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PubMed2007

Characterization of early retinal progenitor microenvironment: presence of activities selective for the differentiation of retinal ganglion cells and maintenance of progenitors.

The maintenance and differentiation of retinal progenitors take place in the context of the microenvironment in which they reside at a given time during retinal histogenesis. To understand the nature of the microenvironment in the developing retina, we have examined the influence of activities present during the early stage of retinal histogenesis on enriched retinal progenitors, using the neurosphere model. Early and late retinal progenitors, enriched as neurospheres from embryonic day 14 (E14) and E18 rat retina, respectively, were cultured in embryonic day 3 (E3) chick retinal conditioned medium, simulating the microenvironment present during early retinal histogenesis. Examination of the differentiation and proliferation of retinal progenitors revealed that the early microenvironment contains at least three regulatory activities, which are partitioned in different size fractions of the conditioned medium with different heat sensitivity. First, it is characterized by activities, present in heat stable <30 kDa fraction, that promote the differentiation of retinal ganglion cells (RGCs), the early born neurons. Second, it contains activities, present in heat-sensitive >30 kDa fraction, that regulate the number of early born neurons and maintain the pool of retinal progenitors. Third, it possesses activities, present in heat-sensitive <30 kDa fraction, that prevent the premature differentiation of early retinal progenitors into the late born neurons. Thus, our observations demonstrate the regulatory influence of microenvironment on the maintenance and differentiation of retinal progenitors and establish neurospheres as a viable model system for the examination of such influences.

Animals↗

PubMed2001

Decomposition of protein tryptophan fluorescence spectra into log-normal components. III. Correlation between fluorescence and microenvironment parameters of individual tryptophan residues.

In our previous paper (Reshetnyak, Ya. K., and E. A. Burstein. 2001. Biophys. J. 81:1710-1734) we confirmed the existence of five statistically discrete classes of emitting tryptophan fluorophores in proteins. The differences in fluorescence properties of tryptophan residues of these five classes reflect differences in interactions of excited states of tryptophan fluorophores with their microenvironment in proteins. Here we present a system of describing physical and structural parameters of microenvironments of tryptophan residues based on analysis of atomic crystal structures of proteins. The application of multidimensional statistical methods of cluster and discriminant analyses for the set of microenvironment parameters of 137 tryptophan residues of 48 proteins with known three-dimensional structures allowed us to 1) demonstrate the discrete nature of ensembles of structural parameters of tryptophan residues in proteins; 2) assign spectral components obtained after decomposition of tryptophan fluorescence spectra to individual tryptophan residues; 3) find a correlation between spectroscopic and physico-structural features of the microenvironment; and 4) reveal differences in structural and physical parameters of the microenvironment of tryptophan residues belonging to various spectral classes.

Analysis of Variance↗

PubMed2007

The tumour microenvironment as a target for chemoprevention.

New data indicate that primary dysfunction in the tumour microenvironment, in addition to epithelial dysfunction, can be crucial for carcinogenesis. These recent findings make a compelling case for targeting the microenvironment for cancer chemoprevention. We review new insights into the pathophysiology of the microenvironment and new approaches to control it with chemopreventive agents. The microenvironment of a cancer is an integral part of its anatomy and physiology, and functionally, one cannot totally dissociate this microenvironment from what have traditionally been called 'cancer cells'. Finally, we make suggestions for more effective clinical implementation of this knowledge in preventive strategies.

Chemoprevention↗

PubMed2004

Microenvironment design considerations for cellular scale studies.

In vivo cellular microenvironments are not well-mimicked in present in vitro cell culture systems. Microtechnology, and microfluidics in particular, provides the tools to create in vivo-like cellular microenvironments in vitro. Features of in vitro cellular microenvironments are discussed and compared to macroscale cell culture environments; the concept of an effective culture volume (ECV) is introduced to facilitate the comparison. Current research using microtechnology to investigate in vitro cellular microenvironments is presented and areas where more research is needed in characterizing the in vitro microenvironment are outlined.

