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PubMed2026

Methylation profiling of normal tissue adjacent to breast tumors reveals two distinct groups with divergent tumor microenvironment features.

We previously identified diverse genetic evolutionary patterns in whole-genome sequencing of paired normal tissue adjacent to tumor (NAT) and tumor tissues from Hong Kong breast cancer (HKBC) patients. Here, we investigated whether DNA methylation (DNAm) contributes to NAT heterogeneity and shapes the tumor microenvironment (TME). Genome-wide DNAm profiling was performed on paired NAT and tumor tissues from 188 HKBC patients using the Infinium 850 K array. RNA-seq data were available for 76 NATs and 177 tumors. Cellular composition was inferred using MethylCIBERSORT, CIBERSORTx, and EpiDISH, and histopathologic features were assessed on 115 H&E-stained sections. Unsupervised clustering identified two distinct NAT subtypes with divergent TME characteristics. Cluster 1 (N = 139) showed higher epithelial and fibroblast content and enrichment of estrogen response pathways. Cluster 2 (N = 49) exhibited an immune-metabolic phenotype characterized by increased fat and immune cells, stromal disruption, inflammatory pathway activation, and greater macrophage infiltration. Cluster 2 patients also demonstrated significantly younger epigenetic age estimated using multiple epigenetic clocks. These DNAm-defined NAT subtypes and associated TME features were validated in 97 NAT samples from TCGA breast cancer patients. Overall, our findings identify DNAm-driven NAT heterogeneity with distinct TME landscapes, providing new insights into field cancerization and tumor evolution in breast cancer.

Journal Article↗
PubMed1995

The relevance of cell microenvironments for the appearance of lympho-haemopoietic tissues in primitive vertebrates.

In higher vertebrates, mainly in mammals, a role for the non-lymphoid components of lymphoid organs in governing the maturation and functioning of immune system has been largely demonstrated. In contrast, such a role in the evolution of the vertebrate immune system has only been evidenced indirectly. In the present review we summarize histophysiological results which emphasize the relevance of lympho-haemopoietic stromal elements in the emergence and evolution of vertebrate lymphoid organs. The most primitive vertebrates, the Agnatha, have no true lymphoid organs and, accordingly, their immune responses seem more related to the non-anticipatory defence mechanisms of invertebrates than to the immune responses of vertebrates. So, the appearance and evolution of vertebrate lymphoid organs seems closely related with the emergence of immune capacities. Thymus, spleen and gut-associated lymphoid organs appear early in phylogeny whereas lymph nodes and bone marrow are late phylogenetical adquisitions. However, bone marrowless vertebrates contain numerous organs (i.e., gonads, kidney, brain, etc...), the cell microenvironments of which support lympho-haemopoiesis mimicking the condition of higher vertebrate bone marrow. On the other hand, the lack of germinal centres, another feature of the lymphoid organs of ectothermic vertebrates which impedes the selection of B cells raised after somatic hypermutation, presumably reflects the absence of some of the elements necessary for this organization.

Animals↗
PubMed2004

Tissue regeneration patterns in acellular bovine pericardia implanted in a canine model as a vascular patch.

