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PubMed1989

Regulation of a membrane-bound proteinase in mammalian cells.

Cellular proteolytic enzymes are regulated by multiple mechanisms that affect gene expression, enzyme concentration, and enzyme activity. The expression of the membrane-bound metallo-endopeptidase, meprin, in different mammalian species, strains, tissues and cell types is highly variable. Meprin is exclusively localized to the plasma membrane, and this determines the types of substrates the enzyme will encounter and the microenvironment for activity. Recent studies have revealed an inactive form of a meprin-like proteinase that can be activated in vitro by proteases, and this raises the possibility of regulation of enzyme activity at the cell surface in response to environmental stimuli. In this chapter, the current knowledge about meprin, and the meprin-like inactive forms in mouse kidney is discussed.

Animals↗
PubMed1987

Immunoperoxidase demonstration of the cellular composition of the normal and coeliac small bowel.

Immunohistological analysis of the cellular composition of the small intestinal mucosa in a group of untreated and treated coeliac patients and non-coeliac control subjects was performed using monoclonal antibodies and an immunoperoxidase technique. A characteristic cellular distribution was observed within the normal mucosa. The intraepithelial and lamina propria compartments were occupied mainly by T suppressor/cytotoxic and T helper/inducer cells respectively. Further subdivision of lamina propria T helper/inducer cells with the Leu 8 antibody revealed that these were of the Leu 3a+ Leu 8- phenotype. Macrophages, defined by the RFD7 antibody, were seen to occupy the same microenvironment as T helper/inducer cells. T cells expressing the T cell activation antigen defined by anti-Ta1 were found with the normal lamina propria, although few cells were identified by the anti-Tac antibody. HLA-Dr antigens were expressed by stellate cells within the lamina propria, and also by the epithelial cells of the villi, but not by normal crypt epithelial cells. In untreated coeliac patients the distribution of the various cell types was essentially unchanged, although the number of these cells was markedly increased, including those which expressed the Ta1 antigen. A significant deviation from normal in the expression of HLA-DR antigens was found in the coeliac small bowel: these antigens were expressed not only on the villous epithelial cells but also on the epithelial cells of the crypts. Immunohistological findings in the treated coeliac patients were intermediate between the normal and untreated coeliac groups, and were completely normal in those patients with complete histological resolution of their disease. These results suggest that coeliac disease is accompanied by an enhanced stimulation of the normal mucosal immune response and do not imply a primary pathogenic role for the immune system in this disease.

Antigens, Surface↗
PubMed2004

NFAT5/TonEBP mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment.

Osmotic stress responses are critical not only to the survival of unicellular organisms but also to the normal function of the mammalian kidney. However, the extent to which cells outside the kidney rely on osmotic stress responses in vivo remains unknown. Nuclear factor of activated T cells 5 (NFAT5)/tonicity enhancer binding protein (TonEBP), the only known osmosensitive mammalian transcription factor, is expressed most abundantly in the thymus and is induced upon lymphocyte activation. Here we report that NFAT5/TonEBP is not only essential for normal cell proliferation under hyperosmotic conditions but also necessary for optimal adaptive immunity. Targeted deletion of exons 6 and 7 of the Nfat5 gene, which encode a critical region of the DNA-binding domain, gave rise to a complete loss of function in the homozygous state and a partial loss of function in the heterozygous state. Complete loss of function resulted in late gestational lethality. Furthermore, hypertonicity-induced NFAT5/TonEBP transcriptional activity and hsp70.1 promoter function were completely eliminated, and cell proliferation under hyperosmotic culture conditions was markedly impaired. Partial loss of NFAT5/TonEBP function resulted in lymphoid hypocellularity and impaired antigen-specific antibody responses in viable heterozygous animals. In addition, lymphocyte proliferation ex vivo was reduced under hypertonic, but not isotonic, culture conditions. Direct measurement of tissue osmolality further revealed lymphoid tissues to be hyperosmolar. These results indicate that lymphocyte-mediated immunity is contingent on adaptation to physiologic osmotic stress, thus providing insight into the lymphoid microenvironment and the importance of the NFAT5/TonEBP osmotic stress response pathway in vivo.

Animals↗
PubMed2006

Oncogenic properties of the endogenous fatty acid metabolism: molecular pathology of fatty acid synthase in cancer cells.

