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At least 631 records · Page 35Linked to original sources

PubMed2000

Cerebrovascular smooth muscle cell surface fibrillar A beta. Alteration of the proteolytic environment in the cerebral vessel wall.

Cerebrovascular deposition of the amyloid beta-protein (A beta) is a common pathologic event in patients with Alzheimer's disease (AD) and certain related disorders including hereditary cerebral hemorrhage with amyloidosis Dutch-type (HCHWA-D). A beta deposition occurs primarily in the medial layer of the cerebral vessel wall in an assembled fibrillar state. These deposits are associated with several pathological responses including degeneration of the smooth muscle cells in the cerebral vessel wall. Severe cases of cerebrovascular A beta deposition are also accompanied by loss of vessel wall integrity and hemorrhagic stroke. Although the reasons for this pathological consequence are unclear, altered proteolytic mechanisms within the cerebral vessel wall may be involved. Recent studies from our laboratory have shown that cell-surface assembly of A beta into fibrillar structures causes cellular degeneration via an apoptotic pathway and creates an altered proteolytic microenvironment on the cell surface of human cerebrovascular smooth muscle cells (HCSM cells). For example, HCSM cell-surface A beta fibrils serve as a site for tight binding of cell-secreted amyloid beta-precursor protein (A beta PP). Since A beta PP is a potent inhibitor of key proteinases of coagulation cascade, its enhanced localization on the A beta fibrils would provide an strong anticoagulant environment. In addition, HCSM cell-surface A beta fibrils are potent stimulators of tissue plasminogen activator (tPA) creating a profibrinolytic milieu. Our findings indicate that A beta fibril assembly on the HCSM cell surface causes cellular degeneration and results in both a strong anticoagulant and fibrinolytic environment. Together, these altered proteolytic events could create a setting that is conducive to loss of vessel wall integrity and hemorrhagic stroke.

Alzheimer Disease↗

PubMedDate not supplied

Cancer, aging and cellular senescence.

Normal cells do not divide indefinitely due to a process termed cellular or replicative senescence. Several lines of evidence suggest that replicative senescence evolved to protect higher eukaryotes, particularly mammals, from developing cancer. Senescent cells differ from their presenescent counterparts in three way: 1) they arrest growth and cannot be stimulated to reenter the cell cycle by physiological mitogens; 2) they become resistant to apoptotic cell death; 3) they acquire altered differentiated functions. Replicative senescence occurs because, owing to the biochemistry of DNA replication, cells acquire one or more critically short telomere. The mechanism by which a short telomere induces the senescent phenotype is unknown. Recent findings suggest that certain types of DNA damage and inappropriate mitogenic signals can also cause cells to adopt a senescent phenotype. Thus, cells respond to a number of potentially oncogenic stimuli by adopting a senescent phenotype. These findings suggest that the senescence response is a fail-safe mechanism that protects cells from tumorigenic transformation. Despite the protection from cancer conveyed by cellular senescence and other mechanisms that suppress tumorigenesis, the development of cancer is almost inevitable as mammalian organisms age. Why is this the case? Certainly, aging predisposes cells to accumulate mutations, several of which are necessary before malignant transformation occurs, particularly in humans. However, many benign or relatively well-controlled tumors may also harbor many potentially oncogenic mutations, suggesting that the tissue microenvironment can suppress the expression of many malignant phenotypes. Although the idea remains controversial, cellular senescence has also been proposed to contribute to organismal aging. Senescent cells have recently been shown to accumulate with age in human tissues. One possibility is that the tissue microenvironment is disrupted by the accumulation of dysfunctional senescent cells. Thus, mutation accumulation may synergize with the accumulation of senescent cells, leading to increasing risk for developing cancer that is a hallmark of mammalian aging.

Aging↗

PubMed2000

Pathophysiologic interactions in skeletal metastasis.

