Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “microenvironment”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 181 records · Page 10Linked to original sources
PubMed2006

Nitrification in a biofilm at low pH values: role of in situ microenvironments and acid tolerance.

The sensitivity of nitrifying bacteria to acidic conditions is a well-known phenomenon and generally attributed to the lack and/or toxicity of substrates (NH3 and HNO2) with decreasing pHs. In contrast, we observed strong nitrification at a pH around 4 in biofilms grown on chalk particles and investigated the following hypotheses: the presence of less acidic microenvironments and/or the existence of acid-tolerant nitrifiers. Microelectrode measurements (in situ and under various experimental conditions) showed no evidence of a neutral microenvironment, either within the highly active biofilm colonizing the chalk surface or within a control biofilm grown on a nonbuffering (i.e., sintered glass) surface under acidic pH. A 16S rRNA approach (clone libraries and fluorescence in situ hybridizations) did not reveal uncommon nitrifying (potentially acid-tolerant) strains. Instead, we found a strongly acidic microenvironment, evidence for a clear adaptation to the low pH in situ, and the presence of nitrifying populations related to subgroups with low Km s for ammonia (Nitrosopira spp., Nitrosomonas oligotropha, and Nitrospira spp.). Acid-consuming (chalk dissolution) and acid-producing (ammonia oxidation) processes are equilibrated on a low-pH steady state that is controlled by mass transfer limitation through the biofilm. Strong affinity to ammonia and possibly the expression of additional functions, e.g., ammonium transporters, are adaptations that allow nitrifiers to cope with acidic conditions in biofilms and other habitats.

Biofilms↗
PubMed2005

Application of a pH-sensitive fluoroprobe (C-SNARF-4) for pH microenvironment analysis in Pseudomonas aeruginosa biofilms.

An important feature of microbial biofilms is the development of four-dimensional physical and chemical gradients in space and time. There is need for novel approaches to probe these so-called microenvironments to determine their effect on biofilm-specific processes. In this study, we describe the use of seminaphthorhodafluor-4F 5-(and-6) carboxylic acid (C-SNARF-4) for pH microenvironment analysis in Pseudomonas aeruginosa biofilms. C-SNARF-4 is a fluorescent ratiometric probe that allows pH quantification independent of probe concentration and/or laser intensity. By confocal scanning laser microscopy, C-SNARF-4 revealed pH heterogeneity throughout the biofilm in both the x,y and x,z planes, with values ranging from pH 5.6 (within the biofilm) to pH 7.0 (bulk fluid). pH values were typically remarkably different than those just a few micrometers away. Although this probe has been successfully used in a number of eukaryotic systems, problems have been reported which describe spectral emission changes as a result of macromolecular interactions with the fluorophore. To assess how the biofilm environment may influence fluorescent properties of the dye, fluorescence of C-SNARF-4 was quantified via spectrofluorometry while the probe was suspended in various concentrations of representative biofilm matrix components (i.e., proteins, polysaccharides, and bacterial cells) and growth medium. Surprisingly, our data demonstrate that few changes in emission spectra occur as a result of matrix interactions below pH 7. These studies suggest that C-SNARF-4 can be used as a reliable indicator of pH microenvironments, which may help elucidate their influence on the medical and geobiological roles of natural biofilms.

Benzopyrans↗
PubMed1983

Alkaline and acid transients in cerebellar microenvironment.

