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E A Turley

Publications and source records attributed to E A Turley.

At least 37 records · Page 2Linked to original sources
PubMed1995

Characterization of the murine gene encoding the hyaluronan receptor RHAMM.

We describe the isolation and characterization of the murine gene encoding RHAMM, a hyaluronan receptor which regulates focal adhesion turnover, is required for cell locomotion and is a critical downstream regulator of ras transformation. The RHAMM gene spans at least 20 kb and comprises 14 exons ranging in size from 75 to 1099 bp. Primer extension studies indicate that the major transcription start point is in position -31, relative to the start Met. Northern blot analysis of mouse fibroblast RNA identified two hybridizing species of 4.2 and 1.7 kb. Comparison of cDNA clones and RT-PCR products with the genomic clones identified alternately spliced exons in both the coding and 5' noncoding regions of RHAMM. In the coding region exon 4 is alternately spliced. The major RHAMM transcript (RHAMM1) in 3T3 fibroblasts does not contain exon 4 and encodes a protein of 70 kDa. A minor transcript containing exon 4, namely RHAMM v4, encodes a 73-kDa protein, as demonstrated by isoform-specific antibodies. Western analysis demonstrated both a major 70-kDa (RHAMM 1) and minor 73-kDa RHAMM protein (v4) in 3T3 murine fibroblast cell lysates. The functional significance of these two isoforms is currently being investigated.

Amino Acid Sequence↗
PubMed1995

Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation.

Overexpression of the RHAMM gene by transfection into fibroblasts is transforming and causes spontaneous metastases in the lung. H-ras-transformed fibrosarcomas transfected with a dominant suppressor mutant of RHAMM exhibit a so-called revertant phenotype and are completely nontumorigenic and nonmetastatic. Conversely, fibroblasts stably expressing low levels of RHAMM as a result of antisense transfection are resistant to ras transformation. Collectively, these results indicate that RHAMM acts downstream of ras. The loss of functional RHAMM ablates signaling within focal adhesions, in particular changes in focal adhesion kinase phosphorylation, and as a result these focal adhesions are unable to turn over in response to hyaluronan. These results provide evidence of the oncogenic potential of a novel extracellular matrix receptor and establish a functional link between transformation by ras and signaling within focal adhesions that are required for transformation by this oncogene.

Amino Acid Sequence↗
PubMed1995

Hyaluronan: RHAMM mediated cell locomotion and signaling in tumorigenesis.

Extracellular matrix molecules and their receptors are important regulators of cell movement, adhesion and cytoskeletal organization. Adhesion molecules can also serve to mediate signal transduction and can influence, and sometimes direct, the events required for tumorigenesis. The extracellular matrix molecule, hyaluronan and its receptors have been implicated in transformation and metastasis, in particular the processes of tumor cell motility and invasion. RHAMM (receptor for hyaluronan mediated motility) is required for the cell locomotion of ras-transformed fibrosarcoma cells, cytokine stimulated fibrobasts and T lymphocytes, malignant B cells, and breast carcinoma cells. HA:RHAMM interactions promote cell locomotion via a protein tyrosine kinase signal transduction pathway that targets focal adhesions. The tyrosine kinase pp60c-src is associated with RHAMM in cells and is required for RHAMM mediated cell motility. It is possible that a RHAMM/src pathway induces focal adhesions to signal the cytoskeletal changes required for elevated cell motility seen in tumor progression, invasion and metastasis.

Animals↗
PubMed1995

Migration of bovine aortic smooth muscle cells after wounding injury. The role of hyaluronan and RHAMM.

The migration of smooth muscle cells is a critical event in the pathogenesis of vascular diseases. We have investigated the role of hyaluronan (HA) and the hyaluronan receptor RHAMM in the migration of adult bovine aortic smooth muscle cells (BASMC). Cultured BASMC migrated from the leading edge of a single scratch wound with increased velocity between 1 and 24 h. Polyclonal anti-RHAMM antisera that block HA binding with this receptor abolished smooth muscle cell migration following injury. HA stimulated the random locomotion of BASMC and its association with the cell monolayer increased following wounding injury. Immunoblot analysis of wounded monolayers demonstrated a novel RHAMM protein isoform that appeared within one hour after injury. At the time of increased cell motility after wounding, FACS analysis demonstrated an increase in the membrane localization in approximately 25% of the cell population. Confocal microscopy of injured monolayers confirmed that membrane expression of this receptor was limited to cells at the wound edge. Collectively, these data demonstrate that RHAMM is necessary for the migration of smooth muscle cells and that expression and distribution of this receptor is tightly regulated following wounding of BASMC monolayers.

