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PubMed2006

Adenosine upregulates CXCR4 and enhances the proliferative and migratory responses of human carcinoma cells to CXCL12/SDF-1alpha.

The level of expression of the chemokine receptor CXCR4 has been shown to play a crucial role in determining the ability of cancer cells to metastasize from the primary tumor and become established in tissue sites that are rich in the CXCR4 ligand CXCL12/SDF-1alpha. High CXCR4 expression on cancer cells is associated with an increased risk of recurrence and poorer overall survival. We propose that local tissue mediators within the primary tumor or at secondary sites may modulate the level of CXCR4 expression and, therefore, potentially affect the ability of the cancer cells to metastasize. The purine nucleoside adenine-9-beta-D-ribofuranoside (adenosine) is generated at high concentrations within the extracellular fluid of solid tumors because of their hypoxia. We show here that adenosine acts through A(2A) and A(2B) adenosine receptors on human colorectal carcinoma cells to upregulate CXCR4 mRNA expression up to 10-fold and selectively increases cell-surface CXCR4 protein up to 3-fold. This increase in cell-surface CXCR4 enables the carcinoma cells to migrate toward CXCL12, and enhances their proliferation in response to CXCL12. Adenosine may therefore be one of the factors within the tumor microenvironment that facilitates tumor dissemination, by upregulating CXCR4 on certain cancer cells and enhancing cellular responses to CXCL12.

Adenosine↗

PubMed2005

Adipocyte differentiation in Sod2(-/-) and Sod2(+/+) murine bone marrow stromal cells is associated with low antioxidant pools.

OBJECTIVE: Adipocytogenesis in bone marrow stromal cells (BMSCs) from manganese-superoxide dismutase-deficient (Sod2(-/-)) and wild-type (Sod2(+/+)) mice and the effect of antioxidant pool size were determined. METHODS: BMSCs from Sod2(-/-) or Sod2(+/+) mice were cultured with and without adipocytogenic supplements including: 10 mug/mL insulin, 1 muM dexamethasone, and 100 muM indomethacin. Oil Red-O-positive cells and reverse-transcriptase polymerase chain reaction measurement of peroxisome proliferator-activated receptor-gamma (PPARgamma) and lipoprotein lipase (LPL) were measured. Antioxidant glutathione levels (GSH) and glutathione peroxidase activity (GPX) were determined. RESULTS: Sod2(-/-) cells demonstrated constitutive adipocytogenesis in basal medium and generated 34% more adipocytes in adipocytogenic media. Growth of cells in the free radical scavenger antioxidant, amifostine (WR2721; 4 mM) decreased numbers of adipocytes in Sod2(-/-) BMSCs in both basal (38.0%, p = 0.037) and adipocytogenic (37.5%, p = 0.021) media and reduced to undetectable the levels of expression of PPARgamma and LPL. In contrast, Sod2(+/+) cells showed no detectable constitutive adipocytogenesis but formed adipocytes in adipocytogenic medium, with a decrease (43.7%, p = 0.001) by addition of WR2721. In basal conditions, Sod2(-/-) cells had lower GSH (78.6%; p = 0.0089) and GPX (52.7%; p < 0.001) levels than did Sod2(+/+) cells, which were increased in either medium by WR2721 treatment of Sod2(-/-) or Sod2(+/+) cells (all p < 0.001). Differentiation of BMSCs to adipocytes was inversely correlated with the level of GSH (r = -0.9427, p = 0.0167). Sod2(-/-) long-term bone marrow cultures had decreased hematopoiesis compared to those from Sod2(+/-) or Sod2(+/+) mice. CONCLUSION: The cellular redox pathway has a role in adipocyte differentiation of cells of the hematopoietic microenvironment.

Adipocytes↗

PubMed2004

Anatomical features of anti-viral immunity in the respiratory tract.

