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PubMed1996

The ABL genes in normal and abnormal cell development.

Genetic alteration of the c-abl protooncogene has led to abnormal cellular development, primarily within the hemopoietic system. Different forms of oncogenic alteration have variations in biological strength for cellular transformation. The abnormal Abl oncoproteins are known to suppress apoptosis, which may be the basis for causing leukemia development. However, recent evidence also shows that c-abl proto-oncoprotein can inhibit apoptosis. Expression of the Abl oncoprotein in hemopoietic stem cells (HSCs) also results in alteration in the expression of certain cell surface molecules such that the interaction between HSCs and their marrow stroma microenvironment has become abnormal. The basis for the genetic alteration of the c-abl protooncogene in patients with chronic myelogenous leukemia may or may not be due to genetic imprinting.

Animals↗

PubMed2003

Human CD4+ T cells present within the microenvironment of human lung tumors are mobilized by the local and sustained release of IL-12 to kill tumors in situ by indirect effects of IFN-gamma.

By implanting nondisrupted pieces of human lung tumor biopsy tissues into SCID mice, it has been possible to establish viable grafts of the tumor, as well as the tumor-associated microenvironment, including inflammatory cells, fibroblasts, tumor vasculature, and the extracellular matrix. Using this xenograft model, we have evaluated and characterized the effects of a local and sustained release of human rIL-12 (rhIL-12) from biodegradable microspheres. In response to rhIL-12, the human CD45+ inflammatory cells present within the xenograft mediate the suppression or the complete arrest of tumor growth in SCID mice. Analysis of the cellular events reveals that human CD4+ and CD8+ T cells are induced by rhIL-12 to produce and secrete IFN-gamma. Serum levels of human IFN-gamma in mice bearing rhIL-12-treated tumor xenografts correlate directly with the degree of tumor suppression, while neutralizing Abs to human IFN-gamma abrogate the IL-12-mediated tumor suppression. Gene expression profiling of tumors responding to intratumoral rhIL-12 demonstrates an up-regulation of IFN-gamma and IFN-gamma-dependent genes not observed in control-treated tumors. Genes encoding a number of proinflammatory cytokines, chemokines (and their receptors), adhesion molecules, activation markers, and the inducible NO synthase are up-regulated following the introduction of rhIL-12, while genes associated with tumor growth, angiogenesis, and metastasis are decreased in expression. NO contributes to the tumor killing because an inhibitor of inducible NO synthase prevents IL-12-induced tumor suppression. Cell depletion studies reveal that the IL-12-induced tumor suppression, IFN-gamma production, and the associated changes in gene expression are all dependent upon CD4+ T cells.

Animals↗

PubMed1994

Peptides and growth regulatory factors in bone.

All bone is remolded by bone resorbing (osteoclasts) and bone forming (osteoblasts) cells that are under the regulatory control of local factors generated in the bone cell microenvironment. These local factors are comprised of peptides and nonpeptides, including arachidonic acid metabolites such as prostaglandins of the E series and the leukotrines. Most is known of the peptides the stimulate or inhibit osteoclastic bone resorption, but information is also now accumulating on the peptide growth factors that are incorporated into the bone matrix, released in an active form when bone is resorbed, and stimulate those cellular events that result in bone formation. In this article these control mechanisms are reviewed.

Animals↗

PubMed1999

The proliferative capacity of neonatal skin fibroblasts is reduced after exposure to venous ulcer wound fluid: A potential mechanism for senescence in venous ulcers.

