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PubMed1999

Mathematical modelling of tumour acidity: regulation of intracellular pH.

Measurements of extracellular pH (pHe) in vivo have shown that the microenvironment in tumours is more acidic than in normal tissue. However, both human and animal tumour cells have been shown to have an intracellular pH (pHi) on the alkaline side of neutrality (pH 7.1-7.2). This gives rise to a reversed pH gradient between tumours and normal tissue which implies that cells within solid tumours are capable of maintaining their level of pHi at physiological levels, despite lower than normal levels of pHe. In this paper the authors describe a mathematical model that provides a possible explanation for the altered pH gradient observed in tumours. The authors examine the influence of changes in the microenvironment on the activity of several membrane based ion transport systems. Using qualitative analysis the authors show that the pHi of tumour cells is less sensitive to external pH than for normal cells, because of their increased reliance on the inefficient glycolytic pathway for energy production. It is shown that under aerobic conditions the lactate-/H+ symporter could be the most active exchanger in the regulation of pHi in tumour cells. However, under more hypoxic conditions lactate extrusion is reduced, and so this exchanger has little effect on resting pHi in these regions. The authors also consider an extended model which incorporates the transfer of acids from the cytosol into acidic organelles. The model demonstrates that one of the major factors involved in the maintenance of cytosolic pH to physiological levels, despite an acidic extracellular pH in hypoxic areas of tumour tissue (median, 6.9-7.0), is enhanced sequestration of cytosolic protons into acidic cellular vesicles such as endoplasmic reticulum, golgi, endosomes, and lysosomes.

Animals↗

PubMed1990

Ki-M6 immunostaining in routinely processed sections of reactive and neoplastic human lymphoid tissue.

A monoclonal antibody, termed Ki-M6 (CD68), which shows a restricted reactivity to cells of the monocyte/macrophage system, has been evaluated primarily with the use of cryostat sections. In this study the authors could assess that the Ki-M6 antibody recognizes a fixation-resistant epitope in most human macrophages. The Ki-M6 immunoreactivity with monocyte/macrophage-related cells was established by testing on routinely processed samples of reactive and neoplastic lymphoid tissues; it was compared with the staining for vimentin (V9) and S-100 protein antibodies, with visualization of the stationary elements of lymphoid tissues, with the aim of establishing its value in the study of the nonlymphoid microenvironment. The Ki-M6 antibody reactivity could be achieved with Bouin-fixed, paraffin-embedded tissue sections, without any proteolytic treatment, with the use of the avidin-biotin complex (ABC) method, especially after overnight incubation time at 4 degrees C. Some reduction in antigenic reactivity was observed in B5- or formaldehyde-fixed samples. The antibody reacted with macrophages of all different lymph node compartments; a broad reactivity against cells of macrophage lineage, including multinucleated giant cells, was observed in epithelioid granulomas. Ki-M6-positive cells other than classic macrophages were the so-called "plasmacytoid T-cells" and cells displaying elongated cytoplasms with fibroblastic-like features. Granulocytes, follicular dendritic reticulum cells, and interdigitating reticulum cells did not reveal any reactivity with Ki-M6 antibody. In malignant lesions, neoplastic cells of follicular and diffuse B- and T-cell lymphomas, including large cell non-Hodgkin's lymphomas, and Reed-Sternberg cells of Hodgkin's disease were negative in all cases studied. This study shows that Ki-M6 seems to be another anti-macrophage-specific antibody that reacts, in routinely processed tissue sections, with tissue macrophages but not with accessory cells. Thus, it may be a valuable addition to vimentin and S-100 protein antibodies for investigation of the microenvironmental organization of lymphoid tissues both in normal and neoplastic conditions.

Antibodies, Monoclonal↗

PubMed2002

VEGF increases engraftment of bone marrow-derived endothelial progenitor cells (EPCs) into vasculature of newborn murine recipients.