PURPOSE OF REVIEW: This review documents our rapidly changing perspectives on the function of fatty acid synthase-catalyzed endogenous fatty acid biogenesis in cancer biology. RECENT FINDINGS: Up-regulation of fatty acid synthase gene expression and fatty acid synthase biosynthetic activity are molecular events accompanying the pathogenesis and natural history of cancer disease. First, the increased fatty acid synthase gene expression in precursor, preinvasive and invasive cancer lesions appears to represent an indirect, early epiphenomenon, occurring in response to a microenvironment containing regions of poor oxygenation and high acidity due to, for example, lack of an adequate angiogenesis and/or nutritional supply. Second, aberrant transduction cascades driven by cancer-associated oncogenic changes subvert the downregulatory effects of circulating fatty acids. Third, fatty acid synthase-dependent endogenous fatty acid metabolism actively contributes to cancer evolution by specifically regulating the expression, activity and/or cellular localization of proteins closely related to malignant transformation and/or cancer progression. SUMMARY: Fatty acid synthase-catalyzed endogenous fatty acid metabolism appears to be an obligatory acquisition selecting a biologically aggressive sub-group of cancer cells capable of growth and survival upon stresses such as hypoxia, low pH and/or nutritional deprivation. Considering that an ever-growing body of evidence demonstrates that fatty acid synthase-driven signalling actively regulates key cancer-controlling networks, we may hereafter redefine fatty acid synthase as a metabolic oncogene in human cancer cells.

Dietary Fats↗
PubMed2005

Regulation of WUSCHEL transcription in the stem cell niche of the Arabidopsis shoot meristem.

Pluripotent stem cells are localized in specialized microenvironments, called stem cell niches, where signals from surrounding cells maintain their undifferentiated status. In the Arabidopsis thaliana shoot meristem, the homeobox gene WUSCHEL (WUS) is expressed in the organizing center underneath the stem cells and integrates regulatory information from several pathways to define the boundaries of the stem cell niche. To investigate how these boundaries are precisely maintained within the proliferating cellular context of the shoot meristem, we analyzed the transcriptional control of the WUS gene. Our results show that the WUS promoter contains distinct regulatory regions that control tissue specificity and levels of transcription in a combinatorial manner. However, a 57-bp regulatory region is all that is required to control the boundaries of WUS transcription in the shoot meristem stem cell niche, and this activity can be further assigned to two adjacent short sequence motifs within this region. Our results indicate that the diverse regulatory pathways that control the stem cells in the shoot meristem converge at these two short sequence elements of the WUS promoter, suggesting that the integration of regulatory signals takes place at the level of a central transactivating complex.

Arabidopsis↗
PubMed2006

FAK signaling in neoplastic disorders: a linkage between inflammation and cancer.

Focal adhesion kinase (FAK), a nonreceptor protein tyrosine kinase, is frequently overexpressed in various tumors and its expression shows good correlation with the progression of tumor. FAK is involved in a diverse range of critical cellular events including spreading, proliferation, migration, and invasion. In addition to these cellular functions, we found that FAK signaling played a critical role in the production of matrix metalloproteinases (MMP) such as MMP-2 and MMP-9 and subsequently activated tumor invasion. Moreover, we found that tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine that acts as an endogenous tumor promoter, activated FAK signaling and enhanced tumor invasion. Since the tumor microenvironment that is largely orchestrated by cytokines is a critical component of tumor progression, these results suggest the importance of FAK as a signaling molecule involved in tumorigenesis. Here, we review the general structure and binding partners of FAK, its regulatory mechanism, and expression in tumors. By summarizing our recent studies, we focus on the critical role of FAK that links cancer with inflammation.

Animals↗
PubMed2002

Angiogenesis and mineralization during distraction osteogenesis.

Distraction osteogenesis is currently a standard method of bone lengthening. It is a viable method for the treatment of short extremities as well as extensive bone defects, because large amounts of bone can be regenerated in the distraction gap. Mechanical stimulation by distraction induces biological responses of skeletal regeneration that is accomplished by a cascade of biologic processes that may include differentiation of pluripotential tissue, angiogenesis, mineralization, and remodeling. There are complex interactions between bone-forming osteoblasts and other cells present within the bone microenvironment, particularly vascular endothelial cells that may be pivotal members of a complex interactive communication network in bone. Regenerate bone forms by three modes of ossification, which include intramembranous, enchondral, and transchondroid ossifications, although intramembraneous bone formation is the predominant mechanism of ossification. In this review we discussed the coupling between angiogenesis and mineralization, the biological and mechanical factors affecting them, the cellular and molecular events occurring during distraction osteogenesis, and the emerging modalities to accelerate regenerate bone healing and remodeling.