PURPOSE: We have previously shown that fibroblasts cultured from venous ulcers display characteristics of senescence and have reduced growth rates. Susceptibility of young fibroblasts to the microcirculatory changes associated with venous ulcers, such as macrophage trapping and activation, could explain the prevalence of senescent fibroblasts in these wounds. METHODS: We tested the in vitro effect of venous ulcer wound fluid (VUWF), as well as pro-inflammatory cytokines known to be present in VUWF (TNF-alpha, IL-1beta, and TGF-beta1), on neonatal foreskin fibroblasts (NFFs). NFF growth rates, cellular morphology, and senescence-associated beta-galactosidase (SA-beta-Gal) activity were determined in the presence or absence of VUWF and the above cytokines. VUWF TNF-alpha concentration and the effect of anti-TNF-alpha antibody on VUWF inhibitory activity were determined in samples obtained from four patients with venous ulcers. RESULTS: NFF growth rates were significantly reduced by VUWF (42,727 +/- 6301 vs 3902 +/- 2191 P =. 006). TNF-alpha also significantly reduced NFF growth rates in a dose-dependent manner (P =.01). No significant growth-inhibitory activity was seen for IL-1alpha or TGF-beta. Incubation with VUWF significantly increased the percentage of SA-beta-Gal-positive fibroblasts in vitro on culture day 12 (P =.02). TNF-alpha and TGF-beta1 had similar effects. TNF-alpha was detected in all VUWF tested, with a mean of 254 +/- 19 pg/mL. CONCLUSION: These data suggest that the venous ulcer microenvironment adversely affects young, rapidly proliferating fibroblasts such as NFFs and induces fibroblast senescence. Pro-inflammatory cytokines such as TNF-alpha and TGF-beta1 might be involved in this process. The role of other unknown inhibitory mediators, as well as pro-inflammatory cytokines, in venous ulcer development and impaired healing must be considered.

Adult↗

PubMed2026

MS4A3 as a potential prognostic biomarker for colon cancer: integrated analysis of expression patterns and immune cell infiltration.

BACKGROUND: Membrane Spanning 4-Domains A3 (MS4A3) has been confirmed to possess significant tumor-suppressive potential in various malignancies. However, its expression characteristics and clinical prognostic value in colon cancer (CC) still lack systematic and in-depth investigation. This study aimed to systematically investigate the expression pattern, prognostic value, immune microenvironment association, and biological function of MS4A3 in CC through integrated bioinformatics analyses and experimental validation. METHODS: This study utilized The Cancer Genome Atlas-Colon Adenocarcinoma (TCGA-COAD) cohort to screen for genes significantly associated with CC and combined multiple independent Gene Expression Omnibus (GEO) datasets to validate the expression patterns and prognostic significance of MS4A3. Key biological pathways were identified through gene set enrichment analysis (GSEA), and tumor immune infiltration characteristics were evaluated using the CIBERSORT algorithm. Additionally, the expression of MS4A3 and its impacts on cellular functions were validated at the cellular level through quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, Cell Counting Kit-8 (CCK-8), EdU, Transwell, and TUNEL assays. RESULTS: Analysis of public datasets revealed that MS4A3 is significantly downregulated in CC tissues, and its low expression is an independent risk factor for shortened overall survival (OS). GSEA indicated that MS4A3 downregulation is closely associated with the aberrant activation of the pentose phosphate pathway. Immune infiltration analysis showed that low MS4A3 expression is closely linked to the enrichment of M2 macrophages and neutrophils, as well as the upregulation of multiple immune checkpoint genes. In vitro experiments further confirmed that MS4A3 was lowly expressed in CC cell lines. Its overexpression significantly inhibited CC cell viability, proliferation, migration, and invasion, while simultaneously promoting cell apoptosis. CONCLUSIONS: MS4A3 expression is significantly decreased in CC tissues and is significantly correlated with poor prognosis, suggesting that this gene may serve as a potential prognostic biomarker.

MS4A3↗

PubMed2002

Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease.