BACKGROUND: This review summarizes evidence that the formation of bone metastases is the result of multiple synergistic cellular and molecular interactions between metastatic cells and the unique microenvironment in bone. METHODS: Molecular technologies have been used to detect cancer cells in bone and to define their genotypic and phenotypic properties. Bone organ cultures have been employed to analyze the ability of tumor cells to modulate bone resorption and to study the effects of resorption products on the phenotypic properties of cancer cells. Experimental models of bone metastasis provide the ability to examine the effects of modulating specific host or tumor properties in vivo by quantifying their effects on the formation of bone tumors. RESULTS: By means of the blood stream, cells from many common neoplasms seed bone marrow as an early clinical event. The subsequent growth of these cells into clinically significant metastatic lesions is associated with their ability to stimulate bone resorption through osteoclasts and macrophages or through a direct action on bone. In turn, the products of bone resorption, which include matrix-derived growth factors, act on the tumor cells to stimulate the expression of properties that promote their metastatic competence. These include the induction of integrin adhesion molecules, the stimulation of cell motility and chemotaxis, the enhanced expression of matrix metalloproteinases, and the stimulation of tumor cell growth. CONCLUSIONS: The interdependency of tumor cells and bone was recognized by Steven Paget over 100 years ago, and it provides a rational basis for the development of current therapeutic strategies against bone metastasis.

Bone Neoplasms↗

PubMed1992

Suppressor genes in breast cancer: an overview.

It is apparent that multiple genetic events occur in the development and progression of breast cancer. From the limited data available, no consistent temporal pattern of mutational events is required. This conclusion is consistent with data in colorectal carcinoma, where the number of mutational events, and not the order, appears to be relevant. Several authors have questioned whether the multiple mutational events occur independently or whether significant associations were evident. Cropp et al. postulated that two sets of mutational events occurred simultaneously in a higher degree of breast tumors than expected based on chance: Set 1 consisted of deletions on 11p, 17p, 18q, and int-2 and myc amplifications; set 2 consisted of 17q, 1p, and 3p deletions. Sato et al., analyzing another tumor cohort for simultaneous mutations, noted a correlation of 17p and 16q deletions, 13q and 17p deletions, and 17p deletion with erbB-2 amplification. Clearly, concordant data on this issue will require the use of large breast tumor cohorts for a comprehensive set of probes. The reasons why mutations to specific genes on different chromosomes tend to occur coordinately is unknown, but may involve common flanking and/or intron sequences at high risk for certain types of mutational events. Another interesting question is the degree to which alterations, but not homozygous inactivation, of suppressor genes occur and its phenotypic consequences. In this chapter, evidence was presented for the amplification of a DCC allele in breast cancer and for variable RB protein expression in breast tumors as a consequence of allelic deletion. For many of the metastasis suppressor genes, a simple reduction in their expression, or an alteration in their expression over the normal cellular regulatory controls, may be sufficient to fuel the metastatic process. The data suggest a more complex regulation of the cancer phenotype by suppressor genes than by recessive inactivation alone. Why do many sporadic cancers, including breast cancer, appear to require alterations to multiple suppressor genes, as compared to diseases such as retinoblastoma, where a single suppressor gene appears to control the cancer phenotype? The answer to this question is unknown, but most theories are based on the hypothesis that suppressor genes act to control cellular responses to either other cells or signals in the microenvironment. In retinoblastoma all cells can carry a germ-line mutation. Cells carrying the RB mutation can interact with both the embryonic and differentiated microenvironments; the specific interaction of mutated cells with the embryonic retinal microenvironment may trigger the onset of retinoblastoma.(ABSTRACT TRUNCATED AT 400 WORDS)

Alleles↗

PubMed1992

Hemopoietic functions of marrow-derived osteogenic cells.

