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Results for “Cellular Microenvironment”

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PubMed1981

Haematopoiesis in mice heterozygous for the W trait: defective formation of transient endogenous spleen colonies.

It has been determined that W/+ and Wv/+ heterozygous mice, as compared with normal +/+ homozygous littermates, form significantly lower numbers of transient 5-day endogenous spleen colonies in response to X-irradiation. This defect was evident for doses of irradiation between 2-6 Gy (200-600 rad) and was associated with a slightly increased radiosensitivity of the assayed precursor cells (TE-CFU) in W heterozygotic mice. Moreover, the defect was transplantable, i.e., intrinsic to the marrow cells and not to the microenvironment, and was not associated with a similar decrease in cells which form erythropoietic bursts in vitro (BFUe). This study provides a cellular basis for increased radiosensitivity of W/+ and Wv/+ mice and suggests that the 'W' mutation is semi-dominant, both with respect to the white spotting and TE-CFU formation.

Anemia, Macrocytic↗

PubMed2006

The intraductal approach to the breast: raison d'être.

Opportunities for the detection, prediction, and treatment of breast cancer exist at three biological levels: systemically via the blood, at the whole organ level, and within the individual ductal lobular structures of the breast. This review covers the evaluation of approaches targeted to the ductal lobular units, where breast cancer begins. Studies to date suggest the presence of 5 to 12 independent ductal lobular systems per breast, each harboring complex cellular fluids contributed by local and systemic processes. New techniques for accessing and interrogating these systems offer the potential to gauge the microenvironment of the breast and distill biological risk profiles.

Breast Neoplasms↗

PubMed1992

Is the thymus a target organ in infectious diseases?

The thymus is a central lymphoid organ, in which T cell precursors differentiate and generate most of the so-called T cell repertoire. Along with a variety of acute infectious diseases, we and others determined important changes in both microenvironmental and lymphoid compartments of the organ. For example, one major and common feature observed in acute viral, bacterial and parasitic diseases, is a depletion of cortical thymocytes, mostly those bearing the CD4-CD8 double positive phenotype. This occurs simultaneously to the relative enrichment in medullary CD4 or CD8 single positive cells, expressing high densities of the CD3 complex. Additionally we noticed a variety of changes in the thymic microenvironment (and particularly its epithelial component), comprising abnormal location of thymic epithelial cell subsets as well has a denser Ia-bearing cellular network. Moreover, the extracellular matrix network was altered with an intralobular increase of basement membrane proteins that positively correlated with the degree of thymocyte death. Lastly, anti-thymic cell antibodies were detected in both human and animal models of infectious diseases, and in some of them a phenomenon of molecular mimicry could be evidenced. Taken together, the data reviewed herein clearly show that the thymus should be regarded as a target in infectious diseases.

Acquired Immunodeficiency Syndrome↗

PubMed1990

Modulation of respiration during brain hypoxia.

This review is a summary of the effects of brain hypoxia on respiration with a particular emphasis on those studies relevant to understanding the cellular basis of these effects. Special attention is given to mechanisms that may be responsible for the respiratory depression that appears to be the primary sequela of brain hypoxia in animal models. Although a variety of potential mechanisms for hypoxic respiratory depression are considered, emphasis is placed on changes in the neuromodulator constituency of the respiratory neuron microenvironment during hypoxia as the primary cause of this phenomenon. Hypoxia is accompanied by a net increase in neuronal inhibition due to both decreased excitatory and increased inhibitory neuromodulator levels. A survey of hypoxia-tolerant cellular systems and organisms suggests that hypoxic respiratory depression may be a manifestation of the depression of cellular metabolism, which appears to be a major adaptation to limited oxygen availability in these systems.

Animals↗

PubMed1995

Amino acid transport systems modulate human tumor cell growth and invasion: a working hypothesis.