Recent evidence suggests that bone marrow-derived angioblasts or endothelial progenitor cells circulate in peripheral blood and can incorporate at sites of pathologic neovascularization or during the ovarian cycle. However, the incorporation of endothelial progenitor cells into vessels of nonischemic tissues in adult animals has not been observed. We hypothesized that the vascular microenvironment differs between newborn and adult animals, and that donor endothelial cell progenitors would engraft in rapidly growing normal tissues during the neonatal period. After nonablative administration of bone marrow cells either at birth or at 4 weeks of age, donor-derived endothelial cells were found only in the neovasculature of the newborn recipients. Both the incorporation of donor endothelial cells into the newborn neovasculature as well as tissue vascularity were significantly increased by coadministering vascular endothelial growth factor with bone marrow cells. These findings suggest that bone marrow-derived endothelial progenitor cells can contribute to neovascularization during the newborn period and are responsive to vascular endothelial growth factor.

Animals↗

PubMed1992

Novel factors from stromal cells: bone marrow and thymus microenvironments.

The microenvironments contained within mammalian bone marrow and thymus play major roles in the life-long process of myeloid and lymphoid cell development and renewal. The cells that give architecture to these microenvironments are collectively referred to as stromal cells, and these cells grow as adherent cell types in cell culture. Stromal cells are predominantly a mixture of fibroblasts, cells of macrophage/dendritic lineages, epithelial and endothelial cells. There are at least three mechanisms that govern the interaction of stromal cells with hematopoietic and lymphoid cells: soluble factors, or cytokines, membrane-anchored growth factors and cell surface recognition molecules, such as integrins and selections. Little is known of the mechanisms that preserve the integrity of local microenvironments and how subpopulations of cells are transiently retained in microenvironments during various maturational states. Different lymphoid cells develop in bone marrow and thymus despite the similarities in stromal cells of these tissues. It remains a major quest to determine how the components of microenvironments of these organs regulate lineage-specific differentiation. The focus here is on stromal cells, the early development of myeloid cells and B lymphocytes in bone marrow and T lymphocytes in the thymus.

Animals↗

PubMed2026

Moving Beyond Morphology to Multiplexed Molecular Imaging as the Next Frontier in Diagnostic Pathology.

Diagnostic pathology has long relied on the morphologic interpretation of hematoxylin and eosin-stained tissues to guide diagnosis and assess prognostic features. Although pathologists intuitively recognize spatial patterns and architectural organization, these assessments remain largely qualitative and difficult to quantify systematically. Immunohistochemistry and immunofluorescence have introduced molecular specificity but are limited in multiplexing capacity, whereas bulk genomic and transcriptomic assays provide high molecular depth but lose spatial context by averaging signals across heterogeneous cell populations. Recent advances in spatial proteomics-including mass spectrometry-based imaging and cyclic immunofluorescence-now enable multiplexed, single-cell protein analysis within intact tissue architecture. These technologies have revealed complex immune and stromal microenvironments, spatially organized biomarkers predictive of therapeutic response, and molecular gradients underlying disease progression. By integrating histologic and molecular information, spatial proteomics bridges traditional microscopy with high-dimensional omics, allowing quantitative, spatially resolved insights into tissue organization and disease mechanisms. This review summarizes recent developments in multiplexed spatial proteomics from both scientific and pathologic perspectives, highlighting how these technologies extend beyond morphology to quantify histologic patterns, refine biomarker discovery, and facilitate clinical translation. The review also examines translational challenges and barriers to clinical implementation, including costs, standardization requirements, and workflow integration.

Humans↗

PubMed2026

Tissue-derived extracellular matrix hydrogels instruct epigenetic adaptation in metastatic colonization.

