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At least 793 records · Page 44Linked to original sources
PubMed2005

Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression.

EphA2 belongs to a unique family of receptor tyrosine kinases that play critical roles in development and disease. Since EphA2 is required for ephrin-A1 ligand-induced vascular remodeling and is overexpressed in a variety of vascularized human adenocarcinomas, we assessed tumor angiogenesis and metastatic progression in EphA2-deficient host animals. 4T1 metastatic mammary adenocarcinoma cells transplanted subcutaneously and orthotopically into EphA2-deficient female mice displayed decreased tumor volume, tumor cell survival, microvascular density, and lung metastasis relative to tumor-bearing littermate controls. To determine if the phenotype in EphA2-deficient mice was endothelial cell intrinsic, we also analyzed endothelial cells isolated from EphA2-deficient animals for their ability to incorporate into tumor vessels in vivo, as well as to migrate in response to tumor-derived signals in vitro. EphA2-deficient endothelial cells displayed impaired survival and failed to incorporate into tumor microvessels in vivo, and displayed impaired tumor-mediated migration in vitro relative to controls. These data suggest that host EphA2 receptor tyrosine kinase function is required in the tumor microenvironment for tumor angiogenesis and metastatic progression.

Adenocarcinoma↗
PubMed1997

Brain cell microenvironment effects on neuron excitability and basal metabolism.

In a model of neurons in a brain cell assembly, changes in volume of the extracellular space affect neuronal excitability and basal metabolism. A widely applicable coefficient of excitability with respect to a variation of the volume fraction has been determined. Calculations suggest that chloride increases membrane stability by indirectly promoting an acceleration of the metabolic pumping rate as a response to a diminished extracellular volume fraction. Volume fraction changes induced by cell swelling in a compact and highly tortuous microenvironment may play a role in epilepsy and, following brain damage, in cell death and recovery.

Basal Metabolism↗
PubMed1991

Cellular pathology of the nerve microenvironment in galactose intoxication.

The effect of chronic hyperglycemia and polyol pathway activation on the Schwann cell has not been resolved although injury to this cell has long been suspected in diabetic neuropathy. Hyperglycemia, resulting from galactose intoxication of four months duration, induces dose-dependent accumulations of endoneurial fluid sodium and chloride that are linked to polyol pathway activity and associated with dose-dependent increases in sciatic nerve water content, endoneurial fluid pressure and (Na+, K+)-ATPase activity. In order to understand the impact of these changes on the nerve microenvironment, cellular elements of the endoneurium were quantitatively and qualitatively assessed in rats receiving 0%, 10%, 20% or 40% galactose diets. After four months of galactose intoxication, dose-dependent changes in the size distribution of myelinated nerve fibers were apparent. A shift in size-frequency histograms of galactose-intoxicated animals towards smaller fibers was accompanied by a decrease in axon diameter and the volume fraction ratio of axon to myelinated nerve fibers. In the sciatic nerve of all 40% galactose-fed rats examined by electron microscopy, Schwann cells of myelinated fibers showed both reactive and degenerative changes. Demyelination was preceded by splitting at the intraperiod line. Remyelination was identified by axons with disproportionately thin myelin sheaths. Axonal dystrophy and degeneration were infrequently seen, but there was axonal regeneration. Dose-dependent increases in mast cell number were observed with degranulation apparent in rats receiving 20% and 40% galactose. Endothelial cell number and basal lamina thickness were increased in the endoneurial vessels of galactose-intoxicated rats. Increased cytoplasmic area and degenerative changes in pericytes were also noted. These observations indicate that significant morphologic changes accompany the hyperosmotic imbalance resulting from galactose intoxication of four months duration. Schwann cell injury and demyelination are present in a disorder linked to polyol metabolism since aldose reductase, the anabolic enzyme of the polyol pathway, is localized to this myelin-forming cell.

Animals↗
PubMed2002

Factors in the fracture microenvironment induce primary osteoblast angiogenic cytokine production.