Animals↗
PubMed1995

Requirement of the hyaluronan receptor RHAMM in neurite extension and motility as demonstrated in primary neurons and neuronal cell lines.

The recently cloned and characterized hyaluronan (HA) receptor RHAMM (receptor for HA-mediated motility) has been shown to play a critical role in mechanisms underlying the motile capacity of a variety of peripheral cell types. Similarities in molecular processes that govern cell locomotion and growth cone migration prompted us to investigate whether RHAMM also contributes to neurite migration in vitro. In immunohistochemical studies of PC12 cells, NG108-15 cells and a neuroblastoma/spinal cord neuronal hybrid cell line (NSC-34 cells) as well as rat and human primary neurons, a punctiform RHAMM labeling pattern was detected in cell bodies, along processes, and at growth cones. By Western blot analysis, the cells lines expressed major RHAMM forms with apparent MW of 60, 75, and 116 kDa. Treatment of NG108-15 cells with dibutyryl-cAMP led to a clear increase in immunolabeling for RHAMM and enhanced expression of the 60 and 75 kDa forms. A polyclonal anti-RHAMM antibody that interferes with HA/RHAMM interaction significantly reduced neurite migration of each cell type examined, while another directed against a RHAMM repeat sequence thought to promote RHAMM receptor aggregation significantly stimulated neurite migration of NSC-34 and rat primary neurons. Different monoclonal anti-RHAMM antibodies had differential inhibitory actions on neurite movement. Low concentrations (ng/ml) of a peptide corresponding to an HA binding domain within RHAMM inhibited neurite migration. These results are the first to implicate RHAMM in the mediation of neurite motility and migration and to point to the potential importance of HA in this process.

Animals↗
PubMed1995

The role of hyaluronan and its receptors in restenosis after balloon angioplasty: development of a potential therapy.

Atherosclerosis is a progressive condition that is initiated by endothelial injury, promoted by growth factors, and which results in the formation of fibrofatty plaques that narrow the affected blood vessel. Balloon angioplasty is used to dilate these plaques in the coronary circulation so as to prevent occlusion of this critical blood supply. However, 30-50% of balloon dilatations end in restenosis within six months of the procedure. The pathogenesis of both atherosclerosis and restenosis after balloon angioplasty involves the migration of medial smooth-muscle cells across the internal elastic lamina to form a neointima. Proliferation of these cells and their elaboration of an extracellular matrix results in stenosis of the affected area. Investigation of several animal models, as well as of the human condition, indicates the presence of an ongoing inflammatory reaction involving T cells and other leukocytes which probably maintain smooth-muscle cell migration, proliferation and matrix deposition. We have shown that the stenotic response involves the expression of HA (hyaluronan) receptors on both the infiltrating white cells and on smooth-muscle cell populations. Thus, in vitro, the locomotion and chemotaxis of these cells in response to injury is inhibited by reagents that block HA-receptor interactions including HA-binding peptides and high doses of HA. Further, the expression of these HA receptors is up-regulated after balloon-catheter injury of the rat carotid artery, and exposure of injured arteries to high concentrations of HA in vivo results in significant inhibition of neointimal formation. The possible clinical benefits of this response are discussed.

Angioplasty, Balloon↗
PubMed1994

Identification of a common hyaluronan binding motif in the hyaluronan binding proteins RHAMM, CD44 and link protein.