It was noted in our previous study that acellular tissues can provide a natural microenvironment for host cell migration and proliferation to accelerate tissue regeneration. The purpose of this study was to further investigate the tissue regeneration patterns in acellular bovine pericardia fixed with glutaraldehyde or genipin as a biological patch to repair a defect in the pulmonary trunk in a canine model. The implanted samples were retrieved at distinct durations postoperatively. The structural remodeling of retrieved samples was then examined. It was found that the degree of inflammatory reaction observed for the genipin-fixed acellular patch was significantly less than its glutaraldehyde-fixed counterpart. At 1 month postoperatively, intimal thickening was found on the inner surfaces of both studied groups. The intimal thickening observed on the glutaraldehyde-fixed acellular patch was significantly thicker than its genipin-fixed counterpart. An intact layer of endothelial cells was found on the intimal thickening of the genipin-fixed acellular patch, whereas endothelial cells did not universally and totally cover the entire surface of the glutaraldehyde-fixed acellular patch. Additionally, fibroblasts with neocollagen fibrils and myofibroblasts were observed in the acellular patches for both studied groups, an indication of tissue regeneration. This phenomenon was more prominent for the genipin-fixed acellular patch than its glutaraldehyde-fixed counterpart. At 6 months postoperatively, foci of chondroid and/or bony metaplasia were found in each retrieved sample for both studied groups. The observed adverse response of chondroid metaplasia may be attributed to a compliance mismatch at the implanted site of the canine pulmonary trunk after implantation or a lack of angiogenesis in the regenerated tissue observed at 1 month postoperatively. Bony metaplasia may then develop as in other chondroid tissues. It was reported that ischemia is a usual cause of metaplasia.

Animals↗
PubMed1990

Tissue inhibitor of metalloproteinases from human bone marrow stromal cell line KM 102 has erythroid-potentiating activity, suggesting its possibly bifunctional role in the hematopoietic microenvironment.

In this study, we demonstrated that tissue inhibitor of metalloproteinases (TIMP) produced by human bone marrow stromal cell line KM-102 had erythroid-potentiating activity (EPA) which stimulates the proliferation of erythroid progenitor cells. We, then, propose a scheme for the bifunctional role of TIMP/EPA in hematopoietic microenvironment, that is, the maintenance of the integrity of bone marrow matrix and the proliferation of erythroid progenitor cells proceeding on the matrix.

Bone Marrow↗
PubMed1991

Ultrastructure of bone marrow tissue in so-called primary (idiopathic) myelofibrosis-osteomyelosclerosis (agnogenic myeloid metaplasia). II. The myeloid stroma (hematopoietic microenvironment).

An ultrastructural study was performed on bone marrow tissue in 8 patients revealing early and late stages of so-called primary (idiopathic) myelofibrosis - osteomyelosclerosis (agnogenic myeloid metaplasia) to evaluate the constituents of the hematopoietic microenvironment (myeloid stroma). A survey of the stroma cells disclosed an overall increase, particularly in so-called undifferentiated (primitive - pluripotent), but also in transitional (fibroblastic) reticular cells and myofibroblasts. The most primitive reticular cells were characterized by their stellate aspect with elongated slender cytoplasmic processes traversing the interstitial space, and by the scarcity of organelles. The transition into a fibroblast was preceded by the appearance of branching cisternal structures of the rough endoplasmic reticulum, extensively developed Golgi fields and an abundance in mitochondria. Frequently, so-called myofibroblasts were encountered displaying bundles of filaments along the subplasmalemmal region. Extracellularly fibrillar material with an irregular cross-banding as well as microfibrils could be observed. The many vascular structures (sinusoids and capillaries) exhibited a multilayered basement membrane-like material including many fibrils and adventitial cells (pericytes, smooth muscle and transitional reticular cells) with numerous cytoplasmic processes. Undifferentiated and transitional reticular cells as well as myofibroblasts seem to form an integral part of the hematopoietic microenvironment in OMF and are assumed to play an important role for the evolution of the disease-specific myelofibrosis in this disorder.

Bone Marrow↗
PubMed2001

Tissue engineering strategies for adipose tissue repair.

Tissue engineering is a relatively young field that combines engineering, clinical science, and life sciences to, in part, repair or regrow tissues. Adipose tissue has recently become a focus area for tissue engineering, encouraged by the large number of reconstructive, cosmetic, and correctional indications that could be addressed with clinically translatable adipose tissue engineering strategies. This review discusses the three aspects of an adipose construct, namely cell types, scaffold, and microenvironment, and presents current tissue engineering strategies under pursuit.

Adipose Tissue↗
PubMedDate not supplied

[Biological foundations for neurotransplantation].

