Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p21(WAF1/cIP1) cyclin-dependent kinase (cdk) inhibitor is a regulator of the G(1)-S cell cycle checkpoint. Despite the importance of p21 in cell cycle inhibition, its role as a tumor suppressor is uncertain. p21 mutations are infrequent in human tumors, and p21 null mice exhibit no increased tumor incidence. To ascertain whether p21 could influence tumor formation or progression in the context of other oncogenic stimuli, we crossed p21-deficient mice with mammary tumor susceptible Wnt-1 transgenic mice. The p21+/+, p21+/-, and p21-/- Wnt-1 transgenic female offspring were monitored for mammary tumor incidence and growth rates. p21 status had no effect on the age at which mammary tumors formed. However, p21+/- mammary tumors grew significantly faster than p21+/+ and p21-/- mammary tumors. The increased growth rates were confirmed by mitotic index counts and by BrdUrd labelling assays, indicating that a significantly higher percentage of p21+/- tumor cells were in S phase and mitosis than their p21+/+ and p21-/- counterparts. Moreover, cyclin D1-associated phosphorylation of retinoblastoma protein was significantly increased in p21+/- tumor lysates compared with p21+/+ and p21-/- lysates. These results are consistent with data indicating that reduced levels of p21 can facilitate cyclin/cdk complex formation while enhancing cdk activity. Thus, a reduction of p21 dosage may promote tumor progression in the presence of other oncogenic initiators. The dependence of p21 on prior oncogenic stimuli for its tumor-promoting activities suggests that it may behave as a tumor modifier gene rather than as a tumor suppressor gene.
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PMID:Heterozygosity of p21WAF1/CIP1 enhances tumor cell proliferation and cyclin D1-associated kinase activity in a murine mammary cancer model. 1031 91

Decorin is a member of the small leucine-rich proteoglycan (SLRP) gene family that has recently become a focus in various areas of cancer research. The decorin protein consists of a core protein and a covalently linked glycosaminoglycan chain. Decorin binds to collagens type I, II and IV in vivo and promotes the formation of fibers with increased stability and changes in solubility. Further, the decorin core protein binds to growth factors, including transforming growth factor-beta (TGF-beta), to other intercellular matrix molecules such as fibronectin and thrombospondin, and to the decorin endocytosis receptor. Decorin may directly interfere with the cell cycle via the induction of p21WAF1/CIP1 (p21), a potent inhibitor of cyclin-dependent kinases (CDKs). Here, we discuss interactions of decorin with TGF-beta and with p21, both of which are relevant to carcinogenesis and tumor progression. TGF-beta is released by tumors of various histogenetic origins and promotes immunosuppression in the host and tumor immune escape by induction of growth arrest and apoptosis in immune cells, by downregulation of MHC II antigen expression and by changes in the cytokine release profiles of immune and tumor cells. Moreover, TGF-beta may modulate tumor growth in an autocrine and paracrine fashion, may mediate drug resistance, and may facilitate tumor angiogenesis. Decorin binds to TGF-beta, thus inhibiting its bioactivity, and is a direct or indirect negative modulator of TGF-beta synthesis. Ectopic expression of decorin results in the regression of rat C6 gliomas, an antineoplastic effect attributed to the reversal of TGF-beta-induced immunosuppression. On the other hand, de novo expression of decorin in colon cancer cells and some other tumor cells, even though not in glioma cells, results in an upregulation of p21 expression and a cell cycle arrest, presumably in a TGF-beta-independent manner. Decorin expression is downregulated in many tumors but upregulated in the peritumoral stroma. By virtue of its growth regulatory and immunomodulatory properties, decorin promises to become a novel target for the experimental therapy of human cancers.
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PMID:Transforming growth factor-beta and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth. 1038 66

Galectin-3 is a member of a growing family of animal beta-galactoside-binding proteins shown to be involved in cell growth, differentiation, apoptosis resistance, and tumor progression. In the present study, we investigated whether galectin-3 can protect against apoptosis induced by the loss of cell anchorage (anoikis). Because studies suggest that cellular sensitivity to anoikis is associated with cell cycle regulation, we examined the role of galectin-3 on cell cycle regulation. Although BT549 cells (human breast epithelial cells) undergo anoikis, galectin-3-overexpressing BT549 cells respond to the loss of cell adhesion by inducing G1 arrest without detectable cell death. Galectin-3-mediated G1 arrest involves down-regulation of G1-S cyclin levels (cyclin E and cyclin A) and up-regulation of their inhibitory protein levels (p21(WAF1/CIP1) and p27KIP1). After the loss of cell anchorage, Rb protein becomes hypophosphorylated in galectin-3-overexpressing cells, as predicted from the flow cytometric analysis and immunoblot analysis of cyclins and their inhibitors. Interestingly, galectin-3 induces cyclin D1 expression (an early G1 cyclin) and its associated kinase activity in the absence of cell anchorage. On the basis of these results, we propose that galectin-3 inhibition of anoikis involves cell cycle arrest at an anoikis-insensitive point (late G1) through modulation of gene expression and activities of cell cycle regulators. The present study suggests that galectin-3 may be a critical determinant for anchorage-independent cell survival of disseminating cancer cells in the circulation during metastasis.
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PMID:Cell cycle arrest and inhibition of anoikis by galectin-3 in human breast epithelial cells. 1046 21

