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PubMed2001

Expression of nitric oxide synthase isoforms and nitrotyrosine immunoreactivity by B-cell non-Hodgkin's lymphomas and multiple myeloma.

AIMS: Nitric oxide synthases (NOS) are isoenzymes that catalyse the synthesis of nitric oxide (NO). The three main NOS isoforms are: NOS1 or neuronal, NOS2 or inducible, and NOS3 or endothelial. NO plays both physiological and pathological roles, depending on its rate of synthesis and concentration, cellular source and microenvironment. Apoptosis is an important biological factor in low-grade lymphomas, and NO is able to prevent apoptosis. In-situ expression of NOS and synthesis of NO have been shown in several malignant tumours, but not in lymphoid neoplasms. This study evaluates whether human B-cell neoplasms express NOS isoforms, and nitrotyrosine (NY), which is usually interpreted as a marker of NO. METHODS AND RESULTS: We studied the expression of NOS-IR isoforms and NY-IR in 16 cases of B-cell non-Hodgkin's lymphoma (NHL) (five follicle centre cell lymphoma, four small lymphocytic/CLL, and seven diffuse large cell lymphoma), and 10 cases of multiple myeloma (MM). NOS1 was expressed in 5/10 cases of MM, and 15/16 cases of NHL. NOS2 was detected in all cases of MM, and in 14/16 cases of NHL, whereas NOS3 was positive in 3/10 of MM and in only in 1/16 cases of NHL. The expression of NY-IR was observed in 70% of MM cases, and in all cases of B-cell NHL, in a dot-like pattern in few tumour cells. CONCLUSIONS: B-cell neoplasms express neuronal and inducible NOS, and nitrotyrosine. Taken together, our results suggest that B-cell neoplasms can produce NO. The role of NO in the biology, diagnosis and prognosis of B-cell neoplasms remains to be established.

Adult↗
PubMed1997

Hematopoietic activity of a stromal cell transmembrane protein containing epidermal growth factor-like repeat motifs.

Primitive hematopoietic stem cells are closely associated with discrete in vivo microenvironments. These "niches" are thought to provide the molecular signals that mediate stem cell differentiation and self-renewal. We have dissected the fetal liver microenvironment into distinct cellular components by establishing an extensive panel of stromal cell lines. One particular cell line maintains repopulating stem cells for prolonged in vitro culture periods. A subtraction cloning strategy has yielded a cDNA that encodes a cell surface glycoprotein with a restricted pattern of expression among stromal cell lines. This molecule, previously identified as delta-like/preadipocyte factor-1, contains epidermal growth factor-like repeats that are related to those in the notch/delta/serrate family of proteins. We have investigated the potential role of this molecule in hematopoietic stem/progenitor cell regulation. We show that the delta-like protein displays activity on purified stem cells by promoting the formation of "cobblestone areas" of proliferation. These cobblestone areas contain both primitive high-proliferative potential progenitors and in vivo repopulating stem cells.

Animals↗
PubMed2000

Endometrial-myometrial interface: relationship to adenomyosis and changes in pregnancy.

The endometrial-myometrial interface (EMI) is an important region of the human uterus, which has attracted little research attention. This mucosal-muscular interface has characteristic features when compared with other similar interfaces in the human body. It lacks an intervening tissue layer and as a result, the endometrium sits directly on the myometrium rendering it vulnerable to invasion by the endometrium. Both endometrium and myometrium are sensitive to sex steroids, and their structure and function depend to a large extent on the sex hormonal milieu. Endometrium, which forms one border of the EMI, is a complex tissue consisting of several polarized microenvironments. At a cellular level, sex steroids interact with local mediators secreted by a variety of cell types and are important in maintaining the complex structure and function of the endometrium. Basal endometrium contains prominent aggregates of leukocytes that may be important in controlling local cell growth and function. Myometrium also has a distinct zonal anatomy. The recently described junctional zone differs structurally and functionally from the outer myometrium, although these functions are not yet clearly understood. Embryologically, it originates from müllerian ducts together with endometrium, whereas the outer myometrium has a non-müllerian origin. During early pregnancy, the EMI is disturbed by invading trophoblast. Alterations of myometrial intercellular matrix proteins together with expression of appropriate receptors by the trophoblast seem to regulate this unique interaction. The EMI also is disrupted in adenomyosis. The sequence of events taking place at the EMI during development of this pathology is still debated.