Thymus-dependent reconstitution of the peripheral T-cell compartment is critical for the successful outcome of bone marrow transplantation. However, graft-versus-host disease (GVHD) affects thymic stromal function and thus prevents normal T-cell maturation and selection. To determine whether cytoprotection of thymic epithelial cells (TECs) by keratinocyte growth factor (KGF) averts GVHD-related injury to the thymus, a nonirradiated murine parent-->F(1) transplantation model was investigated. Administration of KGF between days -3 and +3 of GVHD induction preserved normal thymic size, cellularity, and thymocyte phenotype when measured 2 weeks after transplantation and compared with saline-treated parent-->F(1) mice that received allogeneic transplants. Moreover, the characteristic GVHD-induced impairment in cell cycle progression of pro- and pre-T cells was prevented by KGF. However, the normal phenotypic and functional status of the thymus did not correlate with the higher number of GVHD-inducing mature donor T cells in thymi of KGF-treated mice. Importantly, extensive analysis of the different TEC populations within the thymic cortex and medulla revealed an almost normal stromal architecture and composition in GVHD mice treated with KGF. These observations are likely to reflect an indirect effect of KGF on thymopoiesis as KGF-receptor expression was demonstrated to be restricted to TECs. Thus, pharmacologic doses of KGF appear to exert a potent effect on TEC function, which in turn allows for normal T lymphopoiesis to occur during acute GVHD.

Animals↗

PubMed2007

Tumor microenvironment: the role of the tumor stroma in cancer.

The tumor microenvironment, composed of non-cancer cells and their stroma, has become recognized as a major factor influencing the growth of cancer. The microenvironment has been implicated in the regulation of cell growth, determining metastatic potential and possibly determining location of metastatic disease, and impacting the outcome of therapy. While the stromal cells are not malignant per se, their role in supporting cancer growth is so vital to the survival of the tumor that they have become an attractive target for chemotherapeutic agents. In this review, we will discuss the various cellular and molecular components of the stromal environment, their effects on cancer cell dynamics, and the rationale and implications of targeting this environment for control of cancer. Additionally, we will emphasize the role of the bone marrow-derived cell in providing cells for the stroma.

Animals↗

PubMed1989

Recent advances in the cellular and molecular biology of mast cells.

The mast cell is now considered to play a pivotal role not only in allergic reactions but also in a number of inflammatory disorders. After immunological activation via the IgE receptor, the mast cell releases a variety of cytokines, lipid-derived mediators, amines, proteases and proteoglycans--all of which can regulate adjacent cells and the metabolism of the extra-cellular matrix of connective tissues. While it had been known for some time that mast cells differ in a number of properties in varied tissue sites, it was not known why or how this heterogeneity occurred. The development of in-vitro techniques to culture mast cells and the reconstitution of mast-cell-deficient mice are two major approaches that have facilitated analyses of how the tissue microenvironment regulates the phenotype of mast cells. In this review by Richard L. Stevens and K. Frank Austen, some of the recent findings on the molecular biology of mast cell secretory granule proteins and proteoglycans, and the interaction of mast cells with fibroblasts in the presence and absence of interleukin 3(IL-3) are highlighted.

Animals↗

PubMed2006

Targeting the lymphotoxin-beta receptor with agonist antibodies as a potential cancer therapy.

The lymphotoxin-beta receptor (LT beta R) is a tumor necrosis factor receptor family member critical for the development and maintenance of various lymphoid microenvironments. Herein, we show that agonistic anti-LT beta R monoclonal antibody (mAb) CBE11 inhibited tumor growth in xenograft models and potentiated tumor responses to chemotherapeutic agents. In a syngeneic colon carcinoma tumor model, treatment of the tumor-bearing mice with an agonistic antibody against murine LT beta R caused increased lymphocyte infiltration and necrosis of the tumor. A pattern of differential gene expression predictive of cellular and xenograft response to LT beta R activation was identified in a panel of colon carcinoma cell lines and when applied to a panel of clinical colorectal tumor samples indicated 35% likelihood a tumor response to CBE11. Consistent with this estimate, CBE11 decreased tumor size and/or improved long-term animal survival with two of six independent orthotopic xenografts prepared from surgical colorectal carcinoma samples. Targeting of LT beta R with agonistic mAbs offers a novel approach to the treatment of colorectal and potentially other types of cancers.

