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)

Ultraviolet (UV) irradiation causes human skin aging and skin cancer through the activation of matrix metalloproteinases (MMPs) which are responsible for the degradation of collagen and tumor progression in human skin. The molecular mechanisms of UV-induced MMPs are yet to be defined. Our previous studies and others suggest that i) the transient activation of cell surface receptors and subsequent activation of MAP kinase cascade contributes to the transcriptional up-regulation of MMPs; and ii) UV-induced expression of pro-inflammatory cytokines such as IL-1 beta and TNF-alpha may also account for the expression of MMPs. However, signaling pathway through which cytokines induce MMP expression remains to be unraveled. In this study, we investigated the pathway that leads to the IL-1 beta-induced up-regulation of MMP-1 in human keratinocytes. IL-1 beta activated epidermal growth factor (EGF) receptor in cultured human keratinocytes in a time- and dose-dependent manner. IL-1 beta-induced EGF receptor tyrosine phosphorylation started at 5 min and peaked at 10 min and remained elevated up to 40 min post IL-1 beta treatment. EGF receptor kinase inhibitor PD153035 and AG1478 inhibited IL-1 beta-induced EGF receptor tyrosine phosphorylation. To test the effect of EGF receptor transactivation on downstream components, we examined the ERK activation by IL-1 beta. We found that IL-1 beta-induced ERK phosphorylation, PD153035 and MEK inhibitor PD98059 blocked IL-1 beta-induced ERK activity. Furthermore, both inhibitors also dramatically reduced IL-1 beta-induced expression of c-jun and c-fos mRNA which are required for up-regulation of MMPs. EGF receptor kinase inhibitor PD153035 and AG1478 and MEK inhibitor PD98059 also blocked IL-1 beta induction of MMP-1 in cultured human keratinocytes. Collectively, our data indicate that IL-1 beta-induced expression of MMP-1 is mediated by transactivation of EGF receptor and through ERK pathway in human keratinocytes.
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PMID:Transmodulation of epidermal growth factor receptor mediates IL-1 beta-induced MMP-1 expression in cultured human keratinocytes. 1117 16

E-Cadherin and its undercoat proteins, alpha- and beta-Catenins, which connect cadherins to actin filaments and establish firm cell-cell adhesion, act as an invasion suppressor system. It was demonstrated that transcriptional inactivation of E-Cadherin expression occurred frequently in tumor progression, and that E-Cadherin expression in human cancer cells was regulated by CpG methylation around the promoter region. In diffusely infiltrating cancers, mutations were found in the genes for E-Cadherin and alpha- and beta-Catenins. The E-Cadherin-mediated cell-adhesion system is inactivated by tyrosine phosphorylation of beta-Catenin at the invading front of cancers with high metastatic ability. An attempt was made to identify the kinases that participate in the aberrant tyrosine phosphorylation, and c-erbB-2 protein was found to be directly associated with beta-Catenin. Transfection of N-terminally deleted beta-Catenin, which binds to c-erbB-2 but not to cadherin, markedly reduced peritoneal dissemination and hematogenous metastasis of gastrointestinal cancer cells in mouse inoculation models. Regulation of the E-Cadherin-mediated cell adhesion system by tyrosine phosphorylation of beta-Catenin is important in determining the biological properties of human cancers. Tumor cells are dissociated throughout the entire tumor masses of diffuse-type cancers, whereas those of solid tumors with high metastatic potentials are often focally dissociated or dedifferentiated at the invading fronts. Thus, both irreversible and reversible mechanisms for inactivating the E-Cadherin-mediated cell adhesion system well correspond to the pathological features of human cancers.
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PMID:Molecular aspects of adhesion-epigenetic mechanisms for inactivation of the E-Cadherin-mediated cell adhesion system in cancers. 1121 45

