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PubMed1991

Examination of phenylalanine microenvironments in proteins by second-derivative absorption spectroscopy.

We have employed near ultraviolet derivative absorption spectroscopy to study the microenvironments of phenylalanine residues in proteins. The use of second-derivative uv spectra in the 250- to 270-nm range effectively suppresses spectral contributions from tryptophan and tyrosine residues. Fitting a polynomial to the numerically calculated second-derivative spectrum allows precise determination of the position of the negative derivative peak near 258 nm. This position is shown to be correlated with the polarity of the microenvironments of phenylalanine residues. This approach allows monitoring of changes in the state of phenylalanine side chains during folding/unfolding of the proteins. In addition, this method permits perturbation of protein samples with ethylene glycol to be used to establish the relative degree of solvent exposure of protein phenylalanine.

Animals↗
PubMed1992

Lack of bone resorption in osteosclerotic (oc/oc) mice is due to a defect in osteoclast progenitors rather than the local microenvironment provided by osteoblastic cells.

In a co-culture system of mouse spleen cells and osteoblastic cells, we have demonstrated that a suitable microenvironment must be provided by osteoblastic cells in order for osteoclast-like multinucleated cell (MNC) formation. Using this co-culture system, we examined the pathogenetic mechanism underlying the lack of bone resorption in osteosclerotic oc/oc mice. Numerous tartrate-resistant acid phosphatase (TRAP, an osteoclast marker enzyme)-positive MNCs were formed in response to 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] both in co-cultures of oc/oc spleen cells and normal osteoblastic cells and in those of normal spleen cells and oc/oc osteoblastic cells. TRAP-positive MNCs derived from normal spleen cells tended to spread out on culture dishes, whereas those from oc/oc spleen cells remained as small, compact MNCs. When TRAP-positive MNCs enriched from co-cultures of normal spleen cells and oc/oc osteoblastic cells were cultured on dentine slices, they formed numerous resorption pits with ruffled borders and clear zones. In contrast, none of the TRAP-positive MNCs derived from oc/oc spleen cells formed either ruffled borders or resorption pits. These results indicate that the lack of bone resorption in oc/oc mice is due to a defect in osteoclast progenitors rather than the local microenvironment provided by osteoblastic cells.

Acid Phosphatase↗
PubMed1994

Age-related decreases in the reconstituting ability of hemopoietic cells and the ability of hemopoietic microenvironment to support hemopoietic reconstitution in senescence accelerated (SAM-P) mice.

The effect of the aging process on the hemopoietic system in senescence-accelerated (SAM-P) mice with respect to the reconstituting ability of hemopoietic cells and the ability of the microenvironment to support hemopoietic reconstitution was investigated by bone marrow transplantation (reconstitution assay). When the bone marrow cells, obtained from young or old mice, were transplanted to lethally irradiated young SAM-P mice no difference in the reconstituting pattern of femoral spleen colony-forming units (CFU-S), splenic CFU-S and splenic granulocyte macrophage colony-forming units (CFU-GM) was observed between the mice transplanted with young and old donor cells. However, the reconstitution of femoral CFU-GM in mice transplanted with old donor cells was delayed compared to that in mice transplanted with young donor cells. Moreover, the recovery of WBC in mice transplanted with old donor cells was noticeably delayed. When the bone marrow cells obtained from young mice were transplanted to young or old recipient mice, no difference in the reconstituting pattern of femoral CFU-S and CFU-GM as well as splenic CFU-S and CPU-GM was observed between young and old recipient mice. However, the recovery of WBC in old recipient mice was noticeably delayed. These data indicate that the functions of both the hemopoietic cells and the hemopoietic microenvironment deteriorated with age in SAM-P mice.

Aging↗
PubMed1984

Evidence for a stem cell common to hematopoiesis and its in vitro microenvironment: studies of patients with clonal hematopoietic neoplasia.