The mucosal surfaces of the lungs are a major portal of entry for virus infections and there are urgent needs for new vaccines that promote effective pulmonary immunity. However, we have only a rudimentary understanding of the requirements for effective cellular immunity in the respiratory tract. Recent studies have revealed that specialized cellular immune responses and lymphoid tissues are involved in the protection of distinct anatomical microenvironments of the respiratory tract, such as the large airways of the nose and the alveolar airspaces. This review discusses some of the anatomical features of anti-viral immunity in the respiratory tract including the role of local lymphoid tissues and the relationship between effector and memory T cells in the airways, the lung parenchyma, and lymphoid organs.

Animals↗

PubMed2002

IL-10 is highly expressed in the cryptorchid cryptepididymal epithelium: a probable mechanism preventing immune responses against autoantigenic spermatozoa in the epididymal tubule.

The expression of several immunoregulatory adhesion proteins and cytokines was studied in the normal epididymis, cryptorchid cryptepididymis, the epididymis of oestrogen-treated mice and the epididymis of non-obese diabetic (NOD) mice at the protein level to see which of these immunoregulatory proteins may be involved in lymphocyte regulation in the normal or pathological epididymis and if cytokine balance in this organ is on the cellular or humoral side. The aim of the study was to characterize the immunological microenvironment of the epididymis to explain the survival of the autoantigenic spermatozoa in this site. In the 6-week-old BALB/c or NOD mouse epididymis there were some CD18 and CD44 expressing cells in the interstitial tissue. There were no differences between these strains in the expression of the studied antigens, except that some CD4 positive cells were present in the interstitial tissue of BALB/c mice. In the cryptorchid cryptepididymis CD4, CD8, CD18, CD44, CD54 and CD106 expressing cells were occasionally present in the connective tissue surrounding the epididymal tubule. In the epididymis of the oestrogen-treated mice these antigens were not expressed. In the cryptorchid cryptepididymis the epithelial cells expressed IL-10 highly and the myoid peritubular cells IL-6. The present results suggest that the epididymal epithelial IL-10 suppressing TH0, TH1 and TH2 immune responses may be involved in the protection of autoantigenic spermatozoa from immune destruction.

Animals↗

PubMed2026

Follicular Lymphoma Transformation is Characterized by Cytokine-associated Remodeling of Stromal and Macrophage Compartments.

Across cancer, one of the most frequent examples of histologic transformation is the evolution of follicular lymphoma (FL) to an aggressive large cell lymphoma. Despite recent progress, understanding of the molecular and cellular underpinnings of transformation remains incomplete. Here, we dissect the interplay of tumor and microenvironment cell populations across transformation through a multimodal investigation of 95 FL and transformed FL (tFL) samples, including single-cell and bulk RNA-sequencing alongside spatial transcriptomics and proteomics, and validate findings across independent FL-tFL pairs. Upon transformation, fibroblasts and GPNMB+ macrophages increase while lymph-node organizing follicular dendritic and CCL21+ fibroblastic reticular cells were lost, resulting in an altered spatial distribution of cytokines that impacts T cell infiltration and macrophage differentiation and function. Secreted stromal and macrophage signals were further evident by non-invasive plasma proteomics. Taken together, our data reveal expansion of macrophages and fibroblasts as key features of transformation with potential diagnostic and therapeutic implications.

Journal Article↗

PubMed2003

Matrix metalloproteinase-9 in lung remodeling.

Matrix metalloproteinase (MMP)-9 (Gelatinase B, 92-kD type IV collagenase, EC 3.4.24.35) is an MMP that is present in low quantities in the healthy adult lung, but much more abundant in several lung diseases, including asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD). Despite numerous reports of MMP-9 in these and other lung diseases, whether MMP-9 is causal in lung remodeling or part of the inflammatory and reparative response remains to be determined. Many intrinsic lung cells can be stimulated to produce MMP-9, but much of the information regarding MMP-9 in the lung deals with MMP-9 from inflammatory cells. The multiple locations and cell types producing MMP-9 are consistent with multiple functions in different microenvironments. In addition to digestion of structural proteins and antiproteases, MMP-9 can modify cellular function by regulation of cytokines and matrix-bound growth factors. Determining the role of MMP-9 in health and disease will be important, because broad spectrum and specific inhibitors will soon be available to enable conversion of the bench knowledge to bedside practice. This review addresses the current understanding of MMP-9 in human asthma, IPF, and COPD, and in animal models of these conditions.