We have previously identified two hyaluronan (HA) binding domains in the HA receptor, RHAMM, that occur near the carboxyl-terminus of this protein. We show here that these two HA binding domains are the only HA binding regions in RHAMM, and that they contribute approximately equally to the HA binding ability of this receptor. Mutation of domain II using recombinant polypeptides of RHAMM demonstrates that K423 and R431, spaced seven amino acids apart, are critical for HA binding activity. Domain I contains two sets of two basic amino acids, each spaced seven residues apart, and mutation of these basic amino acids reduced their binding to HA--Sepharose. These results predict that two basic amino acids flanking a seven amino acid stretch [hereafter called B(X7)B] are minimally required for HA binding activity. To assess whether this motif predicts HA binding in the intact RHAMM protein, we mutated all basic amino acids in domains I and II that form part of these motifs using site-directed mutagenesis and prepared fusion protein from the mutated cDNA. The altered RHAMM protein did not bind HA, confirming that the basic amino acids and their spacing are critical for binding. A specific requirement for arginine or lysine residues was identified since mutation of K430, R431 and K432 to histidine residues abolished binding. Clustering of basic amino acids either within or at either end of the motif enhanced HA binding activity while the occurrence of acidic residues between the basic amino acids reduced binding. The B(X7)B motif, in which B is either R or K and X7 contains no acidic residues and at least one basic amino acid, was found in all HA binding proteins molecularly characterized to date. Recombinant techniques were used to generate chimeric proteins containing either the B(X7)B motifs present in CD44 or link protein, with the amino-terminus of RHAMM (amino acids 1-238) that does not bind HA. All chimeric proteins containing the motif bound HA in transblot analyses. Site-directed mutations of these motifs in CD44 sequences abolished HA binding. Collectively, these results predict that the motif of B(X7)B as a minimal binding requirement for HA in RHAMM, CD44 and link protein, and occurs in all HA binding proteins described to date.

Amino Acid Sequence↗
PubMed1994

Astrocyte and microglial motility in vitro is functionally dependent on the hyaluronan receptor RHAMM.

RHAMM (Receptor for Hyaluronic Acid Mediated Motility) has been identified as a receptor for the extracellular matrix component hyaluronan (HA) and was recently shown to be essential for the locomotion of normal and transformed peripheral cells. Until now the potential role of RHAMM in the motility of neural-derived cells has not been investigated. Here, we report that cultured primary astrocytes, astrocyte cell lines, and microglia express this receptor and exhibit RHAMM-dependent motility. Immunocytochemical localization of RHAMM showed that it was often present as aggregates at the periphery of cells in contact with one another or concentrated on protruding processes of isolated cells. Glial cells contained 50 and 72 kDa forms of RHAMM, and both of these forms were found to have HA binding capacity. Time lapse imaging of cell locomotion revealed a significant inhibition of motility and process elongation by neutralizing anti-RHAMM antibodies and by peptides corresponding to the HA binding domains of RHAMM. These results demonstrate that RHAMM serves a role in glial cell locomotion in vitro and provide the basis for investigations of the motile behavior of glial cells in vivo after CNS injury.

Animals↗
PubMed1994

Identification of a novel heparin binding domain in RHAMM and evidence that it modifies HA mediated locomotion of ras-transformed cells.

We have previously reported that the hyaluronan (HA) receptor RHAMM (Receptor for HA Mediated Motility) [Turley et al., 1991] contains two HA binding motifs located within a 35 amino acid region of its C-terminus end [Yang et al., 1993] and that HA stimulation of the motility of ras-transformed fibroblasts is mediated via its interaction with RHAMM. Here we show that RHAMM also contains binding sites for heparin (HP) and that interaction of HP with these sites can regulate the locomotion of ras-transformed fibroblasts. At low concentrations (0.01 mg/ml), HP inhibited HA-induced locomotion of ras-transformed cells in a manner independent of RHAMM. At higher, but still physiological concentrations (0.1 mg/ml), HP alone stimulated cell locomotion and this stimulation appeared to be RHAMM-dependent as it was blocked by anti-RHAMM antibodies. Other related glycosaminoglycans such as chondroitin sulfate and dermatin sulfate had no effect on cell motility. In ligand blotting assays, GST-RHAMM fusion protein was shown to bind biotin-labelled HP and this binding was displaceable with unlabelled HP. In similar ligand binding analyses conducted with truncations of RHAMM fusion protein, the HP binding region was found to be localized in the same 35 amino acid segment of RHAMM that contains the two HA binding domains. Synthetic peptides corresponding to these HA binding domains were retained on and bound effectively to an HP-Sepharose affinity column. Fusion proteins generated by linkage of these peptides to the non-HP binding amino terminus of RHAMM conferred HP binding capacity to the genetically engineered proteins. Conversely, deletion of the HA binding domains of RHAMM resulted in fusion proteins devoid of HP binding activity. The relative affinities of RHAMM for HA and HP, as determined by competition and transblot assays as well as quantification of binding at various salt concentrations, indicated that RHAMM had lower affinity for HP than that for HA. These results demonstrate the existence of a new HP binding motif that has biological relevance to cell locomotion.

