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Stromal
Terms modified by Stromal Selected AbstractsIncreased expression of SDF-1/CXCR4 is associated with lymph node metastasis of invasive micropapillary carcinoma of the breastHISTOPATHOLOGY, Issue 6 2009Fangfang Liu Aims:, Stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 are implicated in tumour chemotaxis and metastasis. The aim was to examine their roles in the metastasis of invasive micropapillary carcinoma (IMPC) of the breast, a tumour with a high propensity for nodal spread. Methods and results:, We compared the expression of SDF-1 and CXCR4 in 103 cases of breast cancer containing IMPC components with a control group of 96 cases of invasive ductal carcinoma (IDC), not otherwise specified type by immunohistochemistry and chemical in situ hybridization (CISH). The results showed that the predominant cytoplasmic expression of both SDF-1 and CXCR4 was greater in tumour cells of the IMPC components than in those of the non-IMPC components and the control IDC cases, and was correlated significantly with the number of positive lymph nodes (P < 0.05). SDF-1 expression on cell membranes was less frequently identified in IMPC than IDC (P = 0.021). Immunohistochemical detection of SDF-1 in endothelial cells of lymphatic vessels was more common in IMPC (P = 0.007) and correlated significantly with lymph node status (P = 0.002), although SDF-1 mRNA was rarely detected by CISH. Conclusions:, This study suggests that up-regulation of cytoplasmic expression of SDF-1/CXCR4 might be one of the molecular mechanisms facilitating lymph node metastasis of IMPC. [source] Stromal cell-derived factor-1 promotes migration of cells from the upper rhombic lip in cerebellar developmentJOURNAL OF NEUROSCIENCE RESEARCH, Issue 13 2010Tao Yu Abstract During cerebellar development, the chemokine stromal cell-derived factor-1, (SDF-1,) has been shown to play an important role in recruiting cells from the upper rhombic lip (URL) and external granule cell layer (EGL). However, its function in cerebellar development is still poorly understood. Our results have demonstrated that SDF-1 is necessary for EGL development, and URL cells stream to the SDF-1 source in vitro. Results of embryonic URL explant assays and transwell assays indicated that SDF-1 induces neural cell migration from the URL region in chemotactic and chemokinetic responses. The time-lapse results showed that the migration speed of granule cell progenitors out of the URL was accelerated by the addition of recombinant SDF-1,. Collectively, our study shows that SDF-1 increases the motility of URL cells in the absence of a gradient and promotes the migration of granule cell progenitors during cerebellar development. © 2010 Wiley-Liss, Inc. [source] Stromal cell-secreted factors promote the survival of embryonic stem cell-derived early neural stem/progenitor cells via the activation of MAPK and PI3K-Akt pathwaysJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2010Seiji Ishii Abstract Neural stem/progenitor cells (NS/PCs) have been studied extensively with the hope of using them clinically to repair the damaged central nervous system. However, little is known about the signals that regulate the proliferation, survival, and differentiation of NS/PCs in early development. To clarify the underlying mechanisms, we took advantage of an in vitro ES cell differentiation system from which we can obtain neurospheres containing NS/PCs with characteristics of the early caudal neural tube, by treating embryoid bodies (EBs) with a low concentration of retinoic acid (RA). We found that conditioned medium from the PA6 stromal cell line (PA6CM) increased the efficiency of neurosphere formation by suppressing apoptosis and promoting the survival of the NS/PCs. PA6CM also induced the phosphorylation of Erk1/2 and Akt1 in cells derived from the EBs. Furthermore, inhibitors of the MAPK and PI3K-Akt signaling pathways, U0126 and LY294002, attenuated the effects of PA6CM, significantly increasing the number of apoptotic cells and decreasing the number of viable cells among the ES cell-derived NS/PCs. Thus, PA6CM appears to contain soluble factors that promote the survival of ES cell-derived early NS/PCs through the activation of the MAPK and PI3K-Akt pathways. © 2009 Wiley-Liss, Inc. [source] Bone marrow-derived stem cells in liver repair: 10 years down the lineLIVER TRANSPLANTATION, Issue 2 2010Eleanor S. Gilchrist Hematopoietic stem cells have potential in the field of regenerative medicine because of their capacity to form cells of different lineages. Bone marrow stem cells have been shown to contribute to parenchymal liver cell populations, and although this may not be functionally significant, it has sparked interest in the field of autologous stem cell infusion as a possible treatment for cirrhosis. In this review, we will examine the evidence for the contribution of bone marrow-derived cells to populations of liver cells and for the functional contribution of bone marrow-derived cells to both liver fibrosis and repair. The mechanisms by which cells are trafficked from the bone marrow to the liver are complex; the stromal derived factor-1/CXC receptor 4 axis is central to this process. There are limited data in liver injury, but we will examine findings from the bone marrow transplantation literature and discuss their relevance to liver disease. Stromal derived factor-1 also has a role in endogenous liver stem cell accumulation. Some groups have already started infusing autologous bone marrow cells into patients with cirrhosis. We will review these trials in the context of the basic science that we have discussed, and we will consider targets for investigation in the future. Liver Transpl 16:118,129, 2010. © 2010 AASLD. [source] ORIGINAL ARTICLE: Keratinocyte Growth Factor Stimulates Macrophage Inflammatory Protein 3, and Keratinocyte-derived Chemokine Secretion by Mouse Uterine Epithelial CellsAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 3 2010Severina N. Haddad Citation Haddad