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PubMed2006

Effects of endothelin-1 on differentiation of cardiac myocyte induced from rabbit bone marrow stromal cells.

BACKGROUND: Cardiomyocyte transplantation for the therapy of myocardial ischaemia is being paid close attention. However, how the microenvironment controls the differentiation of transplanted bone marrow stromal cells (BMSCs) is unknown. Endothelin-1 (ET-1), a cytokine, increases during myocardial infarction, but it is not known whether ET-1 is responsible for the fate of transplanted BMSCs. In the present study, we investigated the effects of ET-1 on differentiation and maturation of induced rabbit BMSCs, in vitro, to elucidate the cellular biological mechanisms. METHODS: The proliferation of BMSCs isolated from femur of rabbits was induced by ET-1 only, by 5-azacytidine (5-aza) or ET-1 combined with 5-aza. After 4 weeks of induced culturing, the differentiation rate and the diameter of induced myocyte like cells were estimated and the expressions of GATA-4 protein and phosphorylation level were assayed by Western-blot, RT-PCR analysis of beta-myosin heavy chain (MHC). mRNA expression, levels of troponin-I by immunohistochemical staining and ultrastructure of induce-cultured BMSCs were also determined. RESULTS: By induction with ET-1 and 5-aza, mean cell diameter of induced BMSCs was larger than induced with 5-aza [(6.26 +/- 0.22) microm cf (5.29 +/- 0.19) microm] (P < 0.001). There was no difference in rate of differentiation of myocyte like cells between the groups induced with 5-aza and ET-1 combined with 5-aza [(29.82 +/- 0.23)% cf (29.94 +/- 0.18)%] (P > 0.05). The expressions of GATA-4 protein and phosphorylation were enhanced significantly in groups induced with ET-1 combined with 5-aza (P < 0.05). In the group induced with ET-1 combined with 5-aza, expression of beta-MHC mRNA was higher than control [(0.122 +/- 0.008) cf (0.022 +/- 0.003)] (P < 0.01), and more troponin-I positive cells were also detected in this group. Differentiated BMSCs showed formations of myofilaments and primitive sarcomere, i.e., morphological characteristics of myocyte like cells. CONCLUSIONS: This study suggests that induced culturing of BMSCs by ET-1 combined with 5-aza can express cardiomyocytic characteristics whereas ET-1 alone could not induce BMSCs to differentiate to myocyte like cells. ET-1 upregulates the expression of GATA-4 protein and phosphorylation level of induced BMSCs, and rapidly promotes the differentiation and maturation of myocyte like cells from BMSCs.

Animals↗
PubMedDate not supplied

Acute ethanol effects on cell volume regulation.

In this work, the effects of ethanol on cellular osmoregulation were studied in isolated proximal renal tubules of Carassius auratus (goldfish). In hypotonic solutions the tubule cells swell rapidly (osmometric phase) and subsequently shrink towards isotonic volumes (volume regulatory decrease phase, VRD). The osmometric phase depends on the water permeability of the cell membrane and the magnitude of the osmotic gradient. The VRD phase is complex and is a function of activation of osmotic transporters with net KCl efflux followed by osmotically, obligated water. At 7, 10, and 12 mM ethanol, the membrane water permeability and osmotic ionic effluxes were increased. At higher ethanol concentrations (14 and 28 mM), the osmometric phase was moderately inhibited and VRD was abolished. The stimulatory effects of ethanol (7, 10, and 12 mM) on cellular osmoregulation are probably due to enhanced membrane fluidity (water permeability) and increased membrane calcium release (activation of KCl efflux). Inhibitory effects of ethanol (14 and 28 mM) on cell volume control are due to a combined decrement in water and KCl effluxes. This dose-related inhibition is likely due to incorporation of the amphipathic ethanol molecules with decreased hydrophobicity of the microenvironment of channels and transporters owing to displacement of structural lipids. In this system the threshold for osmoregulatory inhibition is between 12 and 14 mM.

Animals↗
PubMed1996

Enhanced growth of murine melanoma in ultraviolet-irradiated skin is associated with local inhibition of immune effector mechanisms.

