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PubMed2004

Incorporating pathologists' criteria of malignancy into the evolutionary model for cancer development.

A wide variety of alterations in cell and tissue structure still form the basis for cancer diagnosis by pathologists. Cancer development is recognized to be an evolutionary process [Foulds, 1954; Cairns, 1975; Nowell, 1976; Sager, 1982; Tomlinson et al., 1996; Cahill et al., 1999; Tomlinson and Bodmer, 1999], but the phenotypic changes diagnostic of cancer (pathologists' "criteria of malignancy") have not been integrated into the existing evolutionary framework. Since phenotypic changes bear an important relationship to the genetic and physiologic changes underlying Darwinian evolution, we propose that diagnostic structural alterations also bear an important and predictable relation to both the cancer genes and the functional alterations active at any particular step in the development of a cancer. Cancer genes are predicted to mediate the acquisition of cellular-level diagnostic criteria and the diagnostic cellular-level structural changes should reflect in a useful manner the altered cell physiology required for the cell to achieve increased "cellular fitness" at any particular step of colonal evolution. Tissue-level criteria of malignancy should relate less directly to specific cancer genes, but tissue-level criteria should still provide essential insight into the interplay of the altered cellular fitness with the constraints imposed by the cells' microenvironment. The evolutionary framework allows tissue-level criteria of malignancy to be expressed in terms of viable hypotheses for the mechanism of clonal expansion at any particular step in cancer development. This approach to conveying the tissue-level criteria of malignancy complements pattern recognition approaches to diagnosis, and establishes common ground between pathology and cell biology. When viewed from this perspective, the functions of cancer genes appear quite different from those predicted by the "Gatekeeper, Caretaker" or "Hallmarks of Cancer" models. Finally, a full evolutionary framework incorporating the criteria of malignancy restores congruity between the histogenetic classification and the emerging molecular classification of cancer.

Cell Transformation, Neoplastic↗
PubMed2006

TIMP-3 deficiency in the host, but not in the tumor, enhances tumor growth and angiogenesis.

Tumor cells, stromal cell compartment and the extracellular matrix (ECM) together generate a multifaceted tumor microenvironment. Matrix metalloproteinases and their tissue inhibitors (TIMPs) provide a means for tumor-stromal interaction during tumorigenesis. Among TIMPs, TIMP-3 is uniquely localized to the ECM and is frequently silenced in human cancers. Here, we asked whether the absence of TIMP-3 in the tumor cell or the host affects the process of tumorigenesis. Timp-3(-/-) ES-cell clones were generated and used to develop teratomas in nude mice. Timp-3(-/-) teratomas showed similar tumor take, growth, and angiogenesis compared to timp-3(+/+) teratomas. To study the effect of TIMP-3 ablation in the host stroma, we measured the growth kinetics of subcutaneous B16F10 melanomas in timp-3(-/-) and wild-type littermates. Tumors grew significantly faster in timp-3(-/-) than in wild-type mice and their CD31 content was significantly higher indicating increased angiogenesis. Augmented angiogenesis in timp-3(-/-) mice was directly tested using Matrigel plug and Gelfoam assays. In response to FGF-2, timp-3(-/-) endothelial cells invaded more efficiently, leading to enhanced formation of functional blood vessels. Thus, TIMP-3 deficiency in the host, but not in the tumor per se, leads to enhanced tumor growth and angiogenesis. TIMP-3 located within the tumor microenvironment inhibits tumorigenesis.

Animals↗
PubMed2004

Two-photon analysis of calcium signals in T lymphocytes of intact lamina propria from human intestine.