Interactions between the extracellular matrix (ECM) and the neoplastic cells they envelop are thought to play a fundamental role in those cells' ability to invade, one of the key events in the metastatic cascade. Cellular transport of amino acids, in turn, is known to be mediated by functionally distinct membrane transport systems and is modulated by substrate bioavailability in the microenvironment. We postulate that certain advantages enjoyed by a neoplastic cell population over their normal counterparts (for example, increased proliferating capability and invasiveness across ECM barriers) are linked to changes in the cells' differential control of amino acid transport (aaT) via host ECM-tumor cell generated signals. Our studies suggest that active transport of neutral amino acids modulates a cells' functional behavior among phenotypically distinct human transformed cell types, irrespective of whether they are categorized as a sarcoma, melanoma, or carcinoma. We present preliminary laboratory evidence which has lead us to formulate a series of working hypotheses as follows: 1. aaT systems operating in both non-transformed and transformed human cells exhibit differential transport kinetics; 2. adaptive regulation of certain amino acids via cell-specific aaT systems alters a cell's ability to invade human ECM; and 3. aaT induction involves changes both at the cellular and molecular levels. This report, therefore, provides experimental support, and suggests a possible mechanism, to explain how neutral amino acids, acting as nutrient signalling factors (along with other biologic elements) within the cell milieu, have the capability of regulating the phenotypic nature of human neoplastic cells.

Amino Acid Transport Systems↗

PubMed2006

Glycolysis inhibition for anticancer treatment.

Most cancer cells exhibit increased glycolysis and use this metabolic pathway for generation of ATP as a main source of their energy supply. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental metabolic alterations during malignant transformation. In recent years, there are significant progresses in our understanding of the underlying mechanisms and the potential therapeutic implications. Biochemical and molecular studies suggest several possible mechanisms by which this metabolic alteration may evolve during cancer development. These mechanisms include mitochondrial defects and malfunction, adaptation to hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes. Importantly, the increased dependence of cancer cells on glycolytic pathway for ATP generation provides a biochemical basis for the design of therapeutic strategies to preferentially kill cancer cells by pharmacological inhibition of glycolysis. Several small molecules have emerged that exhibit promising anticancer activity in vitro and in vivo, as single agent or in combination with other therapeutic modalities. The glycolytic inhibitors are particularly effective against cancer cells with mitochondrial defects or under hypoxic conditions, which are frequently associated with cellular resistance to conventional anticancer drugs and radiation therapy. Because increased aerobic glycolysis is commonly seen in a wide spectrum of human cancers and hypoxia is present in most tumor microenvironment, development of novel glycolytic inhibitors as a new class of anticancer agents is likely to have broad therapeutic applications.

Antineoplastic Agents↗

PubMed1984

Generation of phenotypic diversity and progression in metastatic tumor cells.

The emergence of diversified tumor cell subpopulations in malignant neoplasms accounts for their heterogeneous cellular phenotypes and virtually ensures that some tumor cells will ultimately evolve with the most favorable properties for their enhanced abilities to survive, grow, invade and metastasize (tumor progression). The rates of cellular phenotypic diversification appear to vary greatly among different tumors and within the same tumor, and they are probably controlled, at least in part, by cellular instability due to chromosomal defects and random somatic mutational events, the rates of which are known to be higher in more malignant cells, and by epigenetic events, which may vary widely depending on the nature of the tumor cells and their microenvironments. As tumor progression proceeds, the most malignant cell subpopulations appear to lose their responsiveness to changes in tumor microenvironment while maintaining their high rates of phenotypic diversification. Tumor and normal cell-cell and cell-extracellular matrix interactions, as well as tumor cell nutrients, oxygen, hormones, growth factors, inducers and other regulatory molecules provide individual malignant cells with microenvironmental signals that could act through epigenetic cellular modifications, such as DNA methylation, and transcriptional, posttranscriptional, translational and posttranslational controls, or combinations of these. In addition, integration of viral gene sequences or viral modification of host DNA in critical regions could affect phenotypic stability. Finally, manipulation of tumor cells by antitumor therapy can also have profound effects on the rates of phenotypic diversification of the surviving tumor cells. A model for generating cellular phenotypic diversity based on the proposed mechanism for rapid generation of immunoglobulin molecular diversity in B cells may be applicable to malignant cells and to cells in general. In this model the expression and activity of gene products from multigene families are affected by a variety of genetic and epigenetic controlling mechanisms, and alterations in regulatory genes caused by recombination, methylation, mutation, or other changes could lead to differences in gene expression, resulting in widespread quantitative (and perhaps some qualitative) changes in particular gene products or their activities. As they proceed down different pathways of gene expression, each cell would be exposed to continual host selection pressures creating diverse, ever-changing malignant cell-populations.