1. Extracellular pH (pHo) was measured in the cerebellar cortex of the rat using a recently developed liquid membrane ion-selective micropipette (ISM). pHo was determined during stimulus-evoked neuronal activity, elevated extracellular potassium concentration, [K+]o, spreading depression (SD), and complete ischemia. In many experiments [K+]o was simultaneously determined. 2. A train of local surface stimuli (LOC) produced an initial alkaline shift in pHo from a base line of 7.20-7.30 to 7.25-7.35. This was followed by a long-lasting acid phase that reached a plateau of 7.05-7.15 after 64 s of stimulation. pHo decrease was related to stimulus frequency, intensity, and duration. 3. Superfusion with Ringer solution containing manganese ions rapidly abolished parallel fiber-induced Purkinje cell synaptic depolarization together with the alkaline shifts while enhancing the acid shifts. 4. Superfusion of the cerebellar cortex with Ringer solution containing increasingly elevated [K+] progressively lowered pHo to a plateau of 6.95-7.05. The acidification occurred in the presence of ouabain but was reversed on return to the normal [K+]o or with the addition of the glycolytic blocker, fluoride. Stimulus-evoked alkaline shifts were enhanced by K+-Ringer superfusion. These experiments suggested that the acid shift was due to the metabolic production of an anion, possibly lactate. 5. Elevation of [K+]o above 8-12 mM often produced oscillation in pHo and [K+]o with a period of about 40 s. Sometimes these oscillations ended in a spontaneous SD or SD could be evoked by stimulation. Under these conditions of raised [K+]o, the SD consisted of a very pronounced alkaline transient followed by a small, long-lasting acid shift. When SD was induced by conditioning the cerebellum with proprionate or lowered NaCl, the alkaline phase was reduced and the acid enhanced. 6. Complete ischemia began with a progressive decrease of pHo and rise in [K+]o. When [K+]o reached 12 mM, a second more rapid rise in [K+]o to 40 mM or more occurred. This was correlated with 0.1-0.2 pHo transient increase similar to that seen during SD. pHo eventually reached a plateau of 6.60-6.80, close to neutrality. 7. Superfusion with Ringer solution containing acetazolamide immediately altered pHo homeostasis by increasing base-line pHo by about 0.10 and enhanced the induced pHo changes. These results suggest that carbonic anhydrase (CA) is important for acute buffering of the brain extracellular microenvironment. 8. The above results were interpreted in terms of changes in extracellular strong ion concentration differences ( [SID]o), extracellular concentration of total weak acid ( [Atot]o) and partial pressure of CO2 (Pco2) in the brain microenvironment. The results indicate that neuronal activity produces changes in many of the constituents of the microenvironment.

Acetazolamide↗
PubMed1993

Phenotypic mapping of the chicken embryonic thymic microenvironment developing within an organ culture system.

The chicken thymic microenvironment, as it developed in an embryonic thymus organ culture system, was phenotypically mapped using a panel of mAb defining both epithelial and nonepithelial stromal cell antigens. We have previously reported that thymocyte proliferation and differentiation with proceed for up to 6-8 days in thymus organ culture, hence demonstrating the functional integrity of the thymic microenvironment in vitro. During this time, the stromal component reflected that of the normal embryo with cortical and medullary epithelial areas readily identifiable by both morphology and surface-antigen expression. An abundance of subcapsular and cortical epithelial antigens was detected in the cultured thymus, particularly those normally expressed by the epithelium lining the capsule, trabeculae, and vascular regions (type I epithelium) in the adult and embryonic thymus. Medullary epithelial antigens developed in organ culture, although were present in lower frequency than observed in the age-matched embryonic thymus. MHC class II expression by both epithelial and nonepithelial cells was maintained at high levels throughout the culture period. With increasing time in culture, the ratio of epithelial to nonepithelial cells decreased, concurrent with a decrease in thymocyte frequency and suggestive of a bidirectional interaction between these two cell types. Thus, a functionally intact thymic microenvironment appears to be maintained in embryonic thymus organ culture, a model that is currently being exploited to assess the role of stromal antigens, as defined by our mAb, in the process of thymopoiesis.

Animals↗
PubMed1997

A comparative analysis of the murine thymic microenvironment in normal, autoimmune, and immunodeficiency states.

It is widely accepted that the thymic microenvironment regulates normal thymopoiesis through a highly coordinated and complex series of cellular and cytokine interactions. A direct corollary of this is that abnormalities within the microenvironment could be of etiologic significance in T-cell-based diseases. Our laboratory has developed a large panel of monoclonal antibodies (mAbs) that react specifically with epithelial or nonepithelial markers in the thymus. We have taken advantage of these reagents to characterize the thymic microenvironment of several genetic strains of mice, including BALB/cJ, C57BL/6J, NZB/BlnJ, SM/J, NOD/Ltz, NOD/Ltz-scid/sz, C57BL/6J-Hcphme/Hcphme, and ALY/NscJcl-aly/aly mice, and littermate control animals. We report herein that control mice, including strains of several backgrounds, have a very consistent phenotypic profile with this panel of monoclonal antibodies, including reactivity with thymic epithelial cells in the cortex, the medulla and the corticomedullary junction, and the extracellular matrix. In contrast, the disease-prone strains studied have unique, abnormal staining of thymic cortex and medulla at both the structural and cellular levels. These phenotypic data suggest that abnormalities in interactions between developing thymocytes and stromal cells characterize disease-prone mice.