Adsorption↗

PubMed2003

Minimum specific cost control of technological processes realized in a living objects-containing microenvironment.

The purpose of the present work is to work out an approach for the development of software and the choice of hardware structures when designing subsystems for automatic control of technological processes realized in living objects containing limited space (microenvironment). The subsystems for automatic control of the microenvironment (SACME) under development use the Devices for Air Prophylactic Treatment, Aeroionization, and Purification (DAPTAP) as execution units for increasing the level of safety and quality of agricultural raw material and foodstuffs, for reducing the losses of agricultural produce during storage and cultivation, as well as for intensifying the processes of activation of agricultural produce and industrial microorganisms. A set of interconnected SACMEs works within the framework of a general microenvironmental system (MES). In this research, the population of baker's yeast is chosen as a basic object of control under the industrial fed-batch cultivation in a bubbling bioreactor. This project is an example of a minimum cost automation approach. The microenvironment optimal control problem for baker's yeast cultivation is reduced from a profit maximum to the maximization of overall yield by the reason that the material flow-oriented specific cost correlates closely with the reciprocal value of the overall yield. Implementation of the project partially solves a local sustainability problem and supports a balance of microeconomical, microecological and microsocial systems within a technological subsystem realized in a microenvironment maintaining an optimal value of economical criterion (e.g. minimum material, flow-oriented specific cost) and ensuring: (a) economical growth (profit increase, raw material saving); (b) high security, safety and quality of agricultural raw material during storage process and of food produce during a technological process; elimination of the contact of gaseous harmful substances with a subproduct during various technological stages; (c) improvement of labour conditions for industrial personnel from an ecological point of view (positive effect of air aeroionization and purification on human organism promoting strengthened health and an increase in life duration, pulverent and gaseous chemical and biological impurity removal). An alternative aspect of a controlled living microenvironment forming is considered.

Agriculture↗

PubMed2006

The tumor microenvironment: key to early detection.

The tumor microenvironment plays an important role equal to the tumor cell population in the progression of cancer. Consisting of stromal fibroblasts, inflammatory cells, components of the vasculature, normal epithelia, and extracellular matrix, the surrounding environment interacts or "cross-talks" with tumor cells through the release of growth factors, cytokines, proteases, and other bioactive molecules. Tumor growth, formation of new vascular networks, evasion of the host immune system, and invasion and metastasis are processes that co-evolve and become finely optimized and regulated within the tumor microenvironment. However, relatively recent reports on three areas of study have come together to add new levels of complexity to the tumor microenvironment. These include ectodomain shedding of proteins, shedding of membrane-derived vesicles, and novel roles for phospholipids. These dynamic changes that take place in the tumor microenvironment provide new avenues for study and for the early detection of cancer, whereas proteomic technologies provide the means to detect these unique proteins and lipids. Here we review the evolving concepts of the tumor microenvironment that, together with advances in proteomic technologies, hold the promise to facilitate the detection of early-stage cancer.

Allantois↗

PubMed1983

Fluorescence studies on lipoamide dehydrogenases of pig heart. II. Microenvironments of tryptophan residues.

The tryptophan residues of two forms of pig heart lipoamide dehydrogenase (LD(I) and LD(II] were investigated fluorometrically. The tryptophan contents of LD(I) and LD(II) determined by the fluorescence method were 3 mol and 2 mol per mol of FAD, respectively. These values were in good agreement with those found by the MCD method. The microenvironments of the tryptophan residues were investigated by fluorescence quenching titration with acrylamide. The tryptophan residues of both enzymes were in heterogeneous microenvironments, and CD spectra showed some differences between these microenvironments in the two enzymes. Energy transfer from tryptophan residues to bound FAD was equally efficient in the two enzymes. It seems probable that the three tryptophan residues in LD(I) are all in different microenvironments, but that two of them are in microenvironments almost identical to those of the corresponding residues in LD(II).