SN, Wira CR. Keratinocyte growth factor stimulates macrophage inflammatory protein 3, and keratinocyte-derived chemokine secretion by mouse uterine epithelial cells. Am J Reprod Immunol 2010; 64: 197,211 Problem, Communication between uterine epithelial cells and the underlying stromal fibroblasts is critical for proper endometrial function. Stromal fibroblast-derived growth factors have been shown to regulate epithelial immune functions. The purpose of this study was to determine whether keratinocyte growth factor (KGF) regulates uterine epithelial cell chemokine and antimicrobial secretion. Method of study, Uterine epithelial cells were isolated from Balb/c mice and cultured in either 96-well plates or transwell inserts. Epithelial cells were treated with KGF, epidermal growth factor (EGF), or hepatocyte growth factor (HGF). Macrophage inflammatory protein 3, (MIP3,) and keratinocyte-derived chemokine (KC) levels were measured by ELISA. Results, Keratinocyte growth factor stimulated the secretion of MIP3, and KC. The effects on MIP3, by KGF were specific because EGF and HGF had no effect. In contrast, KGF, EGF, and HGF had similar effects on KC. Furthermore, KGF administered to the apical side of epithelial cells had no effect on MIP3, or KC secretion, indicating that the KGF receptor is located on the basolateral surface of uterine epithelial cells. Conclusion, We demonstrate that KGF plays a role in uterine epithelial cell secretion of MIP3, and KC, key immune mediators involved in the protection of mucosal surfaces in the female reproductive tract. [source] Reciprocal chemokine receptor and ligand expression in the human placenta: Implications for cytotrophoblast differentiationDEVELOPMENTAL DYNAMICS, Issue 4 2004Penelope M. Drake Abstract At the onset of pregnancy, the human placenta, which forms the interface between the embryo/fetus and the mother, must rapidly develop into a life-sustaining organ. The many unusual processes entailed in placental development include the poorly understood phenomenon of maternal tolerance of the hemiallogeneic cells of the conceptus, including, most remarkably, placental trophoblasts that invade the uterine wall. To investigate whether this fetal organ exerts control over the maternal immune system at the level of leukocyte trafficking, we examined placental expression of chemokines, well-known cytokine regulators of leukocyte movements. In situ hybridization revealed abundant expression of 13 chemokines in the stromal but not the trophoblast compartment of chorionic villi. Potential roles for these molecules include recruitment of the resident macrophage (Hofbauer cell) population to the villi. In parallel, cytotrophoblast production of a panel of nine chemokine receptors was assessed by using RNase protection assays. The numerous receptors detected suggested the novel possibility that the paracrine actions of chemokine ligands derived from either the villous stroma or the decidua could mediate general aspects of placental development, with specific contributions to cytotrophoblast differentiation along the pathway that leads to uterine invasion. Developmental Dynamics 229:877,885, 2004. © 2004 Wiley-Liss, Inc. [source] Btk and phospholipase,C,2 can function independently during B cell developmentEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2007Kristina Abstract The pre-BCR and the BCR regulate B cell development via a signalosome nucleated by the adaptor protein B cell linker protein (BLNK). Formation of this complex facilitates activation of phospholipase,C (PLC),,2 by Bruton's tyrosine kinase (Btk). To determine whether Btk and PLC,2 also have separate functions, we generated Btk,/,PLC,2,/, mice. They demonstrated a block in development at the pre-B,stage and increased pre-BCR surface expression. This phenotype was more severe than that of Btk,/, or PLC,2,/, mice. Although both Btk and PLC,2 were required for proliferation of splenic B cells in response to BCR cross-linking, they contributed differently to anti-IgM-induced phosphorylation of ERK. Btk,/, and PLC,2,/, mice each had a reduced frequency of Ig,-expressing B cells and impaired migration of pre-B cells towards stromal cell-derived factor,1. However, the increase in pre-B cell malignancy that occurs in BLNK,/, mice in the absence of Btk was not observed in the absence of PLC,2. Thus, Btk and PLC,2 act both in concert and independently throughout B cell development. [source] Post-translational and cell type-specific regulation of CXCR4 expression by cytokinesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2003Hilke Brühl Abstract We have investigated the regulation and function of the chemokine receptor CXCR4 on neutrophils. CXCR4 is hardly detectable on neutrophils in the peripheral blood. However, overnight culture strongly up-regulates CXCR4 expression on the cell surface. The functional activity of CXCR4 on cultured neutrophils was confirmed by stromal cell-derived factor (SDF)-induced migration and up-regulation of the integrins CD11b and CD11c. CXCR4 surface expression on neutrophils but not on lymphocytes and monocytes is rapidly down-regulated after stimulation with TNF-, and IFN-,, resulting in significantly decreased SDF-induced functional responses of neutrophils. In contrast to surface expression, CXCR4 mRNA expression was several-fold increased in cytokine-stimulated neutrophils, suggesting a post-translational regulation. By confocal microscopy we demonstrate that CXCR4 is internalized after stimulation with TNF-, and IFN-,. The down-modulation of CXCR4 surface expression in response to TNF-, and IFN-, was fully reversible after cytokine removal. Further, CXCR4 down-modulation could be completely blocked by hypertonic sucrose and significantly reduced by chlorpromazine indicating the involvement of clathrin-coated pits. Internalization of CXCR4 by cytokines in a cell type-specific manner is a novel and functionally important mechanism of chemokine receptor regulation. [source] Structure,function relationship of novel X4 HIV-1 entry inhibitors , L- and D-arginine peptide-aminoglycoside conjugatesFEBS JOURNAL, Issue 24 2007Ravi Hegde We present the design, synthesis, anti-HIV-1 and mode of action of neomycin and neamine conjugated at specific sites to arginine 6- and 9-mers d - and l -arginine peptides (APACs). The d -APACs inhibit the infectivity of X4 HIV-1 strains by one or two orders of magnitude more potently than their respective l -APACs. d -arginine conjugates exhibit significantly higher affinity towards CXC chemokine receptor type 4 (CXCR4) than their l -arginine analogs, as determined by their inhibition of monoclonal anti-CXCR4 mAb 12G5 binding to cells and of stromal cell-derived factor 1, (SDF-1,)/CXCL12 induced cell migration. These results indicate that APACs inhibit X4 HIV-1 cell entry by interacting with CXCR4 residues common to glycoprotein 120 and monoclonal anti-CXCR4 mAb 12G5 binding. d -APACs readily concentrate in the nucleus, whereas the l -APACs do not. 9-mer- d -arginine analogues are more efficient inhibitors than the 6-mer- d -arginine conjugates and the neomycin- d -polymers are better inhibitors than their respective neamine conjugates. This and further structure,function studies of APACs may provide new target(s) and lead compound(s) of more potent HIV-1 cell entry inhibitors. [source] Transient expression of endothelins in the amoeboid microglial cells in the developing rat brainGLIA, Issue 6 2006Chun-Yun Wu Abstract Amoeboid microglial cells (AMC) which transiently exist in the corpus callosum in the postnatal rat brain expressed endothelins (ETs), specifically endothelin-1 (ET-1) and ET3 as revealed by real time RT-PCR. ET immunoreactive AMC occurred in large numbers at birth, but were progressively reduced with age and were undetected in 14 days. In rats subjected to hypoxia exposure, ET immunoexpression in AMC was reduced but the incidence of apoptotic cells was not increased when compared with the control suggesting that this was due to its downregulation that may help regulate the constriction of blood vessels bearing ET-A receptor. AMC were endowed ET-B receptor indicating that ET released by the cells may also act via an autocrine manner. In microglia activated by lipopolysaccharide (LPS), ET-1 mNA expression coupled with that of monocyte chemoattractant protein (MCP-1) and stromal derived factor-1 (SDF-1) was markedly increased; ET-3 mRNA, however, remained unaffected. AMC exposed to oxygen glucose deprivation (OGD) in vitro resulted in increase in both ET-1 and ET-3 mRNA expression. It is suggested that the downregulated ETs expression in vivo of AMC subjected to hypoxia as opposed to its upregulated expression in vitro may be due to the complexity of the brain tissue. Furthermore, the differential ET-1 and ET-3 mRNA expression in LPS and OGD treatments may be due to different signaling pathways independently regulating the two isoforms. The present novel finding has added microglia as a new cellular source of ET that may take part in multiple functions including regulating vascular constriction and chemokines release. © 2006 Wiley-Liss, Inc. [source] Stromal cells promote bone invasion by suppressing bone formation in ameloblastomaHISTOPATHOLOGY, Issue 4 2008G S A Sathi Aims:, To study the stromal variation and role of stromal,tumour cell interaction in impaired bone formation as well as enhanced bone resorption in ameloblastoma. Methods and results:, Four types of stroma were observed histologically; fibrous, desmoplastic, myxoid and myxoid with hyalinization. Osteoblast and osteoclast were counted using haematoxylin and eosin sections and immunohistochemistry with CD68. After histomorphometric analysis, only fibrous and myxoid types of stroma were distinctly identified. Secreted frizzled-related peptide (sFRP)-2, transforming growth factor-beta 1 and receptor activator of nuclear factor-,B ligand (RANKL) revealed strong expression in myxoid type compared with the normal stroma. Bone morphogenetic protein (BMP)-2 was negative in myxoid type, but positive in normal stroma. Fibrous-type stroma showed weak expression of all antigens except RANKL compared with myxoid type. Conclusions:, The results suggest that stroma does not act only in bone resorption, but also in the suppression of new bone formation. sFRP-2 is the main factor for impaired bone formation. The expression of markers related to osteoclastogenesis and suppression of osteoblast formation is higher in myxoid-type than in fibrous-type stroma. Tumour cells create a favourable environment for impaired bone formation by secreting sFRP-2 as well as bone resorption by secreting RANKL and interleukin-6. [source] Tenascin-C in primary malignant melanoma of the skinHISTOPATHOLOGY, Issue 4 2004S Ilmonen Aims :,To investigate the expression and the prognostic role of glycoprotein Tenascin-C (Tn-C) in primary melanoma of the skin. Methods and results :,The immunohistochemical expression of Tn-C was studied in 98 primary melanomas and related to inflammation, invasion, and patient outcome. Patients were followed up for disease recurrence for 0.04,7.4 years (median 3.9) and for survival for 0.5 to 12.1 years (median 9.3). The expression of Tn-C was evaluated for each tumour invasion border; the stromal and intracytoplasmic Tn-C of the melanoma islets were also recorded. Tn-C is widely expressed in primary melanoma samples, the staining pattern varying from focal to diffuse in different parts of the tumour. No correlation existed between intensity of Tn-C staining and inflammation. No stromal Tn-C was detected at the upper dermal lateral border in 12 patients, nor at the deep, dermal or subcutaneous border in 14 patients. These patients showed better disease-free survival (DFS) than did those cases with focal or diffuse staining (P = 0.06, P = 0.05). Also, absence of intracytoplasmic Tn-C was a beneficial prognostic factor for DFS (P = 0.04). In multivariate analysis, tumour ulceration and intracytoplasmic Tn-C expression of melanoma cells were independent adverse prognostic factors for DFS. Conclusions :,In primary melanoma