Animals↗
PubMed1999

American Association for Cancer Research--90th annual meeting. 10-14 April 1999, Philadelphia, PA, USA.

A major focus of this year's American Association for Cancer Research (AACR) meeting was the microenvironment of the tumor and tumor angiogenesis, as well as the development of drugs that affect tumor growth by use of extratumoral targets. Other areas of interest were advances in chemoprevention, cancer vaccines, gene therapy approaches and drug-resistance features. As before, many novel compounds affecting tumor cells were introduced, either being analogs of standard cytostatic agents or directed against new cellular targets. Mechanisms of action were further unraveled and emphasis was put on the various signals within a tumor cell to enter cell death through apoptosis. Molecular biology technology was dedicated to the development of tests to measure gene expression in small tissue samples.

Journal Article↗
PubMedDate not supplied

Ovarian follicular lipoapoptosis: structural, cytochemical and metabolic basis of reproductive tract atrophy following expression of the hypogonadal diabetes (db/db) syndrome.

The diabetes (db/db) mutation (i.e., leptin membrane receptor defect) promotes a progressive, hypercytolipidemia within ovarian follicular granulosa, thecal and interstitial layers of C57BL/KsJ mice which manifests an infertile, acyclic hypogonadal syndrome. The current studies focus on the structural, cytochemical and gluco-/lipo-metabolic changes which induce cellular lipoapoptosis and the resulting cytostructural disruption of db/db follicular populations, relative to littermate control indices, following the expression of progressive ovarian hypercytolipidemia. Control (normal: +/+ and +/?) and diabetes (db/db) genotype groups were prepared for high resolution light microscopic (HRLM) analysis of cytolipidemia and nuclear apoptosis (TUNEL-labeled 3'-DNA fragmentation) indices and compared to the transmission electron (TEM) microscopic analysis of ovarian follicular samples collected from 8-16-week-old groups. Compared to controls, the db/db mutation induced a dramatic increase in cytolipid vacuole volume and density within all ovarian follicular layers. TEM analysis revealed that the lipid vacuoles initially aggregated along the inner membrane compartments of affected thecal and granulosa cells in response to the interstitial and vaso-lipidemic-hyperglycemic conditions which characterized the ovarian microenvironment of db/db follicles. Progressive cytoplasmic movement of lipid pools into the perinuclear compartment of affected granulosa cells induced nuclear isolation from cytoplasmic organelles that were displaced towards peripheral intracellular compartments. Cytochemical analysis of lipid vacuole accumulations indicated attraction towards, and incorporation within, the nuclear envelope of hyperlipidemic cells. Co-localization of nuclear apoptotic 3'-DNA fragments within identified hyperlipidemic granulosa cells was coincident with the cytochemical and ultrastructural identification of lipid penetration through the nuclear envelope in db/db mutants. These results are the first cytochemical evidence that the lipometabolic disturbances in db/db mutants, which promote hypercytolipidemia-induced premature ovarian involution, are coincident with lipoapoptosis-induced nuclear dissolution within follicular granulosa layers. The lipidemia-induced alterations in cellular and nuclear architecture suggests that the disturbances in glucose and lipid metabolic cascade activities in diabetes (db/db) mutants disrupts follicular cytointegrity, culminating in nuclear disregulation (as indicated by lipoapoptosis) which results in premature reproductive tract organo-involution and manifest reproductive sterility.

Adipocytes↗
PubMed1995

Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages.

Studies over the past 20 years have established that the development of new capillaries from an existing vascular network (a process called angiogenesis) is an essential component of tumor growth. Malignant tumors do not grow beyond 2-3 mm3 in size unless they stimulate the formation of new blood vessels and thus provide a route for the increased inflow of nutrients and oxygen and outflow of waste products. Tumor angiogenesis also provides an essential exit route for metastasizing tumor cells from the tumor to the bloodstream. Indeed, extensive neovascularization is a poor prognostic factor in several forms of human cancer. Angiogenesis is a complex, multistep process driven by many local signals within the tumor. This involves the degradation of the extracellular matrix around a local venule after the release of collagenases and proteases, the proliferation and migration of capillary endothelial cells, and their differentiation into functioning capillaries. Cytokines produced by various cell types present within the microenvironment of solid tumors form a complex, dynamic network in which they have multiple effects on tumor progression. Herein we review our work on the presence, and possible regulatory influence on tumor angiogenesis, of a number of these cytokines within invasive breast carcinomas. We have combined immunocytochemistry with a single cell cytokine release assay called the reverse hemolytic plaque assay to investigate the cellular sources of the key angiogenic cytokines, vascular endothelial growth factor, basic fibroblast growth factor, and tumor necrosis factor-alpha. Tumor-associated macrophages in the stromal compartment of these tumors and/or malignant epithelial cells were seen to be a major producer cell for these cytokines, whereas tumor necrosis factor-alpha receptors were expressed by leukocytes, malignant cells, and endothelial cells in tumor blood vessels.