Lamina propria (LP) T cells of the human intestinal mucosa usually do not develop systemic immune responses despite permanent exposure to foreign antigens. The mechanisms maintaining this hyporeactivity in the normal gut are poorly understood. It is, at present, not clear what role the microenvironment of the mucosa plays for low T cell reactivity and in the pathogenesis of mucosal inflammation. Despite the importance of cytosolic Ca(2+) signals for T lymphocyte activation, intracellular Ca(2+) concentration measurements have so far only been performed in dissociated T cells, following disruption of the microenvironment. We used two-photon technology to measure Ca(2+) signals in identified T lymphocytes within the intact mucosa to minimize impact on tissue integrity while preserving the cellular microenvironment. We show that Ca(2+) signals in LP T cells correlate with the hyporeactivity of T cells in the intestinal immune system and furthermore link Ca(2+) signals with inflammatory bowel disease. Our data implicate that Ca(2+) signals in LP T cells do not depend on the microenvironment of the intact mucosa, since they are very similar to Ca(2+) signals in dissociated LP T cells.

Calcium↗
PubMed2005

Cell and tissue responses to genotoxic stress.

Cancers arise as a consequence of the accumulation of multiple genetic mutations in a susceptible cell, resulting in perturbation of regulatory networks that control proliferation, survival, and cellular function. Here, the sources of cellular stress that can cause oncogenic mutations and the responses of cells to DNA damage are reviewed. The role of different repair pathways and the potential for cell- and tissue-specific reliance on individual repair mechanisms are discussed. Evidence for cell- and tissue-specific activation of p53-mediated growth arrest and apoptosis after exposure to an individual genotoxin is assessed and some of the potential mediators of these different responses are provided. These cell- and tissue-specific responses to particular forms of DNA damage are likely to be key determinants of tissue-specific tumour susceptibility, and there is good evidence for genetic variations in these responses. The role that genotoxic agents play in altering the microenvironment to produce indirect effects on tumourigenesis through altered production of free radicals and cytokines that are characteristic of inflammatory-type processes is also evaluated. Changes to the microenvironment as direct or indirect effects of genotoxic stress can be involved in both tumour initiation and progression and may even be a prerequisite for tumourigenesis. Therefore, tumour susceptibility after endogenous or exogenous genotoxic stress represents a balance between cell-intrinsic responses of target cells and changes to the microenvironment. A fuller understanding of cell- and tissue-specific responses, alterations to the microenvironment, and genetic modifiers of these responses could lead to novel prevention and therapeutic strategies for common forms of human malignancy.

Animals↗
PubMed1993

Microenvironment changes in human blood platelet membranes associated with binding of tissue-type plasminogen activator.

Whole washed platelets were labelled with the free radicals [2-(14-carboxytetradecyl)-2-ethyl-4,4-dimethyl-3-oxazolidinylox y] (16-DOXYL-Ste) or [2-(3-carboxypropyl)-4,4-dimethyl-2-tridecyl-3- oxazolidinyloxy] (5-DOXYL-Ste) and incubated with recombinant tissue-type plasminogen activator (rt-PA). Changes in the membrane fluidity caused by rt-PA were detected by alterations in h+1/h0 calculated from the ESR spectra for 16-DOXYL-Ste and 5-DOXYL-Ste incorporated into the lipid bilayer (h+1 and h0 are the heights of the low-field and middle-field lines of the spectra, respectively). Interaction of rt-PA with both resting and stimulated platelets resulted in increased rigidity of the membrane lipid bilayer as indicated by the reduced value of h+1/h0. This phenomenon can be explained either by conformational changes of membrane receptors caused by the attachment of rt-PA and the subsequent rearrangement of the lipid matrix of platelet membranes, or by the direct association of rt-PA with membrane phospholipids and thus partial embedding of protein molecules into the lipid bilayer restraining lipid mobility.

Blood Platelets↗
PubMedDate not supplied

Mechanism of action of PROMOGRAN, a protease modulating matrix, for the treatment of diabetic foot ulcers.