The extracellular matrix (ECM) plays a central role in regulating tumor progression and metastatic colonization by providing biochemical and mechanical signals that shape cancer cell fate. However, most organoid culture systems rely on basement membrane extracts that fail to reproduce the tissue-specific extracellular environments encountered during metastasis. Here, we develop tissue-derived decellularized matrix hydrogels to reconstruct organ-specific microenvironments and investigate epigenetic adaptation to ECM cues during metastatic colonization. Patient-derived colorectal cancer organoids cultured in colon-derived matrices exhibited enhanced maintenance of stem-like phenotypes and colon-specific chromatin accessibility landscapes compared with cultures grown in basement membrane extracts, demonstrating improved physiological relevance for primary tumor modeling. When exposed to matrices derived from secondary organs, the organoids showed distinct growth phenotypes accompanied by rapid, tissue-dependent chromatin accessibility remodeling, indicating that ECM composition alone can reshape regulatory programs governing metastatic adaptation. Notably, liver-derived matrices selectively activated hepatocyte nuclear factor 4 alpha (HNF4A)-associated transcriptional networks and created a context-specific dependence on c-MET signaling for survival. Functional perturbation of HNF4A or c-MET signaling confirmed that both are required for organoid formation specifically within the liver matrix environment. Together, these findings establish tissue-derived matrix hydrogels as instructive bioactive materials that actively regulate cancer cell epigenetic states and reveal microenvironment-specific therapeutic vulnerabilities during early metastatic colonization.

Journal Article↗

PubMed1992

Immunophenotypic characterisation of human peritoneal and alveolar macrophages and of human blood monocytes differentiated in the presence of either GM-CSF or M-CSF or a combination of GM-CSF/M-CSF.

In vivo, circulating blood monocytes (Mo) migrate into the various tissues where they undergo terminal maturation into macrophages (M phi) with morphological and sometimes functional properties that are characteristic for the tissue in which they reside. This tissue-specific M phi heterogeneity results from the immediate microenvironment, but may also originate from genetically distinct Mo subpopulations. The in vitro transformation of Mo to M phi is thought to reflect the events of the in vivo maturation and thus is widely used as a model to analyse M phi development. To study the heterogeneity within the mononuclear phagocyte system, we have investigated the phenotypic characterisation of mature tissue M phi, blood Mo and Mo-derived M phi cultured in medium with either GM-CSF, M-CSF or a combination of both cytokines. Tissue peritoneal and alveolar M phi showed different antigenic specificities, particularly concerning the transferrin receptor and CD68 and CD14 antigens. M-CSF-derived M phi when compared to the other M ø populations also exhibited a significantly increased expression of transferrin receptor and CD68 antigen. In contrast, GM-CSF treated cells which exhibited a better long term survival, showed notably more positivity for CD11b and CD32 antigens. These results show that the phenotypic heterogeneity of the different M phi populations is limited and appears to result from discrepancies in the differentiation and/or activation of the cells. The location of the CD68 antigen, which is generally considered to be an intracellular protein, was investigated at the ultrastructural level and found to be exclusively situated at the outer cell membrane.

Antibodies, Monoclonal↗

PubMed2005

Functional interaction between p75NTR and TrkA: the endocytic trafficking of p75NTR is driven by TrkA and regulates TrkA-mediated signalling.

The topology and trafficking of receptors play a key role in their signalling capability. Indeed, receptor function is related to the microenvironment inside the cell, where specific signalling molecules are compartmentalized. The response to NGF (nerve growth factor) is strongly dependent on the trafficking of its receptor, TrkA. However, information is still scarce about the role of the cellular localization of the TrkA co-receptor, p75NTR (where NTR is neurotrophin receptor), following stimulation by NGF. It has been shown that these two receptors play a key role in epithelial tissue and in epithelial-derived tumours, where the microenvironment at the plasma membrane is defined by the presence of tight junctions. Indeed, in thyroid carcinomas, rearrangements of TrkA are frequently found, which produce TrkA mutants that are localized exclusively in the cytoplasm. We used a thyroid cellular model in which it was possible to dissect the trafficking of the two NGF receptors upon neurotrophin stimulation. In FRT (Fischer rat thyroid) cells, endogenous TrkA is localized exclusively on the basolateral surface, while transfected p75NTR is selectively distributed on the apical membrane. This cellular system enabled us to selectively stimulate either p75NTR or TrkA and to analyse the role of receptor trafficking in their signalling capability. We found that, after binding to NGF, p75NTR was co-immunoprecipitated with TrkA and was transcytosed at the basolateral membrane. We showed that the TrkA-p75NTR interaction is necessary for this relocation of p75NTR to the basolateral side. Interestingly, TrkA-specific stimulation by basolateral NGF loading also induced the TrkA-p75NTR interaction and subsequent p75NTR transcytosis at the basolateral surface. Moreover, specific stimulation of p75NTR by NGF activated TrkA and the MAPK (mitogen-activated protein kinase) pathway. Our data indicate that TrkA regulates the subcellular localization of p75NTR upon stimulation with neurotrophins, thus affecting the topology of the signal transduction molecules, driving the activation of a specific signal transduction pathway.