We have developed a model for studying the role of local immunologic mechanisms in tumor development, in which injection of K1735 melanoma cells into the UV-irradiated ears of C3H mice results in a significantly higher incidence of tumors than injection into unirradiated ears. This effect of UV irradiation is immunologically mediated. We hypothesized that UV blocks the efferent arm of the immune response, thereby facilitating tumor development within the irradiated site. We demonstrate that elicitation of a delayed type hypersensitivity response to alloantigen is diminished in UV-irradiated ears. in addition, tumor rejection is impaired in melanoma-immune mice challenged in UV-irradiated ears, even though such mice exhibit systemic immunity when challenged in a nonirradiated site. The ability of immune lymphoid cells to inhibit melanoma growth when mixed with tumor cells and injected into the ears was inhibited by prior UV irradiation of the ears, indicating that the activity of immune effector cells is abrogated in the UV-irradiated microenvironment. Analysis of lymphoid cells in growing tumors indicated that the number of CD8+ T lymphocytes was reduced in the UV-irradiated site. We conclude that efferent immune responses are impaired in UV-irradiated tissue and suggest that the impairment may involve reductions in both the number and the activity of immune effector cells. These studies illustrate that conditions in the local microenvironment during the early stages of tumor growth may profoundly influence the outcome of the host-tumor interaction.

Animals↗
PubMed1996

Osteogenic growth peptide increases blood and bone marrow cellularity and enhances engraftment of bone marrow transplants in mice.

The osteogenic growth peptide (OGP) was characterized recently in regenerating bone marrow (BM) and normal serum. In vitro, the OGP regulates stromal-cell proliferation and differentiated functions. In vivo, an increase in serum OGP accompanies the osteogenic phase of postablation BM regeneration. The present results in normal mice show that OGP induces a balanced increase in WBC counts and overall BM cellularity. In mice receiving myeloablative irradiation and syngeneic or semiallogeneic BM transplants, OGP stimulates hematopoietic reconstruction and doubles the survival rate; these effects are dependent on initiating the OGP administration before irradiation. Chimerism measurements in semiallogeneic graft recipients suggest no preferential effect of OGP on residual host cells. The data implicate OGP in the acceleration of hematopoiesis secondary to expansion of the stromal microenvironment and/or enhancement of stroma-derived signals to stem cells. The low-dose effectiveness of OGP is explained by the demonstration of an autocrine positive feedback loop that together with the OGP-binding protein sustains high serum levels of the peptide. A potential OGP-based treatment in combination with chemoradiotherapy is attractive because of the OGP-induced balanced multi-lineage enhancement of hematopoiesis and possible replacement of expensive recombinant cytokines by a readily synthesized peptide.

Animals↗
PubMed1998

Differential regulation of cyclin-dependent kinase inhibitors in monolayer and spheroid cultures of tumorigenic and nontumorigenic fibroblasts.

The Ras proto-oncogene has been implicated in the in vivo development of tumors and in the in vitro transformation of cultured cell lines. In both of these conditions, Ras-mediated disruption of cell cycle-regulatory mechanisms leads to unregulated cellular proliferation, although the exact mechanisms by which Ras accomplishes this are not clear. Using as a model the M1 and MR1 rat fibroblast cell lines, which differ in the expression of a regulated Ras (M1 cells) versus a constitutively active Ras (MR1 cells), we examined the role of Ras in the control of cellular proliferation in two-dimensional (monolayer) and three-dimensional (spheroid) cell cultures. These cell lines are very similar in their monolayer growth characteristics, but M1 cells will arrest their cell cycle progression in aggregate culture, whereas MR1 cells proliferate normally as small spheroids. We report here that G1-phase arrest in plateau-phase monolayer cultures of both M1 and MR1 cells correlates with up-regulated expression of the cyclin-dependent kinase (CDK) inhibitor p18INK4c. Enhanced p18INK4c expression was also observed in G1-arrested M1 cells cultured as multicellular spheroids but was not induced in small proliferating MR1 multicellular spheroids. The kinetics of G1 arrest in M1 cells after inoculation into aggregate culture correlated well with the induction of p18INK4c expression. Conversely, resumption of proliferation in monolayer culture of arrested M1 cells isolated from spheroids coincided with the loss of expression of p18INK4c. After extended culture, cells in the inner region of MR1 spheroids arrested in the G1 phase without any up-regulation of p18INK4c expression. In this case, the CDK inhibitor p21(Cip1/Waf1) was selectively induced in the inner regions of large MR1 spheroids, concomitant with a decrease in cyclin and CDK expression. Thus, Ras-dependent regulation of p18INK4c expression seems to control the ability of rat embryo fibroblasts to proliferate as small multicellular aggregates, whereas p21(Cip1/Waf1) expression seems to regulate the G1-phase arrest induced by the stressful microenvironment found within the inner region of large spheroids.