The origin and nature of cells forming the in vitro microenvironment in long-term cultures of human marrow were studied in five patients with clonal myeloproliferative disorders who were heterozygous for glucose-6-phosphatase dehydrogenase (G6PD). The results showed that cells in the adherent stromal layer forming the in vitro microenvironment were derived from the same clonal progenitors involved by the neoplasm in the four patients whose diseases originated in multipotent stem cells. In contrast, stromal cells were derived from normal progenitors in a patient with acute non-lymphocytic leukemia whose clone showed differentiative expression confined to cells in the granulocytic lineage. Mixing experiments demonstrated that the G6PD type displayed by the adherent marrow stromal cells was not obscured by contaminating non-adherent hematopoietic cells or marrow fibroblasts. The data suggest the existence of a pluripotent cell in normal hematopoiesis that gives rise to hematopoietic cells and to their micro-environment.

Adult↗
PubMed1985

Responsiveness of the in vitro hematopoietic microenvironment to platelet-derived growth factor.

The adherent or stromal cells in human long-term marrow cultures, a possible in vitro counterpart of the in vivo microenvironment, were investigated for responsiveness to platelet-derived growth factor (PDGF). Many stromal cells from cultures derived from normal donors as well as from patients with chronic myelogenous leukemia, bore receptors to PDGF and were stimulated to incorporate [3H]-thymidine by highly purified PDGF and to a lesser extent by epidermal growth factor (EGF). These data suggest that PDGF and perhaps EGF may be involved in the regulation of the in vitro microenvironment and, therefore, of normal and possibly neoplastic hematopoiesis.

Autoradiography↗
PubMedDate not supplied

Effects of aging and vincamine derivatives on pericapillary microenvironment: stereological characterization of the cerebral capillary network.

Changes in the pericapillary microenvironment of adult (18-month-old) and senescent (27 1/2-month-old) Fischer-344 rats treated for 6 weeks with daily IP injections of brovincamine or apovincamine (0, 2.5, 5, 10 mg/kg) were correlated with spontaneous locomotor activity and [14C]-2-deoxyglucose uptake of the brain. The animals were tested for spontaneous locomotor activity in a tunnel maze. Twenty-four hr after behavioral testing and subsequently after a [14C]-2-deoxyglucose injection, brains were removed and capillaries stained with alkaline phosphatase reaction, being later measured with an optical-electronic image analysis technique. Results revealed an increase in intercapillary distance, as a sensitive parameter for capillary density, in the hippocampus (CA1) and in the parietal cortex (area 39) in association with aging. Capillary diameter in the parietal cortex was found to be increased age dependently. A similar age-related increase was also observed in the CA1 field but this age trend was not significant. Chronic treatment with the vincamines produced a dose-dependent reduction in intercapillary distance in senescent animals which approached the level of untreated adult control rats. Significant negative correlations were found between maze locomotion and intercapillary distance among senescent rats. Furthermore, intercapillary distance and local relative 2-deoxyglucose uptake tended to be negatively correlated in both age groups. These findings provide evidence for the working hypothesis that mean intercapillary distance can be considered as an indicator of neuronal activity in the pericapillary microenvironment.

Aging↗
PubMed1985

Target cells and thymus microenvironment in the pathogenesis of thymic lymphomas in C57BL/Ka mice.

In C57BL/Ka mice, the induction of thymic lymphomas either by inoculation of radiation leukemia virus (RadLV) or by a split dose irradiation requires complex cellular events: Target cells are found among the population of thymic subcapsular blast cells, or, alternatively, of marrow or spleen prothymocytes; Progression of target cells to lymphoma growth requires a multi-step process, which occurs only within thymic microenvironment; Target cells are rapidly induced as "preleukemic" cells; After inoculation of RadLV, the initial events occur when target cells are in close association with cells of a specialized component of thymic epithelium, i.e., the so-called "nurse cells"; The leukemogenic agents induce damages to the thymic microenvironment itself; Lymphoma prevention by marrow grafting after irradiation results from mechanisms still unknown which inhibit the progression of "preleukemic" cells to neoplastic growth.