Antigens, CD↗
PubMed1993

Mathematical models of marrow cell kinetics: differential effects of protracted irradiations on stromal and stem cells in mice.

UNLABELLED: It is known that hematopoiesis is supported by bone-marrow stem cells, but those cells must seed and grow on a stromal microenvironment. Typically, studies have shown that a surviving fraction of about 30 hematopoietic stem cells (HSCs) (i.e., about 0.04%) correspond to the LD50, although other studies have shown that marrow can repopulate from a single viable cell under strong regiments of antibiotics and infusions of irradiated blood elements. PURPOSE: This paper describes comparisons between our results (from maximum-likelihood estimation techniques for cellular damage, repair, and compensatory repopulation) and published experimental data on marrow stromal cells. METHODS AND MATERIALS: After biophysical consideration of the rate constants that were derived by maximizing the likelihood function (a consideration necessary to extend the model to cell populations not indicated by the model as "critical" for recovery), the rate constants for cellular damage to stem cells are fitted to experimental data. Rate constants for repair and proliferation of stem cells are assigned based on published data on repair/proliferation half-times, and these assignments affect the evaluation of the rate constants for cellular damage. From the two models, that is one for "critical" cells (having radiosensitive and repopulation characteristics similar to stromal cells) and another for stem cells, effects on two cell populations of different radiosensitivities and repopulation rates can be demonstrated for complex schedules of protracted irradiations which could reduce either cell population below a critical need for marrow repopulation. RESULTS: Our analysis of animal mortality data has indicated that recovery of an animal from potentially lethal irradiation is dominantly regulated by cells with survival and repopulation characteristics similar to those of stroma cells. CONCLUSION: In contrast to the surviving fraction of hematopoietic stem cells, it appears that the probability of an animal's recovery is high if the "critical" population of cells is above 1% (our "best" maximum likelihood estimate, from mouse data, with the corresponding lower confidence bound at about 0.2%). Of course, a few stem cells--perhaps only one--must maintain a potential for repopulation of blood and marrow.

Animals↗
PubMed2005

Tumours can adapt to anti-angiogenic therapy depending on the stromal context: lessons from endothelial cell biology.

It has long been recognized that interference with the blood supply of a tumour is an effective way to halt tumour progression, and even induce tumour regression. This can be accomplished by anti-angiogenic treatment which prevents the formation of a tumour neovasculature, or anti-vascular treatment, which aims at destruction of existent tumour vessels. The latter has received relatively little attention because there is a lack of specific tumour-endothelial markers. Instead, the current detailed knowledge on the factors and mechanisms, involved in angiogenesis, has enabled the development of a variety of angiogenesis inhibitors, especially those that target cellular signalling by vascular endothelial growth factor-A (VEGF-A), the most potent angiogenic factor known. These inhibitors have received lots of attention because they effectively inhibit tumour growth in pre-clinical models. However, in clinical trials these same inhibitors showed very poor anti-tumour activity. In this review we discuss this discrepancy, and we show that the tumour microenvironment is crucial to the sensitivity of tumours to anti-angiogenic therapy.

Angiogenesis Inhibitors↗
PubMed2006

Albumin marks pseudopodia of astrocytoma cells responding to hepatocyte growth factor or serum.

