Altered Expression of G1 Regulatory Proteins in Human Soft Tissue Sarcomas

2002 ◽  
Vol 126 (5) ◽  
pp. 567-573 ◽  
Author(s):  
Jinyoung Yoo ◽  
Sonya Y. Park ◽  
Seok Jin Kang ◽  
Sang In Shim ◽  
Byung Kee Kim
Keyword(s):  
Cell Cycle ◽  
Soft Tissue ◽  
Cyclin D1 ◽  
Soft Tissue Sarcomas ◽  
Tumor Grade ◽  
Regulatory Proteins ◽  
Nuclear Accumulation ◽  
Cyclin D ◽  
P53 Pathway ◽  
Altered Expression

Abstract Context.—Soft tissue sarcomas constitute a heterogeneous group of tumors for which tumorigenesis is not fully understood. Altered cell-cycle regulation may underlie the development and/or progression of human malignancies. However, data concerning the occurrence of cell-cycle aberrations in soft tissue sarcomas are very limited. Objectives.—To detect the abnormal features of cell-cycle regulatory proteins in soft tissue sarcomas and to determine the potential role of these proteins in clinical behavior. Design.—The p53 and Rb–cyclin D pathways were investigated by immunohistochemical studies of p53, mdm2, pRb, p16, cyclin D1, and cdk4 proteins, respectively. Results.—Of the 67 sarcomas analyzed, nuclear accumulation of p53 was detected in 25 samples (37%), and overexpression of mdm2 was found in 16 samples (24%). Both p53 and mdm2 expression correlated with tumor grade. Abnormalities involving the Rb–cyclin D pathway were identified in all of the tumors by the altered expression of either pRb (72%) or p16 (94%). Fourteen (21%) and 64 (96%) cases demonstrated cyclin D1 or cdk4 expression, respectively. Overexpression of cyclin D1 showed an association with pRb and p53. There was no correlation between pRb, p16, cyclin D1, or cdk4 and tumor grade or relapse. Conclusion.—Disturbance in the cell-cycle regulatory system involving the p53 pathway and the Rb–cyclin D pathway is relatively frequent in soft tissue sarcomas and may be a contributing factor in the tumorigenesis of these tumors. The alterations in the Rb–cyclin D pathway probably constitute an early event, whereas the abnormalities in the p53 pathway seem to be involved in tumor progression. It is noteworthy that cyclin D1 may play a key role in linking both pathways.

scholarly journals Expression of regulatory proteins and proliferative activity in relation to phenotypic characteristics of upper urothelial carcinoma

2011 ◽  
Vol 68 (7) ◽  
pp. 567-574 ◽  
Author(s):  
Zana Dolicanin ◽  
Ljubinka Jankovic-Velickovic ◽  
Biljana Djordjevic ◽  
Milan Visnjic ◽  
Ivana Pesic ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Molecular Markers ◽  
Urothelial Carcinoma ◽  
Cyclin D1 ◽  
Regulatory Proteins ◽  
High Expression ◽  
Phenotypic Characteristics ◽  
Ki 67 ◽  
Altered Expression ◽  
Her 2

Background/Aim. Deregulation of the normal cell cycle is common in upper urothelial carcinoma (UUC). The aim of this study was to investigate the expression of regulatory proteins of the cell cycle (p53, p16, cyclin D1, HER-2) and proliferative Ki-67 activity in UUC, and to determine their interaction and influence on the phenotypic characteristics of UUC. Methods. In 44 patients with UUC, histopathological and immunohistochemical analyses (p53, p16, cyclin D1, HER-2, and Ki-67) of tumors were done. Results. Overexpression/ altered expression of p53, p16, cyclin D1 or HER-2 was detected in 20%, 57%, 64%, and 57% of tumors, respectively. Eleven (25%) UUC had a high proliferative Ki-67 index. Forty patients (91%) had at least one marker altered, while four (9%) tumors had a wild-type status. Analysis of relationship between expressions of molecular markers showed that only high expression of p53 was significantly associated with altered p16 activity (p < 0.05). High Ki-67 index was associated with the high stage (p < 0.005), solid growth (p < 0.01), high grade (p < 0.05), and multifocality p < 0.05) of UUC, while high expression of p53 was associated with the solid growth (p < 0.05). In regression models that included all molecular markers and phenotypic characteristics, only Ki-67 correlated with the growth (p < 0.0001), stage (p < 0.01), grade (p < 0.05) and multifocality (p < 0.05) of UUC; Ki-67 and HER-2 expression correlated with the lymphovascular invasion (p < 0.05). Conclusions. This investigation showed that only negative regulatory proteins of the cell cycle, p53 and p16, were significantly associated in UUC, while proliferative marker Ki-67 was in relation to the key phenotypic characteristics of UUC in the best way.