Animals↗
PubMed2004

Follicular development: the role of the follicular microenvironment in selection of the dominant follicle.

The importance of endocrine signals in the regulation of follicular development has long been recognized. However, the follicular microenvironment also plays a critical role in determining follicular fate. This review summarizes our studies on the role of the intrafollicular IGF system in selection of the dominant follicle (DF) in cattle. During the bovine estrous cycle, the largest antral follicles develop in two or three successive waves of follicular recruitment and selection of a DF. High concentrations of estradiol in the follicular fluid are the hallmark of dominant and preovulatory follicles and are associated with lower concentrations of low molecular weight (MW) insulin-like growth factor binding proteins (IGFBP-2, -4, and -5), which can prevent binding of IGF to its receptor. Our studies have shown that dominant and preovulatory follicles also have much higher levels of an IGFBP-4/-5 protease activity, which is the bovine equivalent of the human IGFBP-4 protease, pregnancy-associated plasma protein-A (PAPP-A). Studies of follicles isolated just after the emergence of the DF showed that PAPP-A is present in the follicular fluid of the DF as soon as it can be detected as morphologically dominant. To examine whether higher levels of PAPP-A in one follicle of the cohort (the future DF) precedes morphological dominance, the four largest follicles were isolated from pairs of bovine ovaries obtained before one follicle of the cohort was significantly larger the others, around the time that one follicle was first detected as morphologically dominant and after dominance was well established. Analysis of the temporal sequence of changes in estradiol, low MW IGFBPs, free IGF, and PAPP-A in the follicular fluid suggested that an increase in PAPP-A is the earliest biochemical difference yet detected in the future DF and that follicular selection is the result of a progressive series of changes beginning with the acquisition of PAPP-A, which leads to a decrease in IGFBP-4 and -5 and an increase in free IGF, which synergizes with FSH to increase estradiol production. Co-dominant follicles, induced by injection of small doses of recombinant bovine (rb) FSH, both had levels of PAPP-A similar to the single DF of control heifers, supporting the hypothesized role of FSH in the induction of PAPP-A in the DF. Taken together, these results suggest a critical role for FSH-induced PAPP-A, and thus for free IGF, in the selection of the DF. In contrast, other experiments provided evidence for a deleterious effect of IGF on the initiation of bovine follicular growth and the survival of primordial and primary follicles in vitro. These results underscore the importance of the follicular microenvironment in determining follicular fate and indicate that its effects can be stage-specific.

Animals↗
PubMed2004

Selection of a highly aggressive myeloma cell line by an altered bone microenvironment in the C57BL/KaLwRij mouse.

In multiple myeloma (MM), bone marrow microenvironment has an important role for the survival and growth of plasma cells. We previously showed that a high bone turnover, induced by ovariectomy, increased MM cells growth in the 5T2MM model. The present study characterized a new plasma cell line (5THL) which was isolated from 5T2MM mice previously ovariectomized. Cells were propagated unchanged in normal C57BL/KaLwRij mice during six generations. 5THL was compared to the original 5T2MM phenotype. Paraproteinemia was detected 6 weeks post injection in 5THL mice and after 8 weeks in 5T2MM mice. All 5THL mice developed a hind-limb paralysis after 10 weeks. 5T2MM mice were euthanized at 16 weeks, due to a more progressive development of the disease. In 5THL mice, osteolytic lesions were observed after 8 weeks and severe bone destruction was evidenced at 10 weeks. In 5T2MM mice, minimal lesions were observed only after 10 weeks. Like in 5T2MM mice, no extra osseous lesions were observed in 5THL mice. The 5THL MM model closely mimics human myeloma with higher and faster bone aggressiveness. This new aggressive cell line, with a preserved phenotype, was selected by an altered microenvironment due to an increased bone turnover.

