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Results for “Cell Proliferation”

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PubMed1993

The development of autoimmunity in C57BL/6 lpr mice correlates with the disappearance of natural killer type 1-positive cells: evidence for their suppressive action on bone marrow stem cell proliferation, B cell immunoglobulin secretion, and autoimmune symptoms.

F1 hybrid mice are able to acutely reject parental marrow grafts, a phenomenon that is due to natural killer type 1-positive (NK1+) cells. Circumstantial evidence had suggested that the antigenic determinants recognized by these cells are self-antigens, leading to the hypothesis that the physiological role of NK1+ cells is a downregulatory or suppressive function on bone marrow stem cell proliferation and lymphocyte function. In analyzing this hypothesis it is shown here that in young mice there is a temporal correlation between appearance of NK1+ cells in the spleen and the ability to reject allogeneic marrow or to suppress endogenous stem cell proliferation. The reverse situation exists in mice expressing the homozygous lpr gene. Whereas in young mice cells with NK1+ phenotype are demonstrable, these cells disappear with age, i.e., at the time autoimmunity develops. Concomitant with the disappearance of NK1+ cells, the ability to reject marrow grafts and to control endogenous stem cell proliferation also vanishes. The suggestion that the development of autoimmunity is causally related to the disappearance of NK1+ cells is supported by experiments in which NK1+ cells were either eliminated by antibody injection or increased by adoptively transferring cell populations enriched for NK1+ cells into lpr mice. It is shown that removal of cells enhances autoimmunity, whereas injection of NK1+ cells delays the onset of autoimmunity. In vitro assays are presented that demonstrate that suppression of autoantibody-secreting B cells is due to two NK1+ cell populations, one that expresses CD3 and causes specific suppression and one that lacks CD3 and causes nonspecific suppression.

Aging↗

PubMed1975

Kinetics of cell proliferation and cell loss in the peripheral and central parts of Walker tumours growing in rats and nude mice.

In previous experiments it was shown that, in the submucosal part of Walker tumours transplanted to the gastric wall of rats, a lower rate of cell proliferation was seen in the peripheral zone, defined as the outer 100-120 mu of the tumours, than in the main tumour mass. The purpose of the present experiments was to investigate whether such differences are independent of the location of the Walker tumour, or were caused by local factors specific for the gastric mucosa, and whether specific cellular immunity cell proliferation at the periphery of a transplanted tumour. Cells from Walker 256 tumour were injected into the subcutaneous space in rats and in mutant nude mice, which lack T lymphocytes. In one series, the rats and mice were injected with 3H-TDR at different time intervals before sacrifice. In a second series vinblastine sulfate was injected 3 hours before sacrifice. Although all the animals were given the same tumour dose, the tumours in mice increased in size more slowly than those in rats. In the first-mentioned series, the mitotic counts, the labelled cells and the percentage labelled mitoses (PLM) in the main tumour mass and at the tumour perphery were counted. In the second series the mitotic rate in the same two regions was determined. A significantly lower rate of cell proliferation was demonstrated at the periphery compared to the main tumour mass in both rats and mice. Differences between the PLM curves in the two regions were also found. Possible explanations of these findings are discussed. It is concluded that the described growth pattern is probably a general characteristic of the Walker tumour, and that the low rate of proliferation at the periphery is not caused by specific immunological mechanisms mediated through T lymphocytes. If the growth rates were calculated on the assumtion that the actual tumour growth followed a Gompertz function, then the rate of cell loss in the tumour in mice was higher than that in the tumour in rats.

Animals↗

PubMed2002

Cell proliferation and cell death in periodontal ligaments during orthodontic tooth movement.

