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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis is a vital process for organism development and, when disrupted, can lead to abnormalities including cancer and autoimmune diseases. We demonstrate a novel multicolor flow cytometry approach for quantifying apoptosis and cell cycle information of phenotypically distinct populations, using less than 2 x 10(5) cells per sample. We used incorporation of Cy5-dUTP into DNA strand breaks by the terminal dUTP nucleotide end labeling (TUNEL) method to determine apoptosis, while cell cycle information was assessed with an ultraviolet DNA binding dye, DAPI. To simultaneously determine surface phenotype, we used paraformaldehyde fixation and a gentle permeabilization protocol combined with FITC- and PE-labeled surface antibodies. Using these fluorochromes, and three-laser instrumentation, we quantified apoptosis and cell cycle phase in lymphocyte subpopulations from heterogeneous human and murine cell sources, subjected to various culture conditions. Further, we used this method to detect divergent rates of apoptosis in a human, heterogeneous lymphocyte tumor population, demonstrating a potential application for clinical and/or research settings. Thus, we describe a six-parameter, four-color flow cytometry approach for evaluating apoptosis and cell cycle with dual surface labels. This method may also be useful as a generalized scheme to assess simultaneously two intracellular targets in a mixed cell population.
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PMID:Novel approach for simultaneous evaluation of cell phenotype, apoptosis, and cell cycle using multiparameter flow cytometry. 958 25

We examined the relationship between apoptosis induced by 5-fluorouracil (5-FU) that was given preoperatively to colorectal cancer patients and DNA ploidy pattern, and investigated the cell cycle changes, and the expression of Ki-67. Twenty-nine patients with advanced colorectal cancer were divided into four groups, 3 days, 5 days, 7 days, and 10 days. Groups received continuous intravenous 5-FU at 500 mg/body/day preoperatively. Then, patients were divided into two groups by DNA ploidy pattern, diploid(D) and aneuploid(A). Apoptotic cells were stained by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method. The expression of Ki-67 was examined by immunohistochemical staining. We used flow cytometry (FCM) for analysis of cell cycle distribution. Apoptosis of cancer cells was mostly increased in 7 days 5-FU administration in both D and A groups. The expression of Ki-67 was reduced according to the prolongation of the term of 5-FU administration in both D and A groups. We assessed S-phase fraction (SPF) to evaluate the cell cycle changes by 5-FU. Tumor samples of all patients after injection of 5-FU showed S-phase accumulation. The ratio of SPF (after 5-FU/before 5-FU) was the highest in the 5-day 5-FU administration group in both D and A groups. We concluded that apoptosis and S-phase accumulation were increased, and proliferative activity was decreased by preoperative 5-FU administration in colorectal cancer patients. However, there was no clear correlation between DNA ploidy pattern and these changes.
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PMID:[Enhanced induction of apoptosis of human colorectal cancer cells after preoperative treatment with 5-fluorouracil its relationship to DNA ploidy pattern]. 958 43

Various cancer cell lines express Fas ligand (FasL) and can kill lymphoid cells by Fas-mediated apoptosis in vitro. FasL expression has been demonstrated in several human malignancies in vivo. We sought to determine whether human esophageal carcinomas express FasL, and whether FasL expression is associated with increased apoptosis of tumor-infiltrating lymphocytes (TIL) in vivo, thereby contributing to the immune privilege of the tumor. Using in situ hybridization and immunohistochemistry, respectively, FasL mRNA and protein were colocalized to neoplastic esophageal epithelial cells in all esophageal carcinomas (squamous, n = 6; adenocarcinoma, n = 2). The Extent of FasL expression was variable, with both FasL-positive and FasL-negative neoplastic regions occurring within tumors. TIL were detected by immunohistochemical staining for the leukocyte common Ag, CD45. FasL expression was associated with a mean fourfold depletion of TIL when compared with FasL-negative areas within the same tumors (range 1.6- to 12-fold, n = 6,p < 0.05). Cell death of TIL was detected by dual staining of CD45 (immunohistochemistry) and DNA strand breaks (TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling). There was a mean twofold increase in detectable cell death among TIL in FasL-positive areas compared with FasL-negative areas (range 1.6- to 2.4-fold, n = 6, p < 0.05). In conclusion, we demonstrate a statistically significant, quantitative reduction of TIL concomitant with significantly increased TIL apoptosis within FasL-expressing areas of esophageal tumors. Our findings suggest Fas-mediated apoptotic depletion of TIL in response to FasL expression by esophageal cancers, and provide the first direct, quantitative evidence to support the Fas counterattack as a mechanism of immune privilege in vivo in human cancer.
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PMID:The Fas counterattack in vivo: apoptotic depletion of tumor-infiltrating lymphocytes associated with Fas ligand expression by human esophageal carcinoma. 960 74

