Exercise-modulated mitochondrial phenotype; sensors and gene regulation.
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Animals↗
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In vitro infection of aortic endothelial cells by caprine arthritis encephalitis virus enhances in vitro transmigration of peripheral blood leukocytes and modulates their phenotypic expression.
Infection of goats by caprine arthritis-encephalitis virus (CAEV) provides a convenient example of the infiltration of various tissues by leukocytes following a natural lentiviral infection. This event is important in determining organ susceptibility and local immunity. Caprine vascular endothelial cells are susceptible to infection by CAEV in vitro, so we have investigated the consequences of this infection on the transmigration of uninfected leukocytes in an in vitro model. After in vitro infection by CAEV or stimulation by TNFalpha, the endothelial cells allowed the passage of tenfold more leukocytes from uninfected donors than did the uninfected endothelial cells. The transmigrating leukocytes were enriched in CD8+ lymphocytes, and the leukocytes appeared to have been activated during transmigration, as demonstrated by their expression of IL2R, MHC class II antigens and gamma-delta T-lymphocyte markers. CD4+, CD8+ and B-lymphocytes all proliferated in culture after transmigration. These results suggest that any possible infection or specific stimulation of endothelia in an infected animal could profoundly influence the choice of target organs and could activate the cells involved in local mucosal immune responses.
Animals↗
Cytokines modulate fibroblast phenotype and epithelial-stroma interactions in rat intestine.
BACKGROUND & AIMS: Homeostasis of the intestinal epithelium depends on interactions with the underlying connective tissue that may be altered during the pathogenesis of disease. The aim of this study was to establish whether fibroblast phenotype can influence morphogenesis and differentiation of the gut epithelium. METHODS: Permanently growing, nontumorigenic, homogenous fibroblast lines were established from postnatal rat intestinal mucosa. Their phenotypic characterization included their growth response to cytokines and expression of cytoskeletal and membrane markers, as well as expression of basement membrane components, laminin 1 and collagen IV. Their influence on epithelial growth, functional polarization, and morphogenesis was analyzed using coculture and tissue grafting of the fibroblast lines with fetal gut endoderm. RESULTS: Two intestinal fibroblast lines are described, one that supports normal intestinal morphogenesis and differentiation, and one that induces growth of fetal epithelial cells. Among the phenotypic differences between the two lines, the former differentiates into myofibroblasts in response to transforming growth factor beta1 and, in basal conditions, expresses twice as much laminin than the latter. The growth of the two lines is also affected differentially by transforming growth factor beta1 and interleukin 2. CONCLUSIONS: Cytokines, which are expressed in association with inflammation, regulate fibroblast differentiation. Fibroblasts may modify the function and organization of the overlying intestinal epithelium.
Animals↗
Hsp70 and Hsp40 chaperones do not modulate retinal phenotype in SCA7 mice.
Nine neurodegenerative diseases, including spinocerebellar ataxia type 7 (SCA7), are caused by the expansion of polyglutamine stretches in the respective disease-causing proteins. A hallmark of these diseases is the aggregation of expanded polyglutamine-containing proteins in nuclear inclusions that also accumulate molecular chaperones and components of the ubiquitin-proteasome system. Manipulation of HSP70 and HSP40 chaperone levels has been shown to suppress aggregates in cellular models, prevent neuronal death in Drosophila, and improve to some extent neurological symptoms in mouse models. An important issue in mammals is the relative expression levels of toxic and putative rescuing proteins. Furthermore, overexpression of both HSP70 and its co-factor HSP40/HDJ2 has never been investigated in mice. We decided to address this question in a SCA7 transgenic mouse model that progressively develops retinopathy, similar to SCA7 patients. To co-express HSP70 and HDJ2 with the polyglutamine protein, in the same cell type, at comparable levels and with the same time course, we generated transgenic mice that express the heat shock proteins specifically in rod photoreceptors. While co-expression of HSP70 with its co-factor HDJ2 efficiently suppressed mutant ataxin-7 aggregation in transfected cells, they did not prevent either neuronal toxicity or aggregate formation in SCA7 mice. Furthermore, nuclear inclusions in SCA7 mice were composed of a cleaved mutant ataxin-7 fragment, whereas they contained the full-length protein in transfected cells. We propose that differences in the aggregation process might account for the different effects of chaperone overexpression in cellular and animal models of polyglutamine diseases.
