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents and synaptic responses by slowing receptor deactivation. Their efficacy varies greatly between classes of neurons and brain regions, but the factor responsible for this effect remains unclear. Ampakines also increase agonist affinity in binding tests in ways that are related to their physiological action. We therefore examined 1) whether ampakine effects on agonist binding vary across brain regions and 2) whether they differ across receptor subunits expressed alone and together with transmembrane AMPA receptor regulatory proteins (TARPs), which associate with AMPA receptors in the brain. We found that the maximal increase in agonist binding (E max ) caused by the prototypical ampakine 1-(1,4-benzodioxan-6-ylcarbonyl)-piperidine (CX546) differs significantly between brain regions, with effects in hippocampus and cerebellum being nearly three times larger than that in thalamus, brainstem, and striatum, and cortex being intermediate. These differences can be explained at least in part by regional variations in receptor subunit and TARP expression because combinations prevalent in hippocampus (GluA2 with TARPs ␥3 and ␥8) exhibited E max values nearly twice those of combinations abundant in thalamus (GluA4 with ␥2 or ␥4). TARPs seem to be critical because GluA2 and GluA4 alone had comparable E max and also because hippocampal and thalamic receptors had similar E max after solubilization with Triton X-100, which probably removes associated proteins. Taken together, our data suggest that variations in physiological drug efficacy, such as the 3-fold difference previously seen in recordings from hippocampus versus thalamus, may be explained by region-specific expression of GluA1-4 as well as TARPs.Ampakines are benzamide compounds that allosterically potentiate ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents, prolong synaptic responses (Arai et al., , 2002Arai and Kessler, 2007), facilitate long-term potentiation (Arai et al., 2004), and enhance memory encoding in animals and humans (Staubli et al., 1994;Lynch et al., 1997;Hampson et al., 1998). They also have shown therapeutic potential for various pathological conditions such as Alzheimer's disease, schizophrenia, and depression (Lynch, 2006).In two earlier studies, we found that ampakine effects vary greatly between neurons. In hippocampus, 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546) was nearly 10-fold more effective in prolonging excitatory postsynaptic currents in pyramidal cells than in interneurons or in stratum radiatum giant cells, an ectopic version of pyramidal cells . Major differences were likewise seen between hippocampal and thalamic neurons, i.e., prolongation of excitatory postsynaptic current duration by CX546 was approximately 3-fold larger in hippocampal CA1 pyramidal cells than in two subdivisions of the thalamus . Understanding the causes for these differences is important for an...
Suramin is a large naphthyl-polysulfonate compound that inhibits an array of receptors and enzymes, and it has also been reported to block currents mediated by glutamate receptors. This study shows that suramin and several structurally related compounds [8,8Ј-[carbonylbis(imino- Inhibition often was less than complete at saturating drug concentrations and thus seems to be noncompetitive in nature. Pyridoxal-5Ј-phosphate-6-(2Ј-naphthylazo-6Ј-nitro-4Ј,8Ј-disulfonate) (PPNDS) is a potent antagonist of purinoceptors that shares some structural elements with suramin yet is smaller than the latter. PPNDS also had potent effects on AMPA receptors (EC 50 value of 4 M) but of a kind not seen with the other compounds in that it increased binding affinity for radioagonists severalfold. In addition, PPNDS slowed association and dissociation rates more than 10 times. In physiological experiments with GluR2 receptors, PPNDS at 50 M reduced the peak current by 30 to 50% but had only small effects on other waveform aspects such desensitization and steady-state currents. This pattern of effects differentiates PPNDS from other compounds such as thiocyanate and up-modulators, which increase agonist binding by enhancing desensitization or slowing deactivation, respectively. Receptor model simulations indicate that most effects can be accounted for by assuming that PPNDS slows agonist binding/ unbinding and stabilizes the bound-closed state of the receptor. By extension, suramin is proposed to stabilize the unbound state and thereby to reduce affinity for agonists. These drugs thus act through a novel type of noncompetitive antagonism.Suramin is an extended molecule with a symmetrical backbone of amide-linked aromatic rings and with three negatively charged sulfonate substituents on each of the terminal naphthyl elements (Fig. 1). As such, it shares many structural similarities with a broader class of polysulfonated compounds that include the azo-dyes trypan blue, Evans blue, Chicago sky blue, and basilen blue (also called reactive blue 2). Like many of the latter, suramin has a remarkably diverse range of pharmacological actions, yet the mechanisms underlying these effects are in most instances still obscure. Suramin was developed 80 years ago and is still occasionally used for the treatment of trypanosomiasis and onchocerciasis (Wang 1995). In vitro, suramin affects a bewildering array of molecular and cellular processes. It inhibits numerous signaling proteins, including growth factors and interleukins (Voogd et al., 1993); among its many other targets are G proteins (Freissmuth et al., 1996) and enzymes such as reverse transcriptase (De Clercq, 1987) and ectonucleotidases This work was supported by National Institutes of Health grant NS41020. Article, publication date, and citation information can be found at
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