Endometriosis↗
PubMed2001

Stimulated healing of recalcitrant wounds by topical application of enriched cell culture medium: a clinical report.

This study was designed to test the efficacy of enriched cell culture medium as a wound dressing. The rationale was to create within the wound space an optimal microenvironment, conducive to cellular proliferation, vascular granulation tissue formation, and epithelialization. This study was performed on various wounds that failed to respond to previous conventional treatments.A total of 288 wounds were within the inclusion criteria, with only contaminated and neoplastic wounds excluded. Most of the patients (80 percent) were ambulatory, and the wounds were examined by the attending physician once every 7 to 14 days at an outpatient clinic. The remaining 20 percent of patients were admitted to the study while hospitalized. Cell culture medium MCDB, supplemented with insulin, thyroxin, and growth hormone, was gelled. The gel was self-applied once a day to freshly washed wounds, covered with a gauze pad, and anchored with netting. Healing started 7 to 14 days after the initiation of treatment with enriched cell culture medium. However, the criterion for success of the treatment was determined on complete wound closure, which was achieved in 189 of 288 wounds (65.6 percent). Wound closure was correlated with the initial wound volume, stage, and origin. The average time required for closure of wounds caused by systemic pathologies (n = 181) and those based on regional status (n = 107) were 12.0 and 4.4 weeks, respectively, compared with 290 and 10.3 weeks of the previous conventional treatment. In 19 extensive wounds, when vascularized granulation tissue was established, a successful surgical closure was attained. Most wounds of patients who did not continue the enriched cell culture medium treatment (34.4 percent) manifested reduced wound volume, ranging from 11 to 98 percent of initial volume. Discontinuation of treatment was associated with difficulties in reaching the clinic for the weekly examination, rather than for reasons directly related to the treatment itself, and occurred significantly earlier during the treatment period.Thus, enriched cell culture medium was effective in stimulating wound healing in recalcitrant wounds. The healing was rapid with minimum scarring and pain. No side effects or allergic reactions were reported or observed.

Administration, Topical↗
PubMed1998

Neuroendocrine control of the thymus.

Thymocytes undergo a complex process of differentiation, largely dependent on interactions with the thymic microenvironment, a tridimensional cellular network formed by epithelial cells, macrophages, dendritic cells, and fibroblasts. One key cellular interaction involves the TCR-CD3 complex expressed by thymocytes with MHC-peptide complexes present on microenvironmental cells. Additionally, thymic epithelial cells (TEC) interact with thymocytes via soluble polypeptides such as thymic hormones and interleukins, as well as through extracellular matrix (ECM) ligands and receptors. Such types of heterotypic interactions are under neuroendocrine control. For example, thymic endocrine function, represented by thymulin production, is up-regulated, both in vivo and in vitro, by thyroid and pituitary hormones, including prolactin and growth hormone. We also showed that these peptides enhance the expression of ECM ligands and receptors, as well as the degree of TEC-thymocyte adhesion. In addition, we studied the thymic nurse cell complex, used herein as an in vitro model for ECM-mediated intrathymic T-cell migration. We observed that T-cell migration is also hormonally regulated as ascertained by the thymocyte entrance into and exit from these lymphoepithelial complexes. Taken together these data clearly illustrate the concept that neuroendocrine circuits exert a pleiotropic control on thymus physiology. Lastly, the intrathymic production of classic hormones such as prolactin and growth hormone suggests that, in addition to endocrine circuits, paracrine and autocrine interactions mediated by these peptides and their respective receptors may exist in the thymus, thus influencing both lymphoid and microenvironmental compartments of the organ.

Animals↗
PubMed1988

Cell and environment interactions in tumor microregions: the multicell spheroid model.

Abnormal vascularization of malignant tumors is associated with the development of microregions of heterogeneous cells and environments. Experimental models such as multicell spheroids and a variety of new techniques are being used to determine the characteristics of these microregions and to study the interactions of the cells and microenvironments. The special cellular microecology of tumors influences responsiveness to therapeutic agents and has implications for future directions in cancer research.

Antineoplastic Agents↗
PubMed1975

Functional anatomy of lymph nodes. I. The paracortical cords.