Animals↗
Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome.
Mutations in the FBN1 gene, which encodes fibrillin-1, cause Marfan syndrome (MFS) and have been associated with a wide range of milder, overlap phenotypes. The factors that modulate phenotypic severity, both between and within families, remain to be determined. This study examines the relationship between the FBN1 genotype and phenotype in families with extremely mild phenotypes and in those that show striking clinical variation among apparently affected individuals. In one family, clinically similar but etiologically distinct disorders are segregating independently. In another, somatic mosaicism for a mutant FBN1 allele is associated with subdiagnostic manifestations, whereas germ-line transmission of the identical mutation causes severe and rapidly progressive disease. A third family cosegregates mild mitral valve prolapse syndrome with a mutation in FBN1 that can be functionally distinguished from those associated with the classic MFS phenotype. These data have immediate relevance for the diagnostic and prognostic counseling of patients and their family members.
Adult↗
TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells.
Metastasis of epithelial tumor cells can be associated with the acquisition of fibroblastoid features and the ability to invade stroma and blood vessels. Using matched in vivo and in vitro culture systems employing fully polarized, mammary epithelial cells, we report here that TGF-beta1 brings about these changes in Ras-transformed cells but not in normal cells. When grown in collagen gels in the absence of TGF-beta, both normal and Ras-transformed mammary epithelial cells form organ-like structures in which the cells maintain their epithelial characteristics. Under these conditions, treatment of normal cells with TGF-beta results in growth arrest. The same treatment renders Ras-transformed epithelial cells fibroblastoid, invasive, and resistant to growth inhibition by TGF-beta. After this epithelial-fibroblastoid conversion, the Ras-transformed cells start to secrete TGF-beta themselves, leading to autocrine maintenance of the invasive phenotype and recruitment of additional cells to become fibroblastoid and invasive. More important, this cooperation of activated Ha-Ras with TGF-beta1 is operative during in vivo tumorigenesis and, as in wound healing processes, is dependent on epithelial-stromal interactions.
Animals↗
Enzymatic profiles of 11 barophilic bacteria under in situ conditions: evidence for pressure modulation of phenotype.
Barophilic bacteria are microorganisms that grow preferentially (facultative barophiles) or exclusively (obligate barophiles) under elevated hydrostatic pressure. Barophilic bacteria have been isolated from a variety of deep-sea environments. Attempts to characterize these organisms have been hampered by a lack of appropriate methodologies. A colorimetric method for the detection of 19 constitutively expressed enzymes under in situ conditions of pressure and temperature has been devised, using a simple modification of the commercially available API ZYME enzyme assay kit. By using this method, enzyme profiles of 11 barophilic isolates, including an obligate barophile, were determined. Nine of the 10 facultatively barophilic isolates examined exhibited a change of phenotype in at least one enzyme reaction when tested at 1 atm (1 atm = 101.29 kPa), compared with results obtained under in situ pressure. The assay is simple and rapid and allows for direct determination of enzyme activity under conditions of high pressure and low temperature.
Atmospheric Pressure↗
Modulation of phenotypic and functional properties of normal human mononuclear phagocytes by granulocyte-macrophage colony-stimulating factor.
In asthma, alveolar macrophages (AMs) are hyperreactive releasing large amounts of mediators and expressing high levels of surface markers. Granulocyte-macrophage colony-stimulating factor (GM-CSF) upregulates monocytes and AMs, and may be involved in the hyperreactivity of AMs. The effects of GM-CSF were tested on monocytes and AMs from normal subjects by examining the expression of factors thought to be upregulated in asthma. After various incubation times of GM-CSF, the expression of CD23 and beta 2-integrins (CD11a, CD11b, CD11c) was studied by FACS and the release of sCD23 was measured by ELISA. The priming and stimulatory effects of GM-CSF were tested on monocytes and AMs and the release of leukotriene B4 (LTB4) was measured by ELISA. GM-CSF induced the expression of CD11c and CD23 and the release of sCD23. GM-CSF primed and stimulated monocytes and AMs to release LTB4. The effects of GM-CSF may explain partly the hyperreactivity of AMs in asthma.