Osteoblasts, members of the marrow stromal cellular network, may play an active role in the hemopoietic microenvironment as well as in bone remodeling. In this study, we examined the extent to which marrow-derived osteogenic cells (MBA-15) possess various stromal functions. This marrow stromal-derived cell line was shown by us to exhibit osteoblastic characteristics in culture and to form bone in vivo. These cells are shown here to constitutively produce and secrete cytokines identified as M-CSF, GM-CSF, and IL-6. MBA-15 cells modulate growth of normal and malignant myeloid and lymphoid cells as well as leukemia cell lines in vitro. Cell-cell interactions were studied in co-cultures with adherent MBA-15 cells and the target hemopoietic cells. Growth inhibition effects, observed under various experimental conditions, can be attributed to the presence of different soluble and membrane-bound inhibitory activities produced by MBA-15 cells. Thus, MBA-15 cells spontaneously produce both stimulators and inhibitors that can affect myeloid and lymphoid cell growth. Marrow osteogenic cells may therefore participate in the stromal regulation of hemopoiesis.

Alkaline Phosphatase↗

PubMed1994

Inhibition of P-glycoprotein-mediated vinblastine transport across HCT-8 intestinal carcinoma monolayers by verapamil, cyclosporine A and SDZ PSC 833 in dependence on extracellular pH.

The ability of the multidrug resistance modifiers R- and R,S-verapamil (VPL), cyclosporine A (CsA) and its non-immunosuppressive derivative SDZ PSC 833 (PSC 833) to inhibit P-glycoprotein (P-gp)-mediated transepithelial flux of tritiated vinblastine was investigated using tight and highly resistant (R > 1,400 omega cm2) monolayer cultures of intestinal adenocarcinoma-derived HCT-8 cells grown on permeable tissue-culture inserts. Apical addition of these chemosensitizers inhibited drug flux (137 pmol h-1 cm-2; range, 133-142 pmol h-1 cm-2) in the basal to apical secretory direction at clinically relevant concentrations, with PSC 833 showing the highest activity, exhibiting inhibition at concentrations as low as 10 ng/ml (9 nM). Acidification of the modulator-containing apical compartment to an extracellular pH (pHo) of 6.8 had no influence on MDR reversal by CsA at 1 microgram/ml (0.9 microM; flux inhibition, 52%) or by PSC 833 at 100 ng/ml (0.09 microM; flux inhibition, 60%), in contrast to R,S- and R-VPL, which showed decreased inhibition and caused less accumulation of vinblastine in HCT-8 cells under this condition (flux inhibition of 35% and 23%, respectively, at pHo 6.8 vs 50% and 43%, respectively, at pHo 7.5). P-gp-mediated rhodamine 123 efflux from dye-loaded single-cell suspensions of HCT-8 cells as measured by flow cytometry was not impeded at pHo 6.8 in comparison with pHo 7.5 in standard medium, but at low pHo the inhibitory activity of R-VPL (29% vs 60% rhodamine 123 efflux inhibition) was diminished significantly, again without a reduction in the effect of PSC 833 (rhodamine 123 flux inhibition, 75%). In conclusion, drug extrusion across polarised monolayers, which offer a relevant model for normal epithelia and tumour border areas, is inhibited by the apical presence of R,S- and R-VPL, CsA and PSC 833 at similar concentrations described for single-cell suspensions, resulting in increased (2.2- to 3.7-fold) intracellular drug accumulation. Functional apical P-gp expression, the absence of paracellular leakage and modulator-sensitive rhodamine 123 efflux in single HCT-8 cells indicate a P-gp-mediated transcellular efflux in HCT-8 monolayers. In addition to its high MDR-reversing capacity, the inhibitory activity of PSC 833 is not affected by acidic extracellular conditions, which reduce the VPL-induced drug retention significantly. As far as MDR contributes to the overall cellular drug resistance of solid tumours with hypoxic and acidic microenvironments, PSC 833 holds the greatest promise for clinical reversal of unresponsiveness to the respective group of chemotherapeutics.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1989

Morphological and immunohistochemical studies of Hodgkin's disease in the spleen.

