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

Using a human keratinocyte model of tumor progression, we have examined the regulation of gene expression and secretion of a parathyroid hormone-like peptide (PLP) that has been implicated in the pathogenesis of hypercalcemia in cancer. A rapid and transient induction of PLP mRNA in response to serum stimulation was demonstrated in both established (HPK1A) and malignant (HPK1A-ras) cells; however the dose dependent increases were greater in HPK1A than in HPK1A-ras. Significant inhibition of this induction was noted with the addition of 1,25-dihydroxyvitamin D3 at a lower concentration in HPK1A than in HPK1A-ras. Amino-terminal PLP immunoreactivity and bioactivity correlated well (r = 0.98) when measured in conditioned medium. In the absence of mitogenic stimuli, malignant keratinocytes (HPK1A-ras) secreted significantly more PLP than established (HPK1A) keratinocytes. However, in response to increasing concentrations of epidermal growth factor and fetal bovine serum, PLP release was far greater from HPK1A (maximum 13 x basal) than from HPK1A-ras (maximum 3 x basal) cells. In addition, 1,25-dihydroxyvitamin D3 was more effective in inhibiting both basal and stimulated PLP secretion in HPK1A than in HPK1A-ras cultures. Reduction of extracellular Ca2+ from 2.0 mM to 0.5 mM appeared to be more effective at an early time point in reducing PLP secretion from the established cells compared with the malignant cells. These studies therefore demonstrate a progressive dysregulation of PLP expression and secretion in human keratinocytes in the transformation from established to malignant phenotype and may have important implications for understanding the pathogenetic mechanisms involved in vivo in the development of hypercalcemia in cancer.
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PMID:Dysregulation of parathyroid hormone-like peptide expression and secretion in a keratinocyte model of tumor progression. 174 25

Evaluation of molecular events in human colon polyps and tumors has revealed constitutive elevated expression of c-myc, activation of both ras and src proto-oncogenes, and allelic deletion events involving inactivation of putative regulatory genes, including p53. To evaluate the contribution of each of these events to colon carcinogenesis, it is desirable to establish epithelial cell lines representing different stages of neoplastic progression. Such in vitro models can be used to establish a primary role for different genes implicated in neoplastic transformation, identifying events involved in multistep carcinogenesis and delineating the factors modulating cellular transformation. We present herein a summary of such an in vitro model for colon carcinogenesis using the introduction of relevant genetic elements into normal mucosa to identify the molecular steps and accompanying cellular events underlying neoplastic progression in the colon.
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PMID:Oncogene-mediated transformation. An in vitro model for colon carcinogenesis. 174 51

The use of the mouse skin multistage model of carcinogenesis has aided our understanding of critical target genes in chemical carcinogenesis. The mutagenic activation of the Harvey-ras proto-oncogene has been found to be an early event associated with the initiation of mouse skin tumors by the polycyclic aromatic hydrocarbon 7,12 dimethylbenz[alpha]anthracene and the pure initiator ethyl carbamate (urethane). In contrast to chemical initiation of mouse skin tumors, ionizing radiation-initiated malignant skin tumors have been shown to possess distinct non-ras transforming gene(s). Differential screening of cDNA libraries made from chemically initiated malignant skin tumors has been used to identify a number of cellular gene transcripts that are overexpressed during mouse skin tumor progression. These differentially expressed genes include beta-actin, ubiquitin, a hyperproliferative keratin (K6), a gene whose product is a member of a fatty acid or lipid-binding protein family, and a gene called transin or stromelysin. The overexpression of the stromelysin gene, which encodes a metalloproteinase that degrades proteins in the basement membrane, is hypothesized to play a functional role in malignant tumor cell invasion and metastasis. We believe that the cloning, identification, and characterization of gene sequences that are differentially expressed during tumor progression could lead to the discovery of gene products that either play functional roles in skin tumor progression or in the maintenance of various progressive tumor phenotypes.
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PMID:Differential gene expression during multistage carcinogenesis. 177 1