The purpose of this study was to investigate cellular responses of periodontal ligaments during tooth movement. Twenty-eight male Sprague-Dawley rats, weighing 200-250 g each, were used. To create the orthodontic force, elastic rubber blocks (0.65 mm thick) were inserted between the maxillary first and second molars on both sides. On days 3, 7, 10, 14, 21 and 28 after rubber block insertion, histopathological changes in both the tension and the pressure sides were examined by immunohistochemistry using proliferating cell nuclear antigen (PCNA) and by the TUNEL method. The ratios of PCNA-positive cells on the tension side 3 and 7 days after rubber block insertion were higher than those on the pressure side. The ratios of PCNA-positive cells on the tension side were highest at day 3 after insertion and then decreased during the remainder of the experimental period. On the pressure side, the ratios of PCNA-positive cells increased up to day 10 post insertion, then decreased from 14 to 28 days. The ratios of TUNEL-positive cells on both the tension and the pressure sides increased throughout the entire experimental period. These results indicate that the periodontal ligaments on the tension side are able to respond more promptly to orthodontic forces than those on the pressure side. The data also suggest that the ratios of cell proliferation and of cell death are closely related to the regeneration and reconstruction of periodontal ligaments which reflect the orthodontic force.

Animals↗

PubMed1987

Effect of phytic acid on colonic epithelial cell proliferation.

Cell proliferation was studied in descending, transverse and ascending colonic crypts of rats fed either 0%, 0.6%, 1.2% or 2.0% phytic acid (PA). Significant effects of phytic acid were seen only in the descending colon. No changes in crypt height were observed. Both the 1.2 and 2.0% phytic acid groups exhibited significantly lower uppermost labelled cells than the control group. Animals given 1.2% and 2.0% phytic acid also showed significantly reduced DNA synthetic cells, as indicated by lower labelling indices.

Animals↗

PubMed2000

Programmed cell death, proliferating cell nuclear antigen and p53 expression in mouse colon mucosa during diet-induced tumorigenesis.

Western-style diets (WDs) trigger and sustain the early phases of tumorigenesis in mouse colon, and when continued throughout the life span lead to the development of dysplastic crypts. In order to evaluate the roles both of cell proliferation and programmed cell death (PCD) in WD-induced tumorigenesis, immunohistochemical detection of proliferating nuclear antigen (PCNA), in situ end labeling (TUNEL) of DNA breaks, and p53 protein were carried out in mouse colonic mucosa during prolonged feeding of two WDs. PCNA Labeling Index of colonic crypts was significantly higher in WD-treated animals than in controls only at the beginning of the nutritional study, the gap rapidly bridged by increased cell proliferation spontaneously occurring in the colonic mucosa during aging. A transient early homeostatic activation of PCD at the base of the crypt also was observed in WD groups. No changes in PCD were seen in the upper third of the crypt or in surface epithelium throughout the study, indicating that PCD in that colonic crypt segment produces a constant flux of cell loss, uninfluenced by homeostatic fluctuations. A major finding was an irreversible, progressive, age-related decline of PCD at the crypt base in both control and treated animals that occurred during the second half of the rodents' life span. p53 protein was not immunohistochemically detected, suggesting that neither overexpression of wild-type nor mutated forms of the protein are involved in the above mentioned changes.

Animals↗

PubMed2005

ZNRD1 gene suppresses cell proliferation through cell cycle arrest in G1 phase.

ZNRD1, a transcription-associated gene, was recently found in our laboratory significantly suppress the cell proliferation of stomach cancer cells in vitro and in vivo. In this study, we firstly characterized ZNRD1 expression in a wide spectrum of gastric diseases by immunohistochemistry and RT-PCR. We also investigated its antiproliferative effects and associated molecular alterations in human gastric cancer cell line AGS and mouse fibroblast cell line NIH3T3. Anti-ZNRD1 monoclonal antibody H6 was found to react with 38 (63%) of normal gastric tissues, and 51 (81%) of gastritis. In contrast, no positive expression was found in gastric adenocarcinomas. Thus, the expression of ZNRD1 in normal gastric tissues was significantly higher than that in gastric adenocarcinomas. Compared with the control clones, ZNRD1-transfected cells exhibited significant inhibition of cell growth with G1 cell cycle arrest mediated by the suppression of cyclin D1 expression. These results showed that ZNRD1 may play an important role in the regulation of gastric carcinogenesis and could be used as a new target in treatment of stomach cancer.

Adenocarcinoma↗

PubMed2000

Cell proliferation and cell death in the developing chick inner ear: spatial and temporal patterns.