A review of the mechanisms underlying cytogenesis and of the nervous tissues, the role of microenvironment, cell interactions in differentiation, and plastic rearrangements in the mammalian brain after transplantation of the embryonic nervous tissue. A common concept has been proposed, which unites biological processes involved in neurotransplantation and may serve as a theoretical base for the formation of ideas on pathways of differentiation of the nervous tissue, stimulation of compensatory processes and regeneration in the developing and pathological brain.

Animals↗
PubMed2006

Hypoxia imaging-directed radiation treatment planning.

Increasing evidence supports the role of the tumor microenvironment in modulating cancer behavior. Tissue hypoxia, an important and common condition affecting the tumor microenvironment, is well established as a resistance factor in radiotherapy. Increasing evidence points to the ability of hypoxia to induce the expression of gene products, which confer aggressive tumor behavior and promote broad resistance to therapy. These factors suggest that determining the presence or absence of tumor hypoxia is important in planning cancer therapy. Recent advances in PET hypoxia imaging, conformal radiotherapy, and imaging-directed radiotherapy treatment planning now make it possible to perform hypoxia-directed radiotherapy. We review the biological aspects of tumor hypoxia and PET imaging approaches for measuring tumor hypoxia, along with methods for conformal radiotherapy and image-guided treatment, all of which provide the underpinnings for hypoxia-directed therapy. As a case example, we review emerging data on PET imaging of hypoxia to direct radiotherapy.

Head and Neck Neoplasms↗
PubMed1989

Acid pH in tumors and its potential for therapeutic exploitation.

Measurement of pH in tissue has shown that the microenvironment in tumors is generally more acidic than in normal tissues. Major mechanisms which lead to tumor acidity probably include the production of lactic acid and hydrolysis of ATP in hypoxic regions of tumors. Further reduction in pH may be achieved in some tumors by administration of glucose (+/- insulin) and by drugs such as hydralazine which modify the relative blood flow to tumors and normal tissues. Cells have evolved mechanisms for regulating their intracellular pH. The amiloride-sensitive Na+/H+ antiport and the DIDS-sensitive Na+-dependent HCO3-/Cl- exchanger appear to be the major mechanisms for regulating pHi under conditions of acid loading, although additional mechanisms may contribute to acid extrusion. Mitogen-induced initiation of proliferation in some cells is preceded by cytoplasmic alkalinization, usually triggered by stimulation of Na+/H+ exchange; proliferation of other cells can be induced without prior alkalinization. Mutant cells which lack Na+/H+ exchange activity have reduced or absent ability to generate solid tumors; a plausible explanation is the failure of such mutant cells to withstand acidic conditions that are generated during tumor growth. Studies in tissue culture have demonstrated that the combination of hypoxia and acid pHe is toxic to mammalian cells, whereas short exposures to either factor alone are not very toxic. This interaction may contribute to cell death and necrosis in solid tumors. Acidic pH may influence the outcome of tumor therapy. There are rather small effects of pHe on the response of cells to ionizing radiation but acute exposure to acid pHe causes a marked increase in response to hyperthermia; this effect is decreased in cells that are adapted to low pHe. Acidity may have varying effects on the response of cells to conventional anticancer drugs. Ionophores such as nigericin or CCCP cause acid loading of cells in culture and are toxic only at low pHc; this toxicity is enhanced by agents such as amiloride or DIDS which impair mechanisms involved in regulation of pHi. It is suggested that acid conditions in tumors might allow the development of new and relatively specific types of therapy which are directed against mechanisms which regulate pHi under acid conditions.

Animals↗
PubMed2001

HIV-1 actively replicates in naive CD4(+) T cells residing within human lymphoid tissues.