Cell Line↗

PubMed1998

Activation of the sodium/hydrogen exchanger via the fibronectin-integrin pathway results in hematopoietic stimulation.

The proliferative response of hematopoietic cells is regulated by many factors, including the presence and type of growth factors, the cellular microenvironment, and the physiochemical conditions prevailing in the tissue milieu. A process fundamental to all cells is the regulation of the intracellular acid-base conditions. One of the mechanisms by which intracellular pH (pHi) is regulated is through the sodium/hydrogen exchanger, a ubiquitous membrane protein which exploits the intra- and extracellular sodium ion gradient to drive hydrogen ions out of the cell. However, activation of the exchanger via mitogenic and nonmitogenic signals leads to an increase in pHi which, in turn, may directly or indirectly result in a proliferative response. It has been shown that interaction of fibronectin with its integrin receptor subunits alpha4 and alpha5 can result in activation of the Na+/H+ exchanger. In this report, we demonstrate that when mouse bone marrow cells are physically brought together in a preculture system we designate as high cell density culture (HCDC), in a small volume and at the same cellularity as that in the marrow, hematopoietic stem and progenitor cell populations are stimulated with no additional stimulation in the presence of growth factors. Neutralizing antibodies to the growth factors added to HCDC had little, if any, effect on the degree of stimulation. However, when antibodies to fibronectin or the alpha4 integrin subunit were added to HCDC, inhibition was observed, indicating that the observed hematopoietic stimulation occurred via the fibronectin-integrin pathway. Addition of 5 microM 5-(N,N-hexamethylene) amiloride (5-HMA), a specific inhibitor of the Na+/H+ exchanger, also resulted in inhibition of in vitro hematopoiesis. Since the exchanger was implicated, we then measured the pHi of normal and HCDC-treated bone marrow cells in the absence and presence of 5-HMA by flow cytometry using the fluorescent pH-sensitive indicator, carboxy SNARF-1 AM. It was found that cells subjected to HCDC exhibited a higher pH than normal fresh cells. In each case, the pH was lowered in the presence of 5-HMA. Furthermore, addition of antibodies to fibronectin or the alpha4 integrin subunit to HCDC also reduced the pH, to a similar level to that found for 5-HMA. Our results demonstrate, for the first time, that a hematopoietic stem and progenitor cell proliferative response can be initiated by activation of the Na+/H+ exchanger, leading to an increase in pHi, via cell-cell interaction through the fibronectin-integrin pathway. This pathway could, therefore, be significant not only in normal hematopoietic regulation, but also under pathophysiological conditions.

Amiloride↗

PubMed1987

Alteration in osteoblast cell number and cell activity in the presence of invading malignant fibrous histiocytoma.

Correct prediction of tumor behavior and interpretation of local factors in the tumor microenvironment rely in part upon accurate determination of tissue changes after tumor invasion. The authors examined local bone changes in primary malignant fibrous histiocytoma (MFH) of bone in a 59-year-old woman. Three noninvolved and three tumor-involved sites were evaluated by quantitative determinations of bone structural and dynamic features. Compared to noninvolved sites, tumor-involved bone was characterized by significantly increased osteoblast index (89.4 +/- 15.6 [mean +/- SEM] versus 7.3 +/- 6.0, P = 0.008), percent osteoid area (12.1 +/- 2.7 versus 1.2 +/- 0.5, P = 0.02), percent of trabecular surface covered by osteoid (70.0 +/- 6.0 versus 14.5 +/- 4.8, P = 0.002), and percent osteoid lined by osteoblasts (36.4 +/- 3.6 versus 3.7 +/- 3.0, P = 0.002). Bone 7.8 mm distant from invading tumor cells showed features characteristic of noninvolved sites, whereas bone completely surrounded by tumor showed markedly decreased osteoblast features. Osteoblast function also was affected by tumor; the amount of matrix laid down per day bore a significant positive correlation with the osteoblast index. These data indicate the following: distinctive bone morphologic changes occur in situ during invasion by MFH; changes affect aspects of bone formation but not resorption during invasion; both osteoblast number and osteoblast activity are significantly altered; and changes are local in nature and probably reflect the osteoblast response to local tumor factor(s) and are dependent upon the extent of tumor invasion.