Adult↗
Differential effects of extracellular matrix proteins on human airway smooth muscle cell proliferation and phenotype.
Mature airway smooth muscle cells are characterized by a low proliferative index and expression of contractile marker proteins such as smooth muscle alpha-actin (sm-alpha-actin), calponin, and smooth muscle myosin heavy chain (sm-MHC). In the present study, defined extracellular matrix (ECM) components were examined on the proliferative and phenotypic status of mitogen-stimulated, cultured human airway smooth muscle cells. The results demonstrate that although cells adhered and spread on plates precoated with (1 to 100 microg/ml) of fibronectin (FN), collagen I (Col I), laminin (LN), or Matrigel, their subsequent proliferative response varied qualitatively. FN and Col I enhanced proliferation in response to either platelet-derived growth factor (PDGF)-BB or alpha-thrombin, compared with cells on plastic. LN, however, reduced mitogen-stimulated proliferation. A similar reduction was found in cells cultured on Matrigel. The effect of ECM substrates on contractile phenotype was determined by examining cellular expression of sm-alpha-actin, sm-MHC, and calponin using immunocytochemical and flow cytometric methods. Approximately 75% of PDGF-BB-stimulated cells, cultured on LN or Matrigel, expressed sm-alpha-actin, calponin, and sm-MHC, but only 8 to 10% stained for the Ki67 nuclear antigen proliferation marker. In contrast, more than 75% of cells cultured on FN or Col I were positive for Ki67 antigen, but only 20% were positive for contractile proteins. Flow cytometric analysis of sm-alpha-actin and DNA content confirmed the immunocytochemical findings and showed that the observed reduction in sm-alpha-actin content after culture on FN or Col I, compared with LN and Matrigel, occurred in the majority of the cell population, supporting bidirectional phenotype modulation. Overall, the data suggest that ECM substrates modulate both proliferation and phenotype of human airway smooth muscle cells in culture.
Actins↗
Anti-TNFalpha therapy modulates the phenotype of peripheral blood CD4+ T cells in patients with posterior segment intraocular inflammation.
PURPOSE: Posterior segment intraocular inflammation (PSII) is a putative Th1 CD4+ cell mediated autoimmune disorder. In experimental autoimmune uveoretinitis, neutralization of tumor necrosis factor (TNF)-alpha induces suppression of Th1 cells, macrophage activation, and target organ damage. Previous studies implicated an efficacy of anti-TNFalpha therapies in patients with PSII. This study investigated the immunomodulatory effect of anti-TNFalpha therapy to find predictors of effective immunosuppression in PSII. METHODS: Fifteen patients with PSII refractory to conventional immunosuppressive therapy received a single infusion of a recombinant protein generated by fusing the p55 TNFalpha receptor with human IgG1. During 17 treatment periods, visual acuity (logarithm of the minimum angle of resolution [logMAR]) was monitored as a response criterion. Phenotype markers of CD4+ T cells were analyzed before and 2, 4, and 12 weeks after therapy. Expression of intracellular cytokines (interferon [IFN]-gamma, interleukin [IL]-10, and TNFalpha) and Th1/Th2-specific chemokine receptors (CXCR3, CCR4, and CCR5) on peripheral blood CD4+ T cells was determined using flow cytometry. RESULTS: The fraction of IL-10-expressing CD4+ T cells was increased during 12 of 17 treatment periods within 2 weeks after treatment. During eight treatment periods, this increase was associated with an improvement of visual acuity of at least 0.2 logMAR within 4 weeks (P = 0.029). The ratio between IL-10- and IFNgamma-expressing CD4+ T cells was significantly increased 2 weeks after therapy (P = 0.015). There was no significant change of CXCR3, CCR4, or CCR5 expression. CONCLUSIONS: Neutralizing TNFalpha activity in PSII increases the fraction of peripheral blood CD4+ T cells expressing IL-10, which correlates with a recovery of visual function.
Adult↗
Müller cell production of insulin-like growth factor-binding proteins in vitro: modulation with phenotype and growth factor stimulation.