Adenocarcinoma↗

PubMed1996

Epidemiological studies of the respiratory effects of air pollution.

Environmental epidemiological studies of the health effects of air pollution have been major contributors to the understanding of such effects. The chronic effects of atmospheric pollutants have been studied, but, except for the known respiratory effects of particulate matter (PM), they have not been studied conclusively. There are ongoing studies of the chronic effects of certain pollutant classes, such as ozone, acid rain, airborne toxics, and the chemical form of PM (including diesel exhaust). Acute effects on humans due to outdoor and indoor exposures to several gases/fumes and PM have been demonstrated in epidemiological studies. However, the effects of these environmental factors on susceptible individuals are not known conclusively. These acute effects are especially important because they increase the human burden of minor illnesses, increase disability, and are thought to decrease productivity. They may be related to the increased likelihood of chronic disease as well. Further research is needed in this latter area, to determine the contributions of the time-related activities of individuals in different microenvironments (outdoors, in homes, in transit). Key elements of further studies are the assessment of total exposure to the different pollutants (occurring from indoor and outdoor source) and the interactive effects of pollutants. Major research areas include determination of the contributions of indoor sources and of vehicle emissions to total exposure, how to measure such exposures, and how to measure human susceptibility and responses (including those at the cellular and molecular level). Biomarkers of exposures, doses and responses, including immunochemicals, biochemicals and deoxyribonucleic acid (DNA) adducts, are beginning to promote some basic knowledge of exposure-response, especially the mechanisms. These will be extremely useful additions to standard physiological, immunological, and clinical instruments, and the understanding of biological plausibility. The outcomes of all this work will be the management of risks and the prevention of respiratory diseases related to air pollution.

Air Pollutants↗

PubMed2005

Towards a therapeutic breast cancer vaccine: the next steps.

The genomic revolution has advanced our understanding of breast cancer biology and the molecular basis of antitumor immunity. Trastuzumab, the first monoclonal antibody for breast cancer, is now a routine part of clinical care. Breast cancer vaccines may be more effective by actively recruiting both humoral and cellular immunity to the therapeutic effort. However, immunization alone is unlikely to have significant activity against established breast cancers, where it is limited by potent mechanisms of immune tolerance and the immunobiology of breast cancer itself. The next generation of clinical studies should integrate breast cancer vaccines with standard breast cancer drugs or novel immunotherapeutics in strategic doses and schedules that abrogate immune tolerance and groom the tumor microenvironment for a productive immune response.

Animals↗

PubMed1989

Cell allocation and lineage in the early mouse embryo.

In the early mammalian embryo, initially asymmetric cell contacts appear to induce blastomere polarization, elements of which can persists through cytokinesis. This leads to the generation of inner and outer populations of blastomeres which may subsequently diverge as a result of residing in distinct microenvironments. Similar processes may account for the generation of primitive endoderm versus primitive ectoderm, and that of trophectoderm versus inner cell mass. However, if this is the case, the response of cells to positional cues must change as a function of either their previous positional history or the number of cycles they have completed. Once these primary tissues have been established, specific interactions between them lead to further cellular diversification.

Animals↗

PubMed2001

Stem cells find their niche.

The concept that stem cells are controlled by particular microenvironments known as 'niches' has been widely invoked. But niches have remained largely a theoretical construct because of the difficulty of identifying and manipulating individual stem cells and their surroundings. Technical advances now make it possible to characterize small zones that maintain and control stem cell activity in several organs, including gonads, skin and gut. These studies are beginning to unify our understanding of stem cell regulation at the cellular and molecular levels, and promise to advance efforts to use stem cells therapeutically.

Animals↗

PubMed1991

LIF: not just a leukemia inhibitory factor.