Animals↗

PubMed2001

Regulatory potential of fever-range whole body hyperthermia on Langerhans cells and lymphocytes in an antigen-dependent cellular immune response.

The febrile response is one of the most common features of infection and inflammation. However, temperature is rarely a variable in experimental immunological investigations. To determine whether the thermal microenvironment has any immunoregulatory potential in an Ag-dependent response, we applied a mild fever-range whole body hyperthermia (FR-WBH) protocol to BALB/c mice experiencing the contact hypersensitivity (CHS) reaction. We observed that the timing of this FR-WBH treatment relative to the different phases of the CHS response was crucial to the outcome. FR-WBH treatment before sensitization with a 0.5% FITC solution resulted in a depressed CHS response. This appears to be due to direct effects of FR-WBH on epidermal Langerhans cell trafficking to the draining lymph nodes. In contrast, application of FR-WBH directly after application of the elicitation dose of FITC solution resulted in an enhanced reaction. This result correlates with increased homing of lymphocytes to the site of elicitation. Overall, these data have important implications regarding the role of thermal changes experienced during infection and the clinical use of FR-WBH relative to immunotherapeutic strategies.

Animals↗

PubMed2026

A serpin-myeloid axis in pancreatic cancer heterogeneity and immune evasion.

Pancreatic ductal carcinoma (PDAC) is characterized by a highly immunosuppressive, extracellular matrix-rich microenvironment, yet tumours display marked heterogeneity1-4. This raises the question of whether immune resistance is a global tumour property or is organized within spatially restricted niches. Here, using Perturb-map spatial functional genomics, we determine how different genes shape the growth and cellular environments of PDAC clones across space and time. This analysis revealed early gene-driven remodelling of local immune neighbourhoods preceding late-stage spatial clonal dominance. We identify SERPINE1 (encoding plasminogen activator inhibitor 1 (PAI1)) and SERPINB2 (encoding PAI2) as dominant regulators of tumour microenvironment control and immune evasion. These serpins promote stabilization of fibrin-rich extracellular matrix niches that spatially retain and programme macrophages towards immunosuppressive states while excluding cytotoxic T cells. Loss of Serpine1 or Serpinb2, or pharmacological inhibition of PAI1 or CD18, improves tumour control in mice and synergizes with anti-PD-1. Multimodal spatial analysis of patient tumours revealed that immunosuppressive niches form around rare SERPINB2- and SERPINE1-expressing PDAC subpopulations, dominated by SPP1+/MARCO+ macrophages. These findings identify cancer-derived SERPINE1 and SERPINB2 as local spatial organizers of immune suppression, linking tumour-intrinsic heterogeneity to local microenvironmental control and immunotherapy resistance in PDAC.

Journal Article↗

PubMed1988

The regulation and integration of thyroid follicular differentiation and function.