Hodgkin's disease in the spleen - with the exception of its B cell variant - behaves quite differently from non Hodgkin's lymphomas with respect to both its spread and microenvironment. Each type of HD appears to create its own microenvironment by the secretion of cytokines responsible for the characteristic cellular composition of the infiltrates and thereby alters the normal immunoarchitecture of the spleen profoundly. While some histological findings seem to imply the presence of a host response against HD especially in the nodular sclerosis subtype, morphological and immunohistochemical evidence in the spleen cannot conclusively substantiate this hypothesis.

Adult↗

PubMed1995

Characterization of human thymic epithelial cell surface antigens: phenotypic similarity of thymic epithelial cells to epidermal keratinocytes.

Cellular interactions between developing thymocytes and cells of the thymic microenvironment are necessary for maturation of thymocytes into mature T cells. While much is known about the molecules on developing T cells that mediate these interactions, little is known about the surface molecules of human thymic epithelial (TE) cells. In this study, using a panel of 276 MAb including 255 MAb from the 5th International Workshop on Human Leukocyte Differentiation Antigens (HLDA-V), we have determined the expression of CD1 through CDw130 and other surface molecules on resting and IFN-gamma-activated cultured human TE cells and on resting epidermal keratinocytes (EK). We demonstrate the surface expression of 50 of the 161 molecules assayed for on TE cells, including a number of adhesion molecules, cytokine receptors, Apo-1, and MHC-encoded molecules. While activation of TE cells with IFN-gamma for 48 hr induced a greater than fivefold increase in the expression of four surface molecules (CD38, CD54, MHC class I, and MHC class II), it also induced a greater than 50% increase in the expression of 14 other surface molecules (CD12, CD29, CD40, CD44, CD47, CD49b, CD49c, CD49e, CD55, CD66, CD87, CD104, TE4, and STE3) and a decrease in the expression of three molecules (CDw65, CDw109, and STE2). In comparing the phenotype of TE cells to 83 other cell lines studied in HLDA-V, we found that TE cells were strikingly more similar to EK than to any of the other cell types tested.

Antigens, CD↗

PubMed1984

A minimal living system and the origin of a protocell.

Based on our current knowledge of molecular biology a living entity is a negentropic system, made of specific catalytic and informational macromolecules, which has the ability to reproduce itself, selectively interact with the environment, increase complexity, undergo mutation and evolve by natural selection. At the cellular level the essential molecular attributes of a minimal living system are considered to be the following: (a) Linear informational molecules, protoRNA (protoDNA) at least 10 mononucleotides long, capable to code for at least 2 amino acids; (b) Code-translating molecules, aminoacyl-proto tRNAs at least 5 mononucleotides long; (c) Protenzymes, oligopeptides of at least 2 amino acids, with measurable catalytic activity for phosphodiester, pyrophosphate and peptide bond formation; (d) Protoribosomes, RNA-peptide complexes which facilitate the interaction of the above three types of molecules, and (e) Protomembranes, liposomes made of amphiphilic lipids and peptides which can provide the semipermeability and the proton gradient necessary for the synthesis of pyrophosphate, ATP and other biochemical compounds. The transition from subcellular Lamarckian evolution to cellular Darwinian evolution required the cooperative interaction, within an internal microenvironment, of the above five types of molecular species.

Biological Evolution↗

PubMed2003

Cardiomyocyte-mediated contact programs human mesenchymal stem cells to express cardiogenic phenotype.