Animals↗

PubMed2006

Pathophysiological basis for anticoagulant and antithrombotic therapy in pulmonary hypertension.

In pulmonary hypertension (PH), thrombosis and thromboembolism may occur as primary events associated with inherited or acquired thrombophilia. Alternatively, in situ thrombosis may develop as a complication of pre-existing vasculopathy as in the case of idiopathic PH and related disorders (so called pulmonary arterial hypertension). In these disorders, a number of abnormalities has been described involving endothelial cells, platelets and other circulating cellular and soluble elements. These abnormalities are suggestive of a shift of pulmonary vascular microenvironment toward a procoagulant, prothrombotic and antifibrinolytic pattern. The abnormalities described so far include circulating antiphospholipid antibodies, increased plasma levels of platelet aggregating agents (serotonin, thromboxane), adhesion molecules (P-selectin, von Willebrand factor), antifibrinolytic enzymes (plasminogen activator inhibitor 1) and cytokines. Also, decreased endothelial production of natural anticoagulants (thrombomodulin) and platelet antiaggregating substances (nitric oxide, prostacyclin) have been demonstrated. The present review is focused on the procoagulant, prothrombotic and antifibrinolytic mechanisms so far identified in PH, in both clinical setting and animal models. Understanding of these mechanisms is crucial for a proper selection of anticoagulant and antithrombotic therapies and provides the rationale for development of novel therapeutic options.

Animals↗

PubMed2000

Local application of extracellular matrix proteins fails to reduce the number of axonal branches after varying reconstructive surgery on rat facial nerve.

PURPOSE: A major reason for the poor functional recovery after peripheral nerve injury is the outgrowth of supernumerary axonal branches at the lesion site. Projecting within several nerve fascicles, the branches of one axon often re-innervate synchronously muscles with antagonis-tic functions and impair any coordinated activity. We hypothetized that accelerated axonal elongation through extracellular matrix proteins fos-tering neurite outgrowth might reduce axonal branching and improve recovery of function. METHODS: In a control group of rats, ramus zygomaticus, ramus buccalis, and ramus marginalis mandibulae of the facial nerve were transected and the stumps labeled with DiI, Fluoro-Gold (FG), and Fast Blue (FB). RESULTS: Neuron counts showed that the zygomatic ramus contained axons of 204 +/- 88 DiI-labeled motoneurons in the dorsal facial subnu-cleus. No perikarya were labeled by 2 or 3 tracers. After transection and suture of the facial nerve trunk, the zygomatic ramus contained axons of 328 +/- 50 motoneurons dispersed throughout the whole facial nucleus. The occurrence of double-labeled (DiI+FG and DiI+FB) motoneu-rons showed that about 30 % of all axons in the zygomatic ramus had a twin branch projecting within the buccal and/or mandibular ramus. CONCLUSIONS: Entubulation of transected facial nerve in a silicone tube containing phosphate buffered saline, collagen type I, laminin, fibronectin, or tenascin did not reduce the portion of double-labeled motoneurons. We conclude that (i) axonal branching follows a rather con-stant pattern regardless of changes in the local microenvironment; (ii) despite their known effect to support neurite outgrowth, all tested extra-cellular matrix proteins do not suppress axonal branching in the rat facial nerve model.

Journal Article↗

PubMed2026

Mechanisms linking the gut microbiota to colorectal cancer development and progression.