of the skin, absence of Tn-C in the stroma of invasion fronts and within tumour cells seems to be related to a more benign disease behaviour with a lower risk of developing metastases. [source] Genetic dissection of thymus development in mouse and zebrafishIMMUNOLOGICAL REVIEWS, Issue 1 2003Thomas Boehm Summary:, Lymphoid organs represent a specialized microenvironment for interaction of stromal and lymphoid cells. In primary lymphoid organs, these interactions are required to establish a self-tolerant repertoire of lymphocytes. While detailed information is available about the genes that control lymphocyte differentiation, little is known about the genes that direct the establishment and differentiation of principal components of such microenvironments. Here, we discuss genetic studies addressing the role of thymic epithelial cells (TECs) during thymopoiesis. We have identifed an evolutionarily conserved key regulator of TEC differentiation, Foxn1, that is required for the immigration of prothymocytes into the thymic primordium. Because Foxn1 specifies the prospective endodermal domain that gives rise to thymic epithelial cells, it can be used to identify the evolutionary origins of this specialized cell type. In the course of these studies, we have found that early steps of thymus development in zebrafish are very similar to those in mice. Subsequently, we have used chemical mutagenesis to derive zebrafish lines with aberrant thymus development. Strengths and weaknesses of mouse and zebrafish models are largely complementary such that genetic analysis of mouse and zebrafish mutants may lead to a better understanding of thymus development. [source] Neutrophil mobilization and clearance in the bone marrowIMMUNOLOGY, Issue 3 2008Rebecca C. Furze Summary The bone marrow is the site of neutrophil production, a process that is regulated by the cytokine granulocyte colony-stimulating factor (G-CSF). Mature neutrophils are continually released into the circulation, with an estimated 1011 neutrophils exiting the bone marrow daily under basal conditions. These leucocytes have a short half-life in the blood of ,6·5 hr, and are subsequently destroyed in the spleen, liver and indeed the bone marrow itself. Additionally, mature neutrophils are retained in the bone marrow by the stromal cell-derived factor (SDF-1,)/chemokine (C-X-C motif) receptor 4 (CXCR4) chemokine axis and form the bone marrow reserve. Following infection or inflammatory insult, neutrophil release from the bone marrow reserve is substantially elevated and this process is mediated by the co-ordinated actions of cytokines and chemokines. In this review we discuss the factors and molecular mechanisms regulating the neutrophil mobilization and consider the mechanisms and functional significance of neutrophil clearance via the bone marrow. [source] Diverse roles of 2-arachidonoylglycerol in invasion of prostate carcinoma cells: Location, hydrolysis and 12-lipoxygenase metabolismINTERNATIONAL JOURNAL OF CANCER, Issue 5 2007Michael P. Endsley Abstract Endogenous 2-arachidonoylglycerol (2-AG) is antiinvasive in androgen-independent prostate carcinoma (PC-3) cells. Invasion of PC-3 cells is also inhibited by exogenously added noladin ether, a non-hydrolyzable analog of 2-AG. In contrast, exogenous 2-AG has the opposite effect. Cell invasion significantly increased with high concentrations of exogenous 2-AG. In PC-3 cells, arachidonic acid (AA) and 12-hydroxyeicosatetraenoic acid (12-HETE) concentrations increased along with exogenously added 2-AG, and 12-HETE concentrations increased with exogenously added AA. Invasion of PC-3 cells also increased with exogenously added AA and 12(S)-HETE but not 12(R)-HETE. The exogenous 2-AG-induced invasion of PC-3 cells was inhibited by 3-octylthio-1,1,1-trifluoropropan-2-one (OTFP, an inhibitor of 2-AG hydrolysis) and baicalein (a 12-LO inhibitor). Western blot and RT-PCR analyses indicated expression of 12-HETE producing lipoxygenases (LOs), platelet-type 12-LO (P-12-LO) and leukocyte-type 12-LO (L-12-LO), in PC-3 cells. These results suggest that exogenous 2-AG induced, rather inhibited, cell invasion because of its rapid hydrolysis to free AA, and further metabolism by 12-LO of AA to 12(S)-HETE, a promoter of PC cell invasion. The results also suggest that PC-3 cells and human prostate stromal (WPMY-1) cells released free AA, 2-AG, and 12-HETE. In the microenvironment of the PC cells, this may contribute to the cell invasion. The 2-AG hydrolysis and concentration of 2-AG in microenvironment are critical for PC cell's fate. Therefore, inhibitors of 2-AG hydrolysis could potentially serve as therapeutic agents for the treatment of prostate cancer. © 2007 Wiley-Liss, Inc. [source] Activation of Protease-Activated Receptor-2 Leads to Inhibition of Osteoclast Differentiation,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2004Rosealee Smith Abstract PAR-2 is expressed by osteoblasts and activated by proteases present during inflammation. PAR-2 activation inhibited osteoclast differentiation induced by hormones and cytokines in mouse bone marrow cultures and may protect bone from uncontrolled resorption. Introduction: Protease-activated receptor-2 (PAR-2), which is expressed by osteoblasts, is activated specifically by a small number of proteases, including mast cell tryptase and factor Xa. PAR-2 is also activated by a peptide (RAP) that corresponds to the "tethered ligand" created by cleavage of the receptor's extracellular domain. The effect of activating PAR-2 on osteoclast differentiation was investigated. Materials and Methods: Mouse bone marrow cultures have been used to investigate the effect of PAR-2 activation on osteoclast differentiation induced by parathyroid hormone (PTH), 1,25 dihydroxyvitamin D3 [1,25(OH)2D3], and interleukin-11 (IL-11). Expression of PAR-2 by mouse bone marrow, mouse bone marrow stromal cell-enriched cultures, and the RAW264.7 osteoclastogenic cell line was demonstrated by RT-PCR. Results: RAP was shown to inhibit osteoclast differentiation induced by