Although HIV-1 gene expression is detected in naive, resting T cells in vivo, such cells are resistant to productive infection in vitro. However, we found that the endogenous microenvironment of human lymphoid tissues supports de novo infection and depletion of this population. Cell cycle analysis and DNA labeling experiments established that these cells were definitively quiescent and thus infected de novo. Quantitation of the "burst size" within naive cells further demonstrated that these cells were productively infected and contributed to the local viral burden. These findings demonstrate that lymphoid tissues support active HIV-1 replication in resting, naive T cells. Moreover, these cells are not solely reservoirs of latent virus but are permissive hosts for viral replication that likely targets them for elimination.

CD4-Positive T-Lymphocytes↗
PubMed2004

Functional plasticity of macrophages: reversible adaptation to changing microenvironments.

There has been substantial research activity in the past decade directed at phenotyping macrophage lineages and defining macrophage functional subsets or patterns of activity. The emphasis over the past 2-3 years has been to divide macrophage functional patterns into type 1 (Th1-driven) or type 2 (Th2-driven) functions. However, a huge array of environmental factors (including cytokines, chemokines, pattern recognition receptors, hormones) differentially regulates macrophage response patterns, resulting in the display of numerous distinct, functional phenotypes. Upon stimulation, a macrophage does not display just a single set of functions but rather displays a progression of functional changes in response to the progressive changes in its microenvironment. The remarkable ability of monocytes and tissue macrophages to adapt to changes in their microenvironment challenges the thesis that macrophages displaying unique tissue-specific or response-specific, functional patterns represent distinct lineages. With the exception of mature osteoclasts and mature dendritic cells, evidence supporting stable differentiation as the basis for macrophage functional heterogeneity is equivocal. The concept of whether macrophages develop into functional subsets as opposed to continuously adapting their functional pattern in response to the changing environment of a progressive inflammatory response is important to resolve from the perspectives of therapeutic targeting and understanding the role of macrophages in disease pathogenesis.

Adaptation, Physiological↗
PubMed1999

Chemokines: signal lamps for trafficking of T and B cells for development and effector function.

Chemokines can act as signal lamps for trafficking of lymphocytes at the important crossing points of lymphoid tissues. Lymphoid progenitors at different differentiation stages are differentially localized in primary lymphoid tissues and have differential responsiveness to thymic or bone marrow chemokines: SDF-1, CKbeta-11/MIP-3beta/ELC, SLC/6Ckine/Exodus2, MIP-1beta, and TECK. Naive T cells and B cells circulate to secondary lymphoid tissues for possible activation. Chemokines, SDF-1, SLC/6Ckine/Exodus2, CKbeta-11/MIP-3beta/ELC, BLC/BCA-1, and DC-CK1/PARC, are expressed in the specialized microenvironments of secondary lymphoid tissues and regulate the migration of naive lymphocytes. Effector lymphocytes express a different set of chemokine receptors from naive lymphocytes. T helper (Th) 0 and 1 cells predominantly express CXCR3 and CCR5, whereas Th2 cells express CCR3, CCR4, and CCR8, which, with other factors such as expression patterns of adhesion molecules, likely determine the tissue-specific infiltration of effector lymphocytes.

Animals↗
PubMed1998

Extracellular matrix signaling: integration of form and function in normal and malignant cells.

A growing number of studies have established reciprocal linkages between extracellular matrix (ECM)-integrins, growth factor signaling and cell-cell adhesion molecules. ECM-dependent tissue-specific gene expression has also been linked to chromatin remodeling. With respect to tissue morphogenesis and differentiation, crosstalk has been established between the ECM and the homeobox morphoregulatory genes. Each of these linkages is profoundly influenced by the cell's microenvironment and the resulting tissue form. Thus for a cell to achieve a differentiated phenotype, the ECM molecules and their receptors must integrate both form and function. In contrast, mutated genes and aberrant interactions with the microenvironment conspire to undermine this integration, often resulting in malignant transformation.

Cell Differentiation↗
PubMed2006

Chronic inflammation and pathogenesis of GI and pancreatic cancers.