Amino Acid Sequence↗
PubMed1994

Hyaluronan and the hyaluronan receptor RHAMM promote focal adhesion turnover and transient tyrosine kinase activity.

The molecular mechanisms whereby hyaluronan (HA) stimulates cell motility was investigated in a C-H-ras transformed 10T 1/2 fibroblast cell line (C3). A significant (p < 0.001) stimulation of C3 cell motility with HA (10 ng/ml) was accompanied by an increase in protein tyrosine phosphorylation as detected by anti-phosphotyrosine antibodies using immunoblot analysis and immunofluorescence staining of cells. Tyrosine phosphorylation of several proteins was found to be both rapid and transient with phosphorylation occurring within 1 min of HA addition and dissipating below control levels 10-15 min later. These responses were also elicited by an antibody generated against a peptide sequence within the HA receptor RHAMM. Treatment of cells with tyrosine kinase inhibitors (genistein, 10 micrograms/ml or herbimycin A, 0.5 micrograms/ml) or microinjection of anti-phosphotyrosine antibodies inhibited the transient protein tyrosine phosphorylation in response to HA as well as prevented HA stimulation of cell motility. To determine a link between HA-stimulated tyrosine phosphorylation and the resulting cell locomotion, cytoskeletal reorganization was examined in C3 cells plated on fibronectin and treated with HA or anti-RHAMM antibody. These agents caused a rapid assembly and disassembly of focal adhesions as revealed by immunofluorescent localization of vinculin. The time course with which HA and antibody induced focal adhesion turnover exactly paralleled the induction of transient protein tyrosine phosphorylation. In addition, phosphotyrosine staining colocalized with vinculin within structures in the lamellapodia of these cells. Notably, the focal adhesion kinase, pp125FAK, was rapidly phosphorylated and dephosphorylated after HA stimulation. These results suggest that HA stimulates locomotion via a rapid and transient protein tyrosine kinase signaling event mediated by RHAMM. They also provide a possible molecular basis for focal adhesion turnover, a process that is critical for cell locomotion.

Antibodies↗
PubMed1994

RHAMM, a receptor for hyaluronan-mediated motility, on normal human lymphocytes, thymocytes and malignant B cells: a mediator in B cell malignancy?

RHAMM (Receptor for HA Mediated Motility) is a novel HA receptor that has been linked to regulating cell locomotion and density dependent contact inhibition of fibroblasts, smooth muscle cells, macrophages, lymphocytes, astrocytes and sperm. The ubiquitous expression of RHAMM suggests the existence of multiple isoforms, and indeed, RHAMM is found in various cellular compartments, namely nuclear, cytosolic, membrane-bound and extracellular. In this review, we emphasize the evolving role of RHAMM in B cell malignancies, and examine the function of RHAMM in T cell development in the thymic microenvironment. Both the motile behaviour of progenitor thymocytes (CD3-CD4-CD8-) and malignant B cells from multiple myeloma (MM), plasma cell leukemia, and hairy cell leukemia was blocked by monoclonal antibodies to RHAMM, suggesting that motility may correlate with increased expression of RHAMM at the cell surface. Interestingly, the soluble form of RHAMM is able to inhibit fibroblast locomotion, and it is likely that a balance between expression of both forms determines, in part the motility of cells. RHAMM appears to play a fundamental role in the immune system and the ability of RHAMM to function as a motility receptor is likely to be due to complex variables including the extent to which soluble RHAMM is secreted. RHAMM expression characterizes circulating monoclonal B cells as abnormal. potentially invasive and/or metastatic components of myeloma and may underlie the malignant behavior of these cells.

B-Lymphocytes↗
PubMed1993

A rapid, multiwell colorimetric assay for chemotaxis.