Animals↗
PubMed2026

Athero-oncology: Vascular smooth muscle cell tumor-like transformation in atherosclerosis and therapeutic opportunities.

Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases, and its pathogenesis and treatment strategies remain major challenges. Recent advances in single-cell RNA sequencing and lineage tracing have revealed that vascular smooth muscle cells (VSMCs) are not merely passive structural components of atherosclerotic plaques, but highly plastic participants that undergo clonal expansion, phenotypic modulation, and transdifferentiation into functionally diverse cell states. These findings have prompted the emergence of an "athero-oncology" framework, which explores selected tumor-like cellular programs in VSMCs during AS without equating atherosclerosis with cancer. In this review, we summarize the evidence supporting VSMC-derived clonal expansion and phenotypic diversification in atherosclerotic lesions and discuss key mechanisms involved in this process, including proliferative expansion and survival programs, metabolic reprogramming, epigenetic regulation, DNA damage and genomic stress, VSMC senescence, pathological angiogenesis, and remodeling of the inflammatory and immune microenvironment. We further highlight shared signaling pathways between VSMC-driven plaque remodeling and tumor biology, while emphasizing fundamental differences between AS and malignant disease in growth limitation, mutational burden, metastatic potential, and clinical behavior. Finally, we discuss oncology-inspired therapeutic opportunities and boundaries, including pathway-level targeting of proliferative, metabolic, epigenetic, and inflammatory programs, as well as the risks of directly repurposing anticancer therapies for chronic vascular disease. This framework may provide new insights into vascular biology and therapeutic development.

atherosclerosis↗
PubMed2003

Rapid regulation of NaCl secretion by estuarine teleost fish: coping strategies for short-duration freshwater exposures.

This review summarizes the mechanism of Cl(-) active secretion and its regulation in estuarine teleost fish. Small estuarine fish such as the killifish, Fundulus heteroclitus, forage in shallow water following advancing tides and are exposed regularly to very dilute microenvironments. Using the killifish opercular epithelium and related teleost membranes containing mitochondria-rich cells, the regulation includes a reduction of active Cl(-) secretion and passive diffusive ion loss in a three-stage process spanning approximately 30 min. There is a combination of sympathetic neural reflex mediated by alpha(2)-adrenoceptors operating via intracellular inositol tris phosphate and intracellular Ca(2+) and a cellular hypotonic shock response, followed by covering over of ion-secreting cells by pavement cells. This effectively minimizes salt loss in dilute media. The upregulation of salt secretion on return to full strength seawater may be via hormones (arginine vasotocin and urotensin I) and neurotransmitter (vasoactive intestinal polypeptide) in combination with hypertonic shock. A hypothetical model includes involvement of protein kinase A and C and protein phosphatases 1 and 2A in regulation of the NKCC1 cotransporter on the basolateral side and protein kinase A regulation of the CFTR-like apical anion channel.

Adaptation, Physiological↗
PubMedDate not supplied

Measurement of apoptosis, proliferation and three cytokines in 46 patients with myelodysplastic syndromes.