Transient overexpression of ras, mos, or fos transcribed from various inducible promoters in NIH 3T3 cells causes significant increases in the frequency of chromosomal aberrations and, as shown for fos, in gene mutations. Under the experimental conditions of exponential growth and full serum supply, overexpression of the oncogenes does not increase the proliferation rate of cells. The generation of ras- and mos-induced chromosomal aberrations was suppressed in cells that had been deprived of fos protein by antisense c-fos oligodeoxynucleotides. The induction of chromosomal aberrations by ultraviolet irradiation is also suppressed by antisense c-fos oligodeoxynucleotides. The data suggest that fos protein alone, or a transcription factor that contains fos protein as a subunit, activates or induces the synthesis of one or several mutator functions. Oncogene-driven mutagenesis could account for the accumulation of additional mutations after the activation of an oncogene, which may furnish a mechanistic basis for tumor promotion and tumor progression.
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PMID:Involvement of fos in spontaneous and ultraviolet light-induced genetic changes. 179 85

The process of mouse skin tumor formation is subdivided into three operational stages. These stages include initiation, promotion and progression. Ionizing radiation has been found to be a weak initiating agent in the production of malignant squamous cell carcinomas, a complete carcinogen and an agent effective in causing tumor progression. Four skin tumor histologies have been seen with ionizing radiation: benign papillomas, squamous (SCC) and basal (BCC) cell carcinomas and fibrosarcomas. Distinct non-ras transforming genes have been detected in radiation initiated SCCs. A benign papilloma cell line (308) was used as a model system to study ionizing radiation induced progression. A variant 308 cell line (308 10 Gy 5) derived by irradiation of the parental 308 cell has been characterized. The 308 10 Gy 5 cells unlike the parental 308 cells form malignant tumors in athymic nude mice upon subcutaneous injection. The variant 308 10 Gy 5 cells unlike the parental cells also show by northern analysis high steady state levels of the following gene transcripts: stromelysin, metallothionein II A and the proto-oncogenes c-fos and c-jun. Transient transfection studies with a chimeric mouse stromelysin promoter sequence upstream of a chloramphenicol (CAT) reporter gene into 308 and 308 10 Gy 5 cells indicated that the stromelysin promoter was constitutively active in the 308 10 Gy 5 but not in the 308 cells. The ability to divide the process of carcinogenesis into multiple stages in the mouse skin mode has facilitated mechanistic studies that may elucidate the molecular pathways involved in radiation induced tumor development.
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PMID:Molecular events involved in ionizing radiation induced skin carcinogenesis. 182 59

Expression of myc, fos, src, ras and sis oncoproteins was studied in biopsy material of tumors, metastases and "normal" surrounding tissues from patients with different histological types of stomach and lung cancer, melanoma and other malignancy using immunoblotting. Besides, the immunohistochemical distribution of these oncoproteins under lung cancer and precancer conditions was analysed. The oncoproteins expression was significantly higher in cancer as compared with precancer and "normal' surrounding tissues. C-myc and c-fos gene products were detected in all the malignant tissues irrespectively to histogenesis of tumors, while the level of c-myc expression was rather high. The high level of c-fos expression was observed in stomach carcinomas and at early stages of lung tumor progression. C-src and c-sis genes expression varied in tumors of different histogenesis. C-src proteins were found in 60% of lung cancer but it was practically absent in stomach carcinomas and in melanomas. C-sis gene product was observed in some melanomas and lung carcinomas. Ras gene can be activated at early stages of tumor progression of stomach carcinomas and lung adenocarcinomas and at later stages of tumor progression in melanomas and small-cell lung carcinomas. Thus, there are some correlations between oncoprotein expression and tumor tissue histogenesis and progression.
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PMID:[Synthesis and distribution of oncoproteins in tumor tissue]. 183 74

A novel 21-kDa protein (p21) was isolated from auto-immune complexes, found in sera of 14 patients with malignant urogenital tumors and isolated on Protein A-Sepharose. Isolated complexes were analyzed in 15% polyacrylamide-SDS minigels. After staining with Coomassie blue R, the bands were scanned with a clinical densitometer. The level of p21 in sera of cancer patients was 3 times higher than that found in normal individuals. An attempt was made to correlate consecutive levels of p21 in the sera of these cancer patients with the clinical course. In 4 cases a significant decrease (57-75%) in the level of p21 was observed in parallel with response to treatment. In 9 of 10 cases where no response or tumor progression was observed, the relative abundance of p21 increased or remained unchanged. Thus, the level of p21 was indicative of progression or regression of the disease in 13 out of 14 patients. Similar high levels of p21 in sera were also found in 22 patients with benign hyperplasia of prostate. The p21 protein was not immunoreactive with known anti-ras antibodies such as Y13-259, 142-24E05 and anti-rap1. Partial amino acid analysis of this protein showed no complete homology to any known protein, but a partial homology to known bacterial proteins involved in DNA replication or transcription was observed. Monitoring of the novel p21 levels before and after treatment may be useful in follow-up of cancer patients, providing evidence of response to treatment.
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PMID:A novel 21-kDa protein as a serum marker for benign and malignant urogenital tumors: preliminary communication. 195 89