Animals↗
PubMed2006

Site-directed mutagenesis study of the microenvironment characteristics of Lys213 of Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase.

Saccharomyces cerevisiae phosphoenolpyruvate (PEP) carboxykinase catalyzes the reversible formation of oxaloacetate and adenosine triphosphate from PEP, adenosine diphosphate and carbon dioxide, and uses Mn(2+) as the activating metal ion. Comparison with the crystalline structure of homologous Escherichia coli PEP carboxykinase [Tari et al. Nature Struct. Biol. 4 (1997) 990-994] shows that Lys(213) is one of the ligands to Mn(2+) at the enzyme active site. Coordination of Mn(2+) to a lysyl residue is infrequent and suggests a low pK(a) value for the epsilon-NH(2) group of Lys(213). In this work, we evaluate the role of neighboring Phe(416) in contributing to provide a low polarity microenvironment suitable to keep the epsilon-NH(2) of Lys(213) in the unprotonated form. Mutation Phe416Tyr shows that the introduction of a hydroxyl group in the lateral chain of the residue produces a substantial loss in the enzyme affinity for Mn(2+), suggesting an increase of the pK(a) of Lys(213). A study of the effect of pH on K(m) for Mn(2+) indicate that the affinity of recombinant wild type enzyme for the metal ion is dependent on deprotonation of a group with pK(a) of 7.1+/-0.2, compatible with the low pK(a) expected for Lys(213). This pK(a) value increases at least 1.5 pH units upon Phe416Tyr mutation, in agreement with the expected effect of an increase in the polarity of Lys(213) microenvironment. Theoretical calculations of the pK(a) of Lys(213) indicate a value of 6.5+/-0.9, and it increases to 8.2+/-1.6 upon Phe416Tyr mutation. Additionally, mutation Phe416Tyr causes a loss of 1.3 kcal mol(-1) in the affinity of the enzyme for PEP, an effect perhaps related to the close proximity of Phe(416) to Arg(70), a residue previously shown to be important for PEP binding.

Circular Dichroism↗
PubMed2006

Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment.

Hepatocellular carcinoma (HCC) is an aggressive malignancy mainly due to metastases or postsurgical recurrence. We postulate that metastases are influenced by the liver microenvironment. Here, we show that a unique inflammation/immune response-related signature is associated with noncancerous hepatic tissues from metastatic HCC patients. This signature is principally different from that of the tumor. A global Th1/Th2-like cytokine shift in the venous metastasis-associated liver microenvironment coincides with elevated expression of macrophage colony-stimulating factor (CSF1). Moreover, a refined 17 gene signature was validated as a superior predictor of HCC venous metastases in an independent cohort, when compared to other clinical prognostic parameters. We suggest that a predominant humoral cytokine profile occurs in the metastatic liver milieu and that a shift toward anti-inflammatory/immune-suppressive responses may promote HCC metastases.

Carcinoma, Hepatocellular↗
PubMed2006

Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment.

Emergence of invasive behavior in cancer is life-threatening, yet ill-defined due to its multifactorial nature. We present a multiscale mathematical model of cancer invasion, which considers cellular and microenvironmental factors simultaneously and interactively. Unexpectedly, the model simulations predict that harsh tumor microenvironment conditions (e.g., hypoxia, heterogenous extracellular matrix) exert a dramatic selective force on the tumor, which grows as an invasive mass with fingering margins, dominated by a few clones with aggressive traits. In contrast, mild microenvironment conditions (e.g., normoxia, homogeneous matrix) allow clones with similar aggressive traits to coexist with less aggressive phenotypes in a heterogeneous tumor mass with smooth, noninvasive margins. Thus, the genetic make-up of a cancer cell may realize its invasive potential through a clonal evolution process driven by definable microenvironmental selective forces. Our mathematical model provides a theoretical/experimental framework to quantitatively characterize this selective pressure for invasion and test ways to eliminate it.