Animals↗
PubMed2005

Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment.

Radiation exposure is an important form of environmental carcinogen and has been associated with increased risk of breast cancer. Epigenetic events, especially those involving alterations in the breast stromal microenvironment, may play an important role in radiation-induced carcinogenesis but remain not well understood. We here show that human mammary stromal fibroblasts respond to protracted low-dose ionizing radiation exposures by displaying a senescence-like phenotype. Using a three-dimensional coculture system to model the interactions of different mammary cell types with their neighbors and with their environment, we provide a direct experimental proof that ionizing radiation-induced senescence-like fibroblasts significantly perturb the mammary stromal microenvironment, which is highlighted by impaired formation of pseudopodia networks due to marked cytoskeletal alterations in senescence-like fibroblasts and increased extracellular matrix degradation because of the up-regulation of multiple secreted matrix metalloproteinases. Within such a perturbed environment, mammary ductal morphogenesis is completely disrupted and epithelial cells instead grow into enlarged cystic structures, which further develop and become disorganized cell masses on inactivation of cellular death pathways. Breast carcinoma cells growing in such an environment are enabled to fully express their malignant potential as evidenced by the alpha6beta4 integrin/phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway-dependent invasive growth. Our results suggest that ionizing radiation, in addition to causing gene mutations in epithelial cells, can contribute to breast carcinogenesis by perturbing the tissue microenvironment that leads to dysregulated cell-cell and cell-matrix interactions.

Animals↗
PubMed2005

Epigenetic transdifferentiation of normal melanocytes by a metastatic melanoma microenvironment.

The clinical management of cutaneous melanoma would benefit significantly from a better understanding of the molecular changes that occur during melanocytic progression to a melanoma phenotype. To gain unique insights into this process, we developed a three-dimensional in vitro model that allows observations of normal human melanocytes interacting with a metastatic melanoma matrix to determine whether these normal cells could be reprogrammed by inductive cues in the tumor cell microenvironment. The results show the epigenetic transdifferentiation of the normal melanocytic phenotype to that of an aggressive melanoma-like cell with commensurate increased migratory and invasive ability with no detectable genomic alterations. Removal of the transdifferentiated melanocytes from the inductive metastatic melanoma microenvironment results in a reversion to their normal phenotype. However, a normal melanocyte microenvironment had no epigenetic influence on the phenotype of metastatic melanoma cells. This novel approach identifies specific genes involved in the transdifferentiation of melanocytes to a more aggressive phenotype, which may offer significant therapeutic value.

Cell Differentiation↗
PubMed2006

Chronic bile duct injury associated with fibrotic matrix microenvironment provokes cholangiocarcinoma in p53-deficient mice.

Intrahepatic cholangiocarcinoma (CCA) is a lethal malignancy of the biliary epithelium associated with p53 mutations, bile duct injury, inflammation, and fibrosis. Here, to validate these processes in CCA, we developed a liver cirrhosis model driven by chronic intermittent toxin exposure, which provokes bile duct injury/necrosis and proliferation, fibroblast recruitment, and progressive extracellular matrix (ECM) changes. Fibrotic changes in the matrix microenvironment, typified by increased type I and III collagens and fibroblast recruitment, were shown to stimulate biliary epithelium hyperplasia with subsequent progression to malignant intrahepatic CCA only in mice harboring a p53 mutant allele. These murine CCAs bear histologic and genetic features of human intrahepatic CCA, including dense peritumoral fibrosis, increased inducible nitric oxide synthase, nitrotyrosine, and cyclooxygenase-2 expression, c-Met activation, cErbB2 overexpression, down-regulation of membrane-associated E-cadherin, and p53 codon 248 mutation. Thus, p53 deficiency, chronic bile duct injury/proliferation, and the fibrotic matrix microenvironment cooperate to induce intrahepatic CCA, highlighting the key role of the ECM microenvironment in this common liver cancer.