Extensive apoptosis or programmed cell death (PCD) of both hematopoietic (erythroid, myeloid, megakaryocytic) and stromal cells in myelodysplastic syndromes (MDS) cancels the high birth-rate resulting in ineffective hematopoiesis and has been demonstrated as the probable basis for peripheral cytopenias in MDS by our group. It is proposed that factors present in the microenvironment are inducing apoptosis in all the cells whether stromal or parenchymal. To investigate this hypothesis further, bone marrow biopsies from 46 MDS patients and eight normal individuals were examined for the presence of three cytokines, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and granulocyte macrophage-colony stimulating factor (GM-CSF) and one cellular component, macrophages, by the use of monoclonal antibodies immunohistochemically. Results showed the presence of TNF-alpha and TGF-beta in 41/46 and 40/46 cases of MDS respectively, while only 15 cases showed the presence of GM-CSF. Further a significant direct relationship was found between the degree of TNF-alpha and the incidence of PCD (p= 0.0015). Patients who showed high PCD also had an elevated TNF-alpha level. Thus, the expression of high amounts of TNF-alpha and TGF-beta and low amounts of the viability factor GM-CSF may be responsible for the high incidence of PCD leading to ineffective hematopoiesis in MDS. Future studies will be directed at attempting to reverse the lesion in MDS by using anti-TNF-alpha drugs such as pentoxifylline.

Apoptosis↗
PubMed2006

Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity.

Hypoxia is a feature of the microenvironment of a growing tumor. The transcription factor NFkappaB is activated in hypoxia, an event that has significant implications for tumor progression. Here, we demonstrate that hypoxia activates NFkappaB through a pathway involving activation of IkappaB kinase-beta (IKKbeta) leading to phosphorylation-dependent degradation of IkappaBalpha and liberation of NFkappaB. Furthermore, through increasing the pool and/or activation potential of IKKbeta, hypoxia amplifies cellular sensitivity to stimulation with TNFalpha. Within its activation loop, IKKbeta contains an evolutionarily conserved LxxLAP consensus motif for hydroxylation by prolyl hydroxylases (PHDs). Mimicking hypoxia by treatment of cells with siRNA against PHD-1 or PHD-2 or the pan-prolyl hydroxylase inhibitor DMOG results in NFkappaB activation. Conversely, overexpression of PHD-1 decreases cytokine-stimulated NFkappaB reporter activity, further suggesting a repressive role for PHD-1 in controlling the activity of NFkappaB. Hypoxia increases both the expression and activity of IKKbeta, and site-directed mutagenesis of the proline residue (P191A) of the putative IKKbeta hydroxylation site results in a loss of hypoxic inducibility. Thus, we hypothesize that hypoxia releases repression of NFkappaB activity through decreased PHD-dependent hydroxylation of IKKbeta, an event that may contribute to tumor development and progression through amplification of tumorigenic signaling pathways.

Amino Acid Sequence↗
PubMed1998

Activation of human monocytes induces differential resistance to apoptosis with rapid down regulation of caspase-8/FLICE.

Cells of the monocyte/macrophage lineage play a central role in both innate and acquired immunity of the host. However, the acquisition of functional competence and the ability to respond to a variety of activating or modulating signals require maturation and differentiation of circulating monocytes and entail alterations in both biochemical and phenotypic profiles of the cells. The process of activation also confers survival signals essential for the functional integrity of monocytes enabling the cells to remain viable in microenvironments of immune or inflammatory lesions that are rich in cytotoxic inflammatory mediators and reactive free-radical species. However, the molecular mechanisms of activation-induced survival signals in monocytes remain obscure. To define the mechanistic basis of activation-induced resistance to apoptosis in human monocytes at the molecular level, we evaluated the modulation of expression profiles of genes associated with the cellular apoptotic pathways upon activation and demonstrate the following: (i) activation results in selective resistance to apoptosis particularly to that induced by signaling via death receptors and DNA damage; (ii) concurrent with activation, the most apical protease in the death receptor pathway, caspase-8/FLICE is rapidly down-regulated at the mRNA level representing a novel regulatory mechanism; and (iii) activation of monocytes also leads to dramatic induction of the Bfl-1 gene, an anti apoptotic member of the Bcl-2 family. Our findings thus provide a potential mechanistic basis for the activation-induced resistance to apoptosis in human monocytes.