Adaptation, Physiological↗
PubMed2005

Determination of volatile organic compounds in different microenvironments by multibed adsorption and short-path thermal desorption followed by gas chromatographic-mass spectrometric analysis.

A multiphase assurance approach was developed for the accurate and precise determination of volatile organic compounds (VOCs) in different microenvironments. This approach includes (i) development of a method including adsorption of VOCs onto a multisorbent media followed by short-path thermal desorption (SPTD) pre-concentration and gas chromatography (GC) coupled to a mass spectrometry (MS) quantification, (ii) validation of the sampling and analytical method and (iii) validation of the data using a multidimensional procedure. Tenax TA and Carbopack B sorbent combinations were used to collect 102 individual VOCs ranging from C5 to C12. Method parameters including thermal desorption temperature, desorption time and cryofocusing temperature were optimized. The average recoveries and method detection limits (MDL) for the target analytes were in the range 80-100% and 0.01-0.14 ppbv, respectively. The method also showed good linearity (R2 > 0.99) and precision (<8%) values. Validation of the method was performed under real environmental conditions at a gas station, in an office and a residential household to examine the influence of variation in meteorological conditions such as temperature and relative humidity and a wide range of VOC concentrations. The sampling and analytical method resulted in successful determination of VOC in different microenvironments. Finally, validation of the data was performed by assessing fingerprint and time series plots and correlation matrices together with meteorological parameters such as mixing height, wind speed and temperature. The data validation procedure provided detection of both faulty data and air pollution episodes.

Adsorption↗
PubMed2005

Controlling the thymic microenvironment.

T-cell development in the thymus is a stepwise process, mediated by a variety of stromal cells in different regions of the organ. Although the cellular composition of the thymic microenvironment has been known for over a decade, the molecular cues that govern its formation are only beginning to be understood. Stromal-derived chemokines attract T-cell precursors to the thymus and direct maturing thymocytes to appropriate niches for their further development. Reciprocal signals from developing T cells provide crosstalk that is essential for establishment and maintenance of the thymic microenvironment. Elucidation of the molecular players involved and their context within the organ is the challenge for the field today. This knowledge could then be translated to clinical restoration of thymic function and T-cell reconstitution.

Animals↗
PubMed2004

Regulation of vascular endothelial growth factor (VEGF)-C and VEGF-D expression by the organ microenvironment in human colon carcinoma.

Vascular endothelial growth factor (VEGF)-C and VEGF-D are potent lymphangiogenic factors produced by tumour and stromal cells. The purpose of this study was to investigate the expression of VEGF-C and VEGF-D in the organ microenvironment. We implanted human KM12 colon carcinoma cell lines into the subcutis and caecal wall of nude mice. The expression of VEGF-C and VEGF-D mRNAs and proteins were examined by reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. Under culture conditions, VEGF-C mRNA was not detected in KM12 cells; however, VEGF-C expression was detected after implantation of KM12 cells into nude mice. VEGF-C and VEGF-D protein contents were higher in orthotopic (caecal wall) tumours than in ectopic (subcutis) tumours. Small vessels expressing VEGF receptor-3 were observed in the peripheral portions of caecal tumours. In metastatic liver tumours, VEGF-C and VEGF-D proteins were produced in lower amounts than those in caecal tumours. These data suggest that the expression of lymphangiogenic factors is influenced by the organ microenvironment. Therefore, experimental studies of colon cancer lymphangiogenesis should be performed with orthotopic implantation models.

Animals↗
PubMed2006

The role of the bone microenvironment in the pathophysiology and therapeutic management of multiple myeloma: interplay of growth factors, their receptors and stromal interactions.