Morphogenesis of the inner ear is a complex process in which the balance of cell division and death is presumed to play an important role. Surprisingly, there are no reports of a systematic comparison of these two processes in individual ears at different stages of development. This study presents such an analysis for the chicken otocyst at stages 13-29 (embryonic days 2.5-6). To detect proliferating cells, we used exposure to bromodeoxyuridine. To detect apoptotic cells, we used nuclear condensation and fragmentation or terminal dUTP nick-end labeling (TUNEL). The spatial and temporal locations of proliferating and dying cells were mapped across serial sections, revealing regional differences in proliferation within the otocyst epithelium that are more complex than previously reported. In addition, almost all of the previously identified "hot spots" of cell death correspond spatially to regions of reduced cell proliferation. An exception is the ventromedial hot spot of cell death, which is intermingled with proliferating cells when it first appears at stages 19-23 before becoming a cold spot of proliferation. The results further show that the inferior part of the otocyst has a high level of proliferation, whereas the superior part does not. Since the superior part of the otocyst demonstrates outward expansion that is comparable to the inferior part, it appears that regional outgrowth of the otic vesicle is not necessarily coupled to cell proliferation. This study provides a basis for exploring the regulation and function of cell proliferation and cell death during inner ear morphogenesis.

Animals↗

PubMed2003

Regulation of cell proliferation and cell death by peroxisome proliferators.

Peroxisome proliferators cause increases in liver mass in rodents, linked to changes in cell proliferation and cell death of hepatocytes. These effects are reversible upon cessation of treatment. The underlying mechanism of the response in rodent liver is complex, but clearly dependent on activation of the nuclear receptor PPARalpha. Other signaling pathways have been implicated in this response, but evidence is mixed. Differing sensitivity among various species to effects of peroxisome proliferators has been associated with differences in PPARalpha expression and function. Changes in cell proliferation and cell death in neoplastic hepatocytes also have been found in liver tumors caused by long-term treatment with peroxisome proliferators.

Animals↗

PubMed2002

Genistein inhibits tamoxifen effects on cell proliferation and cell cycle arrest in T47D breast cancer cells.

Tamoxifen is an antiestrogen used in the treatment of estrogen receptor-positive breast cancer in postmenopausal women. It functions by competitively inhibiting the estrogen receptor and inducing apoptosis and G1 cell cycle arrest. Genistein is a soy phytoestrogen that inhibits breast cancer cell growth in vitro at doses of 10 microM or above. At lower doses genistein may stimulate cell growth and entry into the cell cycle. We hypothesized that treatment with low-dose genistein would reverse the inhibitory effects of tamoxifen in estrogen-receptor-positive breast cancer cells. Cell cycle kinetics and cell proliferation in T47-D human breast cancer cells were examined after exposure to genistein and tamoxifen in a low-estrogen environment designed to mimic a post-menopausal state. Cell proliferation was assessed by a colorimetric assay. Cell cycle kinetics were determined by flow cytometry. Tamoxifen caused G1 arrest and a decrease in proliferation. Genistein reversed the inhibitory effects of tamoxifen on both proliferation and G1 arrest. Thus low-dose genistein was able to inhibit the therapeutic effects of tamoxifen in this postmenopausal model of breast cancer.

Antineoplastic Agents↗

PubMed2006

Caveolin-1 controls cell proliferation and cell death by suppressing expression of the inhibitor of apoptosis protein survivin.

Caveolin-1 is suggested to act as a tumor suppressor. We tested the hypothesis that caveolin-1 does so by repression of survivin, an Inhibitor of apoptosis protein that regulates cell-cycle progression as well as apoptosis and is commonly overexpressed in human cancers. Ectopic expression of caveolin-1 in HEK293T and ZR75 cells or siRNA-mediated silencing of caveolin-1 in NIH3T3 cells caused downregulation or upregulation of survivin mRNA and protein, respectively. Survivin downregulation in HEK293T cells was paralleled by reduced cell proliferation, increases in G0-G1 and decreases in G2-M phase of the cell cycle. In addition, apoptosis was evident, as judged by several criteria. Importantly, expression of green fluorescent protein-survivin in caveolin-1-transfected HEK293T cells restored cell proliferation and viability. In addition, expression of caveolin-1 inhibited transcriptional activity of a survivin promoter construct in a beta-catenin-Tcf/Lef-dependent manner. Furthermore, in HEK293T cells caveolin-1 associated with beta-catenin and inhibited Tcf/Lef-dependent transcription. Similar results were obtained upon caveolin-1 expression in DLD1 cells, where APC mutation leads to constitutive activation of beta-catenin-Tcf/Lef-mediated transcription of survivin. Taken together, these results suggest that anti-proliferative and pro-apoptotic properties of caveolin-1 may be attributed to reduced survivin expression via a mechanism involving diminished beta-catenin-Tcf/Lef-dependent transcription.