The INK4A gene, a candidate tumor suppressor gene located on chromosome 9p21, encodes two protein products, p16 and p19(ARF). p16 is a negative cell cycle regulator capable of arresting cells in the G1 phase by inhibiting cyclin-dependent kinases 4 (Cdk4) and 6 (Cdk6), thus preventing pRB phosphorylation. p19(ARF) prevents Mdm2-mediated neutralization of p53. Loss of INK4A is a frequent molecular alteration involved in the genesis of several neoplasms, including tumors of neuroectodermal origin. This study investigated the frequency of INK4A gene alterations in a series of malignant peripheral nerve sheath tumors (MPNSTs) and neurofibromas (NFs). INK4A gene and the p19(ARF)-specific exon 1beta were studied in 11 MPNST samples from 8 patients and 7 neurofibromas. Presence of INK4A deletions was assessed by Southern blotting hybridization and by a multiplex polymerase chain reaction (mPCR). INK4A point mutations were examined by single-strand conformation polymorphism (SSCP) and sequencing. The p16 promoter methylation status was determined by PCR amplification of bisulfite-treated DNA. Homozygous deletions of exon 2, thus affecting both p16 and p19(ARF), were identified in MPNSTs from 4 of 8 patients. Deletions, mutations, or silencing by methylation were not identified in the neurofibromas analyzed. Based on our results, we conclude that INK4A deletions are frequent events in MPNSTs and may participate in tumor progression. Silencing of p16 by methylation, which occurs often in several tumor types, is uncommon in MPNSTs.
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PMID:Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas. 1059 15

E2F-1 is the best known ultimate transcription factor in the cyclin/cyclin-dependent kinase/retinoblastoma gene pathway and is probably involved in carcinogenesis and tumor progression. Because E2F-1 can be detected in paraffin sections using immunohistochemical techniques, it could be a useful tumor/proliferation marker. We studied the expression of this gene product in 130 breast tissue specimens from 100 patients and compared it with the expression of Mib-1, the widely used prognostic/proliferative marker, to assess E2F-1 as a new marker of neoplastic proliferation. The percentage of E2F-1-positive cells increased from 1.9% in the normal breast (NB) to 6.3% in ductal carcinoma in situ (DCIS) and to 15.3% in invasive ductal carcinomas (IDC). In addition, higher-grade tumors as well as advanced-stage disease correlated with higher expression of E2F-1. A similar tendency of Mib-1 expression was observed. There was a positive correlation between the E2F-1 and Mib-1 indices. In an in vitro experiment, we found that a similar difference in the expression of E2F-1 existed between a nontumorigenic breast cell line and two widely used breast carcinoma cell lines. The breast carcinoma cell lines T-47D and MCF-7 had more E2F-1-positive cells than the nontumorigenic cell line MCF-10F by immunohistochemistry and Western blot analysis. Because E2F-1 expression was significantly higher in IDC and DCIS than in NB, this study indicates that deregulation of E2F-1 may be involved in the development of breast IDC. In addition, E2F-1 expression could also be involved in tumor progression because the increased E2F-1 index correlated with the known prognostic predictors of breast cancer, such as histological grade, stage, metastasis status, estrogen receptor/progesterone receptor and Mib-1 expression. Thus, E2F-1 is a promising candidate to become a new prognostic/predictive marker of breast cancer.
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PMID:E2F-1: a proliferative marker of breast neoplasia. 1079 84

Great insight into the molecular details of cell cycle regulation has been obtained in the past decade. However, most of the progress has been in defining the regulation of the family of cyclin-dependent kinases (CDKs). Recent studies of a myriad of eukaryotic organisms have defined both the regulation and substrates of Cdc7p kinase, which forms a CDK-cyclin-like complex with Dbf4p, is necessary for the initiation of DNA replication and has been conserved in evolution. This kinase is also required for the induction of mutations after DNA damage and for commitment to recombination in the meiotic cell cycle. However, less is known about the role of the kinase in these processes. In a manner similar to CDKs, Cdc7p is activated by a regulatory subunit, Dbf4, the levels of which fluctuate during the cell cycle. One or more subunits of the conserved MCM helicase complex at chromosomal origins of DNA replication are substrates for the kinase during S phase. Phosphorylation of the MCM complex by Cdc7p-Dbf4p might activate DNA replication by unwinding DNA. Therefore, activation of Cdc7p is required for DNA replication. Given that Cdc7p-Dbf4 kinase is overexpressed in many neoplastic cells and tumors, it might be an important early biomarker during cancer progression.
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PMID:Cdc7p-Dbf4p becomes famous in the cell cycle. 1082 84