scholarly journals DNA-cytometric characteristics of recurrent soft tissue sarcomas

2018 ◽  
Vol 99 (3) ◽  
pp. 415-420
Author(s):  
E M Nepomnyashchaya ◽  
E P Ul'yanova ◽  
I A Novikova ◽  
O N Selyutina ◽  
E Yu Zlatnik ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Soft Tissue ◽  
Soft Tissue Sarcomas ◽  
Tumor Grade ◽  
Cell Loss ◽  
Biological Potential ◽  
M Phase ◽  
Poorly Differentiated ◽  
G0 Phase ◽  
Well Differentiated

Aim. To determine the content of deoxyribonucleic acid (DNA) and distribution of cells in mitotic phases in patients with recurrent soft tissue sarcomas for the assessment of malignancy of the process. Methods. Tumor tissues of patients with recurrent soft tissue sarcomas were studied. Research methods included histological, DNA-cytometric and statistical methods. Results. Proliferative activity and proliferative index of recurrent sarcomas differed depending on the tumor grade and stage. Differences in the number of diploid, aneuploid and polyploid cells were determined in each group and between the groups depending on the cell cycle phases. Cell cycle parameters were as following: 100% of G1 (well-differentiated) cancer were diploid, as well as 33.3% of G2 (moderately differentiated) and 15% of G3 (poorly differentiated) tumors. Aneuploid tumors prevailed in G2 and G3, the ratio of which was 66.7 and 85%, respectively. The analysis of kinetic parameters of the cell cycle allowed establishing a decrease in the number of cells in G1/G0 phase of the cell cycle from G1 to G3, which was accompanied by a statistically significant increase in the proportion of cells in S-phase (p ˂0.05). Conclusion. The DNA-cytometric study of cell cycle parameters showed high biological potential of recurrent soft tissue sarcomas, which was determined by two indices - the proportion of cells in G2+M-phase and the cell loss factor; 100% of well-differentiated (G1) tumors, 33.3% of moderately differentiated (G2) and 15% of poorly differentiated (G3) tumors were diploid; aneuploid tumors prevailed in G2 and G3.

Targeting the Cyclin D - CDK4/6 - Rb Axis in Mantle Cell Lymphoma with the Novel Translation Inhibitor Silvestrol,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3498-3498
Author(s):  
Lapo Alinari ◽  
Ryan B. Edwards ◽  
Courtney J. Prince ◽  
William H. Towns ◽  
Rajeswaran Mani ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
S Phase ◽  
Cyclin D ◽  
Mantle Cell ◽  
Phase Entry

