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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have developed a novel murine mammary tumor system with variants representing different stages of tumor progression. The MXT-s parental cell line was established from a urethane-induced and hormone-sensitive mammary tumor. MXT-s parental cells are highly tumorigenic but poorly metastatic. MXT clones and variants were selected by either in vitro or in vivo procedures, and they differ in metastatic ability and 17 beta-estradiol dependency for tumor growth. The MXT-c1.1 and MXT-B2 cell lines produced lung metastasis after intravenous injection into 100% of syngenic mice, but only MXT-c1.1 cells were highly metastatic from intramammary tumors. The fingerprints obtained by arbitrarily primed-polymerase chain reaction demonstrated that the metastatic variants and clones had a common genetic background and resulted from clonal selection from the parental cell line. We studied whether the matrix metalloproteinase (MMP) profile is correlated with tumor progression and metastatic ability in the MXT tumor system. Gelatinases A and B were assayed in the cells, both by enzyme activity and mRNA expression. Gelatinase A was expressed in MXT-c1.1 cells, whereas MXT-B2 cells did not express either MMP. In contrast, the mammary fat pad tumors expressed both gelatinases. Membrane Type 1-MMP transcripts were also detected in MXT cells and tumors. Because the mRNA levels of gelatinase. A were low in MXT-B2 tumors, we suggested that exogenous gelatinase A bound the cell membranes of MXT-B2 cells in vivo. Indirect evidence was obtained in vitro by treatment of MXT-B2 cells with NIH/3T3 fibroblast-conditioned medium. After this treatment, we detected a gelatinolytic activity at M(r) 68,000 in the cell-membrane extract of MXT-B2 cells and an increase in migratory ability through type IV collagen matrices. On the other hand, Ha-ras gene dosage correlated positively with metastatic ability but not with either gelatinase A or gelatinase B expression. No significant differences were observed in the expression of stromelysin-1 and tissue inhibitors of MMP. Thus, in the MXT tumor system, the expression of gelatinase A or its cell association and Ha-ras gene dosage independently contribute to the metastatic phenotype.
Mol Carcinog 1997 May
PMID:Metastatic ability of MXT mouse mammary subpopulations correlates with clonal expression and/or membrane-association of gelatinase A. 918 Sep 29

Transgenic mice harboring the SV40 early region genes under transcriptional control of regulatory regions from the human surfactant protein C (SP-C) gene were used to study the progression of pulmonary adenocarcinomas in vivo. SP-C/SV40 early region gene (SP-C/TAg) transgenic mice consistently developed pulmonary adenocarcinomas. Distinct neoplasia was first detected at 4 wk of age and large tumor nodules were observed by 20-29 wk of age. SV40 large T mRNA was detected in distal bronchiolar and alveolar epithelial cells prior to tumor formation and in neoplastic cells at all stages of tumor development. SV40 large T mRNA correlated with cyclin-dependent kinase 1 (cdk1) mRNA expression, a marker of cellular proliferation. The nonciliated bronchiolar cell marker, CC10 mRNA, was detected in the majority of lung tumors at all ages, but was consistently decreased in the larger tumor nodules at later stages of tumor progression. CC10 mRNA was not detected in multiple murine lung epithelial (MLE) cell lines derived from the SP-C/TAg mice when cultured in vitro; but was induced in the MLE-15 clonal cell line when propagated in vivo in the flanks of nude mice. SP-C mRNA, an alveolar Type II cell marker, was also expressed in the MLE-15 cells when grown in nude mice. However, CC10 and SP-C mRNAs were expressed in distinct, nonoverlapping regions of the MLE-15 tumors. These studies support the concept that tumor progression is associated with changes in respiratory epithelial cell differentiation, and that the expression of bronchiolar and alveolar cell specific markers can be induced in a clonal cell line with changes in cellular environment.
Am J Respir Cell Mol Biol 1997 Jun
PMID:Tumor progression and cellular differentiation of pulmonary adenocarcinomas in SV40 large T antigen transgenic mice. 919 73