As in a number of other endocrine tissues in which expression of differentiated function is dependent upon a stable cellular architecture, the control of differentiation of the thyroid follicle requires a coordination between the ultrastructural and morphological responses to a number of endocrine growth factors, which may ultimately involve autocrine or paracrine-mediated effects within the immediate follicular microenvironment. Through analogy with other cell types, expression of appropriate differentiation characteristics within the thyroid follicle may involve the activation of specific c-oncogenes within each of the component cells. With the recent development and application of oncogene transfection technology, application of such procedures to the thyroid follicular cell should prove to be a particularly fruitful area for future research within the thyroid gland, leading to elucidation of the mechanisms whereby the cellular responses to growth and tissue-differentiating factors are mediated. Clearly however, further consideration must also be made of the roles played in maintaining follicular stability by both physical and chemical interactions between the component cells and the immediate extracellular environment. The contributory roles played by basement membrane and cell-surface components in cellular recognition, together with the physical effects imposed upon the apical surfaces of the follicle by luminal thyroglobulin have already been identified as fundamental factors in this respect. It is also readily apparent that morphological differentiation of the follicle bears critically upon the chemical characteristics of the microenvironment through the ability of the latter to promote expression of specific apical/basal recognition characteristics of the component cells, and thus maintain the unidirectional polarity upon which the functional capacity of the thyroid follicle is so critically-dependent.

Cell Differentiation↗

PubMed1994

Increase of basic fibroblast growth factor (bFGF, FGF-2) messenger RNA and protein following implantation of a microdialysis probe into rat hippocampus.

In vivo microdialysis is an established tool for sampling extracellular fluid compartments. However, microdialysis faces the problem that the implantation of the probe damages the microenvironment from which measurements are derived. In this study, we examined the expression of basic fibroblast growth factor mRNA and protein at the cellular level after implantation of a microdialysis probe into the dorsal hippocampus and found that 8 h after inserting the probe bFGF mRNA was markedly increased in a relatively large area centered around the probe, involving both the dorsal hippocampus and the overlying cerebral cortex, as revealed by radioactive in situ hybridization. Using nonradioactive in situ hybridization with digoxigenin-labelled riboprobes, combined with immunohistochemistry for glial fibrillary acidic protein we demonstrated that bFGF mRNA was exclusively increased in astrocytes at the probe insertion site. Using immunohistochemistry we also found that bFGF-like immunoreactivity was increased after implantation of the probe close to the lesion site, as shown by an increased number of bFGF immunoreactive nuclear glial profiles. These results provide evidence that the implantation of a microdialysis probe into the brain induces activation of bFGF gene expression in astrocytes associated with nuclear bFGF-like immunoreactivity. We conclude that lesion-induced effects have to be considered when evaluating microdialysis data, and that mechanical trauma to the brain will activate astroglial trophism, as seen from the increased density of astroglial profiles demonstrating bFGF mRNA and protein levels.

Animals↗

PubMed1991

Keynote address: the influence of microenvironmental factors on the activity of radiation and drugs.

The inherent radio- and chemosensitivity of tumor cells clearly affects their response to treatment. Accumulating evidence, however, suggests that the biochemical and physiological status of the cell during treatment is at least as important. In this review, a critique of the current evidence for, and extent of, microenvironmental heterogeneity in tumors is presented, emphasizing human tumor cells in situ. The expected consequences of those changes on cellular response to radiation and chemotherapy is then briefly reviewed. Finally, the continuing interest in developing new therapeutic strategies for which the tumor microenvironment is an asset (as opposed to a liability) is discussed in the context of the dynamic nature of tumors, and the complexity of adequately analyzing combination treatments.

Acid-Base Equilibrium↗

PubMed2026

Local gene editing of fibroblasts in tumors reveals a new cancer-associated fibroblast state.