Abstract Abstract 3498 During cell cycle progression, D class cyclins activate cyclin dependent kinases (CDK) 4 and 6 to phosphorylate and inactivate Rb, allowing E2F-1 mediated transcription of additional cell cycle genes including cyclin E to drive S phase entry. This critical pathway is nearly universally dysregulated in cancer, providing tumor cells a strong growth advantage and escape from normal mitotic control. Substantial research is being directed toward targeting this pathway in many cancer types, with some preliminary successes being achieved with pharmacologic inhibitors of CDK4/6. However the development of alternative strategies to block this pathway could potentially provide broad therapeutic benefit. A prime example of a tumor with a disrupted cyclin D axis is Mantle Cell Lymphoma (MCL), in which the t(11;14) translocation places CCND1, the gene for cyclin D1, under the control of an immunoglobulin promoter. This results in sustained cyclin D1 expression in tumor cells and concomitant Rb inactivation, S phase entry and cell division. MCL is a relatively uncommon subset of Non-Hodgkin Lymphoma, but accounts for a disproportionate number of deaths. Treatments are limited and relapse is nearly universal; thus, new treatment strategies are essential for this disease. Silvestrol is a structurally unique, plant-derived cyclopenta[b]benzofuran with potent in vitro and in vivo anti-tumor activity in several model systems including B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Silvestrol inhibits the initiation step of translation by preventing assembly of eIF4A and capped mRNA into the eIF4F complex, leading to selective loss of short half-life proteins such as Mcl-1 and cyclin D1. We therefore hypothesized that silvestrol, through the depletion of cyclin D1, would demonstrate efficacy in MCL. Silvestrol showed low nanomolar IC50 values in the JeKo-1 (13 nM), Mino (17 nM) and SP-53 (43 nM) MCL cell lines at 48 hr (MTS assay; cell death confirmed by propidium iodide flow cytometry). This potency was similar in primary MCL tumor cells. Longer exposure times substantially improved the cytotoxicity of silvestrol assessed at 48 hr (approximately 50% effect achieved with a 16 hr exposure vs. 80% effect with a 24 hr exposure), suggesting that the cellular impacts of this agent increase with exposure time. Cyclins D1 and D3 were dramatically reduced in MCL cell lines with just 10 nM silvestrol at 16 hr (cyclin D2 was undetectable in these cells), with subsequent loss of Rb phosphorylation as well as cyclin E mRNA and protein, culminating in G1 cell cycle arrest. Similar to what we previously showed in CLL and ALL cells, silvestrol treatment under these conditions also caused loss of Mcl-1 protein with concurrent mitochondrial depolarization, although the exact mechanism of silvestrol-mediated cytotoxicity in these cells is still under investigation. In an aggressive xenograft mouse model of MCL, silvestrol produced a highly significant improvement in survival [median survival of vehicle vs. silvestrol treated mice (1.5 mg/kg every 48 hr) = 27 vs. 38 days; P<0.0001] without detectable toxicity. Together, these data demonstrate that the translation inhibitor silvestrol has promising in vitro and in vivo activity in MCL preclinical models. Furthermore, as the cyclin D/CDK/Rb axis is disrupted in most tumor types, this strategy may be broadly effective in other cancers as well. Disclosures: No relevant conflicts of interest to declare.

Comparative DNA cytometry of primary and recurrent soft tissue sarcomas.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e22516-e22516
Author(s):  
Irina Dashkova ◽  
Larisa N. Vashchenko ◽  
Oleg Ivanovich Kit ◽  
Inna A. Novikova ◽  
Ekaterina Komarova ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Soft Tissue ◽  
Dna Content ◽  
Soft Tissue Sarcomas ◽  
Literary Analysis ◽  
Proliferation Index ◽  
Cell Distribution ◽  
Dna Cytometry ◽  
Flow Cytofluorometry ◽  
M Phase

e22516 Background: Soft tissue sarcomas (STS) are aggressive tumors with a high degree of recurrence. Radical resection within healthy tissues allows to reduce the recurrence percentage to 25-30% without subsequent therapy. The literary analysis has shown that the study of various biological properties of primary and recurrentsoft tissue tumorsis being conducted. However, currently there is a lack of information to understand the reasons for STS recurrence. The goal of investigation was to reveal the distinctive features of the DNA content and cell distribution in the phases of the cell cycle of recurrent STS. Methods: DNA cytometry in the tumor tissue of 30 primary soft tissue sarcomas and 30 STS recurrences was carried out using the method of flow cytofluorometry. The tumor ploidy and cell distribution in the cell cycle phases were analyzed. Results: A number of differences in the DNA cytometric parameters of primary and recurrent STS have been revealed, they include: an increase in the proportion of aneuploid tumors in case of recurrence, the number of tumors with DNA index within the mitotic cycle, an increase in the proportion of cells in G2+M- phase of diploid and aneuploid tumors and a decrease in S- phase of aneuploid ones. It has been shown that with a G2 differentiation degree, the proportion of cells in G2+M, S- and proliferation index of recurrent STS is significantly lower than the primary parameters. An increase in the proportion of cells in G2+M- phase and a decrease in the rate of proliferation of recurrent STS, depending on the stage, are shown only in case of stage III. Conclusions: The revealed features of DNA content and cell cycle of tumor cells of soft tissue sarcomas will allow to approach to understanding of biological bases of recurrence of this malignant disease.

scholarly journals Prognostic Factors in Extremity Soft Tissue Sarcoma Patients Treated with Preoperative Radiotherapy

