UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among the entire spectrum of astrocytic neoplasms, just anaplastic astrocytoma (or grade III astrocytoma) appears to be a more enigmatic tumor entity with vague criteria for pathological diagnosis, unclear biological behavior and diverse clinical outcome. Attempts have been made to identify biological markers that would be useful in prediction of prognosis of anaplastic astrocytomas but the results obtained are controversial. In the present study, survival data on 63 patients with anaplastic astrocytoma were studied to evaluate a possible association between clinical outcome and expression of some immunohistochemical variables. Both the progression-free (PFS) and overall (OS) survival times were significantly reduced for patients older than 45 years, for anaplastic astrocytomas containing multiple mitoses, for Ki-67 LI > 5%, for cyclin A LI > 4% and for PTEN-negative tumors. We found no differences in survival times in patients with or without p53 immunoreactivity and also in cases with different values of p16 and p27 immunostaining. Multivariate analysis revealed that risk of tumor progression and death is independently associated with tumors containing multiple mitoses and for PTEN-negative tumors. According to the data from the CART modeling, tumors were subdivided based on the three following subsets: (1) Anaplastic astrocytomas with solitary mitosis. (2) Anaplastic astrocytomas with multiple mitoses and PTEN positivity. (3) Anaplastic astrocytomas with multiple mitoses and PTEN negativity. Thus, the results obtained reveal the advantage of combined approach including evaluation of routine histological parameters and immunohistochemical variables for further clinical subdivision of anaplastic astrocytomas.
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PMID:Immunohistochemical markers for prognosis of anaplastic astrocytomas. 1218 56

Multi-cellular spheroids (MCS) generated from tumor cells serve as excellent in vitro models for understanding the mechanisms of tumor progression and micro-metastasis. We have compared the expression of molecular markers with reference to their growth as conventional adherent monolayers (2-D) and anchorage independent cultures (3-D) using two mouse melanoma cell lines, B16F10 and Clone M3. The two cell lines differed in their ability to form spheroids with respect to their aggregation potential, with B16F10 forming large clusters compared to Clone M3. A panel of molecular markers comprising cell adhesion molecules, cyclin dependent kinase inhibitors and members of the cadherin-catenin complex were analyzed by flow cytometry in 2-D and 3-D cultures. There was a distinct difference in the patterns of expression of CD44(S) and variant isoforms v3, v10 in spheroids compared to cells grown as monolayers in both cell lines. Also, there was an increase in cells positive for CDK inhibitor p27 in 3-D cultures from the B16F10 cell line. The expression of alpha and gamma catenin was down regulated in spheroids. As these molecules are implicated in the regulation of cell proliferation, alterations in the expression of these molecules in 3-D cultures compared to their 2-D counterparts suggests the importance of spheroids as experimental model for tumorigenesis.
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PMID:Differential expression of CD44(S) and variant isoforms v3, v10 in three-dimensional cultures of mouse melanoma cell lines. 1219 73

Epidemiological and preclinical studies demonstrate that consumption of diets high in omega-3 polyunsaturated fatty acids reduces the risk of colon cancer. Inhibition of colon carcinogenesis by omega-3 polyunsaturated fatty acids is mediated through modulation of more than one signaling pathway that alters the expression of genes involved in colon cancer growth. In our earlier studies on global gene expression with cDNA microarrays, we have shown that treatment of CaCo-2 colon cancer cells with docosahexaenoic acid (DHA) down-regulated the prostaglandin family of genes, as well as cyclooxygenase 2 expression and several cell cycle-related genes, whereas it up-regulated caspases 5, 8, 9, and 10 that are associated with apoptosis. It is known that nitric oxide activates the cyclooxygenase 2 enzyme, which plays a pivotal role in the progression of colon cancer via prostaglandin synthesis and angiogenesis. The present study was undertaken to examine the multifaceted role of DHA in the expression of inducible nitric oxide synthase (iNOS) and of related proinflammatory genes, as those have been shown to play a role in tumor progression. In addition, we aimed to identify associated target genes by DNA microarray, reverse transcription-PCR analysis, and cellular localization of iNOS expression in CaCo-2 cells. Results of this study demonstrate that treatment with DHA down-regulates iNOS in parallel with a differential expression and down-regulation of IFNs, cyclic GMP, and nuclear factor kappa B isoforms. More importantly, our findings clearly demonstrate the up-regulation of cyclin-dependent kinase inhibitors p21((Waf1/Cip1)) and p27, differentiation-associated genes such as alkaline phosphatases, and neuronal differentiation factors. These finding strongly suggest that the antitumor activity of DHA may be attributed, at least in part, to an effect on iNOS regulatory genes. In addition, our results indicate the presence of specific gene expression profiles in human colon cancer that can be used as molecular targets for chemopreventive agents.
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PMID:Modulation of inducible nitric oxide synthase and related proinflammatory genes by the omega-3 fatty acid docosahexaenoic acid in human colon cancer cells. 1261 11