Neoangiogenesis is essential for successful wound repair. Platelets are among the earliest cells recruited to a site of skeletal injury and are thought to provide numerous factors critical to successful repair. The release of platelet-derived growth factor (PDGF) after skeletal injury increases osteoblast proliferation, chemotaxis, and collagen synthesis; however, its angiogenic effect on osteoblast biology remains unknown. The purpose of this study was to investigate the effect of recombinant human (rh)PDGF-BB on the synthesis of vascular endothelial growth factor (VEGF) by primary neonatal rat calvarial osteoblasts. Furthermore, the authors investigated whether PDGF works in concert with hypoxia, another component of the fracture microenvironment, to additively or synergistically induce VEGF production. Osteoblast cultures were stimulated with varying concentrations of rhPDGF-BB (1, 10, 50, and 100 ng/ml) in normoxic and hypoxic (<1% oxygen) conditions for 0, 3, 6, 12, and 24 hours, and VEGF gene expression was analyzed by Northern blot analysis. To determine whether rhPDGF-BB-induced VEGF messenger RNA (mRNA) expression was transcriptionally mediated or required de novo protein synthesis, transcription, and translation, studies were performed using actinomycin D and cycloheximide, respectively. Treatment with 50 ng/ml rhPDGF-BB resulted in a 2.4-fold increase in VEGF mRNA expression after 3 hours. Interestingly, rhPDGF-BB and hypoxia seemed to have an additive effect, resulting in a 3.7-fold increase in VEGF mRNA expression after 6 hours in primary neonatal rat calvarial osteoblasts. Furthermore, by using actinomycin D and cycloheximide, the authors demonstrated that the rhPDGF-BB-induced VEGF mRNA expression was transcriptionally mediate and not dependent on de novo protein synthesis. These data demonstrate that rhPDGF-BB transcriptionally increases osteoblasts VEGF mRNA expression in vitro. Furthermore, the semiquantitative results suggest that rhPDGF-BB and hypoxia act additively to increase VEGF mRNA expression. It is postulated that similar mechanisms may occur in vivo, at a site of skeletal injury, to induce neoangiogenesis and promote fracture repair.

Animals↗
PubMed1986

The splenic microenvironment and self recognition as factors in allograft rejection in rats. A study using indium-111-labeled cells.

Splenectomy facilitates organ allograft survival in some rat strains, and in weak donor-recipient histoincompatible pairs. We have found using a heart spleen "twin" graft model, using ACI rats as recipients and Lewis rats as donors, that the transplanted heart will survive in most recipients after delayed host splenectomy. The presence of a viable mass of splenic tissue will allow rejection to proceed only when the transplanted spleen is of host origin, and not when it comes from the donor (i.e., when it is allogeneic). The use of 111In-labeled cells has allowed us to show that lymphocyte traffic and trapping is markedly altered in the transplanted allogeneic spleens, when compared with control transplanted syngeneic spleens. Thus, despite the presence of the splenic "microenvironment," cardiac allograft rejection does not occur in the absence of syngeneic splenic tissue. We conclude that the role of the spleen in the immune response is to facilitate the recognition of self and the acquisition of alloreactivity in weak responder rat strains and donor-recipient pairs.

Animals↗
PubMed1991

Prevention of syngeneic graft-versus-host disease by recovery of thymic microenvironment after cyclosporine.

Following a course of cyclosporine, syngeneic rat radiation chimeras consistently develop a GVHD-like syndrome. Correlation of the thymic immunopathology with conditions leading to syngeneic graft-versus-host disease (sGVHD) suggested the hypothesis that reconstitution of the normal thymic microenvironment after CsA is necessary for self-tolerance. When thymic regeneration is impaired, as in rats receiving previous mediastinal irradiation, then self-reactive effector cells are not regulated and proceed to damage the target tissues. Alternately, it could be argued that the observed thymic abnormalities are irrelevant to sGVHD. To test the primary hypothesis, post-CsA thymic reconstitution was prevented by total thymectomy in unirradiated rats. These rats consistently developed acute type sGVHD seen at 7 and 21 days post-CsA while rats from the CsA-treated sham thymectomy control group failed to develop sGVHD. Because thymectomy prior to CsA blocks sGVHD, most likely the peripheral effector cells in the post-CsA thymectomy group were derived from the CsA-altered thymus. The absence of sGVHD in the sham group indicates that the thymus led to active regulation of these cells after stopping CsA. If regeneration of the thymus restored only negative selection, then the sham thymectomy group should have also developed sGVHD. Flow cytometry and morphology of the spleen and lymph nodes demonstrated that the thymectomized rats, like CsA-treated radiation chimeras, experienced a significant delay in maturation of T cells following CsA. In contrast to the usual model in radiation chimeras, however, the post-CsA thymectomized rats did not convert to chronic type sGVHD. The importance of an abnormal thymus for this transition was confirmed in syngeneic radiation chimeras. Thymectomy after CsA in these rats also blocked the rapid transition to chronic sGVHD.