Animals↗

PubMed2006

Meeting report: exploiting the tumor microenvironment for therapeutics.

Recent progress in understanding the role of the tumor microenvironment in cancer progression was the subject of the 2nd International Tumor Metabolism Summit entitled "Exploiting the Tumor Microenvironment for Therapeutics," a meeting held at Palazzo Ducale in Genoa, Italy, October 7 to 8, 2005. One of the major conceptual advances in oncology over the last decade has been the appreciation that all major aspects of cancer biology are influenced by the tumor microenvironment. Two important means by which cancer cells adapt to their microenvironment are by reprogramming cellular glucose/energy metabolism to use pathways that generate ATP in the absence of O(2) and by stimulating angiogenesis to increase O(2) delivery. These responses are principally mediated at the transcriptional level by hypoxia-inducible factor-1. This meeting emphasized the complexity of the tumor microenvironment and opportunities for therapeutic intervention by targeting transcriptional and metabolic pathways that are activated during cancer progression. A better understanding of the crosstalk between signaling pathways and metabolic alterations that contribute to the cancer phenotype may provide insights leading to the development of novel therapeutic strategies.

Animals↗

PubMed2006

Influence of the microenvironment on melanoma cell fate determination and phenotype.

Tumor cells communicate bidirectionally with the surrounding microenvironment, sending and receiving topographical and molecular cues that direct diverse cellular phenomena, including differentiation, growth, and invasion. The microenvironment has long been acknowledged as a facilitator of melanoma progression, and recent studies have illuminated tumor-associated factors, including hypoxia and the extracellular matrix, as important mediators of melanocyte transformation and transdifferentiation. Although these findings portray the microenvironment as a perilous obstacle to the successful treatment of advanced melanomas, it is important to note that certain molecular milieus may be capitalized on as potential treatment modalities. Indeed, our group and others have elucidated the unique ability of embryonic microenvironments to normalize aggressive melanoma cells toward a more benign melanocytic phenotype. The microenvironment therefore presents a novel target for the treatment and ultimately the prevention of melanoma progression and metastasis.

Cell Differentiation↗

PubMed2002

Manipulation of lymphoid microenvironments in nonhuman primates by an inhibitor of the lymphotoxin pathway.

Reticular networks in lymphoid organs play critical roles in the organization of local microenvironments. A number of these elements are maintained by continual signaling through the lymphotoxin system. Evaluation of the lymphotoxin (LT) pathway in primates using a fusion protein decoy provides a unique opportunity to assess modulation of splenic microenvironments in a species with considerably greater background immunological activity compared with rodents. Within the germinal center microenvironment, treatment resulted in a collapse of follicular dendritic cell (FDC) networks and in the disappearance of a ringlike network of immune complex-carrying cells, although some other attributes of the germinal center appeared to be unaltered. Treatment also resulted in changes in the splenic marginal zone, a microenvironment where the architecture is notably different from that of the rodent. Cessation of treatment and recovery allowed us to monitor reemergence of these cell types and revealed that FDCs rely on LT-dependent signals to recompact into appropriately positioned tight networks. Despite the loss of FDC networks, the primary Ab response to keyhole limpet hemocyanin was unaltered over a 20-day period. Manipulation of these microenvironments may represent a novel approach to modulating immune function in human disease.

Animals↗

PubMed2003

Effect of microenvironment pH of swellable and erodable buffered matrices on the release characteristics of diclofenac sodium.