Histological alterations in the paracortical zones of rabbit lymph nodes were produced by the intravenous injection of the acridine dye euchrysin. The paracortical parenchyma was reduced to narrow bands of lymphoid tissue which cuffed and outlined the venules against a distended and cell-filled sinus system. These perivenous lymphocyte cuffs, termed the paracortical cords, represented the basic anatomical unit of the thymus-dependent paracortical area. Both the paracortical cords and sinuses are cell traffic pathways, but during stages of antigen-induced lymphocyte trapping the cords retain more cells than do the sinuses. Proliferation of T cells and differentiation of B cells both occur within these cords in a microenvironment conductive to cellular cooperation.

Acridines↗
PubMed1988

Marrow reticulo-fibroblastoid colonies (CFU-RF derived) spontaneously release an erythroid colony (BFU-E) enhancing factor.

The marrow microenvironment is composed of an extracellular matrix as well as a heterogeneous population of cells. Isolation of the various cell types and analysis of their function is necessary for a better understanding of their roles in hemopoiesis. We have recently reported a colony assay for a cellular component of the marrow microenvironment. The assay consists of a cellular component of the marrow microenvironment. The assay consists of a plasma clot-methylcellulose marrow culture. The stimulator is PHA-stimulated leukocyte conditioned medium (PHA-LCM) and hydrocortisone (5 x 10(-5)M). The fibrin strands appear to act as a substrate for the growth of Reticulo-Fibroblastoid colonies derived from the CFU-RF precursor. RF colonies can be subcultured forming adherent layers when transferred to liquid cultures. Confluent adherent layers can be maintained for long periods of time by changing medium every 3 to 5 days. Supernatants derived from unstimulated RF cultures (RF-CM) were tested for growth promotion of hemopoietic precursors. We found: (1) RF-CM by itself does not induce colony formation. (2) In the presence of erythropoietin, RF-CM enhances the growth of BFU-E. (3) Recombinant IL 4 also enhances BFU-E formation, but in our assays IL 4 induced fewer colonies than RF-CM and the colonies were smaller. (4) Because neither IL 4 nor RF-CM, by themselves, can stimulate colony formation, we compared the effect of RF-CM on assays that are known to show other IL 4 functions. RF-CM did not induce proliferation of PHA induced blast T cells, a known property of IL 4.(ABSTRACT TRUNCATED AT 250 WORDS)

B-Lymphocytes↗
PubMed2025

Tumor-immune partitioning and clustering algorithm for identifying tumor-immune cell spatial interaction signatures within the tumor microenvironment.

BACKGROUND: Growing evidence supports the importance of characterizing the organizational patterns of various cellular constituents in the tumor microenvironment in precision oncology. Most existing data on immune cell infiltrates in tumors, which are based on immune cell counts or nearest neighbor-type analyses, have failed to fully capture the cellular organization and heterogeneity. METHODS: We introduce a computational algorithm, termed Tumor-Immune Partitioning and Clustering (TIPC), that jointly measures immune cell partitioning between tumor epithelial and stromal areas and immune cell clustering versus dispersion. As proof-of-principle, we applied TIPC to a prospective cohort incident tumor biobank containing 931 colorectal carcinoma cases. TIPC identified tumor subtypes with unique spatial patterns between tumor cells and T lymphocytes linked to certain molecular pathologic and prognostic features. T lymphocyte identification and phenotyping were achieved using multiplexed (multispectral) immunofluorescence. In a separate hepatocellular carcinoma cohort, we replaced the stromal component with specific immune cell types-CXCR3+CD68+ or CD8+-to profile their spatial relationships with CXCL9+CD68+ cells. RESULTS: Six unsupervised TIPC subtypes based on T lymphocyte distribution patterns were identified, comprising two cold and four hot subtypes. Three of the four hot subtypes were associated with significantly longer colorectal cancer (CRC)-specific survival compared to a reference cold subtype. Our analysis showed that variations in T-cell densities among the TIPC subtypes did not strictly correlate with prognostic benefits, underscoring the prognostic significance of immune cell spatial patterns. Additionally, TIPC revealed two spatially distinct and cell density-specific subtypes among microsatellite instability-high colorectal cancers, indicating its potential to upgrade tumor subtyping. TIPC was also applied to additional immune cell types, eosinophils and neutrophils, identified using morphology and supervised machine learning; here two tumor subtypes with similarly low densities, namely 'cold, tumor-rich' and 'cold, stroma-rich', exhibited differential prognostic associations. Lastly, we validated our methods and results using The Cancer Genome Atlas colon and rectal adenocarcinoma data (n = 570). Moreover, applying TIPC to hepatocellular carcinoma cases (n = 27) highlighted critical cell interactions like CXCL9-CXCR3 and CXCL9-CD8. CONCLUSIONS: Unsupervised discoveries of microgeometric tissue organizational patterns and novel tumor subtypes using the TIPC algorithm can deepen our understanding of the tumor immune microenvironment and likely inform precision cancer immunotherapy.