This paper describes a colorimetric assay for the rapid quantification of chemotaxis in multiple samples. In this assay, cells that have migrated through polycarbonate membrane filters are collected onto the bottom wells of a chemotaxis chamber after centrifugation then the number of viable cells collected in the bottom well is quantified by measurement of the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenol tetrazolium bromide (MTT). The degree of MTT reduction, which corresponds to the relative cell number, is measured automatically with an ELISA reader. The MTT method of quantitation is as sensitive as the standard manual method, is especially useful for large numbers of samples and requires no specialized laboratory equipment.

Animals↗
PubMed1993

Regulated expression of a receptor for hyaluronan-mediated motility on human thymocytes and T cells.

A receptor for hyaluronan-mediated motility (RHAMM) has been shown to promote cell locomotion. Among human T lineage lymphocytes, RHAMM is expressed only on a subset of thymocytes, being absent on mature peripheral T cells from blood, spleen, and lymph node. Among thymocytes, RHAMM is selectively expressed on a subset of CD3+ CD45RA+R0+ cells, and functions in motility as shown by the ability of anti-RHAMM to reduce the speed of thymocyte locomotion from 11 microns/minute to 3 microns/min. Although freshly isolated multi-negative (MN) thymocytes (CD3-4-8-19-) lack RHAMM, its expression is induced on day 3 of culture in a variety of conditions that support differentiation, as assessed by acquisition of CD3. When MN thymocytes are cultured on plates coated with fibronectin, expression of RHAMM is prolonged, but on uncoated surfaces, its expression is transient and lost by day 7 of culture with PHA or IL-2. Culture of MN thymocytes on thymic epithelial layers, with or without IL-2, resulted in a lack of RHAMM expression. Because in the absence of epithelial cells, RHAMM is expressed, the effect appears to be one of inhibition. Although expression of RHAMM by MN thymocytes cultured with IL-2 on uncoated surfaces is transient, addition of cyclosporin A resulted in prolonged expression. These observations are consistent with the view that cyclosporin A inactivates a RHAMM-directed inhibitory mechanism. Mature peripheral blood T cells transiently express RHAMM upon culture with PHA, PMA, or IL-2. T cells that expressed RHAMM after culture with PMA alone lacked RHAMM when stimulated by mitogenic CD2 antibodies with or without CD28 antibody, indicating inhibition of RHAMM expression. Thus expression of RHAMM is regulated by a RHAMM-directed inhibitory mechanism induced by stimulation through CD2/CD28. A similar mechanism may operate in thymocyte/epithelial cell cultures. These results suggest the inhibition of RHAMM during early, presumably sessile, thymic progenitor development, followed by its induction during developmental stages when locomotion is required. The apparently strong negative regulatory control over RHAMM expression by microenvironmental factors and by known thymic and T cell signaling molecules supports this view.

Antigens, CD↗
PubMed1993

Identification of two hyaluronan-binding domains in the hyaluronan receptor RHAMM.

We have identified two discrete hyaluronan- (HA) binding domains in the HA receptor RHAMM (Receptor for HA-Mediated Motility) that mediates the locomotion of H-ras transformed fibroblasts. A complete RHAMM cDNA (1.43 kilobases (kb)) was expressed as a fusion protein with pGEX-2T in Escherichia coli HB101 and was shown to bind specifically to both biotin-labeled HA in a transblot assay and to HA-Sepharose. The complete cDNA was truncated with restriction endonucleases from the 3' end resulting in 1.30-, 1.02-, 0.71-, and 0.41-kb cDNAs which were then expressed in HB101. Only the fusion peptide expressed from the complete cDNA and the 1.30-kb cDNA bound to HA indicating that the region located between 1.02-1.30 kb of RHAMM cDNA was critical for recognition of this glycosaminoglycan. Deletion of 114 bases in this region virtually eliminated HA binding activity thus defining the major glycosaminoglycan binding region to amino acids 400-434 located near the carboxyl terminus of RHAMM. Two domains containing clusters of basic amino acids were identified within this region. Synthetic peptides mimicking these two domains both inhibited HA binding to the complete 1.43-kb expressed glutathione s-transferase-RHAMM fusion protein, and also directly bound to HA-Sepharose. Random peptides and peptides mimicking other regions in RHAMM did not inhibit HA-RHAMM interactions and bound weakly to HA-Sepharose. Oligonucleotides encoding either of these two peptides were linked to the NH2-terminal 0.71 kb of RHAMM which encoded a peptide that did not contain HA binding activity. Fusion proteins containing either of these recombinant peptides acquired HA binding activity as assessed with a transblot assay. Thus, we have identified two domains within RHAMM that are responsible for its HA binding activity.