In order to identify the prognostic factors that significantly influence the disease-free survival rate after surgical resection of primary breast cancers, we determined tumour and lymph node grades, and immunohistochemical staining for estrogen and progesterone receptors (ER and PR), c-erbB-2, p53, bcl-2, bax and PCNA in 76 patients. Univariate analysis showed that increased grade of tumour and lymph nodes, negative immunostaining for ER, positive immunostaining for c-erbB-2, and a high PCNA index (> or = 30%) negatively influenced the disease-free survival rate, but PR, p53, bcl-2 and bax had no predictive value. Although p53 was not an independent prognostic factor by itself, the combination of p53, bcl-2, and bax proved to correlate with the disease-free survival, with the best prognosis noted in tumours negative for p53 and positive for both bcl-2 and bax, intermediate prognosis in tumours negative for p53 and positive for either bcl-2 or bax and worst prognosis in tumors negative for p53 as well as bcl-2 and bax. Tumour grade correlated positively with PCNA index, while positive staining for ER correlated negatively with tumour grade as well as with PCNA index, although this was statistically insignificant. Immunostaining of breast cancers for bcl-2 correlated negatively with tumour grade and PCNA index. Immunostaining for c-erbB-2 correlated positively with PCNA but not with tumour grade. Immunostaining for p53 tended to correlate positively with PCNA, but not with tumour grade. Immunostaining for PR and bax did not correlate with tumour grade and PCNA index. These results suggest that in addition to tumour size and lymph node involvement, immunostaining for ER, c-erbB-2, and a high PCNA index are important prognostic factors in human breast cancer. Wild-type p53 with preserved bcl-2 and bax gene products is also a favorable prognostic factor indicating breast cancer at an early stage of cancer progression.
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PMID:Prognostic factors affecting disease-free survival rate following surgical resection of primary breast cancer. 1141 68

The adaptor protein Grb2-associated binder-1 (Gab1) is known to bind to the SHP-2 tyrosine phosphatase on epidermal growth factor (EGF) receptor stimulation. To clarify the roles of these two proteins in EGF receptor (EGFR) signaling and determine their possible alteration during neoplastic cell progression, we studied these proteins in a Syrian hamster embryo (SHE) cell line model of neoplastic progression. Specifically, we used asbestos-transformed SHE fibroblasts: the 10W+8 clone, which is immortal but nontumorigenic; and the 10W2T clone, which is tumorigenic. Gab1 was detected, and the EGF-dependent formation of the EGFR-Gab1-SHP-2 complex was observed in 10W+8 cells. After cloning hamster Gab1 cDNA, exogenous expression of Gab1 significantly enhanced EGF-dependent mitogenic activity in 10W+8 cells. On the other hand, Gab1 was not detected in 10W2T cells, and the EGF-dependent association of SHP-2 with EGFR was also absent. Exogenous Gab1 expression in transfected 10W2T cells restored the EGF-dependent association of SHP-2 with EGFR, although it only showed a marginal effect on EGF-dependent mitogenic activity. Thus, Gab1 plays a pivotal role in the EGFR signaling pathway via the formation of the EGFR-Gab1-SHP-2 complex, and alteration in the expression and function of Gab1 is implicated in the neoplastic progression of SHE cells.
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PMID:Identification of epidermal growth factor receptor- Grb2-associated binder-1-SHP-2 complex formation and its functional loss during neoplastic cell progression. 1143 5

Control of cell growth and differentiation occurs via extracellular signals known as growth factors. Growth factors are high affinity ligands for transmembrane receptors belonging to the family of receptor tyrosine kinases (RTKs). A number of genetic evidences have implicated RTKs in human diseases including developmental disorders and cancer. For instance, germline missense mutations involving the Ret receptor are found in patients affected by multiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B) or familial medullary thyroid carcinomas. Somatic mutations in the Kit receptor are found in mastocytomas and in gastrointestinal tumors. Germline and sporadic mutations of the Met receptor have been described in kidney and hepatocellular carcinomas. Overexpression of the HER-2/neu receptor in breast cancer has been associated with tumor progression. The enzymatic activity of RTKs is strictly regulated and is usually inhibited under basal conditions. Receptor activation triggers a biochemical signalling cascade inside the cytoplasm, named signal transduction, which is subverted during the malignant transformation of cells. Signal transduction by RTKs is a multistep process which includes: (i) Ligand binding and receptor dimerization, (ii) receptor phosphorylation on tyrosine residues; (iii) recruitment to the receptor and activation of cytoplasmic signaling molecules that transmit signals to the nucleus. Each of the steps involved in this process can potentially be targeted to block the aberrant properties of tyrosine kinase receptors. By using the MET oncogene as a model this review focuses on the strategies that can be applied to therapeutically target RTKs.
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PMID:Receptor tyrosine kinases as therapeutic targets: the model of the MET oncogene. 1146 38