Animals↗

PubMed1994

Immunocytochemical detection of cell proliferation-related antigens in cytologic smears of human malignant neoplasms using PC10, reactive with proliferating cell nuclear antigen, and Ki-67. A comparative study.

Cytospins of the MCF-7 cell line and 93 consecutive smears of human malignant neoplasms were immunochemically evaluated for the expression of proliferating cell nuclear antigen (PCNA) and Ki-67-related antigen. Results expressed as the labeling index (LI) were compared with histologic sections. The PCNA LI and Ki-67 LI were lower in cytologic smears than in histologic sections, though the differences were not statistically significant. A positive linear relationship was found between these markers in both cytologic and histologic samples. The PCNA LI was generally lower than the Ki-67 LI, but in seven malignant neoplasms, PCNA LI was greater than the corresponding values of the KI-67 LI. We conclude that cell proliferation can be reliably evaluated on cytologic preparations; PCNA may behave as a Ki-67-like reagent in some tumors, and PCNA may sometimes overestimate the cell growth fraction assessed by Ki-67 immunoreactivity.

Antigens, Neoplasm↗

PubMed2003

Prognostic use of growth characteristics of early gastric cancer and expression patterns of apoptotic, cell proliferation, and cell adhesion proteins.

BACKGROUND AND OBJECTIVES: Selection of suitable treatment for early gastric cancers, such as endoscopic mucosal resection or the major surgical option of resection of the cancer together with a radical lymph node dissection, may be assisted by comparing the growth characteristics of the cancer with selected molecular characteristics. The results could be used to predict those cases that have a higher risk of developing secondary metastases. METHODS: A total of 1,196 Japanese patients with early gastric cancers (648 mucosal cancers and 548 submucosal) were included in the selection of two groups: a metastatic group made up 57 cancers with lymph node metastasis (9 mucosal, 48 submucosal), and a nonmetastatic group of 61 cases (6 mucosal, 55 submucosal) without lymph node metastasis. Growth characteristics of the cancers (superficially spreading, penetrating or invasive, lymph node metastasis) were compared with immunohistochemical expression of single-stranded DNA (ssDNA) protein (apoptosis indicator), bcl-2 and p53 (apoptosis-associated), Ki-67 (cell proliferation), and E-cadherin (cell adhesion) proteins. RESULTS: The lesions in the nonmetastatic group had higher levels of apoptosis and lower expression of bcl-2 than in the metastatic group, indicating an inhibitory role for apoptosis in malignant progression. Apoptosis was also higher in the superficial compared with the invasive lesions of both groups. The lesions in the metastatic group had higher p53 expression than that of the nonmetastatic group, whereas apoptosis in the metastatic group was lower than in the nonmetastatic group. An unproved explanation for this finding may be that, although increased, p53 was mutated and ineffective in promoting apoptotic control of metastatic progression. E-cadherin was decreased in the invasive lesions of both groups, indicating a greater ability of these cells to lose adhesion, to invade the submucosa, and to metastasize. Cell proliferation was highest in the superficial lesions of both metastatic and nonmetastatic groups. CONCLUSIONS: Early gastric cancers with low levels of apoptosis, increased bcl-2, and high levels of p53 expression are more likely to invade and metastasize.

Adult↗

PubMed1981

Association of T cells with proliferating cells in lymphoid follicles.