PURPOSE: Müller cells are present in diabetic fibrocontractive ocular tissues and generate tractional forces in response to insulin-like growth factors. Recent studies indicate that diabetes-associated increases in vitreous insulin-like growth factor activity are, in part, attributable to changes in insulin-like growth factor binding proteins (IGFBPs). The objectives of this study were to evaluate Müller cells as a source of IGFBPs and characterize changes associated with cell phenotype and growth factor stimuli known to be present in diabetic vitreous. METHODS: Müller cells isolated from normal porcine retina were maintained in culture for 1 and 5 weeks, yielding phenotypes described as proliferative and myofibroblastic. RNA preparations from porcine liver, retina, and Müller cell cultures were evaluated by RT-PCR and Northern blot analysis. IGFBP production was verified by Western ligand and Western blot analysis of Müller-cell-conditioned media and detergent-extracted proteins. RESULTS: Molecular biological analyses of RNA from normal retina and from proliferative and myofibroblastic Müller cells did not detect message for IGFBP-1, but revealed progressive increases in message abundance for IGFBP-2, -3, -4, and -6. IGFBP-5 message was detected in all samples, but was least abundant in myofibroblastic Müller cells. Stimulation of myofibroblastic Müller cells by IGF-I and -II, but not PDGF, further increased message abundance and production of IGFBP-2, -4, -5, and -6, but not IGFBP-3. CONCLUSIONS: Müller cell production of IGFBPs changes with phenotype and, in most cases, is highest in the cells most likely to participate in fibrocontractive retinal disease. IGFBP production by these cells is further increased by IGF-I and -II, growth factors known to be present and active in proliferative vitreoretinal disorders, suggesting that Müller cells represent a potential source of vitreous IGFBPs in disorders involving this cell type.
Animals↗
The novel A4435G mutation in the mitochondrial tRNAMet may modulate the phenotypic expression of the LHON-associated ND4 G11778A mutation.
PURPOSE: To investigating the role of mitochondrial haplotypes in the development of Leber's hereditary optic neuropathy (LHON) associated with the ND4 G11778A mutation in Chinese families. METHODS: A three-generation Chinese family with LHON was studied by clinical and genetic evaluation as well as molecular and biochemical analysis of mitochondrial (mt)DNA. RESULTS: This family exhibits a high penetrance and expressivity of visual impairment. The average age at onset was 13.9 years in this family. Of the family members, 86% of the male and 29% of the female matrilineal relatives had visual loss, with a wide range of severity, from blindness to nearly normal vision. Molecular analysis of mtDNA identified the homoplasmic ND4 G11778A mutation and 35 other variants, belonging to the Asian haplogroup D5. Of other variants, the novel homoplasmic A4435G mutation absent in 164 Chinese controls is localized at 3' end adjacent to the anticodon, at conventional position 37 (A37), of tRNAMet. The adenine (A37) at this position of tRNAMet is extraordinarily conserved from bacteria to human mitochondria. This modified A37 was shown to contribute to the high fidelity of codon recognition and to the structural formation and stabilization of functional tRNAs. In fact, the significant reduction of the steady state levels in tRNAMet was observed in cells carrying the both the A4435G and G11778A mutations but not cells carrying only the G11778A mutation. Thus, a failure in mitochondrial tRNA metabolism, caused by the A4435G mutation, may worsen the mitochondrial dysfunction associated with the primary G11778A mutation. CONCLUSIONS: The novel tRNAMet A4435G mutation has a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in this Chinese family.
Adolescent↗
Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells.
Tobacco-related diseases such as lung cancer cause over 4.2 million deaths annually, with approximately 400,000 deaths per year occurring in the US. Genotoxic effects of tobacco components have been described, but effects on signaling pathways in normal cells have not been described. Here, we show activation of the serine/threonine kinase Akt in nonimmortalized human airway epithelial cells in vitro by two components of cigarette smoke, nicotine and the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Activation of Akt by nicotine or NNK occurred within minutes at concentrations achievable by smokers and depended upon alpha(3)-/alpha(4)-containing or alpha(7)-containing nicotinic acetylcholine receptors, respectively. Activated Akt increased phosphorylation of downstream substrates such as GSK-3, p70(S6K), 4EBP-1, and FKHR. Treatment with nicotine or NNK attenuated apoptosis caused by etoposide, ultraviolet irradiation, or hydrogen peroxide and partially induced a transformed phenotype manifest as loss of contact inhibition and loss of dependence on exogenous growth factors or adherence to ECM. In vivo, active Akt was detected in airway epithelial cells and lung tumors from NNK-treated A/J mice, and in human lung cancers derived from smokers. Redundant Akt activation by nicotine and NNK could contribute to tobacco-related carcinogenesis by regulating two processes critical for tumorigenesis, cell growth and apoptosis.