BACKGROUND: Intercellular crosstalk and cellular plasticity are key factors in embryogenesis and organogenesis. The microenvironment plays a critical role in directing the progression of stem cells into differentiated cells. We hypothesized that intercellular interaction between adult human mesenchymal stem cells and adult human cardiomyocytes would induce stem cells to acquire the phenotypical characteristics of cardiomyocytes, and we tested the role that direct cell-to-cell contact plays in directing this differentiation process. Human mesenchymal stem cells were cultured in the presence of human cardiomyocytes ("coculture") or in the presence of media conditioned by separate cultures of human cardiomyocytes ("conditioned media"). METHODS: Human cardiomyocytes were labeled with chloromethyl derivatives of fluorescein diacetate. In the coculture experiments, human mesenchymal stem cells and human cardiomyocytes were mixed at a 1:1 ratio in smooth muscle 2 media and seeded at a cell density of 10,000 cells/cm(2). Cells were cocultured in an incubator at 37 degrees C for 48 hours. Subsequently, fluorescence-activated cell sorting was used to extract the differentiating human mesenchymal stem cells. In the conditioned media experiments, human mesenchymal stem cells were incubated in media previously conditioned by cardiomyocytes, in the presence and absence of serum (+/-serum). The conditioned media was changed 3 times, at intervals of 48 hours. Total RNA was isolated and reverse transcriptase-polymerase chain reaction was performed for expression of contractile proteins and cardiac specific genes. Immunostaining against myosin heavy chain, beta-actin troponin-T, and troponin-I was performed. RESULTS: Fluorescence-activated cell sorting analysis identified 66% of the human mesenchymal stem cells in the G1 phase. Differentiated hMSCs from the coculture experiments expressed myosin heavy chain, beta-actin, and troponin-T by reverse transcriptase-polymerase chain reaction. Immunostaining was also positive against myosin heavy chain and troponin-T. In contrast, only beta-actin expression was observed in the human mesenchymal stem cells incubated with conditioned media +/- serum. CONCLUSION: In addition to soluble signaling molecules, direct cell-to-cell contact is obligatory in relaying the external cues of the microenvironment controlling the differentiation of adult stem cells to cardiomyocytes. These data indicate that human mesenchymal stem cells are plastic and can be reprogrammed into a cardiomyogenic lineage that may be used in cell-based therapy for treating heart failure.

Actins↗

PubMed1984

Activity of prostaglandin biosynthetic pathways in rat pancreatic islets.

Isolated pancreatic islets of the rat were either prelabeled with [3H]arachidonic acid, or were incubated over the short term with the concomitant addition of radiolabeled arachidonic acid and a stimulatory concentration of glucose (17mM) for prostaglandin (PG) analysis. In prelabeled islets, radiolabel in 6-keto-PGF1 alpha, PGE2, and 15-keto-13,14-dihydro-PGF2 alpha increased in response to a 5 min glucose (17mM) challenge. In islets not prelabeled with arachidonic acid, label incorporation in 6-keto-PGF1 alpha increased, whereas label in PGE2 decreased during a 5 min glucose stimulation; after 30-45 min of glucose stimulation labeled PGE levels increased compared to control (2.8mM glucose) levels. Enhanced labelling of PGF2 alpha was not detected in glucose-stimulated islets prelabeled or not. Isotope dilution with endogenous arachidonic acid probably occurs early in the stimulus response in islets not prelabeled. D-Galactose (17mM) or 2-deoxyglucose (17mM) did not alter PG production. Indomethacin inhibited islet PG turnover and potentiated glucose-stimulated insulin release. Islets also converted the endoperoxide [3H]PGH2 to 6-keto-PGF1 alpha, PGF2 alpha, PGE2 and PGD2, in a time-dependent manner and in proportions similar to arachidonic acid-derived PGs. In dispersed islet cells, the calcium ionophore ionomycin, but not glucose, enhanced the production of labeled PGs from arachidonic acid. Insulin release paralleled PG production in dispersed cells, however, indomethacin did not inhibit ionomycin-stimulated insulin release, suggesting that PG synthesis was not required for secretion. In confirmation of islet PGI2 turnover indicated by 6-keto-PGF1 alpha production, islet cell PGI2-like products inhibited platelet aggregation induced by ADP. These results suggest that biosynthesis of specific PGs early in the glucose secretion response may play a modulatory role in islet hormone secretion, and that different pools of cellular arachidonic acid may contribute to PG biosynthesis in the microenvironment of the islet.

Adenosine Diphosphate↗

PubMed2025

Adjusting the scope of natural killer cells in cancer therapy.