Apoptosis↗
PubMed2005

A scanning electron microscopy study of idiopathic external tooth resorption in the cat.

BACKGROUND: Multiple idiopathic root resorption (MIRR) is a rare condition in man characterized by cervical resorption leading to significant tooth loss. A similar condition, feline osteoclastic resorptive lesions (FORL), affects up to 70% of domestic cats and thus provides a valuable model for investigating the etiopathogenesis of MIRR. The aim of the present study was to establish changes in the surface microanatomy of the tooth in late stage FORL and to identify whether its location has a surface bias. METHODS: Scanning electron microscopy (SEM) was used to analyze the surface features of enamel and cementum of feline teeth affected with advanced FORL. RESULTS: Resorption involved the coronal root at the cementoenamel junction (CEJ) in 95% of teeth and focal resorption of intact enamel was observed in 14% of teeth. In 55% of teeth, the main lesion was on the buccal surface and a distinct circumferential resorption "front" was present at the apical margin of resorption. The root surfaces of most affected teeth either lacked extrinsic fibers or cellular lacunae or featured evidence of cementum remodeling. Woven bone-like tissue was found within lesions, on resorbed dentin, or on the root surface in 27% of teeth. CONCLUSIONS: This study demonstrates that most FORL involve the CEJ, and the presence of focal lesions at this site suggests that this is where resorption is initiated. This implies that local factors in the oral microenvironment play a role in the etiopathogenesis of this condition. The study also shows that FORL are more likely to occur on buccal surfaces and are associated with changes in the microarchitecture of the root surface consistent with destruction of the normal periodontal attachment and stimulation of a reparative response. These findings may be relevant to understanding the etiopathogenesis of multiple idiopathic resorption areas in man.

Animals↗
PubMed1999

Partial blockade of T-cell differentiation during ontogeny and marked alterations of the thymic microenvironment in transgenic mice with impaired glucocorticoid receptor function.

Glucocorticoids (GCs) are widely known to be potent modulators of the immune system. The role of GCs in thymopoiesis as well as the integration of the thymus with the neuroendocrine system is, however, poorly understood. In the present work, we have studied, in transgenic mice with an impaired GC function, the alterations which occur in both T-cell differentiation and thymic stroma maturation, throughout ontogeny as well as in adult condition, analyzing their possible rebounding on the status of adult splenic T lymphocyte populations. These transgenic mice have been described to present a significant decrease (60-70%) of thymic and splenic GC receptor binding capacity but maintain normal their basal plasma ACTH and corticosterone levels. The animals showed a partial blockade of T-cell differentiation and decreased percentages of apoptotic cells during fetal development but not in adult life, when thymic cellularity was significantly increased although thymocyte apoptosis response was not affected. In contrast, thymic stroma was profoundly altered from early fetal stages and large epithelium-free areas appeared in adult thymus. On the other hand, our study revealed a reduction of the splenic TcRalphabeta population accompanied by an increase in the CD4/CD8 ratio. The analysis of different adhesion molecules as well as activation markers demonstrated that most of them (CD5, CD11a, CD11b, CD69 and MHC Class II) were normally expressed in transgenic lymphocytes, whereas CD44 and CD62L expression was altered indicating the existence of an increased proportion of primed T-cells in these animals. In view of the mutual interdependence of thymic stroma and thymocyte maturation, the partial blockade of T-cell differentiation during ontogeny and the profound alterations of the stromal cell compartment in transgenic mice with impaired GR function suggest a key role for GCs in coordinating the physiological dialogue between the developing thymocytes and their microenvironment.

Age Factors↗
PubMed2003

Measuring the mechanical stress induced by an expanding multicellular tumor system: a case study.