The aim of this work is to design pH-dependent swellable and erodable-buffered matrices and to study the effect of the microenvironment pH on the release pattern of diclofenac sodium. Buffered matrix tablets containing diclofenac sodium, physically mixed with hydrophilic polymer (hydroxypropyl methylcellulose [HPMC]) and pH-dependent solubility polymer (Eudragit L100-55) were prepared with different microenvironment pHs. The release of diclofenac sodium from the buffer matrices was studied in phosphate buffer solutions of pH 5.9 and 7.4. The swelling and erosion matrices containing only HPMC and Eudragit L100-55 were studied in phosphate buffer solution of pH similar to the microenvironment pHs of the matrices. Drug release from matrices was found to be linear as a function of time. Amount of drug released was found to be higher in the medium of pH 7.4 than that of pH 5.9. The rate of drug release increased with the increase of the microenvironment pH of the matrices as determined from the slope. The pattern of drug release did not change with the change of microenvironment pH. The swelling and erosion occurred simultaneously from matrices made up of HPMC and Eudragit L100-55. Both extent of swelling and erosion increased with increase of the medium pH. It was concluded from this study that changing the pH within the matrix influenced the rate of release of the drug without affecting the release pattern.

Buffers↗

PubMed2003

The not-so innocent bystander: the microenvironment as a therapeutic target in cancer.

The microenvironment in which cancer arises is often regarded as a bystander to the clonal expansion and acquisition of malignant characteristics of the tumour. However, a major function of the microenvironment is to suppress cancer, and its disruption is required for the establishment of cancer. In addition, tumour cells can further distort the microenvironment to promote growth, recruit non-malignant cells that provide physiological resources, and facilitate invasion. In this review, the authors discuss the contribution of the microenvironment, i.e., the stroma and its resident vasculature, inflammatory cells, growth factors and the extracellular matrix (ECM), in the development of cancer, and focus on two components as potential therapeutic targets in breast cancer. First, the ECM, which imparts crucial signalling via integrins and other receptors, is a first-line barrier to invasion, modulates aggressive behaviour and may be manipulated to provide novel impediments to tumour growth. Second, the authors discuss the involvement of TGF-beta1 as an example of one of many growth factors that can regulate ECM composition and degradation and that play complex roles in cancer. Compared to the variable routes taken by cells to become cancers, the response of tissues to cancer is relatively consistent. Therefore, controlling and eliminating cancer may be more readily achieved indirectly via the tissue microenvironment.

Breast Neoplasms↗

PubMed1991

Growth of primary T-cell non-Hodgkin's lymphomata in SCID-hu mice: requirement for a human lymphoid microenvironment.

We reasoned that the SCID-hu mouse could provide an appropriate lymphoid or stromal microenvironment to support the growth of primary human lymphoma. Heterotransplantation of nine cases of primary T-cell non-Hodgkin's lymphoma (NHL) into untreated SCID mice and SCID mice reconstituted with human fetal thymus, spleen, and liver (SCID-hu) resulted in the development of lymphoid tumors in five (56%) cases. Two clonal T-cell NHL grew after a mean of 90 days after injection of primary lymphoma cell suspensions into the thymus xenografts in SCID-hu mice and failed to grow in a variety of sites in SCID mice, except for small tumors that developed after a long (157-day) latency period after intracranial injection of tumor cell suspensions into weanling SCID mice. Successful serial transplantation of NHL in SCID and SCID-hu mice required the presence of a human lymphoid or tumor microenvironment, and was enhanced by pretreating the SCID mice with 175 rad radiation and antiasialo antisera. Analysis of the primary and transplanted T-cell tumors showed identical patterns of T-cell surface markers by flow cytometry and immunophenotyping of fixed tissue sections, and, in one case, reactivity with a specific monoclonal antibody to V beta 5.1. Genotyping of the transplanted tumors showed T-cell receptor gene rearrangements identical to those present in the primary tumors. In one case, the presence of Epstein-Barr virus-positive B cells in association with the primary tumor resulted in the growth of a lymphoblastoid B-cell neoplasm in addition to the malignant T-cell lymphoma after transplantation of tumor fragments to SCID mice. The data support the hypothesis that a human lymphoid microenvironment enhances the growth of T-cell NHL in SCID mice. The SCID-hu thymus graft provides an apparently unique microenvironment that supports the growth of primary T-cell NHL, and can be used to study the interaction between lymphoma cells, nontransformed lymphoid cells, and the surrounding stromal microenvironment in vivo.