Fibroblasts play critical roles in regulating cellular relationships during tissue homeostasis, immunity, and tumor biology at multiple sites. However, tools to perturb fibroblasts at just one site in vivo are limited, restricting our understanding of how these cellular relationships act locally. We optimized local gene editing of fibroblasts in mouse tumor models to investigate how fibroblast perturbations affect the tumor microenvironment (TME). By knocking out receptors Osmr, Tgfbr2, or Il1r1 on cancer-associated fibroblasts (CAFs), we uncover that TGFBR2 signaling loss induces the emergence of a new Col18a1hi CAF cell state that is associated with worse survival in pancreatic cancer patients. Combinatorial gene KOs in CAFs reveals a circuit where these Col18a1hi CAFs reshape the TME by recruiting Siglec-Fhi neutrophils via Cxcl5 expression, and where this Col18a1hi CAF cell state is dependent on TNFR1 and canonical Wnt signaling. Together, a fast, affordable, and modular engineering method is demonstrated, allowing discovery of modified fibroblast identities and local intercellular relationships in the TME.

Animals↗

PubMed2002

Rationale for the role of osteoclast-like cells in arterial calcification.

Atherosclerotic arteries frequently become calcified, and these calcium deposits are associated with a high risk of adverse clinical events. Descriptive studies suggest calcification is an organized and regulated process with many similarities to osteogenesis, yet the mechanism and its relationship to atherosclerosis remain largely unknown. In bone development and homeostasis, mineral deposition by osteoblasts and mineral resorption by osteoclasts are delicately balanced such that there is no overall gain or loss in bone mass. We hypothesize that there exists in arteries a mechanism that similarly balances mineral deposition with resorption. We propose that the cellular mediators of arterial mineral resorption are osteoclast-like cells (OLCs) derived from hematopoietic precursors of the mononuclear phagocytic lineage. In arterial microenvironments, mononuclear precursors are induced to differentiate toward OLCs by macrophage-colony stimulating factor and receptor activator of NF-kappaB ligand, both of which are necessary and sufficient for osteoclastogenesis and mineral resorption in bone. OLCs may participate in normal mineral homeostasis within the arterial wall or, alternatively, may be recruited to specific sites within developing plaque. Net calcium deposition occurs as a result of focal perturbation of the balance between the activity of osteoblast-like cells and OLCs. Our proposed mechanism thus views arterial mineral deposition not so much as an active pathological process, but as a localized failure of protective mechanisms that actively oppose mineral deposition within the disordered metabolic milieu of developing atherosclerotic plaque.

Animals↗

PubMed2005

Chlamydia pneumoniae infection enhances cellular proliferation and reduces steroid responsiveness of human peripheral blood mononuclear cells via a tumor necrosis factor-alpha-dependent pathway.

BACKGROUND: Although epidemiological studies have found an association between Chlamydia pneumoniae infection and severe asthma, the causality and underlying mechanism are largely unknown. We hypothesized that C. pneumoniae infection increases the proliferation and enhances the survival of immune and inflammatory cells, resulting in reduced responsiveness to corticosteroids and suggesting that the underlying mechanism is related to a TNF-alpha-dependent pathway. METHODS: Human peripheral blood mononuclear cells (PBMCs) were cultured in vitro in the presence or absence of C. pneumoniae infection. Responsiveness to corticosteroids was assayed by adding dexamethasone, and the underlying mechanism was investigated by treating cells with infliximab that is a chimeric anti-TNF-alpha monoclonal antibody. Cellular proliferation and apoptosis was assessed by thymidine uptake and counting apoptotic cells using flow cytometry. RESULTS: Cellular proliferation was significantly higher in C. pneumoniae-infected PBMCs than in uninfected PBMCs, which is more prominent in Th2-dominant microenvironment. The anti-proliferative and pro-apoptotic effect of corticosteroid were significantly reduced in C. pneumoniae-infected PBMCs compared with uninfected PBMCs. The proliferative effect of C. pneumoniae infection and the reduced response to corticosteroid were effectively reversed by blocking the TNF-alpha pathway at least partially. CONCLUSION: C. pneumoniae infection enhanced the proliferation and survival of immune and inflammatory cells, resulting in steroid resistance. The reversal of these phenomena by the TNF-alpha inhibitor suggests that TNF-alpha may play an important role in the induction of steroid dependence or resistance. A TNF-alpha inhibitor may therefore be a candidate agent for managing steroid-dependent or -resistant severe asthma.