The frequency of Ha-ras mutations was determined as a function of neoplastic progression in cell lines derived from rat tracheal implants exposed in vivo to 7,12-dimethylbenz[a]anthracene. Restriction fragment-length polymorphism (RFLP) analysis revealed an A----T transversion in the second base of codon 61 in 2 of 11 cell lines. One of the positive cell lines was tumorigenic, but the other was neither tumorigenic nor anchorage independent, thus indicating a lack of correlation between neoplastic stage and ras mutation. Densitometry analysis of the RFLP bands indicated that approximately 50% of the cells within these two heterogeneous populations contained the mutation. Direct sequence analysis of polymerase chain reaction-amplified DNA confirmed these results and did not reveal any other mutations in this region of the Ha-ras gene.
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PMID:Ha-ras oncogene mutations in cell lines derived from rat tracheal implants exposed in vivo to 7,12-dimethylbenz[a]anthracene. 197 78

Overexpression of an activated ras gene in the rat embryo fibroblast line REF52 results in growth arrest at either the G1/S or G2/M boundary of the cell cycle. Both the DNA tumor virus proteins simian virus 40 large T antigen and adenovirus 5 E1a are able to rescue ras induced lethality and cooperate with ras to fully transform REF52 cells. In this report, we present evidence that the wild-type activity of the tumor suppressor gene p53 is involved in the negative growth regulation of this model system. p53 genes encoding either a p53Val-135 or p53Pro-193 mutation express a highly stable p53 protein with a conformation-dependent loss of wild-type activity and the ability to eliminate any endogenous wild-type p53 activity in a dominant negative manner. In cotransfection assays, these mutant p53 genes are able to rescue REF52 cells from ras-induced growth arrest, resulting in established cell lines which express elevated levels of the ras oncoprotein and show morphological transformation. Full transformation, as assayed by tumor formation in nude mice, is found only in the p53Pro-193-plus-ras transfectants. These cells express higher levels of the ras protein than do the p53Val-135-plus-ras-transfected cells. Transfection of REF52 cells with ras alone or a full-length genomic wild-type p53 plus ras results in growth arrest and lethality. Therefore, the selective event for p53 inactivation or loss during tumor progression may be to overcome a cell cycle restriction induced by oncogene overexpression (ras). These results suggest that a normal function of p53 may be to mediate negative growth regulation in response to ras or other proliferative inducing signals.
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PMID:Mutant p53 tumor suppressor alleles release ras-induced cell cycle growth arrest. 199 96

Methods to isolate and culture intact mouse hair follicles and interfollicular epidermal cells provide a model to test the potential of each to form tumors as a consequence of rasHa gene activation and to determine the risk for progression in the resultant tumors. The v-rasHa oncogene was introduced into intact or dissociated hair follicle cells or interfollicular epidermal cells from newborn mouse skin via a defective retroviral vector. Either immediately after infection or after an additional 6 days of culture, the v-rasHa cells were transferred to nude mice as a skin graft. Both cell populations formed squamous papillomas which were indistinguishable based on morphology and immunocytochemistry. All papillomas expressed epidermal specific markers whether derived from hair follicle or interfollicular cells, and many regressed. After 16 weeks in vivo, 20-30% of the benign skin tumors in all groups converted to malignancy. In addition to papillomas, hair follicle derived populations produced hemangiomas in many animals. None of the groups formed basal cell carcinomas, keratoacanthomas or tumors with characteristics of differentiating hair follicle cells. These studies indicate that ras gene activation can contribute to benign squamous neoplasia originating from several skin-derived cell types. The underlying factors which determine the variable risk for neoplastic progression of skin papillomas after ras gene activation is not simply the origin of the tumor cell from hair follicle or interfollicular epidermis. The activated ras oncogene can also transform skin endothelial cells but does not appear to directly contribute to transformation of the more differentiated cells of the hair follicle.
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PMID:A comparison of interfollicular and hair follicle derived cells as targets for the v-rasHa oncogene in mouse skin carcinogenesis. 204 93


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