Increasingly it seems that many cytokines are pleiotropic, and individual molecules may have critical roles in several different organ systems. LIF exemplifies this phenomenon: it influences embryogenesis, bone and lipid metabolism, and hematopoietic and nervous system function. Many of LIF's effects are reminiscent of those of IL-1, TNF, and TGF-beta. Further, even within a single system, LIF can display totally different effects, i.e. induction of differentiation of one leukemic cell line vs. stimulation of proliferation of another. The corollary to these observations is that there appears to be many parallels in developmental systems. For instance, in the case of neuronal "lineage commitment," the events that relate to migration of neural crest cells along various pathways and their ultimate arrest in different locales demonstrate sufficient analogies to hematopoietic lineage commitment phenomena that, in a provocative review, Anderson coined the term "neuropoiesis". This type of analogy becomes even more intriguing when one realizes that some of the same molecules are regulating neuronal and hematopoietic "lineage" proliferation and differentiation. In this respect, several interleukins in addition to LIF are important in neuronal development, and nerve growth factor turns out to also be a hematopoietic regulatory molecule. Similar parallels are enacted in other organ systems as well. The mediation of identical effects by distinct cytokines bound to unique receptors could conceivably be explained by receptor transmodulation or by overlapping signaling sequences. It is nevertheless also unclear how a single cytokine attached to a single receptor can accomplish varied and opposing effects, although divergent intracellular signaling mechanisms could account for some of these phenomena. Yet another enigma relates to how cells from one system can be properly influenced by a pleiotropic molecule such as LIF without significant "cross-effects" on other potentially responsive systems. Cytokine production that is restricted to certain developmental stages, or very localized distribution and spheres of influence within a microenvironment, could be explanatory. The findings of Rathjan and colleagues, i.e. that LIF exists as both a diffusible molecule and as a molecule incorporated into the extracellular matrix, is of special interest in relation to the above questions. Indeed, the distinctions between the roles of diffusible and immobilized signaling molecules could be crucial to the multiplicity of LIF's actions. Diffusible regulatory factors allow communication between spatially separated cells. Cellular responsiveness to such factors is dictated by the presence of appropriate receptors and postreceptor machinery.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2001

Different therapeutic outcomes in experimental allergic encephalomyelitis dependent upon the mode of delivery of IL-10: a comparison of the effects of protein, adenoviral or retroviral IL-10 delivery into the central nervous system.

Experimental allergic encephalomyelitis (EAE) is a CNS autoimmune disease mediated by the action of CD4(+) T cells, macrophages, and proinflammatory cytokines. IL-10 is a cytokine shown to have many anti-inflammatory properties. Studies have shown both inhibition and exacerbation of EAE after systemic IL-10 protein administration. We have compared the inhibitory effect in EAE of Il10 gene delivery in the CNS. Fibroblasts transduced with retroviral vectors expressing IL-10 could inhibit EAE. This was not associated with a prevention of cellular recruitment but an alteration in their phenotype, notably an increase in the numbers of CD8(+) T and B cells. In marked contrast, CNS delivery of adenovirus coding for mouse IL-10 or IL-10 protein performed over a wide dose range failed to inhibit disease, despite producing similar or greater amounts of IL-10 protein. Thus the action of IL-10 may differ depending on the local cytokine microenvironment produced by the gene-secreting cell types.

Adenoviridae↗

PubMed1992

Phosphoinositide fatty acid composition of peripheral blood lymphocytes from aging humans.

The interaction of the T-cell receptor complex with the ligands is associated with early molecular events involved in the process of signal transduction implicating phosphoinositide breakdown. In elderly people, abnormalities in membrane signal transduction pathways are the basis of the immune deficiency associated with aging. Peripheral blood lymphocytes from aging humans and young subjects were stimulated with anti-CD3 monoclonal antibody and the phosphoinositide fractions were analyzed in order to determine the fatty acid composition in resting and stimulated conditions. In aging humans, in resting conditions, the all three phosphoinositide fractions appeared more saturated than the corresponding fractions in young subjects. Following anti-CD3 stimulation a decrease in arachidonic acid relative molar content was detected in both young and old subjects, but the arachidonic acid content in resting conditions greatly differed between the two groups, suggesting a different modulation of the microenvironment of the T-cell receptor complex in elderly people, so determining alterations in the early activation steps of lymphocytes.