Animals↗

PubMed1997

Age-dependent induction of hepatic tumor regression by the tissue microenvironment after transplantation of neoplastically transformed rat liver epithelial cells into the liver.

Age is the biggest risk factor associated with the development of cancer. Whereas the incidence of neoplastic disease increases dramatically in aging humans and experimental animals, the effects of aging on tumorigenesis are poorly understood. Using a rodent model, we have previously shown that the microenvironment of the hepatic parenchyma regulates hepatic tumor formation from transplanted neoplastic cells in an age-dependent manner. In the current study, we have investigated the mechanistic basis for the age-dependent suppression of tumor formation by transplanted BAG2-GN6TF rat liver epithelial tumor cells. Examination of liver tissue at 7 and 14 days after transplantation of liver tumor cells revealed the presence of injection-site tumors in both young and old animals. With time, these tumors spontaneously regressed from young adult livers, leaving no tumor remnant and without evidence of injury to the parenchyma. In contrast, tumors detected in old animals at early time points after transplantation persisted for the remainder of the life of the host. Reduced cell proliferation and increased apoptotic cell death were detected in hepatic tumors in young rats relative to hepatic tumors in old rats. These observations suggest that the regression of hepatic tumors from young rats was the direct result of an increased ratio of cell death to cell birth, whereas the persistence and expansion of hepatic tumors in old rats was related to increased cell proliferation relative to cell death. Because young adult rats developed persistent (nonregressing) tumors after transplantation of BAG2-GN6TF cells to extrahepatic sites, the consistent regression of BAG2-GN6TF tumors from livers of young rats seemed to be largely a result of interactions between tumor cells and factors specific to the liver microenvironment. These data indicate that the hepatic microenvironment of young rats can negatively regulate the growth of transformed liver epithelial cells, but with increasing age, the ability of the hepatic microenvironment to suppress the growth of neoplastic tissue deteriorates. Age-associated alterations in tissue microenvironments may thus permit the development of tumors late in life.

Age Factors↗

PubMed2026

Tumor microenvironment-simulated organoids for personalized therapy prediction in head and neck squamous cell carcinoma.

Patient-derived organoids (PDOs) have emerged as promising models for predicting personalized drug responses in cancer therapy. However, the absence of essential immune and stromal components limits their ability to recapitulate the tumor microenvironment. Here, we established a total of 30 patient-derived organoids (PDOs) from 79 patients with locally advanced (LA) and recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). These PDOs maintained sustained expansion capacity and preserved the histopathological characteristics and genomic heterogeneity of their parental tumors. By integrating autologous immune cells and cancer-associated fibroblasts (CAFs) into PDOs, respectively, microenvironment-simulated PDOs (MS-PDOs) were established using a feasible co-culture condition. Compared with conventional PDOs, MS-PDOs-PBMC exhibited specific cytotoxicity and responses to PD-1/PD-L1 inhibitors, while MS-PDOs-CAFs showed enhanced tolerance to chemotherapy drugs, indicating that microenvironment components modulate therapeutic responses in HNSCC. The drug response profiles of MS-PDOs exhibited diverse sensitivity to PD-1/PD-L1 inhibitors, chemotherapy drugs, and combination regimens. Notably, the therapeutic predictions of MS-PDOs were consistent with clinical treatment outcomes, supporting their translational relevance. Collectively, MS-PDOs serve as a robust platform for modeling the tumor microenvironment and predicting therapeutic responses, supporting precision medicine-guided clinical decision-making and offering personalized treatment strategies for HNSCC patients.

Humans↗

PubMed2026

Integrated single-cell RNA sequencing and mendelian randomization analysis identifies causal immune-related driver genes in the heart failure inflammatory microenvironment.