Acute Disease↗
PubMed1998

Function of porcine adhesion molecules in a human marrow microenvironment.

BACKGROUND: One way to circumvent the need for chronic immunosuppression in solid organ xenografting may be to induce donor-specific tolerance using bone marrow transplantation. If this approach is to succeed in the pig-to-human species combination, pig marrow must be capable of maturing into relevant tolerance-inducing cells and replenishing itself in host human marrow. One possible barrier is adhesion molecule incompatibility. We have studied the compatibility across the pig-human species barrier of two well-characterized ligands known to be important in hematopoiesis, CD44 and very late antigen (VLA)-4. METHODS: In vitro long-term bone marrow cultures were studied in which the effects of blocking antibodies were assessed by measuring cell numbers and colony-forming units. RESULTS: The blocking of CD44 had a comparable inhibitory effect on the hematopoiesis of human and pig marrow, even if the latter was maintained on a human stromal layer. Both cellular proliferation and colony-forming activity were inhibited by anti-CD44 monoclonal antibody. By contrast, a significant difference was observed in VLA-4 usage by hematopoietic cells of the two species. Blocking VLA-4 markedly inhibited human hematopoietic cellular proliferation but had no effect on pig hematopoiesis, on either porcine or human stroma. CONCLUSIONS: The data suggest that the incompatibility of either CD44 or VLA-4 is unlikely to limit the efficiency of porcine hematopoiesis in a human marrow environment. However, the difference in VLA-4 utilization between these species raises the possibility that other interactions may be important for effective porcine hematopoiesis and that their failure to function between species may contribute to the poor function of porcine hematopoietic cells in primate marrow microenvironments.

Animals↗
PubMed1999

Transplantation of allogeneic or xenogeneic bone marrow within the donor stromal microenvironment.

Successful engraftment of hematopoietic stem cells requires a supportive hematopoietic stromal microenvironment (HSM). Defects in the HSM associated with aplastic anemia, myelofibrosis, or caused by intensive ionizing radiation and chemotherapy generally result in failure of bone marrow (BM) engraftment. Transplantation of donor BM within donor HSM may therefore provide optimal conditions for allogeneic BM transplantation. We have transplanted donor hematopoietic cells together with their own HSM to improve acceptance of allogeneic or xenogeneic BM. The non-myeloablative treatment used induced tolerance to murine allografts and provided conditions for the life-long acceptance of allogeneic HSM. Allogeneic BM transplanted within it's own HSM under the kidney capsule caused less graft-versus-host disease than BM transplanted i.v. Tolerance in mice to xenogeneic (rat) HSM was less complete. Ectopic ossicles were small and contained fewer hematopoietic cells. However, simultaneous transplantation of rat BM and HSM to preconditioned mice improved engraftment of rat BM compared with transplantation of BM alone. Donor hematopoietic cells survived longer on their own HSM than on HSM of recipients.

Animals↗
PubMedDate not supplied

Immune suppression in the tumor microenvironment.

The identification of tumor-expressed antigens that can be recognized by specific T lymphocytes has made it possible both to study the properties of T cells participating in anti-tumor immune responses in patients and also to develop antigen-specific immunotherapies as a treatment modality. Interestingly, moves toward intervention have proceeded at a faster pace than have investigations toward understanding. In melanoma in particular, many clinical trials of active immunization have been performed, and many of these have shown increases in tumor antigen-specific T cells circulating in the blood. However, clinical responses have been infrequent, arguing that mechanisms of resistance downstream from initial T cell priming may be dominant in many cases. In fact, may patients show spontaneous generation of immune effector cells and/or antibodies, implying that the priming phase has occurred already in such individuals even without vaccination. Recent attention has turned toward mechanisms of immune evasion at the effector phase of the anti-tumor immune response, predominantly within the tumor microenvironment. Evidence is accumulating that T cell-intrinsic hyporesponsiveness or anergy, extrinsic suppression by regulatory cell populations, inhibitory ligands such as PD-L1, soluble factors such as TGF-beta, and the activity of nutrient-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO), may contribute to immune escape in different settings. Murine preclinical models have shown that interfering with each of these processes can translate into T cell-mediated tumor control. Clinical studies to estimate the frequency of specific immune evasion mechanisms in individual patients, to correlate specific events with clinical outcome, and to develop strategies to counter resistance mechanisms should receive a high priority.