Targeted Genetics is developing, tgDCC-E1A, a E1A tumor suppressor gene therapy formulated in a non-viral, lipid-based delivery system as a potential treatment for solid tumors which overexpress the her-2/neu oncogene [221611]. Fournier is the European development partner [244180]. Preclinical studies of E1A in mouse models for human breast and ovarian cancer demonstrated inhibition of expression of the her-2/neu oncogene, a significant reduction in tumors and increased survival rate in the treated animals [244180]. Results of a phase I study of intratumoral liposomal-E1A gene therapy in patients with recurrent/refractory breast cancer and head and neck cancer were presented at the 1998 American Society of Clinical Oncology (ASCO) meeting. Results demonstrated that intratumoral delivery of the E1A gene caused a subsequent downregulation of HER-2/neu expression and tumor response. The phase I dose-escalation study treated nine patients with recurrent breast cancer and nine patients with head and neck cancer. In 16 patients evaluable for response, nine had stable disease, five had progressive disease and two had minor responses despite tumor progression at other sites. In one of six patients who had repeat biopsies of treated tumors, no pathological evidence of tumor was found. In four of seven patients evaluated to date (May 1998), evidence of downregulation of HER-2/neu was reported [287387,290118]. The first phase I trial in patients with breast and ovarian cancer was completed by the end of 1997. The second phase I trial, enrolling 12 to 24 patients with solid tumors, was initiated in April 1997. Its aim was to determine dosing and safety of tgDCC-E1A and evaluate levels of gene transfer and tumor response. Patients were administered tgDCC-E1A by intratumoral injections. The company completed this trial by the end of 1997. In October 1998, Targeted Genetics initiated a multicenter, open-label phase II clinical trial of tgDCC-E1A in patients with recurrent head and neck squamous cell carcinoma who have exhibited disease progression despite standard therapies. The study to be conducted at six medical institutions in the US will enrole up to 60 patients with an interim analysis scheduled to be performed after the first 20 evaluable patients have been enrolled. Patients will be treated with ten direct intratumoral injections of the E1A gene over a period of 8 weeks, with follow-up performed at week 12. Patients who demonstrate a response will be eligible for continued treatment and will be monitored for 1 year [300424]. Targeted Genetics has issued three patents covering methods and compositions of use of the E1A and LTgenes (qv) to treat a variety of cancers. US-05651964 covers the use of the E1A gene, US-05643567 and US-05641484 cover the use of either the E1A gene or the LT gene as cancer therapies. These three patents provide the company with broad patent protection for tgDCC-E1A and all future products based on the use of the E1A or LT gene as tumor suppressors [259808].
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PMID:Technology evaluation: tgDCC-E1A, targeted genetics/MD Anderson. 1171 50

Recent evidence shows that the proportion of poorly differentiated prostate carcinoma (Gleason pattern [GP] 4/5) is a surrogate factor for biochemical failure after radical prostatectomy (RP). However, little is known about specific molecular and cytogenetic changes in this aggressive component of localized prostate cancer. We constructed a tissue microarray containing areas of GP 3 and 4 from formalin-fixed radical prostatectomy specimens of 39 patients with Gleason score 7 carcinoma (>or=50% GP 4), known pathologic staging parameters (stage < T3b), and biochemical failure data (mean follow-up, 30 months; range, 5 to 74 months). Interphase fluorescent in situ hybridization (FISH) was performed on 5-microm microarray sections using pericentromeric probes to chromosomes 7, 8, and 17 and probes for the HER-2/neu and epidermal growth factor receptor (EGFR) genes. Low-level amplification of HER-2/neu was found in 26% of cases (3 to 5 signals per nucleus, corrected for chromosome 17 aneusomy). Aneusomy of chromosomes 7, 8, and 17 was identified in 21%, 15%, and 5% of cases, respectively. All aberrations occurred almost exclusively in GP 4 carcinoma (8 of 8 aneusomies 7, 2 of 2 trisomies 17, 9 of 10 HER-2/neu amplifications, and 5 of 6 aneusomies 8; P < .001). The presence of HER-2/neu amplification was associated with high tumor volume (>2.0 cm(3), P = 0.004). Among patients with negative surgical margins, gain of chromosome 7 was associated with biochemical failure after RP (P =.004, log-rank). Amplification of the EGFR gene occurred in only 1 case (3%). Significant differences in HER-2/neu amplification and gain of chromosomes 7, 8, and 17 were detected between GP 4 prostate carcinoma and GP 3. The frequency of aberrations increased with tumor volume. Chromosome 7 abnormalities may play an important role in cancer progression in margin-negative patients. EGFR amplification was rare, suggesting that this oncogene is not altered at the gene copy number level.
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PMID:Aneusomy of chromosomes 7, 8, and 17 and amplification of HER-2/neu and epidermal growth factor receptor in Gleason score 7 prostate carcinoma: a differential fluorescent in situ hybridization study of Gleason pattern 3 and 4 using tissue microarray. 1177 75