Adaptor Proteins, Signal Transducing↗
Variable expression of the V1 vasopressin receptor modulates the phenotypic response of steroid-secreting adrenocortical tumors.
We studied the putative role of the vasopressin receptors in the phenotypic response of steroid-secreting adrenocortical tumors. A retrospective analysis of a series of 26 adrenocortical tumors responsible for Cushing's syndrome (19 adenomas and 7 carcinomas) showed that vasopressin (10 IU, i.m., lysine vasopressin) induced an ACTH-independent cortisol response (arbitrarily defined as a cortisol rise above baseline of 30 ng/mL or more) in 7 cases (27%). In comparison, 68 of 90 patients with Cushing's disease (76%) had a positive cortisol response. We then prospectively examined the expression of vasopressin receptor genes in adrenocortical tumors of recently operated patients (20 adenomas and 19 adrenocortical carcinomas). We used highly sensitive and specific quantitative RT-PCR techniques for each of the newly characterized human vasopressin receptors: V1, V2, and V3. The V1 messenger ribonucleic acid (mRNA) was detected in normal adrenal cortex and in all tumors. Its level varied widely between 2.0 x 10(2) and 4.4 x 10(5) copies/0.1 microgram total RNA, and adenomas had significantly higher levels than carcinomas, although there was a large overlap. Among the 6 recently operated patients who had been subjected to the vasopressin test in vivo, the tumor V1 mRNA levels were higher in the 4 responders (9.5 x 10(3) to 5.0 x 10(4)) than in the 2 nonresponders (2.0 x 10(2) and 1.8 x 10(3)). One adenoma that had a brisk cortisol response in vivo, also had in vitro cortisol responses that were inhibited by a specific V1 antagonist. In situ hybridization showed the presence of V1 mRNA in the normal human adrenal cortex where the signal predominated in the compact cells of the zona reticularis. A positive signal was also present in the tumors with high RT-PCR V1 mRNA levels; its distribution pattern was heterogeneous and showed preferential association with compact cells. RT-PCR studies for the other vasopressin receptors showed a much lower signal for V2 and no evidence for V3 mRNA. We could not establish whether the V2 mRNA signal observed in normal and tumoral specimens was present within adrenocortical cells or merely within tissue vessels. We conclude that the vasopressin V1 receptor gene is expressed in normal and tumoral adrenocortical cells. High, and not ectopic, expression occurs in a minority of tumors that become directly responsive to vasopressin stimulation tests.
Adenoma↗
Coordinate regulation of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 expression in human vascular smooth muscle cells.
The expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) by human vascular smooth muscle cells (SMC) was monitored as a function of the phenotypic modulation in vitro. Cell phenotype was manipulated by varying serum concentration and cell density. Synthetic phenotype was characterized by a minimum expression of the contractile proteins and a maximal proliferation rate. Contractile phenotype was quiescent and expressed a maximal level of contractile proteins. Synthetic cells expressed the highest levels of both MMP-1 and TIMP-1 and displayed maximal collagenolytic activity. No significant change was detected in MMP-2 expression or catalytic activity. Enzyme immunoassays revealed that MMP-1 expression fell by 77+/-2.4-95+/-0.5%, and that of TIMP-1 by 34+/-0.5-59+/-1.9%, as the cells acquired a contractile phenotype. The level of the MMP-1/TIMP-1 complex was similarly reduced by 78+/-2.9-85+/-1.6%. These data demonstrate that the expression of MMP-1 and TIMP-1 are coordinately regulated with SMC phenotype.
Adult↗
Tumor cell invasion of basement membrane in vitro is regulated by amino acids.