Proteases play a critical role in many of the physiologic processes of wound repair. However, if their activity becomes uncontrolled proteases can mediate devastating tissue damage and consequently they have been implicated in chronic wound pathophysiology. Previous studies have shown that chronic wound fluid contains elevated protease levels that have deleterious effects, degrading de novo granulation tissue and endogenous biologically active proteins such as growth factors and cytokines. Therefore, we have proposed that an effective therapeutic approach for chronic wounds would be to modify this hostile environment and redress this proteolytic imbalance. Using an ex vivo wound fluid model, we show the ability of a proprietary new wound treatment to bind and inactivate proteases. We have shown that the addition of this test material to human chronic wound fluid obtained from diabetic foot ulcer patients resulted in a significant reduction in the activities of neutrophil-derived elastase, plasmin, and matrix metalloproteinase when compared to wet gauze. This study provides mechanistic evidence to support the hypothesis that this novel treatment modality for chronic wounds physically modifies the wound microenvironment, and thereby promotes granulation tissue formation and stimulates wound repair.

Adult↗
PubMed1996

Extraosseous primary and recurrent giant cell tumors: transforming growth factor-beta1 and -beta2 expression may explain metaplastic bone formation.

Giant cell tumor (GCT) of bone is a locally aggressive neoplasm with a high incidence of recurrence, usually at the site of previous osseous involvement. Primary and recurrent intraosseous lesions typically are lytic and do not show evidence of tumor-associated osteogenesis. Rarely, GCT recurs or is primary within soft tissue, and not infrequently, these extraosseous lesions show metaplastic bone formation that is visible radiographically. The authors report two recurrent and one primary case of extraosseous GCT, all of which exhibited significant deposits of metaplastic bone localized to the periphery of the lesions. In situ hybridization showed messenger RNA (mRNA) for transforming growth factor beta1 (TGF-beta1) and transforming growth factor beta2 (TGF-beta2) in neoplastic stromal cells and osteoclast-like giant cells within the recurrent and primary extraosseous tumors as well as in active osteoblasts on the surfaces of recently formed spicules of metaplastic bone. In situ hybridization also revealed mRNA for TGF-beta1 and TGF-beta2 in primary intraosseous tumors from these cases and from four cases in which neither extraosseous recurrence nor osseous metaplasia was identified. In the microenvironment of the extraosseous soft tissue, production of these osteoinductive growth factors by GCT may have a paracrine effect on mesenchymal progenitor cells, thereby stimulating the osteoblastic differentiation and metaplastic bone formation associated with these lesions.

Adult↗
PubMed1999

Alterations in proteolytic activity at low pH and its association with invasion: a theoretical model.

The extracellular pH (pHe) of solid tumours is often lower than in normal tissues, with median pH values of about 7.0 in tumours and 7.5 in normal tissue. Despite this more acidic tumour microenvironment, non-invasive measurements of intracellular pH (pHi) have shown that the pHi of solid tumours is neutral or slightly alkaline compared to normal tissue (pHi 7.0-7.4). This gives rise to a reversed cellular pH gradient between tumours and normal tissue, which has been implicated in many aspects of tumour progression. One such area is tumour invasion: the incubation of tumour cells at low pH has been shown to induce more aggressive invasive behaviour in vitro. In this paper the authors use mathematical models to investigate whether altered proteolytic activity at low pH is responsible for the stimulation of a more metastatic phenotype. The authors examined the effect of culture pH on the secretion and activity of two different classes of proteinases: the metalloproteinases (MMPs), and the cysteine proteinases (such as cathepsin B). The modelling suggests that changes in MMP activity at low pH do not have significant effects on invasive behaviour. However, the model predicts that the levels of active-cathepsin B are significantly altered by acidic pH. This result suggests a critical role for the cysteine proteinases in tumour progression.

Cell Movement↗
PubMedDate not supplied

Regeneration in the ears of immunodeficient mice: identification and lineage analysis of mesenchymal stem cells.

Wound healing in the ears of Athymic Nude-nu mice resembles regeneration. Histological analysis of the ear-punched tissues revealed the initial formation of a blastema-like structure followed by dermal, vascular, cartilage, and muscle regrowth exclusively in Athymic Nude-nu mice but not in wild-type controls (C57BL/6J). A subset of stem cells referred to here as ear mesenchymal stem cells (EMSCs) has been isolated from the external ears of regenerative (Athymic Nude-nu) and nonregenerative strains of mice. Morphological, histochemical, and molecular analysis after the induction of EMSC differentiation revealed multiple mesenchymal cell lineages (adipocytes, chondrocytes, and osteocytes) in all murine strains independent of their ability for regeneration. Thus, the absence of regeneration in wounded ears of C57BL/6J wild-type mice is not related to the absence of mesenchymal stem cell differentiation in tissue culture. Because nude mice lack T lymphocytes, it appears that in this model the absence of T lymphocytes in the wounded ears provides a microenvironment conducive to regeneration of mesenchymal tissues. These findings provide a new model to study the influence of the immune system on tissue regeneration.