Human antitumor effector cells include class I major histocompatibility complex (MHC)-restricted T cells and non-MHC-restricted natural killer (NK) cells. These two types of effector cells have not been directly compared for the ability to eliminate tumor cell targets. Here, we compare in vitro and in vivo antitumor functions of two human T-cell lines specific for a shared tumor antigen to the antitumor functions of A-NK cells, a subset of IL-2-activated NK cells. Human squamous cell carcinoma of the head and neck cell lines cultured in suspensions or as spheroids or tumor xenografts established in nude mice were used to evaluate antitumor functions of IL-2-activated and expanded T and NK effector cells in various assays, both in vitro and in vivo. Both tumor cell targets, PCI-13 and OSC-19, expressed class I and II MHC antigens after IFN-gamma pretreatment, gave rise to tumors upon injection into immunosuppressed nude mice, and were resistant to lysis by resting NK cells but sensitive to lysis mediated by A-NK cells or HLA-A2-restricted T-cell lines specific for a shared squamous cell carcinoma of the head and neck antigen. No significant differences were observed in the ability of A-NK cells or tumor-specific T cells to bind to tumor cell monolayers or to enter into spheroids. However, A-NK cells mediated significantly higher killing than tumor-specific CD8+ T cells in 4-h 51Cr-release assays (a measure of cell membrane damage and necrosis), 1-h [3H]thymidine-release assays (a measure of DNA fragmentation and apoptosis), and in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays (a measure of apoptosis). In contrast, CD8+ T cells were consistently more effective than A-NK cells in inducing growth inhibition of tumor cells in 24-h MTT assays. In the presence of tumor-specific antibodies, A-NK cell binding, entry into spheroids, and infiltration into tumor in vivo were significantly increased. In vivo perilesional delivery of effector cells to mice with established tumors indicated that human A-NK cells exert antitumor effects as potent as those of tumor-specific T cells. However, in contrast to tumor-specific T cells, A-NK cells are readily available for cancer therapy, expand rapidly in culture without prior sensitization, and can be armed with antitumor antibodies to increase localization of effector cells to the tumor.
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PMID:Human tumor antigen-specific T lymphocytes and interleukin-2-activated natural killer cells: comparisons of antitumor effects in vitro and in vivo. 960 70

Prostatic adenocarcinoma may manifest with morphologic features that may be mistaken for benign glandular atrophy. The incidence, morphometric extent, and diagnostic attributes of atrophic prostatic adenocarcinoma have not been defined in radical prostatectomy cases. The size, grade, and stage at which prostatic carcinomas manifest atrophic change and whether these atrophic appearing adenocarcinomatous glands are proliferative, quiescent, or dying (apoptotic) also have not been established. To characterize prostatic adenocarcinoma with atrophic features, we studied 202 consecutive completely embedded radical prostatectomy specimens from previously untreated patients. The histomorphologic attributes of atrophic carcinoma were compiled and compared with benign atrophy and usual prostatic adenocarcinoma without atrophic features. The atrophic carcinoma volume was quantitated by image analysis, the proliferation index was determined by Ki-67 immunolabeling, and the apoptosis index was assessed by TdT [terminal deoxynucleotidyl transferase]-mediated dUTP [deoxyuridine triphosphate]-biotin nick end labeling (TUNEL). Of 202 prostatic adenocarcinoma cases, 32 (15.8%) demonstrated atrophic features. The malignant glands resembled benign atrophic glands by showing profound cytoplasmic volume loss, yet these glands almost always (96.4%) exhibited an infiltrative growth pattern, always lacked basal cells (confirmed by 34betaE12 immunostaining), and exhibited nuclear atypia with nucleomegaly and nucleolomegaly. The atrophic carcinoma foci had a mean volume of 0.3 cc (range, 0.01-2 cc), representing a mean of 16% of total carcinoma volume. The mean proliferation index for atrophic prostatic carcinoma was 4% compared with 1.2% for benign atrophy and 5.3% for usual nonatrophic carcinoma. Apoptosis was identified in only 1 of 32 atrophic prostatic carcinomas. Carcinomas with and without atrophic features did not differ in histologic grade, tumor volume, or pathologic stage. Most atrophic carcinomas were moderately differentiated, of Gleason grade 3. We conclude that the atrophic pattern of prostatic carcinoma is a distinctive morphologic presentation of proliferating, intermediate-grade, prostatic adenocarcinoma that has significant diagnostic rather than prognostic implications.
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PMID:Prostatic adenocarcinoma with atrophic features: a study of 202 consecutive completely embedded radical prostatectomy specimens. 962 26