Because most cancer deaths result from disseminated disease, understanding the regulation of tumor invasion and metastasis is a central theme in tumor cell biology. Interactions between extracellular matrices (ECM) and cellular microenvironment play a crucial role in this process. We have tested selected amino acids and polyamines for their ability to regulate RL95-2 cell invasion through both intact human amniotic basement membrane and a novel human ECM (Amgel). Three major systems for neutral amino acid transport, systems L, A, and ASC, are operational in these neoplastic cells. Amino acids entering the cell via transport system A or N, i.e., (methyl amino)-isobutyrate (MeAIB) or Asn, markedly enhanced invasiveness of these human adenocarcinoma cells as measured by a standard 72-hr amnion or Amgel invasion assay. Addition of 2-amino-2-norborane carboxylic acid (BCH; 1 mM), a model substrate of the L transport system, caused a significant decrease in invasive activity when tested in the Amgel assay. Interestingly, Val lowers steady-state levels of MeAIB uptake and blocks the increase in cell invasion elicited by MeAIB. At the same time, these amino acids do not influence cell proliferation activity. Neither the charged amino acid Lys or Asp (not transported by A/N/L systems) nor the polyamines putrescine, spermidine, or spermine modulate invasiveness under similar experimental conditions. Moreover, the observed time-dependent stimulation of system A activity (cellular influx of MeAIB) by substrate depletion is prevented by the addition of actinomycin D (5 microM) or cycloheximide (100 microM), suggesting the involvement of de novo RNA and protein synthesis events in these processes. MeAIB treatment of tumor cells selectively increased the activities of key invasion-associated type IV collagenases/gelatinases. These results indicate that in the absence of defined regulators (growth factors or hormones), certain amino acids may contribute to the epigenetic control of human tumor cell invasion and, by extension, metastasis. We propose that amino acids, acting via specific signaling pathways, modulate phenotypic cell behavior by modulating the levels of key regulatory enzymatic proteins.
Amino Acid Transport Systems↗
Renal proximal tubule cell cultures for studying drug-induced nephrotoxicity and modulation of phenotype expression by medium components.
The characteristics of two established renal cell lines (LLC-PKI and OK) and of primary cultures of rabbit and human proximal tubule cells are described by summarizing the literature about specific properties retained by these cells in culture. Furthermore, comparative biochemical and functional properties are presented including both specific marker enzymes and transport properties of these cells grown in various media. The impact of culture medium composition on the expressed cellular phenotype is discussed and its consequences on the profile of toxic response due to aminoglycoside antibiotics is analyzed. The in vitro nephrotoxicity of three platinum-containing coordination complexes which exhibited different in vivo nephrotoxic potentials is studied by another technique in a model of rabbit proximal tubule cells in primary cultures in order to correlate results to in vivo data and to define reliable and sensitive parameters for the assessment of platinum-derivative-induced nephrotoxicity. Although animal cell lines have been established in serum-supplemented medium, LLC-PK1 and OK cells as well as primary cultures of proximal tubules are successfully grown in hormonally defined medium, the standardization of which is better controlled for nephrotoxicity studies.
Aminoglycosides↗
Culture conditions modulate cell phenotype and cause selection of subpopulations in PC3 prostate cancer cell line.
PC3 cell line contains different cell variants. A first variant grows as spherical multicellular aggregates and shows anchorage-independent growth. A second variant grows as single small rounds and shows anchorage-dependent growth without cell spreading. A third variant, representing the most abundant population, grows as adherent cells. These populations differ in alpha 2 beta 1 and alpha 3 beta 1 integrin expression with low levels in the suspended (S) cells, intermediate in partially adherent (R) cells and high in adherent cells (A). TPA, which up-regulates the expression of beta 1 integrins, increases invasiveness of cells. In addition, PC3 variants differ in MMP9 and uPA secretion and activity. High levels of TIMP1 and PAI1 present in S variant reduce MMP9 and uPA activities, respectively. In conclusion, PC3 cell line shows variants with strong phenotypic heterogeneity reflecting also the in vitro culture condition. Our observations may explain some of the contradictions in the literature. Therefore, the data obtained with this line should be evaluated more carefully, considering morphological and functional characteristics of the possible variants in the cell population. However, this heterogeneity may represent a good model in the study of tumor progression.
Antigens, CD↗