Bone Neoplasms↗

PubMed1993

The effect of changes in iron redox state on the activity of enzymes sensitive to modification of SH groups.

Iron ions in micromolar concentrations induced a rapid and selective inhibition of the activity of skeletal muscle creatine kinase (CK), sarcoplasmic reticulum (SR) Ca(2+)-ATPase, and pyruvate kinase (PK). This effect of iron was dependent on the presence of adenine nucleotides and on the redox state of iron. Changing the redox state of the media created different Fe2+/Fe3+ ratios which selectively depressed different enzymes: depression of PK activity occurred when iron was predominantly in its reduced form and, consequently, when there was a high Fe2+/Fe3+ ratio; depression of SR Ca2+ uptake and SR Ca(2+)-ATPase activity occurred when the Fe2+/Fe3+ ratio was close to 1; depression of CK activity occurred when iron was predominantly in its oxidized form and the Fe2+/Fe3+ ratio was low. All iron-sensitive enzymes possessed sulfhydryl groups, accessible to N-ethylmaleimide (NEM), which were essential for their activity. The rate of inhibition of enzyme activity with NEM increased in the order PK < Ca(2+)-ATPase < CK. Iron-induced depression of CK and PK activities was reversible by dithiotreithol. Results suggest that changes in the redox state of cellular microenvironments, which inevitably occur during reperfusion of ischemic tissue or rapid increase in tissue oxygen consumption, may selectively depress the activity of several enzymes bearing SH groups that are sensitive to modifications and that are essential for their activity. Iron-induced depression of enzyme activity depends on the availability of iron bound to adenine nucleotides and possibly to other low molecular weight chelators and on the Fe2+/Fe3+ ratio generated by the induced redox change.

Animals↗

PubMed2002

Gammadelta T cells: functional plasticity and heterogeneity.

Gammadelta T cells remain an enigma. They are capable of generating more unique antigen receptors than alphabeta T cells and B cells combined, yet their repertoire of antigen receptors is dominated by specific subsets that recognize a limited number of antigens. A variety of sometimes conflicting effector functions have been ascribed to them, yet their biological function(s) remains unclear. On the basis of studies of gammadelta T cells in infectious and autoimmune diseases, we argue that gammadelta T cells perform different functions according to their tissue distribution, antigen-receptor structure and local microenvironment; we also discuss how and at what stage of the immune response they become activated.

Animals↗

PubMed2002

Maintenance of ATP favours apoptosis over necrosis triggered by benzamide riboside.

A new synthetic drug, benzamide riboside (BR) exhibited strong oncolytic activity against leukemic cells in the 5-10 microM range. Higher BR-concentrations (20 microM) predominantly induced necrosis which correlated with DNA strand breaks and subsequent depletion of ATP- and dATP levels. Replenishment of the ATP pool by addition of adenosine prevented necrosis and favoured apoptosis. This effect was not a pecularity of BR-treatment, but was reproduced with high concentrations of all trans-retinoic acid (120 microM) and cyanide (20 mM). Glucose was also capable to suppress necrosis and to favour apoptosis of HL-60 cells, which had been treated with necrotic doses of BR and cyanide. Apoptosis eliminates unwanted cells without affecting the microenvironment, whereas necrosis causes severe inflammation of surrounding tissues due to spillage of cell fluids into the peri-cellular space. Thus, the monitoring and maintenance of cellular energy pools during therapeutic drug treatment may help to minimize nonspecific side effects and to improve attempted drug effects.