Ovarian cancer is a common gynecological malignancy and a leading cause of death in women. Inactivation of the tumor suppressor gene and deregulation of cyclin E are frequent in human ovarian cancer. The objective of this study was to investigate the expressions and roles of cyclin E, p21 and p27 in 7, 12-dimethylbenzanthracene (DMBA)-induced ovarian tumors in rats. The expressions of cyclin E, p21 and p27 were evaluated by immunohistochemistry and western blot analysis. The expressions of cyclin E and p21 in ovarian tumors was higher than that in normal ovarian surface epithelium. In contrast, the expression of p27 in ovarian tumors was lower than that in normal ovarian surface epithelium. But there were no differences among the cancer types. Positive correlation was present between cyclin E and p21. p27 was negatively correlated with cyclin E and p21. These results suggest that the increased expression of cyclin E and p21, and the decreased expression of p27, occur in DMBA-induced rat ovarian carcinogenesis and result in tumor progression.
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PMID:Overexpression of p21, cyclin E and decreased expression of p27 in DMBA (7, 12-dimethylbenzanthracene)-induced rat ovarian carcinogenesis. 1271 63

Galectin-3 (Gal-3), a beta-galactoside-binding protein, has been implicated in a variety of biological functions, including cell proliferation and differentiation, tumor cell adhesion, angiogenesis, apoptosis, tumor progression, and metastasis. We investigated the role of Gal-3 in the development and progression of pituitary tumors. Immunohistochemical and Western blot analysis of normal and neoplastic human pituitaries showed that only lactotroph (PRL) and corticotroph (ACTH) hormone-producing cells and tumors expressed Gal-3. Gal-3 was present in 24 of 38 (63.2%) PRL adenomas, 5 of 6 (83.3%) PRL carcinomas, 19 of 41 (46.3) ACTH adenomas, and 7 of 8 (87.5%) ACTH carcinomas, but not in 112 other pituitary adenomas and carcinomas. Pituitary folliculo-stellate cells, which have macrophage-type functions in the anterior pituitary, also expressed Gal-3. Hyperplastic and neoplastic pituitaries from p27(Kip1) (p27)-null mice, which produce mainly ACTH, showed increased Gal-3 expression levels compared with control mice. Treatment with transforming growth factor beta1, which regulates pituitary cell proliferation, reduced Gal-3 as well as p27 expression levels in cultured HP75 pituitary cells and Gal-3 in cultured pituitary cells from p27-null mice, suggesting that p27 is not necessary for the inhibitory effects of transforming growth factor beta1 on the cell cycle in the pituitary. The role of Gal-3 in pituitary cell function was examined by RNA interference experiments. Inhibition of Gal-3 gene expression by RNA interference decreased HP75 cell proliferation and increased apoptosis. These results indicate that Gal-3 has an important role in pituitary cell proliferation and tumor progression.
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PMID:Differential expression of galectin-3 in pituitary tumors. 1272 47