Overexpression of p185erbB2/neu has been detected in many adenocarcinomas, including prostatic cancer. In this study, a nontumorigenic cell line isolated from the rat prostatic epithelium (NbE) transfected with the activated oncogene p185neu-T was used to investigate the role of this oncogene in tumor progression. When clones overexpressing p185neu-T were injected orthotopically (1.5 to 2 x 10(6) cells) into the dorsal-lateral prostates of nude mice, prostatic tumors were detected in all mice injected and metastasis to the skeletal muscle in the rib area in 60-80% of the mice injected. Tumor and metastasis origin was confirmed by reselection with G418 and reverse transcriptase-polymerase chain reaction. Control cell lines produced no prostatic tumors or metastases. Incubation at low density (12500 cells/2 cm2) in serum-free medium revealed that clones overexpressing p185neu-T had a higher rate of [3H]thymidine incorporation than did control clones on 3, 5, and 7 d after plating (P < or = 0.0001) and constitutively overexpressed the 2.6-kb ornithine decarboxylase transcript. Additionally, clones overexpressing p185neu-T demonstrated an increased expression of epidermal growth factor receptor and p180erbB4, as judged by RNA blot analysis. Together these data support the hypothesis that overexpression of p185neu-T fosters tumor progression by several pathways, including induction of the metastatic cascade, increased proliferative capabilities, and increased expression of other members of the erbB2 gene family.
Mol Carcinog 1997 Jul
PMID:Metastasis induced by overexpression of p185neu-T after orthotopic injection into a prostatic epithelial cell line (NbE). 925 83

The keratin cytoskeleton is formed in different epidermal compartments by distinct polypeptides. Basal, proliferative keratinocytes express keratin (K) 5 and K14, whereas, suprabasal, post-mitotic keratinocytes express K1 and K10. Changes in this keratin pattern have been found to occur in hyperproliferative skin disorders and, in particular, throughout mouse epidermal carcinogenesis. Whereas some keratins not found in normal epidermis (K6, K16, K13, and K8) are induced at different stages of tumor development, K1 and K10 expression is lost. To determine whether K1 and K10 loss is just a consequence of the altered differentiation program or an event required for tumor progression, we generated transgenic mice carrying the human keratin 10 gene (hK10) under the control of a bovine keratin 6 gene regulatory region, which is silent in normal skin but is induced and drives transgene expression in hyperproliferative skin keratinocytes and, therefore, in skin tumors. Transgenic animals subjected to a complete carcinogenesis protocol developed tumors that contained various amounts of transgenic hK10. Although no significant difference was found in tumor number or malignancy, tumor onset was significantly delayed in transgenic mice, indicating that the presence of K10 actually impairs tumor development.
Mol Carcinog 1997 Sep
PMID:Delays in malignant tumor development in transgenic mice by forced epidermal keratin 10 expression in mouse skin carcinomas. 932 31

Programmed cell death (apoptosis) is known to occur not only during normal development and tissue remodeling but also during neoplasia. Despite the suggested role of apoptosis in preventing the proliferation of malignant cells, a positive correlation between tumor progression and the presence of apoptotic cells has been found in different types of cancer, including epithelial tumors. In normal mouse skin, the role of apoptosis is not completely understood, and it has been suggested that terminal differentiation may be a special case of apoptosis. In the work reported here, we counted apoptotic cells in mouse skin tumors generated with a two-stage chemical carcinogenesis protocol. We analyzed papillomas from outbred SENCAR mice at different times during promotion, and to better determine the correlation between apoptosis and tumor progression, we compared papillomas generated from two inbred strains derived from the SENCAR stock that differ in their susceptibility to tumor progression. Our results showed that in mouse skin chemical carcinogenesis, the number of apoptotic cells was greater in papillomas that may have been in the process of progressing to squamous cell carcinomas. This conclusion is also supported by the fact that papillomas from SENCAR P/Bt. mice, a tumor progression-susceptible strain derived from outbred SENCAR mice, had more apoptotic cells than papillomas from progression-resistant SSIN mice.
Mol Carcinog 1997 Sep
PMID:Increased apoptosis during papilloma development in mice susceptible to tumor progression. 932 44

Among the multiple genetic changes that occur during cancer progression are the activation of proto-oncogenes and the inactivation or loss of genes encoding tumor suppressors. The potential roles for these genes in the perturbation of genome stability continues to be of major interest. We have previously shown that conditional expression of H-ras in NIH3T3 cells increases genetic instability in these cells, rendering them more permissive to gene amplification and to the generation of chromosome aberrations which can be induced within a single cell cycle. In the present study we show that genetic instability induced by H-ras expression can be suppressed by co-expression of Rap 1, a Ras-related tumor suppressor gene. An NIH3T3 cell line transformed with activated human H-ras was transfected with Rap 1. Expression of the Rap 1 gene reverted the transformed cells to a flat morphology. The reverted cells reestablished contact inhibition of growth and lost the capacity to form colonies in soft agar. These cells were subsequently studied for the role of Rap 1 on the suppression of genomic instability induced by oncogenic H-ras. Cells transformed with H-ras manifest an increase in methotrexate resistance as measured by an increase in Dhfr gene amplification. Cells which concommitantly express Rap 1 showed reduced levels of methotrexate resistance as well as reduction of gene amplification capacity. Furthermore fluorescent-in-situ hybridization (FISH) with a pancentromeric mouse probe showed that elevated levels of chromosome aberrations in cells expressing H-ras were also suppressed after co-expression of Rap 1.
Somat Cell Mol Genet 1997 Mar
PMID:Expression of Rap 1 suppresses genomic instability of H-ras transformed mouse fibroblasts. 933 Jun 40