Lymphocytes recovered from human tumors or peripheral circulation of patients with advanced cancer have abnormalities in signaling via the T cell receptor (TcR) or Fc gamma RIII. Here we show that in comparison with normal T lymphocytes, those isolated from tumor-involved lymph nodes (LNLs) or blood (PBLs) of patients with head and neck carcinoma (HNC) have a variety of defects in expression and function of signaling molecules, including significantly decreased expression of TcR-associated zeta and epsilon chains, decreased Ca2+ flux, as well as impaired kinase activity following triggering with anti-CD3 antibodies and altered expression of downstream protein tyrosine kinase p56lck. Some of these alterations were demonstrable not only in isolated LNLs or PBLs but also in situ in patients' biopsies. Expression of mRNA for the zeta chain in LNLs was comparable with that seen in normal T cells. Significantly, LNLs of patients with HNC were shown to contain numerous apoptotic, TUNEL+ [TdT-mediated dUTP nick-enol labelling] cells in situ. Co-expression of CD3-epsilon+ and TUNEL+ in the same cells in situ was observed. Co-incubation of normal activated T cells or Jurkat cells with HNC cell lines induced apoptosis in a substantial proportion of lymphocytes. HNC cell lines and HNC in situ were shown to express FasL, while LNLs in tumor-involved lymph nodes were Fas+. These data suggest that signaling defects, which are commonly found in lymphocytes of HNC patients, might be a part of the process of apoptosis induced by the tumor in lymphocytes found in its milieu.
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PMID:Mechanisms responsible for signaling and functional defects. 967 51

In the AH-130 hepatoma, a poorly differentiated tumor, maintained by weekly transplantations in rats, a low percentage of cells spontaneously underwent apoptosis, mainly during the transition from logarithmic- to stationary-growth phase. It was possible to induce massive apoptosis of cells by treating them with clofibrate, a peroxisome proliferator and hypolipidemic drug. Similar results were obtained with HepG2 cells. With 1 mM clofibrate, apoptosis began to manifest itself after 1 h of treatment in vitro, and was assessed by morphological analysis, by DNA fragmentation carried out with agarose gel electrophoresis, and with flow cytometric determination of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling. The mechanisms whereby clofibrate induces apoptosis are still unclear. Since the peroxisome proliferator-activated receptor was expressed at a very low level and was not stimulated by clofibrate in the AH-130 hepatoma cells, its involvement seems unlikely. Moreover, lipid peroxidation was not increased after clofibrate treatment. Phospholipids and cholesterol were significantly decreased. The decreased cholesterol content might suggest an inhibition of the mevalonate pathway and, therefore, of isoprenylation of proteins involved in cell proliferation.
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PMID:Peroxisome proliferators induce apoptosis in hepatoma cells. 967 79

The incidence of primary lymphomas of the central nervous system (CNS) has significantly increased over the last years. However, the pathogenesis of this serious and fatal disease is still largely unknown. The aim of the present study was to investigate whether impairment of apoptosis is involved in the pathogenesis of primary CNS lymphomas. A series of 35 primary CNS lymphomas was investigated for the presence of apoptotic cells and the expression of apoptosis-inhibiting and proapoptotic gene products of the bcl family by application of the terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) technique and immunohistochemistry. The majority (23/35) of the tumors contained no or less than 10% of apoptotic cells. All tumors were MIB-1 positive, and 53% of them showed a high proliferative activity with more than 20% MIB-1-positive cells. The bcl-2 gene was expressed in 54% of the tumors (19/35), whereas bcl-x and bax gene products were present in only a low fraction of these lymphomas (4/35). In contrast, bak and the tumor suppressor gene p53 product were not detectable. These findings indicate that apoptosis is inhibited in the majority of this series of primary CNS lymphomas. Since there was no statistical correlation between the degree of apoptosis and the expression of proteins of the bcl gene family, other apoptosis-inhibiting factors may be involved in the pathogenesis of primary CNS lymphomas.
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PMID:Apoptosis and apoptosis-related gene products in primary non-Hodgkin's lymphoma of the central nervous system. 970 31