Mechanisms underlying the chemopreventive effect of difluoromethylornithine (DFMO) on the development of mammary cancer were investigated utilizing the whey acidic protein promoter-T antigen transgenic mouse model of breast cancer progression. Mice were exposed to four different doses of DFMO in the diet (3.5, 4.9, 7.0 and 10 g/kg diet). Tumor latency was increased in a dose-dependent manner. DFMO at the highest dose significantly delayed tumor onset (131 days as compared to 109 days in control unexposed mice, P=0.018). Analyses of preneoplastic mammary tissue collected 1 month after DFMO treatment demonstrated that DFMO (10 g/kg diet) significantly increased the ratio of apoptotic to proliferative indices (P=0.013) and significantly reduced the percentage of cells demonstrating nuclear localized cyclin D1 (P=0.013). Nuclear localizations of p27, p21 and Stat5a were not affected. Inhibitory effects of DFMO on cell growth and survival were lost as the cells progressed to cancer. In conclusion, the chemopreventive effects of DFMO on mammary cancer progression were mediated by changes in both apoptosis and cell proliferation in preneoplastic cells. Alterations in cyclin D1 activity in preneoplastic cells could represent an early biomarker of chemopreventive action and are consistent with a mechanistic role for cyclin D1 in progression of mammary cancer.
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PMID:Chemoprevention of mammary carcinogenesis in a transgenic mouse model by alpha-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity. 1273 Jun 71

The cell-transforming potential of 1,2-dibromoethane and folpet, two widely used agricultural pesticides that are potential sources of environmental pollution, has been previously ascribed to their promoting activity. In this study, we investigated whether BALB/c 3T3 transformation by these chemicals was associated with the deregulation of signals involved in cell-cycle progression and in cell-cycle checkpoint induction. We found that two BALB/c 3T3 cell clones transformed by in vitro medium-term (8-week) exposure to the carcinogens had a constitutive acceleration of cell transition from G(1) to S phase and an abrogation of the radiation-induced G(1)/S checkpoint. These events involved multiple signals; in particular, the inhibitors of cyclin/cyclin-dependent kinase complexes p21 and p27 were significantly down-modulated and the positive regulators of cell-cycle progression cyclin D(3) and E were up-modulated. As anticipated for cells where the G(1)/S checkpoint was abrogated, the transformed cells exhibited a significant reinforcement of the radiation-induced G(2)/M checkpoint, the only checkpoint remaining to protect genomic integrity. However, cyclin A(1) and B(1) coexpression and cyclin A(1) overexpression were found despite the G2 arrest in irradiated cells and these signals likely attenuate the G(2)/M checkpoint. These alterations to normal cell cycling may promote the emergence of both numerical and structural chromosomal abnormalities and their tolerance. Such a condition could play a key role in neoplastic transformation and be crucial in tumor progression. Furthermore, cyclin A(1) overexpression may play an autonomous role in the neoplastic transformation of BALB/c 3T3 cells, as it does in other cell types of mesenchymal origin.
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PMID:Cell-cycle deregulation in BALB/c 3T3 cells transformed by 1,2-dibromoethane and folpet pesticides. 1280 1

Recently, a close relationship between the cell cycle and apoptosis was confirmed in oral squamous cell carcinoma (SCC). To clarify the expression of cell cycle-related proteins and apoptosis in the oral premalignant state, we investigated the expression of p27, cyclin D1 and proliferating cell nuclear antigen (PCNA) using immunohistochemical staining, and apoptotic index (AI) using ApopTag in situ staining. The positive expression-score of p27 was 42.0% in leukoplakia (34.8% in hyperplasia, 55.4% in dysplasia) and 31.1% in SCC (43.3% in the early stage of SCC, 25.9% in the advanced stage of SCC). The level of p27 expression showed a peak in dysplasia and decreased in SCC. The expression of cyclin D1 was almost constant between hyperplasia and SCC. The expression of PCNA increased sequentially with disease progression. The apoptotic index (AI) in the p27-positive leukoplakia group was significantly higher than that in the p27-negative leukoplakia group (3.9 +/- 3.6 vs. 1.5 +/- 1.6, p = 0.026). From these results, we suggest that the abundance of p27 in oral leukoplakia may inhibit cell proliferation and lead premalignant tumor cells to apoptosis, and thus is concerned with prevention of tumor progression.
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PMID:Expression of p27 and apoptosis in oral leukoplakia. 1282 Mar 81