Animals↗
PubMed2007

Gene expression profile of metastatic human pancreatic cancer cells depends on the organ microenvironment.

To determine the influence of the microenvironment on changes in gene expression, we did microarray analysis on three variant lines of a human pancreatic cancer (FG, L3.3, and L3.6pl) with different metastatic potentials. The variant lines were grown in tissue culture in the subcutis (ectopic) or pancreas (orthotopic) of nude mice. Compared with tissue culture, the number of genes of which the expression was affected by the microenvironment was up-regulated in tumors growing in the subcutis and pancreas. In addition, highly metastatic L3.6pl cells growing in the pancreas expressed significantly higher levels of 226 genes than did the L3.3 or FG variant cells. Growth of the variant lines in the subcutis did not yield similar results, indicating that the orthotopic microenvironment significantly influences gene expression in pancreatic cancer cells. These data suggest that investigations of the functional consequence of gene expression require accounting for experimental growth conditions.

Animals↗
PubMed2006

I2 imaging: cancer biology and the tumor microenvironment.

The use of imaging techniques to understand the role of the tumor microenvironment in cancer progression was the topic of a National Cancer Institute (NCI)-sponsored think tank entitled "I2 Imaging: Cancer Biology and the Tumor Microenvironment," held in Alexandria, Virginia on June 8 to 10, 2006. Participants discussed both recent progress in the use of imaging to dissect cellular and molecular interactions within the tumor microenvironment and the challenges that remain. Recommendations made to the NCI included (a) holding an annual meeting at which biologists, clinicians, and imaging scientists could exchange data, facilitating new collaborations within this multidisciplinary field; (b) funding both research and training specifically designed to foster a cross-disciplinary focus; (c) creating and making available a variety of resources to interested investigators, such as a repository of stromal cells and extracellular matrix molecules; and (d) taking steps to encourage translation of the basic research findings into the clinic.

Biomedical Research↗
PubMed2005

Custom design of the cardiac microenvironment with biomaterials.

Many strategies for repairing injured myocardium are under active investigation, with some early encouraging results. These strategies include cell therapies, despite little evidence of long-term survival of exogenous cells, and gene or protein therapies, often with incomplete control of locally-delivered dose of the factor. We propose that, ultimately, successful repair and regeneration strategies will require quantitative control of the myocardial microenvironment. This precision control can be engineered through designed biomaterials that provide quantitative adhesion, growth, or migration signals. Quantitative timed release of factors can be regulated by chemical design to direct cellular differentiation pathways such as angiogenesis and vascular maturation. Smart biomaterials respond to the local environment, such as protease activity or mechanical forces, with controlled release or activation. Most of these new biomaterials provide much greater flexibility for regenerating tissues ex vivo, but emerging technologies like self-assembling nanofibers can now establish intramyocardial cellular microenvironments by injection. This may allow percutaneous cardiac regeneration and repair approaches, or injectable-tissue engineering. Finally, materials can be made to multifunction by providing sequential signals with custom design of differential release kinetics for individual factors. Thus, new rationally-designed biomaterials no longer simply coexist with tissues, but can provide precision bioactive control of the microenvironment that may be required for cardiac regeneration and repair.

Angiogenesis Inducing Agents↗
PubMed2004

Plasticity of endothelial cells: rapid dedifferentiation of freshly isolated high endothelial venule endothelial cells outside the lymphoid tissue microenvironment.

Endothelial cells display remarkable heterogeneity in different organs and vascular beds. Although many studies suggest that tissues "speak" to endothelial cells, endothelial cell diversity remains poorly characterized at the molecular level. Here, we describe a novel strategy to characterize tissue-specific endothelial cell phenotypes and to identify endothelial cell genes that are under the control of the local microenvironment. By comparing post-capillary high endothelial venule endothelial cells (HEVECs), freshly isolated from human tonsils without any cell culture step, with HEVECs cultured for 2 days, we found that HEVECs rapidly lost their specialized characteristics when isolated from the lymphoid tissue microenvironment. Striking changes occurred as early as after 48 hours, with complete loss of the postcapillary venule-specific Duffy antigen receptor for chemokines (DARCs) and the HEV-specific fucosyltransferase Fuc-TVII. DNA microarray analysis identified several other candidate HEV genes that were rapidly down-regulated ex vivo, including type XV collagen, which we characterized as a novel, abundant HEV transcript in situ. Together, our results demonstrate that blood vessel type-specific and tissue-specific characteristics of endothelial cells are under the control of their microenvironment. Therefore, even short-term primary cultures of human endothelial cells may not adequately mimic the differentiated endothelial cell phenotypes existing in vivo.