PTH, 1,25(OH)2D3, or IL-11. Semiquantitative RT-PCR was used to investigate expression of mediators of osteoclast differentiation induced by PTH, 1,25(OH)2D3, or IL-11 in mouse bone marrow cultures and primary calvarial osteoblast cultures treated simultaneously with RAP. In bone marrow and osteoblast cultures treated with PTH, 1,25(OH)2D3, or IL-11, RAP inhibited expression of RANKL and significantly suppressed the ratio of RANKL:osteoprotegerin expression. Activation of PAR-2 led to reduced expression of prostaglandin G/H synthase-2 in bone marrow cultures treated with PTH, 1,25(OH)2D3, or IL-11. RAP inhibited PTH- or 1,25(OH)2D3 -induced expression of IL-6 in bone marrow cultures. RAP had no effect on osteoclast differentiation in RANKL-treated RAW264.7 cells. Conclusion: These observations indicate that PAR-2 activation inhibits osteoclast differentiation by acting on cells of the osteoblast lineage to modulate multiple mediators of the effects of PTH, 1,25(OH)2D3, and IL-11. Therefore, the role of PAR-2 in bone may be to protect it from uncontrolled resorption by limiting levels of osteoclast differentiation. [source] Secretion of SDF-1, by bone marrow-derived stromal cells enhances skin wound healing of C57BL/6 mice exposed to ionizing radiationJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 6b 2010Yannick Landry Abstract Patients treated for cancer therapy using ionizing radiation (IR) have delayed tissue repair and regeneration. The mechanisms mediating these defects remain largely unknown at present, thus limiting the development of therapeutic approaches. Using a wound healing model, we here investigate the mechanisms by which IR exposure limits skin regeneration. Our data show that induction of the stromal cell-derived growth factor 1, (SDF-1,) is severely impaired in the wounded skin of irradiated, compared to non-irradiated, mice. Hence, we evaluated the potential of bone marrow-derived multipotent stromal cells (MSCs), which secrete high levels of SDF-1,, to improve skin regeneration in irradiated mice. Injection of MSCs into the wound margin led to remarkable enhancement of skin healing in mice exposed to IR. Injection of irradiated MSCs into the wound periphery of non-irradiated mice delayed wound closure, also suggesting an important role for the stromal microenvironment in skin repair. The beneficial actions of MSCs were mainly paracrine, as the cells did not differentiate into keratinocytes. Specific knockdown of SDF-1, expression led to drastically reduced efficiency of MSCs in improving wound closure, indicating that SDF-1, secretion by MSCs is largely responsible for their beneficial action. We also found that one mechanism by which SDF-1, enhances wound closure likely involves increased skin vascularization. Our findings collectively indicate that SDF-1, is an important deregulated cytokine in irradiated wounded skin, and that the decline in tissue regeneration potential following IR can be reversed, given adequate microenvironmental support [source] Decrease in stromal androgen receptor associates with androgen-independent disease and promotes prostate cancer cell proliferation and invasionJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 6b 2008Yirong Li Abstract Androgen receptor (AR) is expressed in both stromal and epithelial cells of the prostate. The majority of studies on AR expression and function in prostate cancer is focused on malignant epithelial cells rather than stromal cells. In this study, we examined the levels of stromal AR in androgen-dependent and -independent prostate cancer and the function of stromal AR in prostate cancer growth and invasion. We showed that stromal AR levels were decreased in the areas surrounding cancerous tissue, especially in androgen-independent cancer. Using two telomerase-immortalized human stromal cell lines, one AR-positive and the other AR-negative, we demonstrated that stromal cells lacking AR stimulated cell proliferation of co-cultured prostate cancer cells in vitro and enhanced tumour growth in vivo when co-injected with PC3 epithelial cells in nude mice. In contrast, stromal cells expressing AR suppressed prostate cancer growth in vitro and in vivo. In parallel with cancer growth, in vitro invasion assays revealed that stromal cells lacking AR increased the invasion ability of PC3 cell by one order of magnitude, while stromal cells expressing AR reduced this effect. These results indicate a negative regulation of prostate cancer growth and invasion by stromal AR. This provides potentially new mechanistic insights into the failure of androgen ablation therapy, and the reactivation of stromal AR could be a novel therapeutic approach for treating hormone refractory prostate cancer. [source] Paradoxical roles for lysyl oxidases in cancer,A prospectJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2007Stacey L. Payne Abstract Lysyl oxidase (LOX) is an extracellular matrix (ECM) enzyme that catalyzes the cross-linking of collagens or elastin in the extracellular compartment, thereby regulating the tensile strength of tissues. However, recent reports have demonstrated novel roles for LOX, including the ability to regulate gene transcription, motility/migration, and cell adhesion. These diverse functions have led researchers to hypothesize that LOX may have multiple roles affecting both extra- and intracellular cell function(s). Particularly noteworthy is aberrant LOX expression and activity that have been observed in various cancerous tissues and neoplastic cell lines. Both down and upregulation of LOX in tumor tissues and cancer cell lines have been described, suggesting a dual role for LOX as a tumor suppressor, as well as a metastasis promoter gene,creating a conundrum within the LOX research field. Here, we review the body of evidence on LOX gene expression, regulation, and function(s) in various cancer cell types and tissues, as well as stromal,tumor cell interactions. Lastly, we will examine putative mechanisms in which LOX facilitates breast cancer invasion and metastasis. Taken together, the literature demonstrates the increasingly important role(s) that LOX may play in regulating tumor progression and the necessity to elucidate its myriad mechanisms of action in order to identify potentially novel therapeutics. J. Cell. Biochem. 