Members of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors are involved in the regulation of proliferation and differentiation of the mammary gland. In order to investigate the role of C/EBPalpha, -beta and -delta in breast cancer, we performed western blot analysis and partly immunohistochemistry in 75 mammary carcinomas, 10 normal mammary tissue samples and four mammary cell lines. Expression levels of both C/EBPalpha isoforms, C/EBPbeta isoforms LAP1, LAP2 (liver-enriched transcriptional activating proteins), and LIP (liver-enriched transcriptional inhibitory protein), and C/EBPdelta in the tumors were correlated with clinicopathological tumor parameters, expression of estrogen and progesterone receptors (ER, PR), Ki67 immunostaining, and expression of seven cell-cycle regulatory proteins which had been analyzed before. High C/EBPalpha and -delta protein levels correlated significantly with expression of cell-cycle promoters (cyclin D1 and E) and cell-cycle inhibitory proteins (Rb, p27, p16), but with none of the established prognostic parameters. In contrast, statistically significant relationships of the full-length C/EBPbeta isoform LAP1 and a negative estrogen receptor status, high grading, nodal involvement, and high cyclin E and p16 expression were found. For the shorter isoform LIP, correlations with an ER-negative phenotype and high Ki67 immunostaining were detected, and high histological grading (G3) correlated with lower LAP/LIP ratio. These results suggest that high C/EBPbeta expression might be involved in tumor progression and indicative of an unfavorable prognosis.
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PMID:Expression of the CCAAT/enhancer-binding proteins C/EBPalpha, C/EBPbeta and C/EBPdelta in breast cancer: correlations with clinicopathologic parameters and cell-cycle regulatory proteins. 1282 52

Inhibins are heterodimeric (alpha:betaA and alpha:betaB) endocrine, paracrine, and autocrine factors of the TGFbeta superfamily that are produced predominantly by ovarian granulosa cells in females and testicular Sertoli cells in males. Control of granulosa and Sertoli cell proliferation is lost in the inhibin alpha (Inhalpha) knockout mouse model, leading to gonadotropin-dependent gonadal tumors of the granulosa/Sertoli cell lineage in both females and males. Castrate Inhalpha knockout mice develop sex steroidogenic tumors of the adrenal cortex. Physiological control of granulosa/Sertoli cell cycle progression depends on p27Kip1 and cyclin D2, which function in the G1-->S phase transition. To study the cell cycle-regulatory factors involved in ovarian, testicular, and adrenal tumor development in vivo, we have bred Inhalpha mutant mice to mice with targeted disruptions of the p27 and cyclin D2 genes. Our previous studies demonstrated that inhibins act cooperatively with p27 to negatively regulate granulosa cell proliferation, as double mutant mice lacking inhibins and p27 develop and succumb to ovarian tumors more rapidly than Inhalpha knockout mice. Here, we report that cyclin D2 antagonizes this inhibition and is key in promoting gonadal growth and tumor development, and tumor development is markedly suppressed in double-mutant mice. We found that double-knockout females lacking cyclin D2 and Inhalpha lived longer than mice lacking inhibins alone; the majority of these double-knockout mice lived longer than 17 wk, as opposed to inhibin alpha single-knockout females with 50% survival at between 12 and 13 wk of age. Moreover, 95% of inhibin alpha knockout males succumb to testicular tumor development by 12 wk of age, whereas double knockouts were protected from early signs of tumor development and had a 50% survival of 40 wk. Interestingly, the results of these studies reflect tissue-specific consequences of loss of these cell cycle regulators. In castrate mice, loss of p27 has little effect on adrenal cortical tumor progression in the absence of inhibins, whereas loss of cyclin D2 prolongs the lifespan of cyclin D2, Inhalpha double knockouts. After gonadectomy, 50% of cyclin D2, Inhalpha double-knockout males live to more than 46 wk of age, 10 wk longer than 50% of littermates lacking only inhibins. Similarly, 50% of female cyclin D2, inhibin alpha double knockouts live to 47 wk of age before succumbing to adrenal tumor development, in contrast to the 50% survival of Inhalpha single-knockout females at between 27 and 28 wk. Thus, identification of genetic modifiers of the Inhalpha knockout tumor phenotype has led us to a better appreciation of how specific components of the cell cycle machinery contribute to tumorigenesis in the ovary, testis, and adrenal gland.
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PMID:Cyclin D2 and p27 are tissue-specific regulators of tumorigenesis in inhibin alpha knockout mice. 1285 47

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