Adult↗

PubMed1996

Spatial relationship of lectin-labelled extracellular matrix and glutamine synthetase-immunoreactive astrocytes in rat cortical forebrain regions.

Extracellular matrix proteoglycans have previously been revealed by immunocytochemical and lectin-histochemical methods as distinct perineuronal nets in the microenvironment of different types of neurons, but also as a diffuse stain throughout the neuropil in region-dependent patterns. Ultrastructural investigations of perineuronal nets in subcortical regions have demonstrated glycan components in the close vicinity of astrocyte processes, suggesting that the extracellular matrix contributes differentially to the glianeuron interface. In the present study the spatial relationship of extracellular matrix components and astrocytes was characterised at the regional and cellular level by lectin histochemistry (soybean agglutinin, Vicia villosa agglutinin, Wisteria floribunda agglutinin) and antiglutamine synthetase immunocytochemistry in the rat neocortex and hippocampus. In most cortical areas layer-specific patterns of diffuse neuropil staining revealed by the lectins could also be recognised after glutamine synthetase (GS) immunostaining. In double-labelling experiments GS-immunoreactive astrocyte processes were found to reach lectin-stained perineuronal nets. GS-immunoreactivity was often parallelled but did not coincide with the lectin label completely, but was observed to form net-like structures similar to the perineuronal lectin staining. Using immunocytochemistry with anti-GS perineuronal, net-like structures were demonstrated on certain parvalbumin-immunopositive neurons which are known to be ensheathed by lectin-stained perineuronal nets. It was evident that a single neuron may receive net-like contacts from several astrocytes and that a single astrocyte can contribute to perineuronal nets on more than one neuron. The findings support the view that N-acetylgalactosamine-containing extracellular matrix molecules and astrocytic processes are topically associated to a high degree. Different proportions of both components may specify the individual neuronal micro-environment.

Acetylgalactosamine↗

PubMed2026

Increased IL4I1 expression predicts poor survival and modulates the immune microenvironment in acute myeloid leukemia.

BACKGROUND: The immunometabolic enzyme Interleukin-4-induced-1 (IL4I1) is implicated in cancer pathogenesis, yet its specific function and clinical relevance in acute myeloid leukemia (AML) remain unclear. METHODS: Comparative analysis of IL4I1 mRNA levels between AML patients and normal controls was performed using the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The Kaplan–Meier survival analysis was conducted to evaluate the prognostic value of IL4I1. Functional insights were derived from analyses of differentially expressed genes (DEGs), Gene Set Enrichment Analysis (GSEA), and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Immune infiltration was evaluated using the ssGSEA, ESTIMATE, quanTIseq and single-cell RNA sequencing (scRNA-seq) analysis. Finally, in vitro and in vivo functional experiments were perfromed to explore the impact of IL4I1 on AML progression and immunoregulation. RESULTS: IL4I1 expression was significantly elevated in AML compared to normal controls (p = 0.0004) and associated with poorer overall survival (p = 0.003). Bioinformatic analysis revealed that IL4I1 was linked to immune-related pathways—including humoral immune response, leukocyte interactions, and chemokine signaling—and to cellular amino acid metabolism. Its expression correlated with immune cell infiltration and checkpoint molecule expression. Experimentally, IL4I1 promoted leukemia cell proliferation in vitro and in vivo (p < 0.05). Furthermore, silencing IL4I1 suppressed M2 macrophage polarization and reduced secretion of inflammatory factors (p < 0.05). CONCLUSIONS: IL4I1 may serve as a potential biomarker for poor prognosis and an attractive target for immune-based therapeutic interventions in AML.

Humans↗