101: 1338,1354, 2007. © 2007 Wiley-Liss, Inc. [source] Stromelysin-3 suppresses tumor cell apoptosis in a murine model,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2001Erxi Wu Abstract Stromelysin-3 (STR-3) is a matrix metalloproteinase with a unique pattern of expression and substrate specificity. During embryogenesis and remodeling of normal adult tissues, STR-3 is produced by stromal cells in direct contact with epithelial cells undergoing regional apoptosis and selective cell survival. STR-3 is also overexpressed by interdigitating stromal cells in primary epithelial malignancies. Although STR-3 does not degrade classic extracellular matrix components, the enzyme promotes the establishment of local tumors in nude mice by as yet undefined mechanisms. STR-3 is induced when malignant epithelial cells come into contact with surrounding stromal elements; the active stromal cell-derived 45 kDa enzyme is subsequently processed to a 35 kDa protein without enzymatic activity. We have generated MCF-7 transfectants expressing wild type or catalytically inactive 45 kDa STR-3 (STR-3wt and STR-3cat- ) or secreted 35 kDa STR-3 (35 kDa STR-3sec) and evaluated their implantation and survival in nude mice. Tumors developed significantly more rapidly in animals receiving STR-3wt, rather than vector-only, STR-3cat- or 35 kDa STR-3sec transfectants. Most importantly, STR-3wt tumors had a significantly lower percentage of apoptotic cells than tumors derived from vector-only, STR-3cat- or 35 kDa STR-3sec transfectants. Taken together, these studies suggest that the active STR-3 enzyme may increase tumor take by suppressing tumor cell apoptosis and that 45 kDa to 35 kDa STR-3 processing limits STR-3 activity at the tumor/stromal interface. Because STR-3 is secreted as an active enzyme rather than a proform, subsequent 45 kDa to 35 kDa STR-3 processing may represent a novel mechanism for regulating enzymatic activity. J. Cell. Biochem. 82: 549,555, 2001. © 2001 Wiley-Liss, Inc. [source] Stromal cell-derived factor-1 promotes migration of cells from the upper rhombic lip in cerebellar developmentJOURNAL OF NEUROSCIENCE RESEARCH, Issue 13 2010Tao Yu Abstract During cerebellar development, the chemokine stromal cell-derived factor-1, (SDF-1,) has been shown to play an important role in recruiting cells from the upper rhombic lip (URL) and external granule cell layer (EGL). However, its function in cerebellar development is still poorly understood. Our results have demonstrated that SDF-1 is necessary for EGL development, and URL cells stream to the SDF-1 source in vitro. Results of embryonic URL explant assays and transwell assays indicated that SDF-1 induces neural cell migration from the URL region in chemotactic and chemokinetic responses. The time-lapse results showed that the migration speed of granule cell progenitors out of the URL was accelerated by the addition of recombinant SDF-1,. Collectively, our study shows that SDF-1 increases the motility of URL cells in the absence of a gradient and promotes the migration of granule cell progenitors during cerebellar development. © 2010 Wiley-Liss, Inc. [source] Optimal conditions for in vivo induction of dopaminergic neurons from embryonic stem cells through stromal cell-derived inducing activityJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2002Asuka Morizane Abstract A method of inducing dopamine (DA) neurons from mouse embryonic stem (ES) cells by stromal cell-derived inducing activity (SDIA) was previously reported. When transplanted, SDIA-induced DA neurons integrate into the mouse striatum and remain positive for tyrosine hydroxylase (TH) expression. In the present study, to optimize the transplantation efficiency, we treated mouse ES cells with SDIA for various numbers of days (8,14 days). SDIA-treated ES cell colonies were isolated by papain treatment and then grafted into the 6-hydroxydopamine (6-OHDA)-lesioned mouse striatum. The ratio of the number of surviving TH-positive cells to the total number of grafted cells was highest when ES cells were treated with SDIA for 12 days before transplantation. This ratio revealed that grafting cell colonies was more efficient for obtaining TH-positive cells in vivo than grafting cell suspensions. When we grafted a cell suspension of 2 × 105, 2 × 104, or 2 × 103 cells into the 6-OHDA-lesioned mouse striatum, we observed only a few surviving TH-positive cells. In conclusion, inducing DA neurons from mouse ES cells by SDIA for 12 days and grafting cell colonies into mouse striatum was the most effective method for the survival of TH-positive neurons in vivo. © 2002 Wiley-Liss, Inc. [source] Stromal laminin chain distribution in normal, hyperplastic and malignant oral mucosa: relation to myofibroblast occurrence and vessel formationJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 4 2010Marcus Franz J Oral Pathol Med (2010) 39: 290,298 Background:, The contribution of stromal laminin chain expression to malignant potential, tumour stroma reorganization and vessel formation in oral squamous cell carcinoma (OSCC) is not fully understood. Therefore, the expression of the laminin chains ,2, ,3, ,4, ,5 and ,2 in the stromal compartment/vascular structures in OSCC was analysed. Methods:, Frozen tissue of OSCC (9× G1, 24× G2, 8× G3) and normal (2×)/hyperplastic (11×) oral mucosa was subjected to laminin chain and ,-smooth muscle actin (ASMA) immunohistochemistry. Results were correlated to tumour grade. The relation of laminin chain positive vessels to total vessel number was assessed by immunofluorescence double labelling with CD31. Results:, Stromal laminin ,2 chain significantly decreases and ,3, ,4, ,5 and ,2 chains and also ASMA significantly increase with rising grade. The amount of stromal ,3, ,4 and ,2 chains significantly increased