Amino Acid Sequence↗
PubMed1993

The hyaluronate synthase from a eukaryotic cell line.

The hyaluronate synthase complex was identified in plasma membranes from B6 cells. It contained two subunits of molecular masses 52 kDa and 60 kDa which bound the precursor UDP-GlcA in digitonin solution and partitioned into the aqueous phase, together with nascent hyaluronate upon Triton X-114 phase separation. The 52 kDa protein cross-reacted with poly- and monoclonal antibodies raised against the streptococcal hyaluronate synthase and the 60 kDa protein was recognized by monoclonal antibodies raised against a hyaluronate receptor. The 52 kDa protein was purified to homogeneity by affinity chromatography with monoclonal anti-hyaluronate synthase.

Animals↗
PubMed1993

Expression and function of a receptor for hyaluronan-mediated motility on normal and malignant B lymphocytes.

Migration through extracellular matrix is fundamental to malignant invasion. A receptor for hyaluronan-mediated motility (RHAMM) has previously been shown to play a fundamental role in locomotion of ras-transformed cells as well as functioning in signal transduction. Expression of RHAMM was characterized on B lymphocytes from normal and malignant lymphoid tissues using multiparameter phenotypic immunofluorescence analysis as well as functional analysis of its role in locomotion of malignant hairy cell leukemia B cells. RHAMM is not detectable on most normal B cells located in blood, spleen, or lymph node, but it is detectable on bone marrow and thymic B cells. Among B-cell malignancies, it is expressed on most terminally differentiated B cells from multiple myeloma bone marrows, is present on a subset of non-Hodgkin's lymphomas, and is absent on B chronic lymphocytic leukemia. Activation of peripheral blood B cells by Staphylococcus A cowan (SAC), but not by pokeweed mitogen, induced transient expression of RHAMM at day 3 of culture, suggesting RHAMM may be used by antigen-activated normal B cells. For malignant cells, expression of RHAMM increased on long-term culture of bone marrow plasma cells from multiple myeloma patients, indicating prolonged expression in contrast to the transient expression on SAC-activated normal B cells. Intriguingly, RHAMM was expressed on hairy leukemia cells located in spleen but absent from those in peripheral blood of the same patient. RHAMM, as expressed on splenic hairy cells, was a 58-Kd molecule that binds hyaluronan, is encoded by a 5.2-kb messenger RNA, and participates in locomotion by these cells. Hairy cells locomoted in response to hyaluronan at 4 mu per minute. Monoclonal antibody to RHAMM inhibited this locomotion almost completely as detected using video time-lapse cinemicrography. These observations are consistent with a role for RHAMM in malignant invasion and metastatic growth.

B-Lymphocytes↗
PubMed1993

Cell motility, invasion, and malignancy induced by overexpression of K-FGF or bFGF.

We have tested the hypothesis that fibroblast growth factors contribute to cell locomotion and invasion, by investigating the properties of NIH-3T3 fibroblasts that secrete K-FGF following transfection with the K-fgf proto-oncogene and NIH-3T3 fibroblasts transfected with either the normal basic fibroblast growth factor (bFGF) coding sequence that lacks a known secretory signal sequence, or a chimeric bFGF sequence fused to an immunoglobulin signal sequence that targets the growth factor to the secretory pathway. The cell lines were tested for altered invasive characteristics on a physiologically relevant collagen substratum, and their motility rates were measured in cell locomotion assays using time-lapse video microscopy in the absence or presence of suramin, an inhibitor of growth factor-receptor interaction. The data were analyzed by comparing the motility rates of all K-fgf- and bFGF-transfected cell lines as a function of malignant potential. These studies show for the first time that K-fgf gene expression potently increases cell motility characteristics. Further, the bFGF transfectants generally exhibited increased rates of cell locomotion which were not dependent upon the presence of a signal sequence for secretion. These results support models of cell locomotion in which stimulation of this process can occur through both autocrine and intracrine pathways. In addition, a significant correlation was found to exist between cell locomotion and malignant potential, supporting the view that growth factor-induced motility, although not sufficient on its own to induce metastasis, is important in the promotion of tumor cell dissemination.

3T3 Cells↗