Colorectal cancer remains a leading cause of global cancer mortality, with a concerning rise in early-onset cases driven by complex interactions between environmental exposures, lifestyle factors, and host genetics. Mounting evidence indicates that gut microbiota dysbiosis critically modulates this oncogenic process, acting as an active participant rather than a passive bystander. This review systematically synthesizes the dichotomous roles of the intestinal microbiome in colorectal tumorigenesis through the conceptual framework of the driver-passenger model. We discuss how early initiating driver bacteria, such as Polyketide synthase-positive Escherichia coli and enterotoxigenic Bacteroides fragilis, compromise mucosal barriers, induce chronic mucosal inflammation, and inflict direct genomic instability. As the local tumor microenvironment undergoes profound metabolic remodeling, opportunistic passenger pathogens, notably Fusobacterium nucleatum, become enriched, further promoting cellular proliferation and facilitating tumor immune evasion. Conversely, protective commensals, exemplified by Clostridium butyricum and Streptococcus thermophilus, exert robust tumor-suppressive effects through multifaceted mechanisms. These beneficial microbes actively antagonize malignant progression by redirecting tumor metabolic fluxes toward oxidative stress, orchestrating deep epigenetic reprogramming, and degrading core oncoproteins to reverse chemoresistance. Transitioning from fundamental mechanisms to clinical application, we evaluate a comprehensive spectrum of microbiota-targeted interventions, encompassing non-invasive diagnostic biomarkers, fecal microbiota transplantation, engineered bacteria, phage therapy, and postbiotics. Finally, we critically address the formidable translational challenges associated with microbial heterogeneity, long-term safety, and regulatory standardization, aiming to provide a balanced perspective on integrating microbiome-based strategies into next-generation precision oncology for colorectal cancer.

Humans↗

PubMed2005

The anticancer activity of the fungal metabolite terrecyclic acid A is associated with modulation of multiple cellular stress response pathways.

Tumors are dependent on cellular stress responses, in particular the heat shock response, for survival in their hypoxic, acidotic, and nutrient-deprived microenvironments. Using cell-based reporter assays, we have identified terrecyclic acid A (TCA) from Aspergillus terreus, a fungus inhabiting the rhizosphere of Opuntia versicolor of the Sonoran desert, as a small-molecule inducer of the heat shock response that shows anticancer activity. Further characterization suggested that TCA also affects oxidative and inflammatory cellular stress response pathways. The presence of an alpha-methylene ketone moiety suggested that TCA may form adducts with sulfhydryl groups of proteins. Reaction with labile intracellular cysteines was supported by our finding that the glutathione precursor N-acetyl-cysteine protected tumor cells from the cytotoxic effects of TCA whereas the glutathione-depleting agent buthionine sulfoximine enhanced its activity. Related sesquiterpenes have been shown to increase levels of reactive oxygen species (ROS) and to inhibit nuclear factor kappaB (NF-kappaB) transcriptional activity. To assess whether TCA could have similar activities, we used a ROS-sensitive dye and flow cytometry to show that TCA does indeed increase ROS levels in 3LL cells. When tested in cells carrying NF-kappaB reporter constructs, TCA also exhibited concentration-dependent inhibition of cytokine-induced NF-kappaB transcriptional activity. These findings suggest that TCA modulates multiple stress pathways-the oxidative, heat shock, and inflammatory responses-in tumor cells that promote their survival. Small-molecule natural products such as TCA may serve as useful probes for understanding the relationships between these pathways, potentially providing leads for the design of novel and effective anticancer drugs.

3T3 Cells↗

PubMed2004

Role of reporter gene imaging in molecular and cellular biology.

Molecular imaging, including reporter gene methods, provides a unique opportunity to study biology in a living subject, thereby allowing physiological events to be monitored in an intact microenvironment. This review takes a molecular and cell biology perspective on recent studies which utilize reporter gene imaging as a tool to non-invasively monitor specific molecular biology pathways in vivo. Studies in rodent models demonstrate the feasibility of reporter gene imaging to visualize and measure key cellular pathways, such as transcription, translation and protein-protein interactions. The review indicates that molecular imaging is likely to be useful in the translation of molecular biology to medicine and biotechnological applications.

Animals↗

PubMed2000

Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential clinical advantages.