Rapid volumetric growth and extensive invasion into brain parenchyma are hallmarks of malignant neuroepithelial tumors in vivo. Little is known, however, about the mechanical impact of the growing brain tumor on its microenvironment. To better understand the environmental mechanical response, we used multiparticle tracking methods to probe the environment of a dynamically expanding, multicellular brain tumor spheroid that grew for 6 days in a three-dimensional Matrigel-based in vitro assay containing 1.0-microm latex beads. These beads act as reference markers for the gel, allowing us to image the spatial displacement of the tumor environment using high-resolution time-lapse video microscopy. The results show that the volumetrically expanding tumor spheroid pushes the gel outward and that this tumor-generated pressure propagates to a distance greater than the initial radius of the tumor spheroid. Intriguingly, beads near the tips of invasive cells are displaced inward, toward the advancing invasive cells. Furthermore, this localized cell traction correlates with a marked increase in total invasion area over the observation period. This case study presents evidence that an expanding microscopic tumor system exerts both significant mechanical pressure and significant traction on its microenvironment.

Brain↗
PubMed1997

Thymocytes and cultured thymic epithelial cells express transcripts encoding alpha-3, alpha-5 and beta-4 subunits of neuronal nicotinic acetylcholine receptors: preferential transcription of the alpha-3 and beta-4 genes by immature CD4 + 8 + thymocytes.

Thymic tissues express transcripts encoding the alpha-3, alpha-5 and beta-4 subunits of nicotinic neuronal acetylcholine receptors (AcChRs) suggesting that neuronal AcChRs similar to those expressed in ganglia are expressed in the thymus. Transcription occurs in both isolated thymocytes and thymic epithelial cells. RT-PCR analyses of thymocyte subsets indicate that immature CD4 + 8 + thymocytes express higher levels of the alpha-3 and beta-4 transcripts than more mature thymocytes. Compared to freshly isolated thymocytes, peripheral blood lymphocytes do not express alpha-3 and beta-4 AcChR subunit transcripts. Cultured thymocytes rapidly down-regulate transcription of the alpha-3 and beta-4 AcChR subunit genes by a process that is not reversed by stimulation with phytohemagglutinin and IL-2. Thus our results indicate that there is transcriptional regulation of neuronal AcChR subunit genes during the process of thymocyte maturation and that factors within the thymic microenvironment influence expression of the alpha-3 and beta-4 AcChR subunit genes by developing T cells.

Amyloid beta-Protein Precursor↗
PubMed1992

Eye-derived cytokines and the immunosuppressive intraocular microenvironment: a review.

The normal aqueous humor contains a variety of soluble immunosuppressive factors, including transforming growth factor-beta, alpha-melanocyte stimulating hormone, and vasoactive intestinal peptide. These factors are largely the secretory products of parenchymal cells of the iris and ciliary body. TGF beta has recently been shown to alter the functional capacity of intraocular antigen presenting cells, such that they are capable of inducing Anterior Chamber Associated Immune Deviation (ACAID). This deviant systemic immune response is characterized by an impaired capacity to mount an effective cell-mediated immune attack directed at antigens that are placed in, or arise within, the eye. A second property of immunosuppressive factors in aqueous humor is to suppress directly the expression of delayed hypersensitivity in the anterior chamber. In fact, even when the intraocular microenvironment is disturbed by local instillation of gamma-interferon, making it possible for limited expression of cell-mediated immunity in the eye, the microenvironment of the anterior chamber remains profoundly immunosuppressive. In this latter instance, prostaglandins replace TGF beta as the major molecular mediators of suppression in the aqueous humor. In the aggregate, factors present in the normal (or perturbed) intraocular microenvironment have the capacity to modify both the afferent and efferent limbs of the systemic immune response, and this accounts for the longstanding observation that the anterior chamber is an immunologically privileged site. Since evidence suggests that the eye can mobilize more than one molecular mechanism in its effort to limit the sight-destroying potential of immunogenic inflammation, we believe that elucidation of intraocular cytokines and factors that create and maintain an immunosuppressive microenvironment will contribute to a better understanding of the pathogenesis of the acute and chronic uveitides, especially those of autoimmune and infectious etiology.

Animals↗
PubMed2026

Patient-derived models of prostate cancer: Capturing tumour complexity from initiation to metastasis.