The pathogenesis of cancer represents a complex and multifactorial process requiring a number of acquired and genetic defects. It is becoming increasingly apparent that many cancers originate from a chronic inflammatory process. The topic of this review is the inflammatory response and development of gastrointestinal (GI) and pancreatic cancers. Here, we describe the development of various gastric colorectal and pancreatic cancers through an inflammatory process. The tumor microenvironment which predisposes to tissue destruction, subsequent attempts at healing and accumulation of cellular damage with loss of cell cycle control mechanisms is discussed. Components of the tumor microenvironment that are important in the final common pathway leading to cancer include the tumor stroma, tumor-associated macrophages, cytokines and chemokines and reactive oxygen and nitrogen species. Common signaling pathways that link inflammation with cancer are described and include the COX-2, NF-kappaB and phosphatidyl inositol 3-kinase (PI3K) pathways. Finally, therapies that can be directed to the inflammatory process as either treatment or prevention of these cancers will be discussed including novel inhibitors of signaling pathways which are currently in development.

Anti-Inflammatory Agents↗
PubMedDate not supplied

Lipid mediator networks and leukocyte transmigration.

In intact tissues, vascular endothelial cells lie anatomically positioned as the central coordinator of inflammation. Endothelia communicate with underlying cells (e.g. smooth muscle, fibroblasts, epithelia) in ways that both coordinate leukocyte trafficking, and control the composition of the inflammatory microenvironment. Such coordination occurs through both direct communication (e.g. cell adhesion) as well as via soluble mediators liberated at sites of inflammation (e.g. chemokines, cytokines, lipids). Locally generated mediators bind to surface receptors, and mediate both physiologic and pathophysiologic functional responses. Important in this regard, both endothelial and subendothelial cell populations express enzymes capable of utilizing arachidonic acid substrates to generate bioactive lipid mediators (e.g. lipoxygenases, cyclooxygenases). Such lipid mediators can signal via autocrine or paracrine pathways and, depending on the tissue microenvironment, can convey a pro- or anti-inflammatory message. This review will highlight recent studies characterizing inflammatory responses to lipid mediators liberated at sites of inflammation, with a particular emphasis on neutrophil (polymorphonuclear leukocyte or PMN) trafficking.

Cyclooxygenase 2↗
PubMed1995

Gamma irradiation of the fetus damages the developing hemopoietic microenvironment rather than the hemopoietic progenitor cells.

Hemopoiesis is the product of two components: the hemopoietic tissue and the regulatory stromal microenvironment in which it resides. Plutonium-239, incorporated during fetal development, is known to cause deficient hemopoiesis. A predetermined equivalent gamma-ray dose has now been used in combination with cross-transplantation experiments to separate these two components and define where the damage arises. It was confirmed that 1.8 Gy gamma irradiation at midterm gestation caused a 40% reduction in the hemopoietic stem (spleen colony-forming) cell population of their offspring which persisted to at least 24 weeks of age. Spleen colony formation after sublethal doses of gamma rays reflected this reduced complement of endogenous stem cells. The regulatory hemopoietic microenvironment, measured as fibroblastoid colony-forming cells, was similarly depleted. Normal growth of the CFU-S population after transplantation into standard recipients showed that the quality of the stem cell population in the offspring of irradiated mothers was not affected. By contrast, when used as recipients of a bone marrow transplant from either normal or irradiated offspring, the offspring of irradiated mothers were unable to support normal growth: there was a twofold difference in the number of CFU-S per femur for at least 100 days after transplantation. There were 70% fewer CFU-F in the femur 1 month after bone marrow transplantation when the offspring of irradiated mothers were used as transplant recipients compared to when normal offspring were used. This not only confirmed their reduced capacity to host normal stem cells but also indicated that CFU-F in the transplant were unable to compensate for the poor microenvironment in the irradiated offspring hosts. It is concluded that irradiation at midterm gestation damages the developing regulatory microenvironment but not the hemopoietic stem cell population that it hosts.

Animals↗