Natural killer (NK) cells have evolved to detect abnormalities in tissues arising from infection with pathogens, genomic damage, or transformation and respond rapidly to the production of potent proinflammatory and cytolytic mediators. While this acute proinflammatory response is highly efficient at orchestrating sterilizing immunity to pathogens in a matter of days, cellular transformation often avoids the innate detection mechanisms of NK cells. When cellular transformation results in malignancy, tumor cells and/or the tumor microenvironment can evolve additional mechanisms to circumvent NK cell responses, and cancer is now a dominant disease burden worldwide. Here, we review recent advances in our understanding of the combined relationship between malignancies and natural killer (NK) cells, learn from recent clinical efforts in therapeutically targeting natural killer (NK) cells in cancer and outline some emerging therapeutic concepts that aim to improve the innate immune response against cancer.

Humans↗

PubMed2006

PET modulated fluorescent sensing from the BF2 chelated azadipyrromethene platform.

A convergent building block synthesis has been applied to new off/on photoinduced electron transfer (PET) modulated fluorescent sensors which are based on a BF(2) chelated tetraarylazadipyrromethene platform and operate in the biomedically important red region of the visible spectrum. Incorporation of diethylamine and morpholine receptors facilitates off/on microenvironment polarity and pH sensing. Aqueous formulation and in vitro cellular imaging demonstrates their potential for intracellular sensing.

Alkenes↗

PubMed2006

Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression.

The hypoxia-inducible transcription factor-1 (HIF-1) is central to a number of pathological processes through the induction of specific genes such as vascular endothelial growth factor (VEGF). Even though HIF-1 is highly regulated by cellular oxygen levels, other elements of the inflammatory and tumor microenvironment were shown to influence its activity under normal oxygen concentration. Among others, recent studies indicated that transforming growth factor (TGF) beta increases the expression of the regulatory HIF-1alpha subunit, and induces HIF-1 DNA binding activity. Here, we demonstrate that TGFbeta acts on HIF-1alpha accumulation and activity by increasing HIF-1alpha protein stability. In particular, we demonstrate that TGFbeta markedly and specifically decreases both mRNA and protein levels of a HIF-1alpha-associated prolyl hydroxylase (PHD), PHD2, through the Smad signaling pathway. As a consequence, the degradation of HIF-1alpha was inhibited as determined by impaired degradation of a reporter protein containing the HIF-1alpha oxygen-dependent degradation domain encompassing the PHD-targeted prolines. Moreover, inhibition of the TGFbeta1 converting enzyme, furin, resulted in increased PHD2 expression, and decreased basal HIF-1alpha and VEGF levels, suggesting that endogenous production of bioactive TGFbeta1 efficiently regulates HIF-1-targeted genes. This was reinforced by results from HIF-1alpha knock-out or HIF-1alpha-inhibited cells that show impairment in VEGF production in response to TGFbeta. This study reveals a novel mechanism by which a growth factor controls HIF-1 stability, and thereby drives the expression of specific genes, through the regulation of PHD2 levels.

Animals↗

PubMedDate not supplied

Gastritis induced by Helicobacter pylori in gnotobiotic piglets.

Helicobacter pylori has recently been recognized as a gastric pathogen in humans. Experimental oral inoculation of gnotobiotic piglets with this organism results in gastritis that exhibits many features of the corresponding disease in humans. In piglets the organism is restricted to the gastric microenvironment and persists in that location despite prompt humoral and cellular responses to antigens of H. pylori. The gnotobiotic piglet model is useful for delineation of the role of suspected bacterial virulence factors (i.e., motility and urease production) in gastric colonization and for preclinical determination of the efficacy of various antimicrobial substances.

Animals↗

PubMed1992

The adherence of endothelial cells to Dacron induces the expression of the intercellular adhesion molecule (ICAM-1).