It is well accepted that dysfunction in the blood brain barrier (BBB) allows permeation of albumin from the bloodstream into astrocytic brain tumors, especially glioblastomas, the most aggressive astrocytomas. In vitro, bovine serum albumin (BSA) aids functional cell assays by maintaining cytokines and growth factors in solution and delivering its cargo of fatty acids. Earlier, we showed that BSA was prominent in lysates prepared from pseudopodia formed by U87 astrocytoma cells. The present studies investigated the association of albumin with pseudopodia formed by U87 and LN229 astrocytoma cells. With hepatocyte growth factor (HGF) stimulation, cell migration was enhanced and BSA, especially its dimerized form, was prominent in pseudopodia compared to unmigrated cells on one-dimensional gels and immunoblots. When lysates were equalized for levels of glyceraldehyde-3-phosphate dehydrogenase, the rise for BSA levels in pseudopodia vs migrated cells was comparable or greater than levels noted for established pseudopodial proteins, beta-actin and ezrin. The increase for dimerized BSA in pseudopodia compared to unmigrated cells was greater than the rise in levels of beta-actin, ezrin, HGF, and phosphorylated Met when pseudopodia were harvested from filters with 1 mum pores using either cell line. Fluorescein (F)-labeled BSA co-localized with HGF on actin-rich cellular protrusions and with CM-DiI labeled pseudopodial plasma membranes. The F-BSA highlighted small, individual pseudopodial profiles more so than complex pseudopodial networks (reticulopodia) or unmigrated cells. Labeled human serum albumin also decorated pseudopodia preferentially. Albumin's association with pseudopodia may help to explain its selective accumulation in astrocytomas in vivo. The leaky BBB permits serum albumin to enter the microenvironment of astrocytomas thus allowing their invasive cells contact with serum albumin as a source of fatty acids that would be useful for remodeling cell membranes in pseudopodia. Thus, albumin potentially aids and marks invasion as it accumulates in these tumors.

Actins↗
PubMed2003

Proliferation and micromilieu during fractionated irradiation of human FaDu squamous cell carcinoma in nude mice.

PURPOSE: Previous functional radiobiological experiments demonstrated a significant acceleration of repopulation after 3 weeks and reoxygenation after 12 days of radiotherapy of FaDu tumours. Owing to the temporal coincidence between repopulation and reoxygenation, it was hypothesized that the improved oxygenation status during fractionated irradiation might be the preceding stimulus for increased proliferation. The study investigated whether these changes in repopulation and re-oxygenation are reflected by histological parameters of proliferation and the tumour micromilieu. MATERIALS AND METHODS: Human FaDu squamous cell carcinomas in nude mice were irradiated with three to 18 fractions of 3 Gy daily or every second day under normal blood flow and clamp hypoxia. At different time points, tumours were excised and stained for Ki67, BrdUrd, epidermal growth factor receptor (EGFR) and markers of the micromilieu (HOECHST 33342, pimonidazole, ER-MP12). RESULTS: On average, Ki67 and BrdUrd labelling indices decreased initially and increased again at later times during the course of fractionated radiotherapy. A similar kinetic pattern was found for the staining intensity of the EGFR. The vascular density in the viable tumour area remained constant during the whole course of irradiation, while the perfused fraction of vessels decreased within the first week of irradiation and returned to baseline values after 2 weeks. There was a corresponding increase in perfusion and a decrease in cellular hypoxia. CONCLUSIONS: The histological results were in surprisingly good agreement with the kinetics of clonogen repopulation and re-oxygenation determined previously using functional assays. The results support that the kinetics of repopulation of FaDu squamous cell carcinoma in response to fractionated irradiation are determined not only by intracellular processes, but also by a complex interaction of proliferation parameters with a changing microenvironment.

Animals↗
PubMed2005

Bone marrow-derived mesenchymal stem cells.

Human mesenchymal stem cells (MSCs) contribute to the regeneration of mesenchymal tissues, and are essential in providing support for the growth and differentiation of primitive hemopoietic cells within the bone marrow microenvironment. Techniques are now available to isolate human MSCs and manipulate their expansion in vitro under defined culture conditions without change of phenotype or loss of function. Mesenchymal stem cells have generated a great deal of interest in many clinical settings, including that of regenerative medicine, immune modulation and tissue engineering. Studies have already demonstrated the feasibility of transplanted MSCs providing crucial new cellular therapy. In this review, many aspects of the MSC will be discussed, with the main focus being on clinical studies that describe the potential of MSCs to treat patients with hematological malignancies who are undergoing chemotherapy and/or radiotherapy.

Bone Marrow Cells↗
PubMed1990

A cell cycle analysis of growth-related genes expressed during T lymphocyte maturation.