Prostate cancer is a growing global health challenge. To identify new ways to improve patient care, researchers need a variety of preclinical models that faithfully recapitulate human tumours across the disease continuum, from initiation to metastasis. These complementary models include primary cultures of prostate epithelial cells (PrECs), co-cultures, patient-derived explants (PDEs), patient-derived organoids (PDOs) and patient-derived xenografts (PDXs). Collectively, these models enable researchers to study tumour biology and therapeutic responses in clinically relevant contexts. Yet, there is still a need to improve the fidelity of preclinical models to human tumours by integrating diverse cell types from the tumour microenvironment and mimicking biomechanical features. By improving culture methods with matrix components that resemble the tumour microenvironment and new formulations of media that imitate human plasma, in vitro models will more accurately reflect human physiology, nutrient availability, and metabolism. In time this may reduce the reliance on animal testing through organ-on-chip and related techniques. These more complex models are suited to more detailed experimental readouts, including single-cell and spatial analyses. Intravital imaging also enables dynamic visualisation of cell-cell interactions and treatment responses in vivo. Collectively, these approaches are facilitating a shift towards sophisticated models that capture patients' tumour heterogeneity, different cellular niches, and provide opportunities to carefully study tumorigenesis, metastasis, lineage plasticity, and therapy resistance. In this review, we discuss the current progress and future directions for patient-derived models of prostate cancer, highlighting how they can be generated, refined, characterised and shared to accelerate the worldwide effort in translational research.

Humans↗
PubMed2002

Absent or low expression of T-cell receptor zeta-chain in T cells infiltrating human pathological skin conditions.

The T-cell receptor (TCR) zeta-chain is involved in signal transduction necessary for T-cell activation and subsequent proliferation. Expression of the TCR zeta-chain in vivo has been studied by a variety of technical approaches on different cell and tissue specimen. However, the in situ situation concerning the expression of the TCR zeta-chain has not yet been investigated on infiltrating T lymphocytes in neoplastic and inflammatory cutaneous diseases. In this study, we analysed the expression of the TCR zeta-chain in a number of skin tissues affected by established inflammatory and neoplastic conditions. Serial sections of different tissue specimens were stained immunoenzymatically for CD3 and TCR zeta-chain expression. No or at most scarce expression of TCR zeta-chain was detectable in the inflammatory and neoplastic skin conditions investigated as compared to CD3-positive cells. It is possible that this TCR zeta-chain deletion is induced by the skin microenvironment as an effect of local immunoregulatory influences. Alternatively, lymphocytes located in the skin may generally not express this molecule. In our study, tumour-infiltrating T lymphocytes of CTCL were negative for TCR zeta-chain expression. It has been hypothesized that downregulation of the TCR zeta-chain on tumour-infiltrating T lymphocytes is a mechanism by which neoplastic cells escape the cellular immune response. Our findings showing the absence or reduction of TCR zeta-chain expression also in inflammatory skin lymphocytic infiltrates is not consistent with a pivotal role of the TCR zeta-chain in the process of immune escape of tumour cells.

CD3 Complex↗
PubMed1989

Tumor necrosis factor-alpha regulates mRNA for urokinase-type plasminogen activator and type-1 plasminogen activator inhibitor in human neoplastic cell lines.

Tumor necrosis factor-alpha (TNF-alpha) was found to induce type-1 plasminogen activator inhibitor (PAI-1) antigen in the human fibrosarcoma cell line HT-1080, and PAI-1 and urokinase-type plasminogen activator (u-PA) antigens in the human carcinoma cell line T-CAR1; tissue-type plasminogen activator (t-PA) antigen was not affected or slightly decreased. The effects in HT-1080 and T-CAR1 cells were preceded by increases in the cellular levels of the corresponding mRNAs. Cycloheximide caused an increase of PAI-1 mRNA in T-CAR1 cells, but not in HT-1080 cells; during this increase the relative abundance of the two PAI-1 mRNA species, of 2.3 kb and 3.4 kb, respectively, changed strongly in favor of the longer transcript. We conclude that TNF-alpha may affect proteolytic activity in the microenvironment of cells in malignant tumors by affecting gene expression of u-PA and PAI-1.

Cycloheximide↗