OBJECTIVES: Marrow stromal cells are mesenchymal stem cells able to differentiate into cardiomyocytes in vitro. We tested the hypothesis that marrow stromal cells, when implanted into myocardium, can undergo milieu-dependent differentiation and express cardiomyogenic phenotypes in vivo. METHODS: Isogenic adult rats were used as donors and recipients to simulate autologous transplantation. Marrow stromal cells isolated from donor leg bones were culture-expanded, labeled with 4;,6-diamidino-2-phenylindole, and then injected into the myocardium of the recipients. The hearts were harvested from 4 days to 12 weeks after implantation, and the implant sites were examined to identify the phenotypes of the labeled marrow stromal cells. RESULTS: Viable cells labeled with 4;, 6-diamidino-2-phenylindole can be identified in host myocardium at all time points after implantation. Implanted marrow stromal cells show the growth potential in a myocardial environment. After 4 weeks, donor cells derived from marrow stromal cells demonstrate myogenic differentiation with the expression of sarcomeric myosin heavy chain and organized contractile proteins. Positive staining for connexin 43 indicates the formation of gap junctions, which suggests that cells derived from marrow stromal cells, as well as native cardiomyocytes, are connected by intercalated disks. CONCLUSIONS: Different cell sources have been used as donor cells for cellular cardiomyoplasty. Our findings indicate that marrow stromal cells can also be used as donor cells. In an appropriate microenvironment they will exhibit cardiomyogenic phenotypes and may replace native cardiomyocytes lost by necrosis or apoptosis. Because marrow stromal cells can be obtained repeatedly by bone marrow aspiration and expanded vastly in vitro before being implanted or used as autologous implants, and because their use does not call for immunosuppression, the clinical use of marrow stromal cells for cellular cardiomyoplasty appears to be most advantageous.

Animals↗

PubMed2005

Functional adaptation: the key to plasticity of cardiovascular "stem" cells?

There is increasing evidence that cells of disparate phenotypes displaying various degrees of proliferative capacity engraft and function heterotopically in adult organisms. Efforts were made to reconcile these findings with the embryologic notions of pluripotent stem or progenitor cell, although the nature of the 'stemness' remained elusive. This topic is particularly important for the cardiovascular system, in which cytotrophoblasts, certain tumor cells, monocytes/macrophages, peritoneal mesothelial cells, and others acquire endothelial properties and/or perform endothelial functions. Here we suggest that this pluripotency reflects a fundamental characteristic of cellular diversity, which is manifested as the adaptive response to a functional pressure exerted by the cell's biochemical and biophysical microenvironments that would drive their differentiation. In this model, differentiation is a dynamic, reversible, and open-ended process where the cells would maintain the flexibility to respond to changing environmental clues with a fine tuning of their structure, a property that was previously called cellular plasticity. Pluripotent adult stem cells that display this property in culture, and, perhaps upon in vivo administration, were described. Therefore, we also suggest that differentiation of stem cells is a form of cellular plasticity within the larger context of functional adaptation, whereas their stemness remains associated with self-renewal.

Animals↗

PubMed1991

Blockade of central and peripheral luteinizing hormone-releasing hormone (LHRH) receptors in neonatal rats with a potent LHRH-antagonist inhibits the morphofunctional development of the thymus and maturation of the cell-mediated and humoral immune responses.