Adenosine↗

PubMed2007

Eosinophilic granulocytes and damage-associated molecular pattern molecules (DAMPs): role in the inflammatory response within tumors.

The development of a tumor over many years typically leads to reciprocal alternations in the host and the tumor, enabling tumor growth paradoxically in the setting of substantial necrosis and inflammation. When evaluating a tumor, it is important to assess 3 elements: (1) the quantity and quality of tumor-associated leukocytes, (2) their state of activation, and (3) tumor microenvironment. Peripheral blood eosinophilia and tumor-associated tissue eosinophilia are frequently associated with some tumor types and also found after immunotherapy with IL-2, IL-4, granulocyte-macrophage colony-stimulating factor, and antibody to CTLA-4. Within several tumor types including gastrointestinal tumors, tumor-associated tissue eosinophilia is associated with a significantly better prognosis. The converse is true in other tumor types such as differentiated oral squamous cell carcinoma. On the basis of the emergent data, tumor-associated eosinophils have at least 2 dominant nonoverlapping activities: (1) destructive effector functions potentially limiting tumor growth as well as causing recruitment and activation of other leukocytes, (2) immunoregulative and remodeling activities which suppress immune response and promote tumor proliferation. The mechanism by which eosinophils in particular are recruited into tumor tissue is largely unknown. Candidates for causing eosinophil chemotaxis into tumor tissue are the released damage-associated molecular pattern molecules (DAMPs) including the nuclear protein high mobility group box 1. High mobility group box 1 is released upon necrotic cell death and secreted by many cells, particularly during periods of nutrient, hypoxic, or oxidant stress. This overview on eosinophil biology in the context of cancer and necrosis, introduces intriguing and novel strategies targeting eosinophils to enable more effective biologic therapy for cancer patients.

Eosinophils↗

PubMed1987

Purification, characterization, and toxicity of the sulfhydryl-activated hemolysin listeriolysin O from Listeria monocytogenes.

We purified and characterized an extracellular hemolysin produced by Listeria monocytogenes. Hemolysin production was greatly enhanced by growing bacteria in resin (Chelex)-treated medium. This hemolysin was separated as a homogeneous protein of 60,000 daltons by using thiol-disulfide exchange affinity chromatography. This protein was a sulfhydryl-activated toxin, termed listeriolysin O, which shared the classical properties of other bacterial sulfhydryl-activated toxins: inhibition by very low amounts of cholesterol; activation by reducing agents and suppression of the lytic activity by oxidation; antigenic cross-reactivity with streptolysin O. However, listeriolysin O differed remarkably from the other sulfhydryl-activated toxins in that its cytolytic activity towards erythrocytes from various animal species was maximum at low pH (approximately 5.5) and was undetectable at pH 7.0. This suggests that the lytic activity of the toxin in host tissues might be better expressed in the acidic microenvironment, including macrophage phagosomes where bacteria presumably replicate. Listeriolysin O was lethal to mice (50% lethal dose of ca. 0.8 microgram) and induced a rapid inflammatory reaction when injected intradermally. These results favor the view that listeriolysin O might play a major role during intracellular replication of L. monocytogenes, ultimately promoting death of infected macrophages.

Animals↗

PubMed2005

Evolution of transcription regulatory genes is linked to niche specialization in the bacterial pathogen Streptococcus pyogenes.

Streptococcus pyogenes is a highly prevalent bacterial pathogen, most often giving rise to superficial infections at the throat or skin of its human host. Three genotype-defined subpopulations of strains exhibiting strong tropisms for either the throat or skin (specialists) or having no obvious tissue site preference (generalists) are recognized. Since the microenvironments at the throat and skin are distinct, the signal transduction pathways leading to the control of gene expression may also differ for throat versus skin strains of S. pyogenes. Two loci (mga and rofA/nra) encoding global regulators of virulence gene expression are positioned 300 kb apart on the genome; each contains alleles forming two major sequence clusters of approximately 25 to 30% divergence that are under balancing selection. Strong linkage disequilibrium is observed between sequence clusters of the transcription regulatory loci and the subpopulations of throat and skin specialists, against a background of high recombination rates among housekeeping genes. A taxonomically distinct commensal species (Streptococcus dysgalactiae subspecies equisimilus) shares highly homologous rof alleles. The findings provide strong support for a mechanism underlying niche specialization that involves orthologous replacement of regulatory genes following interspecies horizontal transfer, although the directionality of gene exchange remains unknown.