Cell Differentiation↗
PubMed2005

CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment.

Signals from the microenvironment have a profound influence on the maintenance and/or progression of hematopoietic and epithelial cancers. Mesenchymal or marrow-derived stromal cells, which constitute a large proportion of the non-neoplastic cells within the tumor microenvironment, constitutively secrete the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). CXCL12 secretion by stromal cells attracts cancer cells, acting through its cognate receptor, CXCR4, which is expressed by both hematopoietic and nonhematopoietic tumor cells. CXCR4 promotes tumor progression by direct and indirect mechanisms. First, CXCR4 is essential for metastatic spread to organs where CXCL12 is expressed, and thereby allows tumor cells to access cellular niches, such as the marrow, that favor tumor-cell survival and growth. Second, stromal-derived CXCL12 itself can stimulate survival and growth of neoplastic cells in a paracrine fashion. Third, CXCL12 can promote tumor angiogenesis by attracting endothelial cells to the tumor microenvironment. CXCR4 expression is a prognostic marker in various types of cancer, such as acute myelogenous leukemia or breast carcinoma. Promising results in preclinical tumor models indicate that CXCR4 antagonists may have antitumor activity in patients with various malignancies. Collectively, these observations reveal that CXCR4 is an important molecule involved in the spread and progression of a variety of different tumors. As such, CXCR4 antagonists, although initially developed for treatment of AIDS, actually may become effective agents for the treatment of neoplastic disease.

Animals↗
PubMed2002

Cultivation of aorta-gonad-mesonephros-derived hematopoietic stem cells in the fetal liver microenvironment amplifies long-term repopulating activity and enhances engraftment to the bone marrow.

During mammalian development, definitive hematopoietic stem cells (HSCs) arise in the aorta-gonad-mesonephros (AGM) region and colonize the fetal liver (FL) before hematopoiesis occurs in the bone marrow. The FL is a unique hematopoietic organ where both HSCs and mature blood cells are actively generated along with functional maturation of hepatic cells as a metabolic organ. To characterize HSCs and FL microenvironments during development, this study establishes a coculture system composed of AGM-originated HSCs and FL nonhematopoietic cells. The results demonstrate that FL cells support significant expansion of lineage-committed hematopoietic cells as well as immature progenitors. More important, long-term repopulating activity was amplified from AGM-originated HSCs in this coculture system. Engraftment of HSCs to the bone marrow was strongly enhanced by coculture. In addition, AGM HSCs produced significantly more hematopoietic cells than E14.5 and E18.5 FL HSCs in vitro. These results suggest that the FL microenvironment not only stimulates expansion of the hematopoietic system, but also possibly modifies the characteristics of AGM HSCs. Thus, this coculture system recapitulates the developmental process of HSCs and the FL microenvironment and provides a novel means to study the development of hematopoiesis.

Animals↗
PubMed2006

Immunohistochemical patterns of reactive microenvironment are associated with clinicobiologic behavior in follicular lymphoma patients.

PURPOSE: Recent molecular data have suggested that non-neoplastic cells are powerful modulators that may confer a selective advantage or disadvantage on the outcome of follicular lymphoma (FL) patients. PATIENTS AND METHODS: The prevalence of the principal inflammatory and immune-infiltrated cells was measured immunohistochemically in the tissue of 211 FL patients, and associations were sought with their traditional clinicobiologic characteristics. RESULTS: Our results confirmed the presence of a large number of T lymphocytes (CD4+ and CD8+) and CD57+ cells and, at a moderate level, the presence of TIA-1+ cytotoxic cells, CD68+ macrophages, CD123+ plasmacytoid cells, and FOXP3+ regulatory T cells among the pool of non-neoplastic cells. In addition to the conventional clinical variables, univariate analysis identified a low level of infiltrated CD8+ T lymphocytes as a significantly negative prognostic factor of overall survival. The following significant differences in the abundance of cells of specific and nonspecific immunity were observed in relation to the clinicobiologic features of FL: (1) a reactive microenvironment mainly made up of T lymphocytes and macrophages was significantly associated with a favorable clinical behavior of FL patients; and (2) a reactive microenvironment infiltrated predominantly by CD57+ T cells was associated with a significantly higher frequency of adverse clinicobiologic manifestations such as "B" symptoms and bone marrow involvement. CONCLUSION: Our results demonstrate the existence of two specific patterns in the reactive microenvironment of FL, an immunosurveillance pattern (T lymphocytes and macrophages) and an immune-escape pattern (CD57+ T cells), that were directly associated with the clinicobiologic features of these patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets.