Frozen sections of lymph nodes from normal mice were examined by immunofluorescence with anti-T lymphocyte and anti-Ig reagents and by autoradiography following [3H]TdR administration. The scattered T lymphocytes present among B lymphocytes of primary follicles were found to be mostly nonproliferating; the few proliferating cells in primary follicles are therefore predominantly B lymphocytes. More than one-half (56%) of these proliferating B lymphocytes were found to be in direct contact with a T lymphocyte; this incidence is 5-fold higher than that expected by random association. In germinal centers, virtually all proliferating cells were found to be non-T lymphocytes as well. The association of proliferating B cells with T cells may be the result of specific cooperation between these two cell types. These data are discussed in the context of what is known of T/B collaboration and of primary follicles as a possible site of this interaction.

Animals↗

PubMedDate not supplied

Evaluation of cell proliferation and cell death based assays in chemosensitivity testing.

BACKGROUND: Drug sensitivity testing (DST) is used to predict the clinical response to chemotherapy with limited success. Our objective was to evaluate assays that measure cell proliferation or apoptosis in determining sensitivity of ovarian cancer cells to cisplatin and paclitaxel. MATERIALS AND METHODS: Four ovarian cancer lines were used. LD10-LD90 doses were determined by viability assays. Assays measuring cell proliferation, sulforhodamine-B (SRB), tritiated thymidine; and cell death, diphenylamine or DNA histone ELISA were compared. RESULTS: SRB assay was consistent and sensitive. Histone ELISA correlated with the viability assay at high doses. The [3H] thymidine test was not sensitive and resulted in false positive responses. While less sensitive, detection of apoptosis by diphenylamine assay shows a similar trend to histone ELISA. CONCLUSIONS: We demonstrate significant differences between the various assays. Most of these assays are better predictors of resistance. Further studies are needed to determine the best correlation between in vitro testing and responses in vivo.

Antineoplastic Agents↗

PubMed2003

Expression of proliferating cell nuclear antigen and CD44 variant exon 6 in primary tumors and corresponding lymph node metastases of colorectal carcinoma with Dukes' stage C or D.

AIM: To study changes in characteristics of colorectal carcinoma during the metastatic process and to investigate the correlation between cell proliferation activity and metastatic ability of patients with Dukes' stage C or D. METHODS: Formalin fixed and paraffin embedded materials of primary tumors and corresponding lymph node metastases resected from 56 patients with Dukes' stage C or D of colorectal carcinoma were stained immunohistochemically with proliferating cell nuclear antigen (PCNA) and CD44 variant exon 6 (CD44v6). RESULTS: Thirty-one of 56 patients (55.4 %) expressed PCNA in the primary sites and 36 of 56 patients (64.3 %) expressed PCNA in the metastatic lymph nodes. A significant relation in PCNA expression was observed between the primary site and the metastatic lymph node (0.010<P<0.025). Forty-one of 56 patients (73.2 %) expressed CD44v6 in the primary site and 39 of 56 patients (69.6 %) expressed CD44v6 in the metastatic lymph node. There was also an significant relationship of CD44v6 between the primary site and the metastatic lymph node (0.005<P<0.010). No difference was observed between expression of CD44v6 and PCNA in the primary site (0.250<P<0.500). CONCLUSION: This study partially demonstrates that tumor cells in metastatic lymph node of colorectal carcinoma still possess cell proliferation activity and metastatic ability of tumor cells in primary site. There may be no association between cell proliferation activity and metastatic ability in colorectal carcinoma.

Adenocarcinoma↗

PubMed2005

The NF2 tumor suppressor gene product, merlin, inhibits cell proliferation and cell cycle progression by repressing cyclin D1 expression.