The effect of pre-operative radio-chemotherapy (RCT) has been examined in a total of 15 oral squamous cell carcinomas (SCCs), in terms of apoptosis (cell loss) and proliferation. All the patients received pre-operative radiation at a dosage of 30 or 40 Gy, as well as anticancer agents including tagaful (FT), 5-fluorouracil (5-FU), bleomycin (BLM) and peplomycin (PEP). Surgical specimens were obtained before and after RCT, and serial sections were prepared for immunohistochemistry for p53 oncoprotein and Ki-67 antigen, as well as for terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL). TUNEL indices (TI; percentage of TUNEL-positive cells in the tumor cells) before and after RCT were 1.2+/-1.1 and 4.7+/-2.9 in the nine well-differentiated oral SCCs, and 1.0+/-0.7 and 3.9+/-2.1 in the six poorly differentiated SCCs, respectively. Similarly, Ki-67 indices (KI; percentage of Ki-67 antigen-positive cells in tumor cells) before and after RCT were 31.1+/-14.2 and 15.8+/-11.1 in the former, and 37.1+/-7.8 and 8.7+/- 13.4 in the latter, respectively. Thus, pre-operative RCT enhanced apoptotic cell death and abated proliferative activity significantly (P<0.05), regardless of histological differentiation. Enhancement of apoptosis was more prominent in the group treated with FT or 5-FU than with BLM or PEP. Oral SCC with >20% of nuclear p53-positive tumor cells was noted in six cases. Enhanced TI and abadement of KI did not differ among the p53-positive and -negative tumors.
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PMID:Pre-operative radio-chemotherapy enhances apoptotic cell death in oral squamous cell carcinoma. 973 27

Recent evidence has emphasized the importance of programmed cell death or apoptosis in the maintenance of tissue homeostasis and pathogenesis of tumors. This study, analyzed in breast cancer, investigates the significance of apoptosis in relation to the expression of p53 and bcl-2 proteins, tissue proliferation defined by Ki-67 expression, hormone receptors and tumor grade. The extent of apoptosis was defined by morphological criteria and the TUNEL (Tdt-mediated dUTP biotin nick end labelling) assay. Immunocytochemistry was performed for p53, bcl-2, estrogen receptor, progesterone receptor and Ki-67 expression. Mutant p53 protein was detected using a mutant specific ELISA. Immunoreactivity of p53 significantly correlated with the presence of mutant p53 protein detected by ELISA (r = 0.654, p = 0.00001). An inverse correlation was observed between bcl-2 expression and the extent of apoptosis (r = -0.33369, p = 0.01912). The extent of apoptosis directly correlated with p53 protein accumulation (r = 0.485, p = 0.00041), Ki-67 immunoreactivity (r = 0.435, p = 0.001), histopathological grade (r = 0.492, p = 0.0003), tumor size (r = 0.326, p = 0.023) and lymph node status (r = 0.287, p = 0.047). A direct correlation was also observed between p53 expression and Ki-67 immunoreactivity (r = 0.623, p = 0.0002). There was no statistically significant association between estrogen and progesterone receptor status and apoptosis. In addition, the TNM stage of the disease correlated with immunoreactivity of p53 (r = 0.572, p = 0.00012) and Ki-67 (r = 0.3744, p = 0.00818). Bcl-2, by inhibiting apoptosis, may cause a shift in tissue kinetics towards the preservation of genetically aberrant cells, thereby facilitating tumor progression. These results imply that rapidly proliferating tumors appear to have a high "cell turnover state" in which there may be an increased chance of apoptosis amongst the proliferating cells. The ability of apoptosis to also occur in the presence of mutant p53 protein suggests the existence of at least two p53-dependent apoptotic pathways, one requiring activation of specific target genes and the other independent of it.
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PMID:Spontaneous programmed cell death in infiltrating duct carcinoma: association with p53, BCL-2, hormone receptors and tumor proliferation. 977 89


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