with rising ASMA positivity. There is a significant decrease in ,3 chain positive vessels with neoplastic transformation. Conclusions:, Mediated by myofibroblasts, OSCC development is associated with a stromal up-regulation of laminin isoforms possibly contributing to a migration promoting microenvironment. A vascular basement membrane reorganization concerning ,3 and ,2 chain laminins during tumour angioneogenesis is suggested. [source] Primary sarcoma of the breastJOURNAL OF SURGICAL ONCOLOGY, Issue 3 2004Manoj Pandey Abstract Background and Objectives Primary sarcoma occurring in breast is rare and comprises 0.5,1% of all breast neoplasm. Majority of the series include both stromal and cystosarcoma phyllodes, only a few hundred cases of sarcomas other then cystosarcoma are reported. Patients and Methods We carried out a retrospective analysis of 19 patients with primary sarcoma of the breast treated between 1982 and 2002. Results Mean age of the patients was 38.6 years (12,70 years). Gradually progressive swelling was the commonest presenting feature. There were eight cases of angiosarcoma, four cases of spindle cell sarcoma, two each of pleomorphic sarcoma and stromal sarcoma, and one each of malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, and sarcoma (NOS). Eight of these were high-grade (42%). Eight patients underwent either radical or modified mastectomy, three underwent wide excisions, and one underwent quadrantectomy. Ten (52.6%) patients received postoperative adjuvant radiation. Two patients received chemotherapy. After a mean follow-up time of 34.5 months (median 25 months), eight patients failed. Failure was local in five, opposite breast in one, and both local and distant in two. The disease free survival at 3-year was 39%. In univariate analysis only the margin of first surgery was found to be a significant predictor of survival (P,=,0.05). Conclusions Primary sarcomas of the breast are aggressive tumors. Surgical treatment should consist of at least simple mastectomy. All attempts should be made to achieve a negative margin as this appears to be the only factor influencing survival in these patients. J. Surg. Oncol. 2004;87:121,125. © 2004 Wiley-Liss, Inc. [source] Bone marrow-derived stem cells in liver repair: 10 years down the lineLIVER TRANSPLANTATION, Issue 2 2010Eleanor S. Gilchrist Hematopoietic stem cells have potential in the field of regenerative medicine because of their capacity to form cells of different lineages. Bone marrow stem cells have been shown to contribute to parenchymal liver cell populations, and although this may not be functionally significant, it has sparked interest in the field of autologous stem cell infusion as a possible treatment for cirrhosis. In this review, we will examine the evidence for the contribution of bone marrow-derived cells to populations of liver cells and for the functional contribution of bone marrow-derived cells to both liver fibrosis and repair. The mechanisms by which cells are trafficked from the bone marrow to the liver are complex; the stromal derived factor-1/CXC receptor 4 axis is central to this process. There are limited data in liver injury, but we will examine findings from the bone marrow transplantation literature and discuss their relevance to liver disease. Stromal derived factor-1 also has a role in endogenous liver stem cell accumulation. Some groups have already started infusing autologous bone marrow cells into patients with cirrhosis. We will review these trials in the context of the basic science that we have discussed, and we will consider targets for investigation in the future. Liver Transpl 16:118,129, 2010. © 2010 AASLD. [source] Evaluation of lactate and alanine as metabolic biomarkers of prostate cancer using 1H HR-MAS spectroscopy of biopsy tissuesMAGNETIC RESONANCE IN MEDICINE, Issue 3 2008May-Britt Tessem Abstract The goal of this study was to investigate the use of lactate and alanine as metabolic biomarkers of prostate cancer using 1H high-resolution magic angle spinning (HR-MAS) spectroscopy of snap-frozen transrectal ultrasound (TRUS)-guided prostate biopsy tissues. A long-echo-time rotor-synchronized Carr-Purcell-Meiboom-Gill (CPMG) sequence including an electronic reference to access in vivo concentrations (ERETIC) standard was used to determine the concentrations of lactate and alanine in 82 benign and 16 malignant biopsies (mean 26.5% ± 17.2% of core). Low concentrations of lactate (0.61 ± 0.28 mmol/kg) and alanine (0.14 ± 0.06 mmol/kg) were observed in benign prostate biopsies, and there was no significant difference between benign predominantly glandular (N = 54) and stromal (N = 28) biopsies between patients with (N = 38) and without (N = 44) a positive clinical biopsy. In biopsies containing prostate cancer there was a highly significant (P < 0.0001) increase in lactate (1.59 ± 0.61 mmol/kg) and alanine (0.26 ± 0.07 mmol/kg), and minimal overlap with lactate concentrations in benign biopsies. This study demonstrates for the first time very low concentrations of lactate and alanine in benign prostate biopsy tissues. The significant increase in the concentration of both lactate and alanine in biopsy tissue containing as little as 5% cancer could be exploited in hyperpolarized 13C spectroscopic imaging (SI) studies of prostate cancer patients. Magn Reson Med 60:510,516, 2008. © 2008 Wiley-Liss, Inc. [source] The organic cation transporters (OCT1, OCT2, EMT) and the plasma membrane monoamine transporter (PMAT) show differential distribution and cyclic expression pattern in human endometrium and early pregnancy deciduaMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 10 2007Barbara Bottalico Abstract The non-neuronal monoamine transporters (OCT1, OCT2, EMT, and PMAT) play a key role in the clearance of monoamines from extracellular compartments. In a previous report we described endometrial distribution and cyclic variation of the vesicular monoamine transporter (VMAT2) mRNA and the neuronal norepinephrine transporter (NET) mRNA. In the present study