Fetal liver or bone marrow-derived T lymphocyte precursors undergo extensive, developmentally regulated proliferation in response to inductive signals from the thymic microenvironment. We have used neonatal mouse thymocytes size-separated by centrifugal elutriation to study the cell cycle stage-specific expression of several genes associated with cell proliferation. These include genes involved in the biosynthesis of deoxyribonucleotide precursors, such as dihydrofolate reductase (DHFR), thymidylate synthase (TS), and the M1 and M2 subunits of ribonucleotide reductase, as well as c-myc, a cellular oncogene of unknown function. Using nuclear run-on assays, we observed that the transcription rates for these genes, with the exception of TS, are essentially invariant not only throughout the cell cycle in proliferating cells, but also in noncycling (G0) cells. The TS gene showed a transient increase in transcription rate in cells which bordered between a proliferating and nonproliferating status. Studies of an elutriated T cell line, S49.1, yielded similar results, indicating that the process of immortalization has not affected the transcriptional regulation of these genes. Analysis of steady-state mRNA levels using an RNase protection assay demonstrated that the levels of DHFR and TS mRNA accumulate as thymocytes progress through the cell cycle. In contrast, only the M2 subunit of ribonucleotide reductase showed cyclic regulation. Finally, in contrast to cultured cell models, we observed an abrupt fivefold increase in the steady-state level of c-myc mRNA in the transition from G1 to S-phase. We conclude from these studies that the transcriptional regulation of specific genes necessary for cellular proliferation is a minor component of the developmental modulation of the thymocyte cell cycle.

Animals↗
PubMed2001

Quantitative expression of adhesion molecules on granulocyte colony-stimulating factor-mobilized peripheral blood, bone marrow, and cord blood CD34+ cells.

The purpose of this study is to investigate the function of the main adhesion receptors on CD34(+) cells during hematopoietic stem cell transplantation. Expression was quantified by flow cytometry using calibration beads. CD34(+) cells were isolated from either bone marrow (BM), cord blood (CB), or peripheral blood (PB) from study patients and a control group after granulocyte colony-stimulating factor (G-CSF) administration. The study of the CD34(+) cell differentiation showed that CD34(+) cells are mainly CD38(+) and HLA-DR(+), whatever the type of harvest. However, quantitative analysis elicited a weaker expression of CD38 on PB and CB CD34(+) cells in comparison to BM CD34(+) cells. The proportions of CD34(+)/CD49d(+) and CD34(+)/CD49e(+) were smaller on PB cells, without quantitative expression variation. This phenotypic variation promotes CD34(+) cells to exit from BM into circulation, inducing the mobilization. The homing of the CD34(+) cells to the BM involves the CD62L receptor. The expression of this receptor was found to be more frequent and stronger on PB cells than on BM or CB cells. The CD11b, CD18, and CD54 receptors are implicated in CD34(+) cell adhesion to BM microenvironment. No significant variation in CD34(+)/CD11b(+) and CD34(+)/CD18(+) cell frequency was noted. Moreover, the CD54 receptor was more frequently expressed on CB and PB cells. Quantitative analysis revealed that CD18 was more strongly expressed on BM than on PB cells to promote progenitors adhesion by interacting with stromal cells. Finally, the quantitative expression of the main receptors on CD34(+) cells explained cellular functions during the different steps of hematopoietic stem cells transplantation.

ADP-ribosyl Cyclase↗
PubMed2001

A novel preclinical model of human malignant melanoma utilizing bioreactor rotating-wall vessels.

Malignant melanoma poses a serious health risk which is becoming more crucial as the incidence of this disease steadily increases. The development of appropriate in vitro models that reflect the in vivo tumor environment is a key factor for the study of this malignancy. The local tumor microenvironment plays a critical role in the ability of tumor cells to proliferate and metastasize. While interactions among various cell types are known to be important for tumor growth, most in vitro models utilize only tumor cells, ignoring the importance of tumor-stroma interactions, as well as the contribution of immune cells, which may be important for potential therapies. In addition, the cellular architecture found in vivo, known to be involved in changes in gene expression, is not reflected in standard two-dimensional culture systems. In this study, we have utilized rotating-vessel bioreactors to culture minced human melanoma specimens, allowing the culture of three-dimensional structures which reflect the cellular architecture and heterogeneous composition of the tumor site in vivo. The viability of the pieces in culture can be maintained for 1-2 wk. Immunohistochemical analysis shows multiple cellular types similar to the in vivo situation. Therefore, this system provides a unique model of human melanoma that mimics the in vivo tumor environment much more closely than current culture methods. This novel system may be utilized to determine the mechanism of action of current therapy protocols, as well as to develop new treatment regimens.

Antigens, CD↗