Inactivation of the NF2 tumor suppressor gene has been observed in certain benign and malignant tumors. Recent studies have demonstrated that merlin, the product of the NF2 gene, is regulated by Rac/PAK signaling. However, the mechanism by which merlin acts as a tumor suppressor has remained obscure. In this report, we show that adenovirus-mediated expression of merlin in NF2-deficient tumor cells inhibits cell proliferation and arrests cells at G1 phase, concomitant with decreased expression of cyclin D1, inhibition of CDK4 activity, and dephosphorylation of pRB. The effect of merlin on cell cycle progression was partially overridden by ectopic expression of cyclin D1. RNA interference experiments showed that silencing of the endogenous NF2 gene results in upregulation of cyclin D1 and S-phase entry. Furthermore, PAK1-stimulated cyclin D1 promoter activity was repressed by cotransfection of NF2, and PAK activity was inhibited by expression of merlin. Interestingly, the S518A mutant form of merlin, which is refractory to phosphorylation by PAK, was more efficient than the wild-type protein in inhibiting cell cycle progression and in repressing cyclin D1 promoter activity. Collectively, our data indicate that merlin exerts its antiproliferative effect, at least in part, via repression of PAK-induced cyclin D1 expression, suggesting a unifying mechanism by which merlin inactivation might contribute to the overgrowth seen in both noninvasive and malignant tumors.

Adenoviridae↗

PubMed1996

Growth kinetics of colorectal adenoma-carcinoma sequence: an immunohistochemical study of proliferating cell nuclear antigen expression.

Tumorigenesis is a multistep process that begins with the abrogation of normal controls of cell proliferation. The authors examined the in vitro growth kinetics and compartment shift through the adenoma-carcinoma sequence of the human colon by determining the labelling indexes of proliferating cell nuclear antigen (PCNA) in normal mucosae (n = 10), adenomas (n = 88), and carcinomas (n = 20). Carcinoma cells had a significantly higher PCNA index than adenomas or control specimens (P = .0001). There also was a difference in the PCNA index between the histological subtypes of adenomas (P = .03), whereas no significant difference was observed for dysplastic grade, tumor size, or location (P > .1). Tubular and tubulovillous adenomas, adenomas with mild dysplasia, small (< 10 mm) adenomas, and proximally located adenomas revealed shift of cell proliferation toward the middle portion of the colonic glands. The PCNA in the villous, moderate or severe dysplastic, larger or distally located adenomas appeared to be diffuse (P = .04, 0.02, 0.07, and 0.06, respectively). In addition, the transitional mucosa neighboring carcinoma showed an elevation of the mean PCNA index together with an upward shift of cell proliferation compared with the controls (P = .03). These results suggest a stepwise increment of proliferating activity with compartment shift of the proliferating zone through the adenoma-carcinoma sequence. The information essentially supports contemporary understanding of the carcinogenic processes in the human colon.

Adenoma↗

PubMed2002

Duodenogastric reflux increases the penetration of N-3H-methyl-N-nitro-N-nitrosoguanidine into the antral mucosa of rats: a possible role for mucosal erosions and increased cell proliferation in gastric carcinogenesis.

Duodenogastric reflux is a risk factor for gastric carcinogenesis, but the pathogenesis is not fully understood. We studied the risk of N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-induced carcinogenesis in the antrum of rats with duodenogastric reflux. Duodenal fluid was directed into the stomach through the pylorus (pyloric reflux group) or through a gastrojejunostomy (jejunal reflux group). After twenty-four weeks, 5-bromo-2-deoxyuridine (BrdU) was injected intravenously and the stomach was exposed to N-(3)H-methyl-N-nitro-N-nitrosoguanidine ((3)H-MNNG). The antral mucosa was examined with immunohistochemistry and autoradiography for identification of proliferating cells (BrdU labelled) and cells at risk of MNNG-induced carcinogenesis ((3)H-MNNG and BrdU-labelled cells). Duodenogastric reflux increased the number of double-labelled cells in the antral mucosa from 4.8 +/- 0.6 per mm in the control group to 11.3 +/- 1.9 in the jejunal reflux group (P < 0.05) and 12.7 +/- 0.9 in the pyloric reflux group (P < 0.05). Mucosal erosions were observed in 15 of 28 animals with pyloric reflux and the number of double-labelled cells in the erosion area (4.3 +/- 0.7) was higher than in the same area of animals without erosion (1.4 +/- 0.5) (P < 0.05). Duodeno-gastric reflux increased the cell proliferation and significantly changed the distance between the surface epithelial lining and the proliferating cells when compared to the controls. These results indicate that duodenogastric reflux increases the penetration of (3)H-MNNG into the antrum mucosa of rats. Increased cell proliferation and erosions increase the number of cells at risk of an initiation process from a penetrating gastric carcinogen.

Animals↗