2019 ◽  
Vol 4 (03) ◽  
Author(s):  
Berrin Inanc, MD ◽  
Kubilay Inanc, MD
Keyword(s):  
Prognostic Factors ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Preoperative Radiotherapy ◽  
Soft Tissue Sarcomas ◽  
Tumor Grade ◽  
Metastatic Recurrence ◽  
Extremity Soft Tissue Sarcoma ◽  
Metastatic Relapse

Purpose: The purpose of the study was to investigate the prognostic factors and survival after preoperative radiotherapy in Extremity Soft Tissue Sarcomas (ESTS). Materials and Methods: In this retrospective study, all patients treated for an extremity sarcoma with pre-operative radiotherapy followed by surgery. Results: The mean follow-up for all 24 ESTS patients was 15.5 (range: 10-39 months). At last follow-up, 9 patients (37%) were alive, 15 patients (62%) had died of distant disease progression. Among the patients died, there were 15 with metastatic relapse (13 lung and 2 cranial metastasis), 5 with both local and metastatic recurrence. The median OS was 16 month. The 2-years actuarial OS rate and 3-years OS rate were 39% and 26%, respectively. The median RFS was 14(12.5-15.4) month. The 2-years and 3-years RFS rate was 71%.The median MFS was 12 months. The 2-years and 3-years MFS rate were 33%, 17%, respectively. The effects of age, sex, histopathologic type, tumor size, tumor localization, tumor grade, tumor depth, radiation doses and recestion margin on OS, RFS, MFS were not observed. In univariate and multivariate model, it was observed that recurrence decreased OS time significantly (p<0.05). Conclusion: Recurrens and metastasis are strong and negative prognostic factor for survival in extremity soft tissue sarcoma patients.

Mdm2 SNP309 Different Genotypes Distribution in Israeli Population and in Patients with Hematological Malignancies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4395-4395
Author(s):  
Avigdor Hevroni ◽  
Svetlana Krichevsky ◽  
Susana Mustafa ◽  
Nadir Arber ◽  
Dina Ben-Yehuda
Keyword(s):  
Soft Tissue ◽  
Hematological Malignancies ◽  
Soft Tissue Sarcomas ◽  
Healthy Population ◽  
Age Group ◽  
Mdm2 Snp309 ◽  
Mdm2 Gene ◽  
P53 Pathway ◽  
First Intron ◽  
Israeli Population

Abstract P53 is a pivotal tumor suppressor gene that is mutated in half of all human cancers. The Mdm2 protein is a major negative regulator of p53. At residue 309 of the Mdm2 gene, there is a single nucleotide polymorphism (SNP) with a T-to-G substitution. Residue 309 is located in the first intron which is the locus of a P53-responsive promoter. The frequencies of the Mdm2 SNP309 variant genotypes have been reported to be 12% G/G, 40% G/T and 48% to T/T (Bond et.al. Cell 2004, Cancer Research 2005). Recent studies in cell lines (Ibid) showed that the G/G genotype confers an increased affinity to the transcriptional activator Sp1, resulting in higher levels of Mdm2 RNA and protein. A subsequent attenuation of the p53 pathway and reduced apoptosis occurs. It was also shown that Li-Fraumeni pts acquire more cancers at an earlier age when harboring the G/G or G/T genotype at SNP309. Similarly, soft-tissue sarcomas pts acquire cancer at an earlier age when harboring the G/G or G/T genotype at this locus. We analyzed the DNA of 353 healthy individuals of various origins, and determined the distribution of the SNP309 genotypes in the Israeli population. We next studied the genotypes in 219 pts with hematological malignancies: NHL (n=102), CLL (n=47) and MM (n=70). We also analyzed the genotype of 90 pts with colon cancer. METHODS: The fragment of the first intron of the Mdm2 gene containing SNP309 was amplified by PCR. Dot Blot analysis with P32 γ-d-CTP labeled oligo-probes corresponding to each SNP variant was performed. The method was validated by direct sequencing. RESULTS: Table 1: Mdm2 SNP309 in Israeli population and different malignancies Published* Israeli pop. Colon Ca. NHL MM CLL *Bond et.al. Cell 2004 n 353 90 102 70 47 G/G 12% 20% 27% 23.5% 26% 21% G/T 40% 49% 53% 53% 43% 51% T/T 48% 31% 20% 23.5% 31% 28% The distribution of the SNP309 different genotypes in Israeli healthy population is significantly different from the distribution published (p<0.0001): T/T 31% and G/T 49% in the Israeli population versus the reported 48% and 40% respectively. These differences may reflect the different ethnic origin of the cohorts tested. It is worth mentioning that we found different trends among the subpopulations. For example, Israeli Arabs seem to harbor less G/G genotype than other Israeli subpopulations. Table 2: Mdm2 SNP309 in Hematological malignancies according to age NHL MM CLL 50y≥ 50y< 50y≥ 50y< 50y≥ 50y< n 50 52 24 46 21 26 G/G 14 (28%) 10 (19%) 6 (25%) 12 (26%) 4 (19%) 6 (23%) G/T 27 (54%) 27 (52%) 6 (25%) 24 (52%) 11 (52%) 13 (50%) T/T 9 (18%) 15 (29%) 12 (50%) 10 (22%) 6 (29%) 7 (27%) No significant differences were found between any of the various tumors studied (Colon ca, NHL, MM, CLL) and the healthy population. Moreover, comparing genotypes between the young age group (≤ 50y) and the old age group (> 50y) within the hematological malignancies did not show any significant differences. In addition, there were no significant differences between the median or average age of the G/G and T/T groups in any of the cancer populations. In conclusion, although it requires further studies, it seems that Mdm2 SNP309 does not play a significant role in the etiology of hematological malignancies compared with the reported role in Li-Fraumeni and soft-tissue sarcomas. These findings may be the consequence of the less prominent role of the p53 pathway in hematological malignancies.