we used in situ hybridization, real-time PCR and immunohistochemistry to reveal tissue distribution and cyclic variation of mRNA for the non-neuronal monoamine transporters in the human endometrium and early pregnancy decidua. We found that non-neuronal monoamine transporters are predominantly expressed in the stroma. The plasma membrane monoamine transporter (PMAT) mRNA expression peaked in the proliferative phase, whereas the extra-neuronal monoamine transporter (EMT) mRNA expression peaked in the secretory phase. The organic cation transporter 2 (OCT2) mRNA expression was exclusively detected in few scattered stromal cells and OCT1 mRNA was not detected at all. Our present results demonstrate that PMAT, EMT, and OCT2 transporters are expressed in the endometrial stroma and can potentially regulate reuptake of monoamines in general and histamine in particular. Taken together with our previous finding of VMAT2 mRNA in epithelial cells, we suggest a paracrine interaction between stromal and epithelial cells, which may modulate certain steps of the reproductive process. Mol. Reprod. Dev. 74: 1303,1311, 2007. © 2007 Wiley-Liss, Inc. [source] Testicular (gonadal stromal) fibroma: Case report and review of the literaturePATHOLOGY INTERNATIONAL, Issue 4 2002M. Salih Deveci A 25-year-old man presented with complaint of a painless enlargement in his left testis. The solid, encapsulated, circumscribed and grayish,white testicular mass displayed the characteristics of testicular fibroma histologically. It was composed of acellular collagenized plaques and hypercellular areas of fibroblastic spindle cells. Immunohistochemically, the neoplastic cells were positive for vimentin and smooth muscle actin, but not for cytokeratin, S-100 protein, desmin, CD99/MIC2 (a protein expressed by Sertoli cells and granulosa cells) and CD34. Only 18 cases of testicular (gonadal stromal) fibroma composed exclusively of spindle cells have been reported to date. An additional case of fibroma, which lacks definite neoplastic sex cord elements, and its differential diagnosis from other mesenchymal lesions of testis are discussed here, together with other cases in the literature. [source] Genome analysis and gene expression profiling of neuroblastoma and ganglioneuroblastoma reveal differences between neuroblastic and Schwannian stromal cellsTHE JOURNAL OF PATHOLOGY, Issue 3 2005Simona Coco Abstract Neuroblastic tumours are a group of paediatric cancers with marked morphological heterogeneity. Neuroblastoma (Schwannian stroma-poor) (NB-SP) is composed of undifferentiated neuroblasts. Ganglioneuroblastoma intermixed (Schwannian stroma-rich) (GNBi-SR) is predominantly composed of Schwannian stromal (SS) and neuroblastic (Nb) cells. There are contrasting reports suggesting that SS cells are non-neoplastic. In the present study, laser capture microdissection (LCM) was employed to isolate SS and Nb cells. Chromosome 1p36 deletion and MYCN gene amplification were found to be associated in two out of seven NB-SPs, whereas no abnormalities were observed in five GNBi-SRs. In some cases, loss of heterozygosity (LOH) at 1p36 loci was detected in Nb cells but not in the bulk tumour by LCM; furthermore, LOH was also identified in both SS and tumour tissue of a GNBi-SR. DNA gain and loss studied by comparative genomic hybridization were observed at several chromosome regions in NB-SP but in few regions of GNBi-SR. Finally, gene expression profiles studied using an oligo-microarray technique displayed two distinct signatures: in the first, 32 genes were expressed in NB-SP and in the second, 14 genes were expressed in GNBi-SR. The results show that NB-SP is composed of different morphologically indistinguishable malignant cell clones harbouring cryptic mutations that are detectable only after LCM. The degree of DNA imbalance is higher in NB-SP than in GNBi-SR. However, when the analysis of chromosome 1p36 is performed at the level of microdissection, LOH is also observed in SS cells. These data provide supportive evidence that SS cells have a less aggressive phenotype and play a role in tumour maturation. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Hypoxic preconditioning protects rat hearts against ischaemia,reperfusion injury: role of erythropoietin on progenitor cell mobilizationTHE JOURNAL OF PHYSIOLOGY, Issue 23 2008Jih-Shyong Lin Preconditioning, such as by brief hypoxic exposure, has been shown to protect hearts against severe ischaemia. Here we hypothesized that hypoxic preconditioning (HPC) protects injured hearts by mobilizing the circulating progenitor cells. Ischaemia,reperfusion (IR) injury was induced by left coronary ligation and release in rats kept in room air or preconditioned with 10% oxygen for 6 weeks. To study the role of erythropoietin (EPO), another HPC + IR group was given an EPO receptor (EPOR) antibody via a subcutaneous mini-osmotic pump 3 weeks before IR induction. HPC alone gradually increased haematocrit, cardiac and plasma EPO, and cardiac vascular endothelial growth factor (VEGF) only in the first two weeks. HPC improved heart contractility, reduced ischaemic injury, and maintained EPO and EPOR levels in the infarct tissues of IR hearts, but had no significant effect on VEGF. Interestingly, the number of CD34+CXCR4+ cells in the peripheral blood and their expression in HPC-treated hearts was higher than in control. Preconditioning up-regulated cardiac expression of stromal derived factor-1 (SDF-1) and prevented its IR-induced reduction. The EPOR antibody abolished HPC-mediated functional recovery, and reduced SDF-1, CXCR4 and CD34 expression in IR hearts, as well as the number of CD34+CXCR4+ cells in blood. The specificity of neutralizing antibody was confirmed in an H9c2 culture system. In conclusion, exposure of rats to moderate hypoxia leads to an increase in progenitor cells in the heart and circulation. This effect is dependent on EPO, which induces cell homing by increased SDF-1/CXCR4 and reduces the heart susceptibly to IR injury. [source] | |||||||||||||||||||||||||||||||