The intercellular adhesion molecule (ICAM-1) is a glycoprotein expressed by endothelial cells activated by cytokines. The lymphocyte-function-associated antigen (LFA-1) is an integrin expressed by activated white blood cells. Together, this receptor-ligand pair is responsible, in part, for the localization of neutrophils at sites of inflammation. Using an in vitro model, the authors studied the binding of antibodies against ICAM-1 by human saphenous vein endothelial cells (HSVEC) adherent to Dacron and control cultureware. After adherence to Dacron pretreated with fibronectin, 24% more HSVEC-bound antibody against ICAM-1 compared with HSVEC on controls. In contrast, 90% more HSVEC adherent to Dacron incubated with whole blood bound anti-ICAM-1 antibodies. These cells bound 17.7-fold greater amounts of antibody compared with HSVEC on controls. Pretreating Dacron with plasma resulted in no increase in antibody binding compared with control. Our studies suggest that the cellular components of blood in contact with Dacron create a microenvironment that activates HSVEC and enhances ICAM-1 expression. Induction of this adhesion molecule may play a pivotal role in the migration and localization of leukocytes at the site of the vascular prosthesis.

Antigens, CD↗

PubMed1997

Therapeutic effect of periocular corticosteroids in experimental proliferative vitreoretinopathy.

OBJECTIVE: To test the therapeutic effect of periocular corticosteroid injection on outcome, vitreous cellular infiltrate, and vitreous soluble growth-stimulating activity in an experimental model of tractional retinal detachment resulting from proliferative vitreoretinopathy. METHODS: An experimental model of proliferative vitreoretinopathy was induced in rabbits, which then were selected randomly to receive either periocular methylprednisolone acetate injection treatment or a placebo injection (control). Animals were examined and monitored to determine the degree of retinal detachment and proliferative vitreoretinopathy at weekly intervals for 4 weeks. Vitreous specimens were obtained each week and analyzed for cell number by flow cytometry and for soluble growth-stimulating activity using a bioassay. RESULTS: Eighty-six percent (12 of 14) of the rabbits receiving periocular steroid injection had retinas that remained attached, whereas only 13 percent (2 of 15) of control animals had retinas that remained attached. Periocular steroid injections were associated with a significant decrease in the vitreous soluble proliferation stimulating activity at all times during experimental proliferative vitreoretinopathy. Vitreous cellular infiltration also was reduced significantly in steroid-treated animals compared with that of control animals. Finally, the magnitude of the soluble growth-stimulating activity at day 7, before onset of proliferative vitreoretinopathy, was highly predictive of outcome 3 weeks later. CONCLUSION: Periocular steroids decreased the incidence of complicated retinal detachment caused by proliferative vitreoretinopathy in this rabbit model. Decreased vitreous cellular infiltrate and soluble proliferation stimulating activity within the vitreous microenvironment also was observed to be associated with successful outcome.

Adrenal Cortex Hormones↗

PubMed2005

Normal human melanocyte homeostasis as a paradigm for understanding melanoma.

Melanocytes, after cell division, separate and migrate along the basement membrane; they extend their dendrites and establish multiple contacts with keratinocytes. Once adhesion is established, keratinocytes control melanocyte growth and expression of cell surface receptors. Most melanomas arise within the epidermis (melanoma in situ) and then invade across the basement membrane. These melanoma cells escape from control by keratinocytes through five major mechanisms: (1) downregulation of receptors important for communication with keratinocytes such as E-cadherin, P-cadherin, and desmoglein, which is achieved through growth factors such as hepatocyte growth factor, platelet-derived growth factor, and endothelin-1 produced by fibroblasts or keratinocytes; (2) upregulation of receptors and signaling molecules important for melanoma cell-melanoma cell and melanoma cell-fibroblast interactions such as N-cadherin, Mel-CAM, and zonula occludens protein-1; (3) deregulation of morphogens such as Notch receptors and their ligands; (4) loss of anchorage to the basement membrane because of an altered expression of cell-matrix adhesion molecules; (5) increased elaboration of metal-loproteinases. Thus, investigating normal melanocyte homeostasis helps us to better define how melanoma cells escape the microenvironment created by epidermal keratinocytes and how they develop new cellular partners in fibroblasts and endothelial cells, which support their growth and invasion.

Cadherins↗