Animals↗
PubMed2002

A new organotypic culture of thyroid tissue maintains three-dimensional follicles with C cells for a long term.

Thyroid follicles embedded in extracellular matrix (ECM) seem to be supplied enough oxygen by a dense network of capillaries in vivo. Air exposure (AE) causes cells to increase oxygen availability in vitro. We speculated that three-dimensional (3D) environment of ECM together with AE may be applied to a thyroid tissue-organotypic culture, simply simulating such a microenvironment of follicles. To address the issue, we performed 3D collagen gel culture of minced thyroid tissues with or without AE. Most follicles in the tissues without AE died within 7 days. In culture with AE, most of the follicles with calcitonin-positive C cells were kept for over one month. Immunohistochemistry showed that thyrocytes displayed thyroglobulin, thyrotropin receptor, thyroid transcription factor-1 (TTF-1), and pendrin, which are all crucial for thyroid function. C cells expressed calcitonin gene-related peptide and TTF-1. Our study is the first demonstration that 3D collagen gel culture with AE retains 3D thyroid follicles with C cells for a long term. This suggests that ECM and oxygen supply together may be crucial for maintenance of 3D follicle structure and function. Our method will possibly open a new path to the study of thyrocyte-C cell interaction and thyroid biology.

Adenosine Triphosphate↗
PubMed1997

Severe combined immunodeficiency mice engrafted with human T cells, B cells, and myeloid cells after transplantation with human fetal bone marrow or liver cells and implanted with human fetal thymus: a model for studying human gene therapy.

To develop an in vivo model wherein human hematopoiesis occurs, we transplanted severe combined immunodeficiency (SCID) mice with either human fetal bone marrow (HFBM) or human fetal liver (HFL). After transplantation of SCID mice with cultured HFBM (BM-SCID-hu mice) or HFL cells (Liv-SCID-hu mice), significant engraftment of the mouse bone marrow (BM) and population of the peripheral blood with human leukocytes was detected. Human colony-forming unit-granulocyte macrophage and burst forming unit-erythroid were detected in the BM of the BM-SCID-hu and Liv-SCID-hu mice up to 8 months after transplantation. When the HFBM or HFL cells were transduced with a retroviral vector before transplantation, integrated retroviral sequences were detected in human precursor cells present in the SCID mouse BM and in leukocytes circulating in the peripheral blood (PB) up to 7 months after transplantation. The PB of the BM-SCID-hu mice also became populated with human T cells after implantation with human thymic tissue, which provided a human microenvironment wherein human pre-T cells from the BM could mature. When the HFBM was retrovirally transduced before transplantation, integrated retrovirus was detected in sorted CD4+CD8+ double positive and CD4+ single positive cells from the thymic implant and CD4+ cells from the PB. Taken together, these data indicated that the BM of our BM-SCID-hu and Liv-SCID-hu mice became engrafted with retrovirally transduced human hematopoietic precursors that undergo the normal human hematopoietic program and populate the mouse PB with human cells containing integrated retroviral sequences. In addition to being a model for studying in vivo human hematopoiesis, these mice should also prove to be a useful model for investigating in vivo gene therapy using human stem/precursor cells.

Animals↗
PubMed1997

The human thymic microenvironment during organ culture.