Animals↗
PubMed2007

Defining the ability of cyclophosphamide preconditioning to enhance the antigen-specific CD8+ T-cell response to peptide vaccination: creation of a beneficial host microenvironment involving type I IFNs and myeloid cells.

Although cyclophosphamide (CTX) has been clearly shown to enhance active specific and adoptive immunotherapies, the mechanism(s) underlying these beneficial effects have not been clearly defined. To define the impact of CTX preconditioning on the antigen-specific CD8 T-cell response to peptide vaccination, we used an adoptive transfer model based on the OT-1 T-cell receptor transgenic mouse. CTX preconditioning dramatically enhanced the antigen-specific CD8 T-cell response to peptide vaccination. Specifically, CTX significantly enhanced the expansion and function of responding CD8 T cells as demonstrated by flow cytometry and cytokine production. In parallel experiments, we attempted to define the mechanism(s) underlying these beneficial effects of CTX therapy. CTX therapy increased the relative number and activation status of myeloid dendritic cells, and was associated with the induction of significant levels of the inflammatory cytokines interferon-alpha, monocyte chemoattractant protein-1, and IL-6. Adoptive transfer experiments into type I IFNR-/- and CR3-/- mice confirmed that the beneficial effects of CTX were at least partially dependent on type I interferons and myeloid cells. Adoptive transfer of up to 150x10(6) naive spleen cells at the time of antigen-specific CD8 T-cell transfer did not abrogate the effects of CTX therapy, suggesting that the creation of a niche in the immune system may not be required. CTX decreased the absolute, but not relative number of CD4+CD25+ Treg cells, consistent with the possibility that regulatory T cells may be targeted by CTX therapy. Of note, combination therapy with CTX and a synthetic TLR3 agonist further enhanced the antigen-specific CD8+ T-cell response. Taken together, our data suggest that CTX modulates specific components of the innate immune system resulting in a beneficial host microenvironment. Specific targeting of these components may enhance the effectiveness of CTX preconditioning for adoptive immunotherapy.

Animals↗
PubMed2006

Polymer scaffolds as synthetic microenvironments for extrahepatic islet transplantation.

BACKGROUND: Problems associated with the hepatic transplantation of islets may preclude the broad application of islet transplantation. Thus, we sought to develop an approach to the extrahepatic transplantation of islets using a synthetic biodegradable polymer scaffold. METHODS: Microporous polymer scaffolds that allow vascular ingrowth and nutrient diffusion from host tissues were fabricated from copolymers of lactide and glycolide. Murine islets were transplanted without or with a scaffold onto intraperitoneal fat of syngeneic diabetic recipients. Bioluminescence imaging using a cooled charge-coupled device camera, immunohistochemistry, and glycemia were used to assess islet engraftment and function posttransplant. RESULTS: By bioluminescence imaging, islets transplanted on a polymer scaffold remain localized to the transplant site and survive for an extended period of time. Islets transplanted on scaffolds retained the architecture of native islets and developed a functional islet vasculature. Transplantation of marginal masses of islets on the polymer scaffold demonstrated improved islet function compared to transplantation without a scaffold as assessed by the effectiveness of diabetes reversal, including mean time required to achieve euglycemia, weight gain, and glucose levels during an intraperitoneal glucose tolerance test. CONCLUSION: These findings indicate that a synthetic polymer scaffold can serve as a platform for islet transplantation and improves the function of extrahepatically transplanted islets compared to islets transplanted without a scaffold. The scaffold may also be useful to deliver bioactive molecules to modify the microenvironment surrounding the transplanted islets and, thus, enhance islet survival and function.

Animals↗
PubMed2006

Imbalance of the osteoprotegerin/RANKL ratio in bone marrow microenvironment after allogeneic hemopoietic stem cell transplantation.