T-cell development is under the tight control of thymic microenvironments. Conversely, the integrity of thymic microenvironments depends on the physical presence of developing thymocytes, a phenomenon designated as 'thymic crosstalk'. We now show, using three types of immunodeficient mice, i.e. CD3(epsilon) transgenic mice, RAG(null) mice and RAG(null)-bone-marrow-transplanted CD3(epsilon) transgenic mice, that the control point in lymphoid development where triple negative (CD3(-),CD4(-),CD8(-)) thymocytes progress from CD44(+)CD25(-) towards CD44(-)CD25(+), influences the development of epithelial cells, critically inducing the extra, third dimension in the organization of the epithelial cells in the cortex. This tertiary configuration of the thymic epithelium is a typical feature for the thymus, enabling lymphostromal interaction during T-cell development. Crosstalk signals at this control point also induce the formation of thymic nurse cells. Moreover, our data indicate that establishment of a thymic cortex is a prerequisite for the development of the thymic medulla. Thus, differentiating thymocytes regulate the morphogenesis of thymic microenvironments in a stepwise fashion.

Animals↗
PubMed2006

Oncostatin m maintains the hematopoietic microenvironment and retains hematopoietic progenitors in the bone marrow.

Bone marrow (BM) functions as the primary hematopoietic tissue throughout adult life by providing a microenvironment for the proliferation, differentiation, and retention of hematopoietic stem cells and progenitors. We describe novel roles for oncostatin M (OSM) in the BM hematopoietic microenvironment. Hematopoietic progenitor activity in OSM-deficient mice was reduced in BM but elevated in the spleen and peripheral blood. The level of circulating granulocyte colony-stimulating factor (G-CSF) was increased, whereas that of stromal cell-derived factor 1 (SDF-1) was decreased in OSM-deficient mice. Moreover, the ability of OSM-deficient BM stromal cells to support hematopoiesis in vitro was significantly reduced. These results indicate that OSM plays a unique role in hematopoiesis by maintaining the proper microenvironment for BM hematopoiesis; it also retains hematopoietic progenitors in BM by regulating G-CSF and SDF-1 levels.

Animals↗
PubMed2003

Endocrine/paracrine/autocrine survival factor activity of bone microenvironment participates in the development of androgen ablation and chemotherapy refractoriness of prostate cancer metastasis in skeleton.

Bone is the most frequent site of metastases of prostate cancer and is almost always the first and frequently the only site of metastases where disease will progress to stage D3. In addition, the number of skeletal metastatic foci is the most powerful independent prognostic factor of limited response to hormone ablation therapy and poor survival of patients with advanced prostate cancer. Furthermore, disease progression frequently occurs in the osteoblastic metastases, even though androgen ablation therapy still provides adequate and sustained control of disease at the primary site. Notably, the management of metastatic disease onto bones has traditionally relied on therapeutic modalities, which almost exclusively aim at directly inducing cancer cell death. However, accumulating pieces of evidence, from both the clinical and the basic research front, point to major limitations of this conventional approach. The in vivo response of malignant cells to anticancer therapies is directly influenced by the local microenvironment in which they metastasize. In particular, organ sites frequently involved in metastatic diseases, such as the bones, appear to confer to metastatic cells protection from anticancer drug-induced apoptosis. This protection is mediated by soluble growth factors and cytokines released by the normal cellular constituents of the host tissue microenvironment. The characterization of bone microenvironment-related survival factors has led to the development of a novel hormone manipulation which can re-introduce clinical responses in patients with stage D3 prostate cancer.

Androgen Antagonists↗