The close relationship between the biological behaviour of malignant cells and the local microenvironment where they reside is a feature of diverse neoplasias. Multiple myeloma (MM) is considered a main disease model for the study of such interactions and the mechanisms that can lead to bone-related clinical complications, as well as the role of these interactions in attenuating the activity of conventional anti-MM therapeutics, such as dexamethasone and cytotoxic chemotherapeutics. This review focuses on recent progress in the study of interactions of MM cells with their local microenvironment. Major emphasis is placed on how bone marrow stromal cells (BMSCs) and other normal constituents of the bone marrow milieu promote, through cell adhesion- and cytokine-mediated mechanisms, the ability of MM cells to resist conventional anti-MM therapies. The review also addresses ongoing research into these mechanisms, which has already provided several new molecular targets and corresponding therapeutic strategies, such as the proteasome inhibitor bortezomib and thalidomide derivatives (e.g. lenalidomide), for the management of myeloma.

Bone Diseases↗
PubMed2005

Changes in the tumor microenvironment during low-dose-rate permanent seed implantation iodine-125 brachytherapy.

PURPOSE: There is a lack of data regarding how the tumor microenvironment (e.g., perfusion and oxygen partial pressure [pO2]) changes in response to low-dose-rate (LDR) brachytherapy. This may be why some clinical issues remain unresolved, such as the appropriate use of adjuvant external beam radiation therapy (EBRT). The purpose of this work was to obtain some basic preclinical data on how the tumor microenvironment evolves in response to LDR brachytherapy. METHODS AND MATERIALS: In an experimental mouse tumor, pO2 (measured by electron paramagnetic resonance) and perfusion (measured by dynamic contrast-enhanced magnetic resonance imaging) were monitored as a function of time (0-6 days) and distance (0-2 mm and 2-4 mm) from an implanted 0.5 mCi iodine-125 brachytherapy seed. RESULTS: For most of the experiments, including controls, tumors remained hypoxic at all times. At distances of 2-4 mm from radioactive seeds ( approximately 1.5 Gy/day), however, there was an early, significant increase in pO2 within 24 h. The pO2 in that region remained elevated through Day 3. Additionally, the perfusion in that region was significantly higher than for controls starting at Day 3. CONCLUSION: It may be advantageous to give adjuvant EBRT shortly (approximately 1 to 2 days) after commencement of clinical LDR brachytherapy, when the pO2 in the spatial regions between seeds should be elevated. If chemotherapy is given adjuvantly, it may best be administered just a little later (approximately 3 or 4 days) after the start of LDR brachytherapy, when perfusion should be elevated.

Animals↗
PubMed2006

Probing the role of microenvironment for microencapsulated Sacchromyces cerevisiae under osmotic stress.

Cell encapsulation opens a new avenue to the oral delivery of genetically engineered microorganism for therapeutic purpose. Osmotic stress is one of the universal chemical stress factors in the application of microencapsulation technology. In order to understand the effect and mechanism of the encapsulated microenvironment on protecting cells from hyper-osmotic stress, yeast cells of Saccharomyces cerevisiae Y800 were encapsulated in calcium alginate micro-gel beads (MB), alginate-chitosan-alginate (ACA) solid core microcapsules (SCM), and ACA liquid core microcapsules (LCM), respectively. The stress-induced intracellular components and enzyme activity including trehalose, glycerol and super oxide dismutase (SOD) were measured. Free cell culture was used as control. The survival of encapsulated cells and the cells released from MB, SCM and LCM after osmotic shock induced by NaCl solution (1, 2 and 3M) was evaluated. An analysis method was established to probe the effect of encapsulated microenvironment on the cell tolerance to osmotic stress. The results showed that LCM gave rise to the highest level of intracellular trehalose and glycerol, and SOD activity, as well as the highest survival rate of encapsulated cells or cells released from microcapsule. It was demonstrated that LCM was able to induce the highest stress response and stress tolerance of cells, which was adapted during culture, while SCM failed. The theoretical analysis revealed that it was the liquid alginate matrix in microcapsule that played a central role in domesticating the cells to adapt to hyper-osmotic stress. This finding provides a very useful guideline to cell encapsulation.

Alginates↗