BACKGROUND: Bone loss is a common complication after allogeneic stem cell transplantation. Osteoprotegerin (OPG) plays a critical role in bone remodeling by neutralizing the effect of receptor activator of nuclear factor-kappaB ligand (RANKL) on differentiation and activation of osteoclasts. We investigated OPG and RANKL in serum and marrow plasma in transplanted patients. MATERIALS AND METHODS: In 36 patients and 36 controls, the relationships among bone mineral density, circulating OPG, RANKL, interferon-gamma, and interleukin-6 levels were investigated; in addition, OPG and RANKL were measured in marrow plasma and in conditioned medium of long-term cultures of marrow mesenchymal-derived osteogenic cells. RESULTS: Lumbar and femoral bone mineral density were lower in patients than in controls (P<0.01). Serum OPG (sOPG) and interferon-gamma were significantly higher in patients than in controls (P<0.05). Patients' interferon-gamma correlated with sOPG levels (r=0.4; P=0.03). Interleukin-6 did not differ between patients and controls. By contrast, OPG levels were lower in patients than in controls in marrow plasma (P<0.001) and in conditioned media after one (P=0.035) and three months (P=0.003) of culture of marrow mesenchymal-derived osteogenic cells. RANKL was similar in patients and controls. The OPG/RANKL ratio "in situ" was significantly lower in patients than in controls (P<0.05). There was no correlation between sOPG and marrow OPG, RANKL levels, densitometric values, and chronic graft-versus-host disease. CONCLUSION: Our findings suggest that after allogeneic stem cell transplantation: 1) sOPG bear no relationship with OPG in the bone marrow; 2) increased sOPG can be the result of its enhanced production in extra bone tissues triggered by inflammatory cytokines; 3) low bone marrow OPG levels may be partly related to the persistent quantitative and qualitative deficit of osteoblastic precursors; and 4) reduced OPG/RANKL ratio in bone microenvironment may increase bone remodeling by promoting bone resorption.

Absorptiometry, Photon↗
PubMed1997

Chronically KIT-stimulated clonally-derived human mast cells show heterogeneity in different tissue microenvironments.

Human mast cell precursors arise in the bone marrow and circulate to different tissue microenvironments, where they develop distinct phenotypes that may be characterized by differential expression of the serine protease, chymase. The growth and development of mast cells is stimulated by mast cell growth factor, which is also known as kit ligand because its obligate receptor is KIT, the protein product of the c-KIT proto-oncogene. The in vivo influence of the KIT-kit ligand axis on the phenotype of human mast cells has not been determined. We used immunohistochemistry to detect in situ expression of tryptase and chymase by mast cells of a patient with urticaria pigmentosa and aggressive systemic mastocytosis, whose pathologic mast cells are clonally derived and chronically stimulated by KIT because they all contain the same point mutation causing constitutive activation of KIT. Mast cells in both spleen and skin expressed tryptase, but only in the skin did a majority of mast cells express chymase. We conclude that chronic stimulation of the KIT-kit ligand axis does not irrevocably commit mast cells to a chymase-positive or chymase-negative phenotype. These findings suggest that factors other than kit ligand predominate in determining mast cell phenotype.

Chymases↗
PubMed2006

Establishment and functioning of intrathymic microenvironments.

The thymus supports the production of self-tolerant T cells from immature precursors. Studying the mechanisms regulating the establishment and maintenance of stromal microenvironments within the thymus therefore is essential to our understanding of T-cell production and ultimately immune system functioning. Despite our ability to phenotypically define stromal cell compartments of the thymus, the mechanisms regulating their development and the ways by which they influence T-cell precursors are still unclear. Here, we review recent findings and highlight unresolved issues relating to the development and functioning of thymic stromal cells.

Animals↗
PubMed1988

Effects of cis-diamminedichloroplatinum (II) upon haemopoietic progenitors and the haemopoietic microenvironment in mice.