BACKGROUND: Heart failure (HF) is a major global cause of cardiovascular death and disability. Chronic inflammation and immune dysregulation are critical in its development. The cardiac immune microenvironment, especially macrophages, drives HF progression, yet its molecular mechanisms and prognostic impact are not fully clear. This study aimed to identify causal immune-related driver genes in the HF inflammatory microenvironment. METHODS: We combined single-cell RNA sequencing (scRNA-seq) and Mendelian randomization (MR) to study how the inflammatory immune microenvironment affects HF risk. Using two public scRNA-seq datasets, we identified differentially expressed genes (DEGs) in HF heart tissues and selected 489 candidate genes. Causal relationships between these genes and HF were tested using expression quantitative trait loci (eQTL) data and HF genome-wide association study (GWAS) summary statistics. RESULTS: MR analysis showed that 65 genes were causally linked to HF risk. These genes were enriched in pathways related to cardiomyopathy, leukocyte migration, natural killer (NK) cell cytotoxicity, neutrophil extracellular traps, and NF-κB signaling. HF hearts displayed increased levels of macrophages, T cells, B cells, lymphoid cells, and mast cells, while neutrophils were reduced. CONCLUSIONS: Our integrated analysis reveals the central role of the cardiac inflammatory immune microenvironment in HF and identifies 65 key genes causally associated with HF susceptibility. These genes influence specific immune pathways and cell infiltration, shaping HF progression, and provide a basis for developing new biomarkers and immune-targeted therapies.

Heart failure (HF)↗

PubMed2005

Tumor microenvironment: what can effusions teach us?

Malignant effusions, which are composed of malignant pleural and peritoneal fluid, are an unusual manifestation of cancer and frequently portend a poor prognosis. Neoplastic cells that disseminate into cavities containing effusions are highly metastatic and possess a strong autonomous proliferative drive while concurrently being stimulatory of exudative effusions. Most effusions will respond to transient therapeutic intervention, including the obliteration of potential space via pleurodesis. Cure, however, is rare, thus making effusions a biologically, biochemically, and clinically important topic of study. The local microenvironment that supports malignant growth, invasion, and dissemination of the solid primary tumor into the vasculature is composed of activated stroma that includes scaffolding consisting of materials that promote the tumor function, and vascular structures to provide conduits for travel and nutrient delivery. Less is understood about the tumor-cell microenvironment in malignant effusions. The fluid nature of such a microenvironment when compared with the solid primary tumor may have significant implications for disease dissemination and progression. Dissecting the signaling activity and components of such microenvironments will improve our understanding and ultimately our ability to provide better patient care.

Ascitic Fluid↗

PubMed2002

MRI of the tumor microenvironment.

The microenvironment within tumors is significantly different from that in normal tissues. A major difference is seen in the chaotic vasculature of tumors, which results in unbalanced blood supply and significant perfusion heterogeneities. As a consequence, many regions within tumors are transiently or chronically hypoxic. This exacerbates tumor cells' natural tendency to overproduce acids, resulting in very acidic pH values. The hypoxia and acidity of tumors have important consequences for antitumor therapy and can contribute to the progression of tumors to a more aggressive metastatic phenotype. Over the past decade, techniques have emerged that allow the interrogation of the tumor microenvironment with high resolution and molecularly specific probes. Techniques are available to interrogate perfusion, vascular distribution, pH, and pO(2) nondestructively in living tissues with relatively high precision. Studies employing these methods have provided new insights into the causes and consequences of the hostile tumor microenvironment. Furthermore, it is quite exciting that there are emerging techniques that generate tumor image contrast via ill-defined mechanisms. Elucidation of these mechanisms will yield further insights into the tumor microenvironment. This review attempts to identify techniques and their application to tumor biology, with an emphasis on nuclear magnetic resonance (NMR) approaches. Examples are also discussed using electron MR, optical, and radionuclear imaging techniques.

Animals↗