Cell cycle progression is facilitated by cyclin-dependent kinases that are activated by cyclins including cyclin D1 and inactivated by cyclin-dependent kinase inhibitors (CDKIs) such as p27. Our previous studies have demonstrated decreased p27 expression in both papillary and more aggressive carcinomas of the thyroid compared to thyroid adenoma and almost similar level of cyclin D1 expression between thyroid adenoma and papillary carcinoma. These results indicate that CDKIs may have an important role in the carcinogenesis of the thyroid and that they probably have a limited role in malignant progression of the thyroid cancer. The role of cyclin D1 in malignant progression of thyroid carcinoma has yet to be established. We studied the expression of cyclin D1 by immunohistochemistry in 34 cases of conventional papillary carcinoma (CPC), 10 cases of minimally invasive follicular carcinoma (MIFC), and 32 cases of more aggressive thyroid carcinoma (ATC), which included 11 tall cell variants, one columnar cell variant of papillary carcinoma, seven insular carcinomas, and 13 anaplastic carcinomas. Cyclin D1 staining was classified by staining score as 0, negative; 1+, less than 25%; 2+, 25 to 50%; and 3+, more than 50% tumor cells staining positive. Kruskal-Wallis one-way ANOVA and Wilcoxon Rank Sum/Mann-Whitney U Test was used to assess the difference in the expression of cyclin D1 between the study groups. Twenty-eight out of the 34 CPCs were cyclin D1 positive, 24 (70%) were 1+, 3 (9%) were 2+, and one (3%) were 3+ positive. Seven of 10 MIFCs were cyclin D1 positive, five (71%) were 1+, and the remaining two (29%) were 2+ positive. On the other hand, 28 of 32 ATCs showed cyclin D1 immunostaining. Of these, three (9%) were 1+, five (13%) were 2+, and 20 (63%) were 3+ positive. This study demonstrates a significant overexpression of cyclin D1 in ATC compared CPC (P < .001) and MIFC (P < .005), suggesting that the cyclin D1 expression may play a role in tumor progression and may have prognostic significance in thyroid cancer.
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PMID:The role of cell cycle regulatory protein, cyclin D1, in the progression of thyroid cancer. 1095 55

Since its discovery as an inhibitor of cyclin-dependent kinases 4 and 6, the tumor suppressor p16 has continued to gain widespread importance in cancer. The high frequency of deletions of p16 in tumor cell lines first suggested an important role for p16 in carcinogenesis. This initial genetic evidence was subsequently strengthened by numerous studies documenting p16 inactivation in kindreds with familial melanoma. Moreover, a high frequency of p16 gene alterations was found in primary tumors, while recent studies have identified p16 promoter methylation as a major mechanism of tumor-suppressor-gene silencing. Additional insight into p16's role in cancer has come from the genetic analysis of precancerous lesions and various tissue culture models. It is now believed that loss of p16 is an early and often critical event in tumor progression. Consequently, p16 is a major tumor-suppressor gene whose frequent loss occurs early in many human cancers.
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PMID:p16(MTS-1/CDKN2/INK4a) in cancer progression. 1123 22

The study was concerned with growth of sarcoma M-1 and basic morphological characteristics of proliferative activity of cells of this strain as well as apoptosis of cells at different stages of tumor progression in rats before and after a single gamma irradiation at 30 Gy. At the parenchymal periphery which determines tumor growth, the PCNA index of proliferating cells was 76.5%; spontaneous cell death--0.28%. During post-irradiation period, the sarcoma PCNA index fell to 62.3% while the apoptotic index rose five-fold. These findings support the concept of radiation-induced apoptosis being a major pathogenetic factor responsible for effectiveness of radiotherapy of tumors. Indirect evidence on PCNA immunostaining suggested that synthesis of this cyclin is sensitive to the level of oxygen input in the cell, yet it offers sufficient resistance to gamma-radiation.
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PMID:[Growth kinetics and functional morphology of M-1 sarcoma in rats before and after gamma-irradiation]. 1154 33

Neoplastic diseases, including lung cancer are characterized by an uncoordinated cell growth. Cellular proliferation follows an orderly progression through the cell cycle, which is governed by protein complexes composed of cyclins and cyclin-dependent kinases. These complexes exert their regulatory function by phosphorylation of key proteins involved in cell cycle transitions. Abnormalities of cyclins and cyclin-dependent kinases have been reported and proposed to be oncogenic events. It appears that the molecular networking of these proteins and complexes exerts an impact on two fundamental cell cycle regulators; p53 and pRb. Interactions between these two nuclear proteins are being delineated, implying potential links between p53 and Rb in cell cycle control, apoptosis, and tumor progression. Furthermore, the detection of alterations in p53 and Rb pathways appears to be of clinical significance.
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PMID:G1 phase of the cell cycle control and lung cancer: biological and clinical implications. Minireview. 1158 82


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