We studied the short- and long-term effects of a fractionated injection of cis-diamminedichloroplatinum (II) (CDDP) upon the haemopoietic stroma and the haemopoietic precursor cell compartment of young and adult mice. The integrity of the stromal microenvironment was investigated using three different assays including quantification of (a) the fibroblastoid progenitor cell compartment, (b) the regenerative capacity after subcutaneous implantation of spleen and femur, and (c) the growth of normal bone marrow progenitors in lethally irradiated CDDP-treated mice. CDDP treatment induced a slight anaemia which lasted for the observation period of 1 year, and could not be restored by infusion of normal bone marrow cells. The population size of haemopoietic progenitors was severely decreased immediately after CDDP treatment and the CFU-S recovery in the bone marrow was slow and temporary. Stromal function was significantly decreased and normalization occurred within approximately 40 d, depending on the stromal parameter measured. Subsequently, the regenerative capacity of the stroma showed a second decrease which was still detected at 1 year. This pattern of stromal damage has not been reported for any other cystostatic agent. Since the other two assays did not detect a second decrement in stromal integrity it is implied that the three stromal assays used detect different stromal functions. We conclude that CDDP treatment of both young and adult mice results in severe short-term damage and a late occurring secondary regenerative defect of the haemopoietic organ stroma.

Animals↗
PubMed1994

Stem cells and the microenvironment in aplastic anaemia.

Normal blast colony-forming cells (BI-CFC) bind to stroma cultured in the presence of methylprednisolone (MP+) but not to MP- stroma. In aplastic marrow, the incidence of BI-CFC is variable (0-4 x normal values) and there is no consistent relationship with the CFU-GM (granulocyte-macrophage colony-forming cell) content. Normal stroma require MP to induce BI-CFC binding function and form fat cells whereas MP- stroma grown from 4/9 aplastic patients formed fat cells and bound BI-CFC. The 5/9 aplastic cases that did not form fat cells spontaneously also bound BI-CFC moderately better than normal stroma. This suggests that the haemopoietic microenvironment in aplastic anaemia responds physiologically to bone marrow failure by increasing its haemopoietic support capacity.

Adipocytes↗
PubMed1995

B lymphocytes with latent EBV infection appearing in long-term bone marrow cultures (HLTBMCs) from haematological patients induce lysis of stromal microenvironment.

Human long-term bone marrow cultures (HLTBMCs) are a valuable in vitro model for studying the role of the haemopoietic microenvironment. Here we report the spontaneous appearance of EBV-positive B cells in 6/40 HLTBMCs from patients with various haematological diseases after 3-5 months of culture. After subcultivation of these cells, a novel type of cell line could be characterized, which displayed surface markers and morphological features typical for EBV transformed B-cell lines. As the deproteinized and ultrafiltrated culture supernatants of these cell lines were found to contain an agent with stroma toxic properties, they were termed SSB lines (stroma-toxic-agent-secreting B-cell lines). This agent also exhibited a colony-inhibitory activity on in vitro myelopoiesis and erythropoiesis. These properties are typical for the two polyamines spermine and spermidine which were detected at elevated levels in the culture supernatants of SSB lines. The hypothesis that latent presence of EBV in bone marrow may induce an increased synthesis of spermine and spermidine, which are known to be associated with malignant haematological diseases and bone marrow aplasia, is discussed.

B-Lymphocytes↗
PubMed1992

Mathematical modelling of microenvironment and growth in EMT6/Ro multicellular tumour spheroids.

In order to determine the role of micromilieu in tumour spheroid growth, a mathematical model was developed to predict EMT6/Ro spheroid growth and microenvironment based upon numerical solution of the diffusion/reaction equation for oxygen, glucose, lactate ion, carbon dioxide, bicarbonate ion, chlorine ion and hydrogen ion along with the equation of electroneutrality. This model takes into account the effects of oxygen concentration, glucose concentration and extracellular pH on cell growth and metabolism. Since independent measurements of EMT6/Ro single cell growth and metabolic rates, spheroid diffusion constants, and spinner flask mass transfer coefficients are available, model predictions using these parameters were compared with published data on EMT6/Ro spheroid growth and micro-environment. The model predictions of reduced spheroid growth due to reduced cell growth rates and cell shedding fit experimental spheroid growth data below 700 microns, but overestimated the spheroid growth rate at larger diameters. Predicted viable rim thicknesses based on predicted near zero glucose concentrations fit published viable rim thickness data for 1000 microns spheroids grown at medium glucose concentrations of 5.5 mM or less. However, the model did not accurately predict the onset of necrosis. Moreover, the model could not predict the observed decreases in oxygen and glucose metabolism seen in spheroids with time, nor could it predict the observed growth plateau. This suggests that other unknown factors, such as inhibitors or cell-cell contact effects, must also be important in affecting spheroid growth and cellular metabolism.

Animals↗