The development of the thymus and the hypothalamic-pituitary-gonadal axis are linked by bidirectional hormonally mediated relationships. In the present study, the direct involvement of the neuropeptide LHRH in the maturation of the thymus and development of the cell-mediated and humoral immune responses were assessed after treatment of neonatal (from post-natal day 1-day 5) female rats with a potent LHRH-antagonist (LHRH-anta, p-Glu-D-Phe 2.6,Pro3-LHRH, 50 micrograms/rat), and the effects compared to those resulting from neonatal castration. Whereas in control animals the maturation of mitogenic potential in thymocyte cultures showed a progressive and age-dependent increase, reaching a maximal activity at 30 days of age and then decreasing after puberty onset, in LHRH-anta-treated rats, the thymocyte's proliferative response was completely blocked at 7 days of age and remained very low at each time interval studied, until 3 months of age. A similar effect of the LHRH-anta treatment on splenocyte cultures was measured. Moreover, a reduced percentage of the T-helper lymphocyte subpopulation followed LHRH-anta administration. By contrast, in neonatally castrated rats, blastogenic activity was significantly higher, compared to control cultures, at each stage studied. Treatment with LHRH-anta produced a significant decrease in thymus wt, an alteration of the maturational pattern characterized by a cellular monomorphism, reduced thymocyte volume, reduction of the cortical area, and depauperation of the epithelial microenvironment. Moreover, a morphometric analysis revealed a selective decrease in the large lymphoid cell population of the subcapsular cortex at 7 and 15 days. On the other hand, neonatal castration produced an opposite effect, leading to a marked hypertrophy of the cortical area, and counteracted the post-puberal thymus atrophy. When LHRH-anta-treated adult (3-month-old) rats were challenged with an antigenic stimulus (multiple sc injections of complete Freund adjuvant and BSA) and antibody (anti-BSA antibodies of the immunoglobulin G class) production measured in the serum after 15 days, a marked and significant decrease in immunoglobulin G levels was observed, compared to the values measured in untreated control. The described immune deficiencies in LHRH-anta-treated rats were associated with a clear inhibition of sexual maturation. This study clearly indicates that the blockade of central and peripheral LHRH receptors during a critical period for maturation of both hypothalamus-hypophyseal-gonadal axis and brain-thymus-lymphoid axis dramatically impairs immune system development, suggesting a potential role of the neuropeptide LHRH in the bidirectional programming of both neuroendocrine and immune functions.

Animals↗

PubMed2002

A novel dynamic model of hematopoietic stem cell organization based on the concept of within-tissue plasticity.

OBJECTIVE: At present, no dynamic quantitative models of stem cell organization are available that fulfill all criteria of the prevalent functional definition of hematopoietic stem cells and, at the same time, provide a consistent explanation of cell kinetic and functional stem cell heterogeneity, reversibility of cellular properties, self-organized regeneration after damage, fluctuating activity and competition of stem cell clones, and microenvironment dependency of stem cell quality. To solve this problem, we propose a new, comprehensive model concept. MATERIALS AND METHODS: A single cell-based stochastic model is described. It makes the novel concept of within-tissue plasticity operational. Within a range of potential options, individual cells may reversibly change their actual set of properties depending on the influence of the local growth environment. Stochastic switching between the growth environments introduces fluctuations that eventually generate heterogeneity. Extensive model simulations are compared with experimental data. RESULTS: Although stemness is not an explicit cellular model property, the system behavior is consistent with the functional definition of stem cells and explains a large set of experimental observations on stem cell function in vivo and in vitro on the level of cell populations and individual cells. Classic results such as the colony-forming unit spleen assay, as well as recent experimental observations on stem cell kinetics, individual clone tracking, and fluctuating clonal contribution, are discussed. CONCLUSIONS: This concept introduces a fundamentally new perspective on stem cell organization treating stemness not as an explicit cellular property but as the result of a dynamic process of self-organization. The model needs to be extended to incorporate lineage specification and tissue plasticity.

Animals↗

PubMed1995

Modulated glycosylation of proteoglycans during differentiation of human B lymphocytes.