Bacterial Proteins↗

PubMed2006

Development of fetal haemoglobin-blood cells (F cells) within colorectal tumour tissues.

AIM: To evaluate the sources of fetal haemoglobin (HbF) as an indicator in cancer. An immunohistochemical study was carried out on some of the most common kinds of cancer. All of these cancers had serologically high levels of HbF as evaluated previously. METHODS: Immunoaffinity-purified anti-HbF was immunohistochemically used to study F cell distribution in the following cancers: colorectal adenocarcinoma, urinary bladder transitional cell carcinoma, brain tumours, lung carcinoma, breast adenocarcinoma, leukaemia, Burkitt's lymphoma and endometrial carcinoma. RESULTS: In colorectal adenocarcinoma, HbF-containing red blood cells (FRBC) were present within thin-walled vessels or were disposed in dense clusters within the tumour. Some of these cells were nucleated or binucleated HbF-erythroblasts or HbF-normoblasts (FNBS). In two cases, high levels of mitoses within HbF-erythroblasts were observed. In half of the cases with transitional cell carcinoma of the urinary bladder, regional intratumoral blood vessels were found to contain 5-50% FRBC. In the other tumours examined, F cells were not observed. FRBCs, however, were occasionally observed in the regional lymph nodes of some of these cancers. CONCLUSIONS: The evaluation of HbF as a potential plasma marker is suggested by the high concentration of FRBCs in colorectal tumours. The apparent development of FRBCs in colorectal tumour tissues is an interesting observation, as these cells were previously thought to develop in medullary or lymphoid tissues. It is thus suggested that the colonic microenvironment may stimulate extramedullary fetal-type haematopoiesis.

Adenocarcinoma↗

PubMed2004

Scaffold topography alters intracellular calcium dynamics in cultured cardiomyocyte networks.

Structural and functional changes ensue in cardiac cell networks when cells are guided by three-dimensional scaffold topography. We report enhanced synchronous pacemaking activity in association with slow diastolic rise in intracellular Ca2+ concentration ([Ca2+]i) in cell networks grown on microgrooved scaffolds. Topography-driven changes in cardiac electromechanics were characterized by the frequency dependence of [Ca2+]i in syncytial structures formed of ventricular myocytes cultured on microgrooved elastic scaffolds (G). Cells were electrically paced at 0.5-5 Hz, and [Ca2+]i was determined using microscale ratiometric (fura 2) fluorescence. Compared with flat (F) controls, the G networks exhibited elevated diastolic [Ca2+]i at higher frequencies, increased systolic [Ca2+]i across the entire frequency range, and steeper restitution of Ca2+ transient half-width (n = 15 and 7 for G and F, respectively, P < 0.02). Significant differences in the frequency response of force-related parameters were also found, e.g., overall larger total area under the Ca2+ transients and faster adaptation of relaxation time to pacing rate (P < 0.02). Altered [Ca2+]i dynamics were paralleled by higher occurrence of spontaneous Ca2+ release and increased sarcoplasmic reticulum load (P < 0.02), indirectly assessed by caffeine-triggered release. Electromechanical instabilities, i.e., Ca2+ and voltage alternans, were more often observed in G samples. Taken together, these findings 1) represent some of the first functional electromechanical data for this in vitro system and 2) demonstrate direct influence of the microstructure on cardiac function and susceptibility to arrhythmias via Ca(2+)-dependent mechanisms. Overall, our results substantiate the idea of guiding cellular phenotype by cellular microenvironment, e.g., scaffold design in the context of tissue engineering.

Animals↗