Cultured human thymic tissue has been transplanted into many patients with T cell dysfunction; however, little is known about the effect of in vitro culture on thymic tissue. Human postnatal thymic organ cultures were established in vitro to study the growth potential of the thymic epithelium and the expression of intracellular and surface antigens with time in culture. Marked depletion of bone marrow-derived cells was observed within 3 weeks of initiation of organ cultures although some viable CD3+ cells could still be detected. Thymic epithelial cells in in vitro explants continued to express MHC class I and class II antigens as well as cytokeratins. Thymic epithelial cells within cultured thymic organ slices maintained their postnatal growth potential, in that cytokeratin-positive epithelial monolayers could be established in vitro from these thymic slices up to 12 weeks after initiation of organ culture. Thus, thymic explants remained viable in culture and could potentially be used to reconstitute immunity in T cell deficient patients.

Antibodies, Monoclonal↗
PubMed1999

Evidence that Langerhans cells in adult pulmonary Langerhans cell histiocytosis are mature dendritic cells: importance of the cytokine microenvironment.

Because Langerhans cells (LC) in peripheral tissues are generally "immature" cells with poor lymphostimulatory activity, the contribution of immune responses initiated by LC to the pathogenesis of pulmonary LC histiocytosis (LCH) has been uncertain. In this study we demonstrate that LC accumulating in LCH granulomas are phenotypically similar to mature lymphostimulatory dendritic cells present in lymphoid organs. LC in LCH granulomas intensely expressed B7-1 and B7-2 molecules, whereas normal pulmonary LC and LC accumulating in other pathologic lung disorders did not express these costimulatory molecules. The presence of B7+ LC in LCH granulomas was associated with the expression in these lesions, but not at other sites in the lung, of a unique profile of cytokines (presence of GM-CSF, TNF-alpha, and IL-1beta and the absence of IL-10) that is known to promote the in vitro differentiation of LC into cells expressing a lymphostimulatory phenotype. Finally, LCH granulomas were the only site where CD154-positive T cells could be identified in close contact with LC intensely expressing CD40 Ags. Taken together, these results strongly support the idea that an abnormal immune response initiated by LC may participate in the pathogenesis of pulmonary LCH, and suggest that therapeutic strategies aimed at modifying the lymphostimulatory phenotype of LC may be useful in the treatment of this disorder.

Adult↗
PubMed2005

Laser-layered microfabrication of spatially patterned functionalized tissue-engineering scaffolds.

Understanding cell behavior inside complex, three-dimensional (3D) microenvironments with controlled spatiotemporal patterning of physical and biochemical factors would provide significant insights into the basic biology of organ development and tissue functions. One of the fundamental limitations in studying such behavior has been the inability to create patterned microenvironments within 3D scaffold structures. Here a simple, layer-by-layer stereolithography (SL) method that can precisely pattern ligands, extracellular-matrix (ECM) components, and growth factors, as well as controlled release particles inside a single scaffold, has been developed. The process also allows fabrication of predesigned internal architectures and porosities. Photocrosslinkable poly(ethylene glycol) dimethacrylate (PEGDMA) was used as the basic structural component of these microfabricated scaffolds. PEG acrylates, covalently modified with the cell adhesive peptide arginine-glycine-aspartic acid (RGD) or the ECM component heparan sulfate, was incorporated within the scaffolds to facilitate cell attachment and to allow spatial sequestration of heparan-binding growth factors. Fluorescently labeled polymer microparticles and basic fibroblast growth factor (FGF-2) were chosen to illustrate the capability of SL to spatiotemporally pattern scaffolds. The results demonstrate that a precise, predesigned distribution of single or multiple factors within a single 3D structure can be created, and specific internal architectures can be fabricated. Functionalization of these scaffolds with RGD is demonstrated, and heparan sulfate allows efficient cell attachment and spatial localization of growth factors. Such patterned scaffolds might provide effective systems to study cell behavior in complex microenvironments and could eventually lead to engineering of complex, hybrid tissue structures through predesigned, multilineage differentiation of a single stem-cell population.

Animals↗
PubMed2006

Targeting the stromal microenvironment in chronic inflammation.