In many tissues the preinvasive stage of neoplastic progression can be identified histologically as dysplasia or in situ disease. There is much interest in defining the molecular events associated with the early stages of neoplasia. Retrieval of histologically recognisable preinvasive neoplastic tissue uncontaminated by inflammatory or stromal cells is important for genetic studies using polymerase chain reaction (PCR) assay. A novel method for microdissection is described in which 10 microns sections are dewaxed, stained with haematoxylin and eosin, dried, covered with Sellotape, and the tissue cut out using a scalpel blade under direct visual control. The method is quick, eliminates problems of operator tremor, preserves the architecture of the micro-dissected tissue (for photographic documentation) and requires no special equipment. The presence of Sellotape and adhesive in the reaction mixture has no detrimental effect on the ability to extract DNA or to perform PCR.
Mol Pathol 1997 Aug
PMID:Microdissection of stained archival tissue. 935 Mar 7

Several different approaches have been used successfully to document some of the molecular genetic events that play a part in colorectal tumorigenesis. This appears to be a multistep process that involves activation of oncogens as well as inactivation of tumor suppressor genes. It is important to see that, while many molecular genetic changes that occur during this process have been well documented, many other are less clear and some not yet identified at all. Studies on colorectal tumor progression are likely to continue producing new data on the initiation and progression of human tumors. An important goal of such studies is the development of molecular markers for clinical use, new prognostic markers, and diagnostic tools. The progress, in view of clinical practise, has been slow, but molecular genetic studies will contribute considerably to clinical management of cancer patients sooner or later.
Cytokines Mol Ther 1996 Jun
PMID:The multistep process of colon carcinogenesis. 938 95

Molecular cytogenetics provides a powerful link between molecular genetic analysis and chromosome morphology, allowing one to pinpoint structurally aberrant chromosome regions on the molecular level. Fluorescence in situ hybridization with selected DNA probes allows the design of efficient and sensitive tools for the diagnosis of chromosomal aberrations present in tumor cells. Comparative genomic hybridization (CGH) allows the identification of chromosomal imbalances in a comprehensive manner, and is applied to solid tumors and hematological malignancies in order to (i) identify clonal differences within a specimen, (ii) contribute to tumor classifications, (iii) identify recurrent chromosomal gains and losses as starting points for the characterization and isolation of pathogenetically relevant genes, such as proto-oncogenes and tumor suppressor genes respectively, (iv) identify imbalances of prognostic relevance, (v) detect high-copy-number amplification and other markers of genetic instability, and (vi) analyze chromosomal imbalances during tumor progression.
Cytokines Mol Ther 1996 Sep
PMID:Efficacy of current molecular cytogenetic protocols for the diagnosis of chromosome aberrations in tumor specimens. 938

An alternatively spliced mRNA coding for a variant estrogen receptor (ER) missing exon 4 (ERdelta4) was detected in the breast tumor cell line MCF7 and meningioma tissue by using the reversed transcriptase PCR technique. The trans-activational properties of this mutant ER were assessed in embryo carcinoma P19EC and human choriocarcinoma JEG3 cells by co-transfection of the ERdelta4 expression vector with an oxytocin promoter construct containing an estrogen-responsive element. ERdelta4 did not trans-activate the oxytocin promoter in either a hormone-dependent or -independent manner. Co-transfection of ERdelta4 together with the wtER did not show any interference of ERdelta4 on the stimulation of the oxytocin promoter by the wtER. ERdelta4 was translated in vitro. Its capacity to bind estradiol, and the binding of the variant to a synthetic estrogen-responsive element were compared to those of the wild-type receptor. ERdelta4 did not bind to a synthetic estrogen-responsive element, nor did it bind estradiol. Hence, ERdelta4 appears to be a silent variant and we speculate that it is without any role in tumor progression.
Mol Cell Endocrinol 1994 May
PMID:Functional analysis of an alternatively spliced estrogen receptor lacking exon 4 isolated from MCF-7 breast cancer cells and meningioma tissue. 939 58


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