Humans↗
PubMed1982

Hematopoietic microenvironment transfer by stromal fibroblasts derived from bone marrow varying in cellularity.

Autologous fibroblast derivatives of red and yellow marrow of rabbits were shown to differ in their capability to transfer a hematopoietic microenvironment upon implantation under the renal capsule. Although a heterotopic ossicle formed in each instance, the quality of the associated medullary tissue mirrored the quality of the bone marrow used to generate the stromal fibroblasts. Thus, fibroblasts cultured from a cellular marrow produced a stroma with numerous hematopoietic foci whereas those cultured from a severely hypocellular marrow produced a stroma with mainly fat cells. The results with 21 implants point to a transmittable regulatory role of a class of stromal fibroblasts.

Animals↗
PubMed2001

The plasticity of human breast carcinoma cells is more than epithelial to mesenchymal conversion.

The human breast comprises three lineages: the luminal epithelial lineage, the myoepithelial lineage, and the mesenchymal lineage. It has been widely accepted that human breast neoplasia pertains only to the luminal epithelial lineage. In recent years, however, evidence has accumulated that neoplastic breast epithelial cells may be substantially more plastic in their differentiation repertoire than previously anticipated. Thus, along with an increasing availability of markers for the myoepithelial lineage, at least a partial differentiation towards this lineage is being revealed frequently. It has also become clear that conversions towards the mesenchymal lineage actually occur, referred to as epithelial to mesenchymal transitions. Indeed, some of the so-called myofibroblasts surrounding the tumor may have an epithelial origin rather than a mesenchymal origin. Because myoepithelial cells, epithelial to mesenchymal transition-derived cells, genuine stromal cells and myofibroblasts share common markers, we now need to define a more ambitious set of markers to distinguish these cell types in the microenvironment of the tumors. This is necessary because the different microenvironments may confer different clinical outcomes. The aim of this commentary is to describe some of the inherent complexities in defining cellular phenotypes in the microenvironment of breast cancer and to expand wherever possible on the implications for tumor suppression and progression.

Biomarkers, Tumor↗
PubMed1991

The role of transforming growth factor-beta in hematopoiesis. A review.

The role of TGF beta hematopoiesis is currently being defined. It does appear that TGF beta and related polypeptides can modulate and regulate bone marrow and thymic-derived cells throughout their functional life span. The effects of TGF beta are pleiotropic and may depend on (a) cell lineage, (b) specific cellular phenotype, (c) stage of differentiation, (d) immediate microenvironment, (e) other cytokines and (f) cellular function. The understanding of TGF beta and its relationship to other cytokines should not only increase our understanding of hematopoiesis but may also have therapeutic implications.

Cell Differentiation↗
PubMed2026

Uncovering Immune Niches in Health and Disease Using Spatial Transcriptomics.

Spatial transcriptomics allows for the investigation of complex cellular ecosystems directly in their native tissues and enables the dissection of immune niches as spatially organized and functionally diverse microenvironments across homeostatic, inflammatory, and malignant settings. In this review, we examine how spatial transcriptomics tools have been applied to interrogate the cellular and molecular architecture of immune niches, including the emerging studies of B and T cell clonal niches. We focus on immune niches in intestinal and tumor tissues due to their importance to both health and pathology, discuss pressing immunological questions these technologies may help to address, and highlight future developments in the field.

Humans↗
PubMed1997

Fibrosis, a common pathway to organ failure: angiotensin II and tissue repair.