Proteoglycans are mediators of cellular adhesion and regulate growth factor activities. Proteoglycans of B lymphocytes undergo structural changes during B cell ontogeny which may correspond to the specific requirements of the respective microenvironment of the maturing cell. We analyzed three human B cell lines representing pre-B cells (Nalm-6), activated B cells (Jok-1) and plasma cells (U266) for their cellular proteoglycans. Gel filtration of the 35S-labeled macromolecules of the three cell lines revealed an increase in size in the order Nalm-6 < Jok-1 < U266. In Jok-1 and U266 cells the major pool of proteoglycans consisted of proteochondroitin sulfates of 50 to 90 kDa. These proteolglycans carried a protein core of approx. 30 kDa to which 1 to 3 glycosaminoglycan chains in the range of 28 to 32 kDa were attached. In Nalm-6 cells only free chondroitin sulfate chains of 23 kDa, but no intact proteoglycans, were detected. Chondroitin sulfate chains were predominantly composed of chondroitin-4-sulfate, those of Nalm-6 and U266 cells additionally contained 10-20% of unsulfated disaccharides. In U266 cells 30% of glycosaminoglycans consisted of heparan sulfate either bound to pure proteoheparan sulfate or to chondroitin sulfate/heparan sulfate hybrid-proteoglycans. Earlier, syndecan-1 was described as a hybrid proteoglycan containing heparan sulfate/chondroitin sulfate chains which is transcribed by murine B cells at early and late maturation stages. In order to see whether syndecan is transcribed by the human B cell lines used here, we measured expression of syndecan mRNA by the reverse transcriptase polymerase chain reaction. Similar to murine lymphocytes, syndecan-specific mRNA was detected in Nalm-6 and U266 cells, equivalent to early and late B cells, but not in lymphoblastoid Jok-1 cells. However, Nalm-6 cells do not produce proteoheparan sulfate. In these cells, syndecan synthesis may be blocked at the translational level. Also, the proteoglycans of U266 are different from syndecan-1 in their composition of glycosaminoglycans and in size of protein cores. Together, these results indicate that the major pool of proteoglycans produced by human B cells consists of proteochondroitin sulfate and additionally in later stages of a smaller proportion of proteoheparan sulfate which is not identical to syndecan-1. During distinct phases of B cell differentiation, modulations in the glycosaminoglycan moiety concerning size and sulfation of glycosaminoglycan chains were also found.

B-Lymphocytes↗

PubMed2001

Differential expression of protease-activated receptors-1 and -2 in stromal fibroblasts of normal, benign, and malignant human tissues.

The serine proteases thrombin and trypsin are among many factors that malignant cells secrete into the extracellular space to mediate metastatic processes such as cellular invasion, extracellular matrix degradation, angiogenesis, and tissue remodeling. The degree of protease secretion from malignant cells has been correlated to their metastatic potential. Protease activated receptors (PAR)-1 and -2, which are activated by thrombin and trypsin respectively, have not been extensively characterized in human tumors in situ. We investigated the presence of PAR-1 and PAR-2 in human normal, benign and malignant tissues using immunohistochemistry and in situ hybridization. Our results demonstrate PAR-1 and PAR-2 expression in the tumor cells, mast cells, macrophages, endothelial cells, and vascular smooth muscle cells of the metastatic tumor microenvironment. Most notably, an up-regulation of PAR-1 and PAR-2 observed in proliferating, smooth muscle actin (SMA)-positive stromal fibroblasts surrounding the carcinoma cells was not observed in normal or benign conditions. Furthermore, in vitro studies using proliferating, SMA-positive, human dermal fibroblasts, and scrape-wounded human dermal fibroblasts demonstrated the presence of PAR-1 and PAR-2 not detected in quiescent, SMA-negative cultures. PAR-1 and PAR-2 in the cells forming the tumor microenvironment suggest that these receptors mediate the signaling of secreted thrombin and trypsin in the processes of cellular metastasis.

Actins↗

PubMed1985

Target cells and thymus microenvironment in the pathogenesis of thymic lymphomas in C57BL/Ka mice.

In C57BL/Ka mice, the induction of thymic lymphomas either by inoculation of radiation leukemia virus (RadLV) or by a split dose irradiation requires complex cellular events: Target cells are found among the population of thymic subcapsular blast cells, or, alternatively, of marrow or spleen prothymocytes; Progression of target cells to lymphoma growth requires a multi-step process, which occurs only within thymic microenvironment; Target cells are rapidly induced as "preleukemic" cells; After inoculation of RadLV, the initial events occur when target cells are in close association with cells of a specialized component of thymic epithelium, i.e., the so-called "nurse cells"; The leukemogenic agents induce damages to the thymic microenvironment itself; Lymphoma prevention by marrow grafting after irradiation results from mechanisms still unknown which inhibit the progression of "preleukemic" cells to neoplastic growth.

Animals↗