Cyclin D1 contributes to regulate G1 progression by forming a complex with different cyclin-dependent kinases. It has oncogenic properties and is frequently overexpressed in several human tumor types. In our study, expression of cyclin D1 and Ki67, a proliferation marker, was evaluated by immunohistochemistry in human papillary superficial (pTa-pT1) bladder cancers and was correlated with p27(Kip1), p21(Waf1) and c-erbB-2 expression, with p53 gene status and protein expression, ploidy and cancer progression. Cyclin D1 expression was neither associated with tumor stage nor with tumor grade but high cyclin D1 expression (> or =25% positive nuclei) was significantly associated with p53 gene mutation (p = 0.012), low p21(Waf1) (p = 0.015) and high p27(Kip1) (p = 0.016) protein expression. Ki67 expression was not associated with tumor stage but a high proliferation index (> or =10% positive nuclei) was significantly associated with high tumor grade (p = 0.001) and with DNA aneuploidy (p = 0.005). There was no significant difference in proliferative activity between high and low cyclin D1 expressor tumors. Patients whose tumors showed high expression of cyclin D1 displayed a significantly longer disease-free survival (p < 0.001 by log-rank test). Increased Ki67 expression was significantly associated with shorter disease-free survival (p = 0.003). Both cyclin D1 (p = 0.027; RR = 1.898) and Ki67 (p = 0.047; RR = 1.932) protein expressions were independent predictors of reduced disease-free survival on a multivariate analysis that also included p27(Kip1) expression and tumor stage. The simultaneous presence of low cyclin D1, low p27(Kip1) and high Ki67 expression defined a "high-risk" group of patients who displayed a significantly increased risk of recurrence (p < 0.0001). These results suggest that evaluation of cell cycle-associated markers can help to identify high-risk patients and may affect the management of patients with papillary superficial bladder cancer.
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PMID:Cyclin D1 expression in papillary superficial bladder cancer: its association with other cell cycle-associated proteins, cell proliferation and clinical outcome. 1180 96

HER-2/neu (p185(HER2)) oncogene represents an attractive target for antibody-mediated immunotherapy. The major problem of combining chemotherapy and immunotherapy is the severe side effects that limit the use of doxorubicin (Doxo) as a cytotoxic drug. We have used virosomes (Vir; reconstituted fusion-active viral envelopes) as a new drug delivery system and have shown that Vir are capable of binding and penetrating into tumor cells, delivering cytotoxic drugs. We have additionally demonstrated that conjugating Fab' fragments of an antirat Neu (anti-rNeu) monoclonal antibody to Vir selectively and efficiently inhibits tumor progression of established rNeu-overexpressing breast tumors. Fab'-Doxo-Vir combine the antiproliferative properties of the monoclonal antibody and the cytotoxic effect of Doxo in vivo. Furthermore, Fab'-Doxo-Vir significantly inhibit tumor formation at a tumor load representing metastatic spread. These results indicate that Vir conjugated with an antibody against a tumor antigen are a promising new selective drug delivery system for the treatment of tumors expressing a specific tumor antigen.
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PMID:Targeting her-2/neu with antirat Neu virosomes for cancer therapy. 1180 93

Concentrations of soluble c-erbB-2 were determined in the sera of 64 patients with distant metastasis from advanced breast cancer receiving second-line hormone or chemotherapy in comparison to 35 breast cancer patients without detectable recurrent disease and 17 healthy blood donors. The sera of non-metastatic breast cancer patients contained s-erbB-2 concentrations similar to those of healthy blood donors. Patients with distant metastasis from advanced breast cancer had significantly higher values of s-erbB-2 in comparison to patients with non-disseminated disease (mean: 59.6 vs. 11.6 U/ml; p = 0.022). A significant correlation was observed between s-erbB-2 serum levels and serum LDH concentrations (p < 0.001), levels of alkaline phosphatase (p < 0.001), and the presence of hepatic metastasis (p = 0.001). Time to tumor progression was significantly shorter in patients with s-erbB-2 levels above 40 U/ml (mean: 23.4 vs. 56.7 months; p = 0.002). Furthermore, breast cancer patients with hepatic metastasis and those with elevated s-erbB-2 serum levels above 40 U/ml had limited response to hormone or chemotherapy. Non-responders had significantly higher s-erbB-2 levels (mean: 270.3, range: 42-500 U/ml;) compared with the responder group (mean: 23.1, range: 0-149 U/ml; p < 0.001). Logistic regression analysis indicated that elevated s-erbB-2 serum levels above 40 U/ml independently predicted an unfavorable response to second-line hormone or chemotherapy in patients with advanced metastatic breast cancer.
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PMID:Clinical relevance of soluble c-erbB-2 for patients with metastatic breast cancer predicting the response to second-line hormone or chemotherapy. 1206 44


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