For heart, kidneys, lungs and liver alike, fibrosis represents a common pathway to their failure. Understanding pathophysiologic mechanisms involved in organ fibrosis are therefore of considerable interest, particularly given the potential for protective pharmacological strategies. Tissue repair involves inflammatory cells, including members of the monocyte/macrophage lineage, integral to initiating the repair process; and myofibroblasts, phenotypically transformed interstitial fibroblasts, responsible for collagen turnover and fibrous tissue formation. Each of these cellular events in the microenvironment of repair are associated with molecular events that lead to the de novo generation of angiotensin II (ANG II). In an autocrine/paracrine manner, this peptide regulates expression of TGF-beta 1 via angiotensin (AT1) receptor-ligand binding. It is this cytokine that contributes to phenotypic conversion of fibroblasts to myofibroblasts (myoFb) and regulates myofibroblast turnover of collagen. Angiotensin-converting enzyme (ACE) inhibition or AT1 receptor antagonism each prevent many of these molecular and cellular responses that eventuate in fibrosis and therefore have been found to be protective interventions.

Angiotensin II↗
PubMed1998

Apolipoprotein B-100 conformation and particle surface charge in human LDL subspecies: implication for LDL receptor interaction.

The plasma low-density lipoprotein (LDL) profile in coronary artery disease patients is characterized by a predominance of small, dense LDL. Small, dense LDL exhibit both high susceptibility to oxidation and low binding affinity for the LDL receptor, suggesting that these particles may be of elevated atherogenic potential. Here we examine whether the variation in biological function is due to differences in apo B-100 conformation that alter the interaction with the cellular LDL receptor. The microenvironments (pKa) of Lys residues in apo B-100 in small, dense, intermediate, and light human LDL subspecies have been compared by 13C NMR, and the net surface charge of these particles has been characterized. Relative to the total LDL fraction, small, dense, and light LDL subspecies have a decreased number of pKa 8.9 Lys, while intermediate density LDL has a consistently higher number of pKa 8.9 Lys. It follows that differences in protein conformation, as reflected in the Lys microenvironments, exist in the different LDL subspecies. Electrophoretic mobility measurements revealed that the light LDL subfractions exhibit a surface charge at pH 8.6 that is from -26 to -34e more negative than the intermediate density LDL subfraction. For the small, dense LDL particles the increments in negative charge range from -7 to -17e relative to the intermediate density LDL subfraction. These results suggest that differences in the conformation of apo B-100 and surface charge between LDL subspecies are major determinants of their catabolic fate. The lower number of pKa 8.9 Lys leads to a reduction in binding of small, dense, and light LDL to the cellular LDL receptor and prolongs their plasma residence time, thereby elevating the atherogenicity of these particles. These data support the proposal that the intermediate LDL subspecies constitute the optimal ligand for the LDL receptor among human LDL particle subpopulations.

Apolipoprotein B-100↗
PubMed1997

Immune response decisions at the single cell level.

Helper T cells regulate the progressive differentiation of antigen-specific B cells in complex and dynamic microenvironments in vivo. In this review, antigen-driven B-cell differentiation will be discussed in three phases: pre-germinal center, germinal center and post-germinal center. Each phase of the response appears to have unique cellular starting points, specialized regional microenvironments and its own set of controls and cellular outcomes. Decisions made by individual lymphocytes at each of these phases determines the shape of protective immunity in vivo.

Animals↗
PubMed2025

3D Cell Culture Models as a Platform for Studying Tumor Progression, Testing Treatment Responses, and Discovering Biomarkers.

In this chapter, we present a detailed protocol for establishing a three-dimensional (3D) multicellular tumor spheroids (MCTSs) model to simulate the tumor microenvironment (ME) associated with metabolic dysfunction-associated steatotic liver disease (MASLD) for the study of hepatocellular carcinoma (HCC) and colorectal cancer (CRC) cell aggressiveness, growth, and metastasis potential. The MASLD microenvironment (MASLD-ME) is recreated by embedding hepatic stellate cells in a collagen I matrix within a Boyden chamber system. The metabolic medium mimics MASLD conditions, enriched with high glucose, fructose, insulin, and fatty acids, to simulate metabolic stresses associated with the disease.In the protocol, cancer cells are loaded in the upper compartment to analyze their migration toward the MASLD-ME, thereby facilitating studies on cancer cell invasiveness and metastatic capacity. This method offers an adaptable, reproducible model to research disease progression and investigate therapeutic interventions, contributing to preclinical research on MASLD-related liver cancer pathophysiology and potential drug responses.

Humans↗