Adrenal Cortex Hormones↗

PubMed2006

Stem cells and their niches.

A constellation of intrinsic and extrinsic cellular mechanisms regulates the balance of self-renewal and differentiation in all stem cells. Stem cells, their progeny, and elements of their microenvironment make up an anatomical structure that coordinates normal homeostatic production of functional mature cells. Here we discuss the stem cell niche concept, highlight recent progress, and identify important unanswered questions. We focus on three mammalian stem cell systems where large numbers of mature cells must be continuously produced throughout adult life: intestinal epithelium, epidermal structures, and bone marrow.

Animals↗

PubMed2005

Altered immunity accompanies disease progression in a mouse model of prostate dysplasia.

Increasing evidence suggests that altered immune function accompanies, and indeed may facilitate, cancer progression. In this study, we sought to determine the nature of, and cellular mechanisms underlying, changes in immune status during disease progression in a transgenic mouse model of prostate dysplasia. Immune cells in the tumor microenvironment, as well as in the secondary lymphoid tissues, displayed altered phenotypes. Although evidence of antitumor immunity was detected, there was a paradoxical decrease in the ability of T cells to proliferate in vitro at later stages of disease progression. Detailed analysis of the draining lumbar lymph nodes revealed an increased frequency and number of CD4(+)CD25(+) T cells and an enhanced production of inhibitory cytokines, which correlated with impaired T-cell function. Functional studies confirmed a role for CD4(+)CD25(+) regulatory T cells in suppressing T-cell proliferation as well as regulating the growth of transplanted prostate tumor cells. In addition, our studies show for the first time that anti-CD25 antibody treatment reduces, but does not prevent, tumor growth in a transgenic mouse model of prostate dysplasia. Taken together, this work provides compelling evidence that prostate tumor progression is accompanied by altered immune function and, moreover, that regulatory T cells play an important role in this process. These studies thus provide the impetus for development of specific and effective strategies to deplete regulatory T cells, or suppress their function, as an alternative or adjunct strategy for reducing tumor growth.

Animals↗

PubMed2006

The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha.

The function of the hypoxia-inducible factor-1 (HIF-1), the key transcription factor involved in cellular adaptation to hypoxia, is restricted to low oxygen tension (pO(2)). As such, this transcription factor is central in modulating the tumor microenvironment, sensing nutrient availability, and controlling anaerobic glycolysis, intracellular pH, and cell survival. Degradation and inhibition of the limiting HIF-1alpha subunit are intimately connected in normoxia. Hydroxylation of two proline residues by prolyl hydroxylase domain (PHD) 2 protein earmarks the protein for degradation, whereas hydroxylation of an asparagine residue by factor-inhibiting HIF-1 (FIH-1 or FIH) reduces its transcriptional activity. Indeed, silencing of either PHD2 or FIH in normoxia partially induced hypoxic genes, whereas combined PHD2/FIH silencing generated a full hypoxic gene response. Given the fact that HIF-1alpha possesses two transcriptional activation domains [TAD; NH(2)-terminal (N-TAD) and COOH-terminal (C-TAD)], we hypothesized on a possible bifunctional activity of HIF-1alpha that could be discriminated by FIH, an inhibitor of the C-TAD. In human cell lines engineered to overexpress or silence FIH in response to tetracycline, we show by quantitative reverse transcription-PCR that a set of hypoxic genes (ca9, phd3, pgk1, and bnip3) respond differently toward FIH expression. This finding, extended to 26 hypoxia-induced genes, indicates differential gene expression by the N-TAD and C-TAD in response to the hypoxic gradient. We propose that the oxygen-sensitive attenuator FIH, together with two distinct TADs, is central in setting the gene expression repertoire dictated by the cell pO(2).

Adenocarcinoma↗