A characteristic feature of chronic inflammatory reactions is their persistence and predilection for certain sites. The molecular basis for such tissue tropism (as, for example, seen with metastatic spread) has until recently remained obscure, but recent studies have strongly implicated tissue-resident, stromal cells, such as macrophages, endothelial cells and fibroblasts. These cell types make attractive therapeutic targets as they help define the three-dimensional structure of tissues and are key orchestrators of the inflammatory infiltrate. Most current anti-inflammatory therapies target immune cells in an attempt to inhibit the production of pro-inflammatory mediators; however, an equally important target is the active induction of anti-inflammatory mediators involved in the resolution of inflammation. Recent work suggests that stromal cells are an important source of these mediators. Targeting of multiple signals may be required to inhibit tissue damage associated with inflammatory disease. Cells of the monocyte lineage are present as tissue-resident cells and interact closely with other stromal populations. These cells form an ideal target for modulation of the inflammatory environment as, in some cases, they appear to induce tissue repair. Therapeutic manipulation of the stromal microenvironment has been particularly effective in treating cancer and is likely to provide a novel method to achieve improved control of chronic inflammatory disease.

Angiogenic Proteins↗
PubMed1995

In situ analysis of cytokine responses in experimental murine schistosomiasis.

BACKGROUND: Infection with schistosomiasis results in CD4+ T helper (Th) cell-dependent granulomatous inflammation around parasite eggs. T cell-derived cytokines play a critical role in the induction and subsequent down-modulation of the granulomas. These cytokine responses have been previously examined in lymphoid cell supernatants or in tissue homogenates but have not been examined directly in the local microenvironment of the lesions or in the reacting lymphoid tissues. EXPERIMENTAL DESIGN: With the use of specific mAb, the cytokines IL-2, IFN gamma, IL-4, and IL-10 were investigated by direct immunocytochemical analysis in situ in hepatic egg granulomas and lymphoid organs from acutely and chronically infected mice. Cytokine expression in situ was compared with cytokine production during a secondary response in vitro. RESULTS: All cytokines examined were detected in various amounts in both the hepatic egg granulomas as well as in mesenteric lymph nodes and spleen. The majority of cells expressing the cytokines was found in lymph nodes, and very few were found in granulomas. Relatively small numbers of granulomas contained most of the cytokine-expressing cells, which tended to localize in their periphery. Granulomas and lymphoid organs in the acute disease contained significantly more cytokine-expressing cells in comparison with those from the chronic disease. This observation correlated well with cytokine production in vitro. CONCLUSIONS: Direct immunocytochemical examination in situ was used to detect and measure cytokine-producing cells in hepatic egg granulomas and reacting lymphoid organs of acute and chronic experimental murine schistosomiasis. Observed cytokine patterns suggest that granulomas contain T lymphocytes of both the Th-1 and Th-2 types and that cytokine production occurs during a limited time in the early granuloma. The immunocytochemical technique affords a direct appraisal of amount, dynamics, and localization of cytokine-producing cells in the unperturbed local environment.

Animals↗
PubMed2006

Infectious tolerance and the long-term acceptance of transplanted tissue.

Short courses of antibody treatment aimed at blocking the coreceptors CD4 and CD8 and/or costimulatory molecules such as CD40L are able to bring about long-term acceptance and tolerance of allogeneic transplants. This tolerant state is operational, in that potential effector cells remain but are tightly regulated through the induction of antigen-specific CD4+ regulatory T cells (Tregs). CD4+ CD25+ FoxP3+ Tregs appear to play a prominent role, although other categories of Tregs have been documented. Transforming growth factor beta (TGFbeta) has been found to play a major role in the induction of the tolerant state with therapeutic antibodies as well as promoting the induction of FoxP3+ T cells from naïve populations. The observation that Tregs can be found in tolerated grafts has led to the idea that they may interact with the grafted tissue to establish a state of acquired privilege symmetrical with a similar privileged microenvironment around antigen-presenting cells in lymphoid tissues. Dampening of aggressive immune responses by Tregs allows antigen to persist and be presented in an innocuous way to promote tolerance in new cohorts of T cells throughout the life of the tolerated graft. Regulation may operate at many stages of an immune response, even as a censor at the terminal differentiation stages of effector function.

Animals↗