Results of immunohistochemical staining for cell cycle regulators predict the recurrence of atypical meningiomas

2014 ◽  
Vol 121 (5) ◽  
pp. 1189-1200 ◽  
Author(s):  
Min Soo Kim ◽  
Kyu Hong Kim ◽  
Eun Hee Lee ◽  
Young Min Lee ◽  
Sung-Hun Lee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Immunohistochemical Staining ◽  
Regulatory Proteins ◽  
Incomplete Resection ◽  
Presenting Symptoms ◽  
Cell Cycle Regulatory Proteins ◽  
Atypical Meningiomas ◽  
Mib 1

Object The aim of this study was to evaluate the role of certain cell-cycle regulatory proteins in the recurrence of atypical meningiomas. These proteins were analyzed with immunohistochemical staining to identify predisposing factors for the recurrence of atypical meningiomas. Methods The authors retrospectively reviewed the medical records of patients with atypical meningiomas diagnosed in the period from January 2000 to June 2012 at the Department of Neurosurgery at Samsung Changwon Hospital and Dong-A University Medical Center. Clinical data included patient sex and age at the time of surgery, presenting symptoms at diagnosis, location and size of tumor, extent of surgery, use of postoperative radiotherapy, duration of follow-up, and recurrence. Immunohistochemical staining for cell-cycle regulatory proteins (p16, p15, p21, p27, cyclin-dependent kinase [CDK] 4 and 6, phosphorylated retinoblastoma [pRB] protein, and cyclin D1) and proliferative markers (MIB-1 antigen, mitosis, and p53) was performed on archived paraffin-embedded tissues obtained during resection. The recurrence rate and time to recurrence were assessed using Kaplan-Meier analysis. Results Of the 67 atypical meningiomas eligible for analysis, 26 (38.8%) recurred during the follow-up period (mean duration 47.7 months, range 8.4–132.1 months). Immunohistochemically, there was overstaining for p16 in 44 samples (65.7%), for p15 in 21 samples (31.3%), for p21 in 25 samples (37.3%), for p27 in 32 samples (47.8%), for CDK4 in 38 samples (56.7%), for CDK6 in 26 samples (38.8%), for pRB protein in 42 samples (62.7%), and for cyclin D1 in 49 samples (73.1%). Multivariate analysis using the Cox proportional-hazards regression model showed that incomplete resection (HR 4.513, p < 0.001); immunohistochemical understaining for p16 (HR 3.214, p < 0.001); immunohistochemical overstaining for CDK6 (HR 3.427, p < 0.001), pRB protein (HR 2.854, p = 0.008), and p53 (HR 2.296, p = 0.040); and increased MIB-1 labeling index (HR 2.665, p = 0.013) and mitotic index (HR 2.438, p = 0.024) predicted the recurrence of atypical meningiomas after resection. Conclusions Findings in this study indicated that p16, CDK6, and pRB protein were associated with the recurrence of atypical meningiomas.

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